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1 52 2 53 3 Abstracts 54 4 55 5 56 6 Scientific Poster Abstracts Selected for the National Lipid 57 7 58 8 Association 2020 Scientific Sessions, December 13-16, 59 9 60 10 2020, Chicago, IL 61 11 62 12 2020 Program Planners: Christie M. Ballantyne, MD, Kevin Meyers, MD, Bernard Rosner, PhD, Joshua Samuels, 63 13 FACP, FACC, FNLA; Anne C. Goldberg, MD, FNLA; MD, MS, Joseph Flynn, MD and the, SHIP AHOY Investigator 64 14 John Casey Elkins, DNP, Med, NP-C, CLS, FNLA; Peter 65 15 H. Jones, MD, FNLA; Carol Kirkpatrick, PhD, RDN, Lead Author’s Financial Disclosure: Grant funding 66 16 MPH, CLS, FNLA; Pamela B. Morris, MD, FNLA; Alan from American Heart Association. 67 17 Thomas Remaley, MD, PhD; Joseph J. Saseen, PharmD, 68 18 CLS, FNLA; Daneil E. Soffer, MD, FNLA Study Funding: American Heart Association SFRN in 69 19 2020 Abstracts Committee: David Davidson, MD; Marlys HTN. 70 20 L. Koschinsky PhD, FAHA, FNLA; Ann Liebeskind, MD, Background/Synopsis: Excess adiposity and dyslipi- 71 21 FNLA (Chair); Scott H. Merryman, MD; Noreen T. Nazir demia are associated with higher arterial stiffness in adults. 72 22 MD, FACC; David Neff, MD; Amy L. H. Peterson, MD; Limited data show similar relationships in youth. 73 23 Kaye-Eileen Willard, MD 74 24 The National Lipid Association (NLA) is pleased to Objective/Purpose: We evaluated the effect of abnor- 75 25 announce that 87 abstracts were accepted for presentation malities in fasting lipid profile and pulse wave velocity 76 26 in the poster format for the NLA 2020 Scientific Sessions. (PWV) in a cohort of youth recruited to study the effect of 77 27 Each abstract was reviewed by the NLA Scientific Sessions blood pressure on cardiovascular (CV) target organ damage. 78 28 Abstracts Committee prior to acceptance. Methods: Youth (N5324) with mean age 15.6 years 79 29 Posters may be viewed from Sunday, December 13 at 6 p.m., (11.1-18.9), 51% male, 65% white, 23% with hypertension, 80 30 through 2 p.m. on Wednesday, December 15. The NLA mean BMI 28 and mean HDL-C 45 (15-88 mg/dl) had 81 31 Young Investigator Awards Ceremony will take place on anthropometrics, BP, labs and PWV measured. Participants 82 32 Tuesday, December 15 from 11:50 a.m. -12:20 p.m. Posters were classified as normal vs. high BMI (.595th%) and 83 33 were judged on quality of science, originality, interest to the normal vs. low HDL-C (,540 mg/dl). Means by HDL 84 34 field of lipidology, and overall impression with cash awards category were evaluated by t-test. PWV stratified by BMI 85 35 of $1,500 for first place, $1000 to second place, and $500 to and HDL-C category was evaluated by ANCOVA. A 86 36 third place. The first place Young Investigator winner also general linear model was constructed to see if HDL 87 37 was selected to give an oral presentation during the sessions. category remained a significant determinant of PWV. 88 38 89 Three additional abstracts are selected to give an oral Results: Participants with low HDL-C were more likely 39 presentation during the abstract session. 90 40 to be male, white and Hispanic. They had higher BMI, SBP, 91 Note: Young Investigator abstract titles are marked with an 41 LDL-C, TG, glucose, insulin, CRP and PWV (all p,0.05). 92 asterisk.* Encore abstracts are marked with a dagger 42 Significant determinants of PWV included age, mean 93 symbol.† The Foundation of the NLA Hunninghake FH 43 ^ 94 Abstract award winner is marked with a caret. 44 95 45 *This award is supported by a donation from Amgen Inc. 96 46 Visceral Obesity, Metabolic Syndrome and 97 47 Atherosclerosis 98 48 99 49 104 100 50 High Body Mass Index and Low HDL 101 51 Interaction Affects Pulse Wave Velocity in 102 Youth: the SHIP AHOY Study Elaine Urbina, MD, MS, (Cincinnati, OH) Amy Shah, MD, MS, Michael Ferguson, MD, Marc Lande, MD, Figure PWV by BMI and HDL-C Categories.

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103 159 104 160 105 Characteristics of the Study Population Stratified by HDL Category (means, standard deviations or percentage) 161 106 HDL .5 40 N5203 HDL , 40 N5121 T test or X2 162 107 163 108 Variable Mean SD Mean SD P value 164 109 Age (years) 15.6 1.7 15.5 1.7 NS 165 110 Sex (% male) 55.0 71.7 0.003 166 111 Race (%Caucasian) 60.5 71.7 0.04 167 112 (% African American) 26.5 22.5 168 113 (% Asian) 7.0 0.8 169 114 (% Other) 6.0 5.0 170 Ethnicity (% Hispanic) 12.5 22.5 0.03 115 171 Height (cm) 169.0 9.5 171.2 10.6 NS 116 Weight (cm) 75.6 23.0 91.4 25.7 0.0001 172 117 Waist circumference (cm) 83.7 16.7 98.1 19.3 0.0001 173 118 Waist/Height ratio 0.5 0.1 0.6 0.1 0.0001 174 119 BMI (kg/m2) 26.4 7.5 30.9 6.8 0.0001 175 120 BMI percentile 75.3 27.1 91.5 14.8 0.0001 176 121 SBP (mmHg) 120.0 13.7 126.2 10.0 0.0001 177 122 SBP percentile 68.6 31.1 82.5 19.7 0.0001 178 123 DBP (mmHg) 71.2 11.2 71.7 9.7 NS 179 124 DBP percentile 63.3 30.2 65.5 27.1 0.0001 180 125 Hypertensive (percent) 39.4 52.1 0.0002 181 Heart Rate (beats/min) 70.1 13.0 72.8 12.4 NS 126 182 Total Cholesterol (mg/dl) 152.9 29.9 151.8 36.4 NS 127 LDL-C (mg/dl) 86.2 26.6 93.1 29.5 0.04 183 128 HDL-C (mg/dl) 52.1 8.7 33.6 4.9 0.0001 184 129 Triglycerides (mg/dl) 79.6 36.4 126.8 71.7 0.0001 185 130 Glucose (mg/dl) 88.3 7.6 91.6 10.7 0.003 186 131 Insulin (microIU/ml) 16.0 11.2 27.7 21.2 0.0001 187 132 HOMA_IR 3.5 2.6 6.4 5.3 0.0001 188 133 C-reactive protein (mg/dl) 1.5 2.7 2.7 3.0 0.0006 189 134 Creatinine (mg/dl) 0.7 0.2 0.7 0.2 NS 190 135 Uric acid (mg/dl) 5.4 1.5 6.2 1.6 0.0001 191 136 Pulse Wave Velocity (m/sec) HIGHER IS STIFFER 5.0 0.8 5.3 0.9 0.0007 192 137 193 138 194 arterial pressure, BMI z-score and BMI z-score by HDL Lead Author’s Financial Disclosure: Nothing to 139 195 category interaction (r2 5 0.19, all parameter estimate disclose. 140 p,0.02). PWV increased (stiffer) across categories from 196 141 Study Funding: Developed through an independent 197 low BMI/high HDL to low BMI/low HDL to high BMI/ educational grant from Kowa. 142 high HDL to high BMI/low HDL (model p , 0.0001). 198 143 Background/Synopsis: Online education has been 199 144 Conclusions: We conclude that the combination of high shown to be an effective method for improving 200 145 BMI and low HDL-C has a deleterious effect on arterial clinician knowledge and competence. Additionally, lipid 201 146 stiffness. Measures to control adiposity and increase management in patients with insulin resistance can be 202 147 physical activity are likely necessary in youth to prevent challenging. 203 148 early vascular aging. Objective/Purpose: We sought to determine if online 204 149 continuing medical education (CME) could improve the 205 150 Diabetes, Insulin Resistance and Dyslipidemia knowledge, competence, and confidence of cardiologists, 206 151 primary care physicians (PCPs) and nurses/nurse practi- 207 152 106 tioners (NPs) related to statin use in patients with insulin 208 resistance. 153 Success of Online CME at Improving 209 154 Knowledge, Competence, and Confidence Methods: The CME activity was a 15-minute video 210 155 Related to Statin Therapy in Patient’s with discussion between 2 experts in the field of lipid manage- 211 156 Insulin Resistance ment. A repeated pairs pre-/post-assessment study design 212 157 was used and chi-square test (P ,.05 is considered signif- 213 158 Amy Larkin, PharmD, (Nicholasville, KY) icant) assessed educational effect for each activity. 214 Julie Schrand, Joy Marko, MS, APN-C, CCMEP Cramer’s V was used to calculate the effect size (0.06-

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215 0.15 is a noticeable effect, 0.16-0.26 considerable, and Background/Synopsis: Lipid guidelines are ever- 271 216 .0.26 extensive). The activity launched June 11, 2019 and evolving, creating confusion for clinicians. 272 217 273 data were collected through July 26, 2019. Objective/Purpose: We sought to determine if online 218 274 Results: In total, 282 cardiologists, 515 PCPs, and 995 continuing medical education (CME) could improve the 219 275 nurses/NPs were included in the study. Overall, there were knowledge, competence, and confidence of cardiologists, 220 276 knowledge, competence and confidence improvements seen primary care physicians (PCPs) and nurses/nurse practi- 221 277 among all groups (P,.01) from pre- to post-assessment: tioners (NPs) related to guideline-based management of 222 278 lipid disorders. 223 Overall: 30% absolute increase among cardiologists 279 224 (P,.001, V5.304), 31% increase among PCPs Methods: The CME activity was a 30-minute video panel 280 225 (P,.001, V5.316), and 22% increase among nurses/ discussion with experts in the field of lipid management. A 281 226 NPs (P,.001, V5.224). repeated pairs pre-/post-assessment study design was used and 282 , 227 36% of cardiologists (P,.0001), 29% of PCPs chi-square test (P .05 is considered significant) assessed 283 228 (P,.0001), and 27% of nurses/NPs (P ,.0001) improved educational effect for each activity. The activity launched March 284 229 at identifying a strategy for measuring hepatic insulin 27, 2019 and data were collected through September 2, 2019. 285 230 sensitivity in vivo. Results: In total, 230 cardiologists, 596 PCPs, and 2.918 286 231 49% of cardiologists (P,.0001), 48% of PCPs nurses/NPs were included in the study. Overall, there were 287 232 (P,.0001), and 33% of nurses/NPs (P ,.0001) improved knowledge and confidence improvements seen among all 288 233 at recognizing effects of pitavastatin on hepatic fat and groups (P,.01) from pre- to post-assessment: 289 234 insulin sensitivity. 12% of cardiologists (P5.35), 18% of PCPs (P5.002), 290 235 14% of cardiologists (P,.001), 18% of PCPs (P,.0001), and 24% of nurses/NPs (P ,.001) improved at identi- 291 236 and 6% of nurses/NPs (P,.01) improved at effectively fying guideline recommendations related to the risk of 292 237 addressing a patient’s concerns related to the impact of new-onset diabetes in patients on statin therapy 293 238 satins on development of diabetes. 29% of cardiologists (P,.001), 35% of PCPs (P,.001), 294 239 55% of cardiologists, 63% of PCPs, and 50% of nurses/ and 31% of nurses/NPs (P ,.001) improved at applying 295 240 NPs reported increased confidence in understanding of guideline recommendations to manage complex meta- 296 241 statin metabolism and impact on insulin sensitivity. bolic patients 297 242 Continued educational gaps: 39% of cardiologists, 42% of PCPs, and 45% of nurses/NPs 298 243 reported increased confidence in applying the updated lipid 299 244 33% of cardiologists, 38% of PCPs, and 58% of nurses/ guidelines to care for complex metabolic patients 300 245 NPs failed to identify the effect of pitavastatin on hepatic Continued educational gaps: 301 fat and insulin sensitivity. 246 26% of cardiologists, 30% of PCPs, and 44% of nurses/ 302 26% of cardiologists, 27% of PCPs, and 50% of nurses/ 247 NPs failed to identify the guideline recommended risk of 303 NPs failed to recognize a strategy for measuring hepatic 248 statin therapy related to new onset diabetes 304 insulin sensitivity in vivo. 249 47-51% of cardiologists, 45-53% of PCPs, and 56-74% 305 250 306 Conclusions: This study demonstrates the success of online, of nurses/NPs failed at applying guideline recommenda- 251 307 CME-accredited, video discussion between experts in the field tions to manage complex metabolic patients (2 different 252 308 on significantly improving knowledge, competence, and con- patient cases used in analysis) 253 309 fidence of cardiologists, PCPs, and nurses/NPs related to statin 254 Conclusions: This study demonstrates the success of 310 use in patients with insulin resistance. Continued gaps were 255 online, CME-accredited, video panel discussion with 311 identified for future educational targets. 256 experts in the field on significantly improving knowledge, 312 257 competence, and confidence of cardiologists, PCPs, and 313 258 Lipid Management in Special Populations nurses/NPs related to guideline-based lipid management in 314 259 complex metabolic patients. Continued gaps were identified 315 260 107 for future educational targets. 316 261 Online CME Effectively Improves 317 262 Understanding and Application of Lipid Hypertriglyceridemia 318 263 Management Guidelines 319 264 108 320 265 Amy Larkin, PharmD, (Nicholasville, KY) How does Burden of Illness of Familial 321 266 Julie Schrand, Joy Marko Chylomicronemia Syndrome Patients Compare 322 267 to a General Population cohort? Results of a 323 268 Lead Author’s Financial Disclosure: Nothing to PSM study 324 269 disclose. Michael Davidson, MD, (Chicago, IL) Nandini Hadker, 325 270 Study Funding: Developed through an independent Sofia Suarez, Caroline Crowson, Aaron Gabriel, 326 educational grant from Kowa. Michael Stevenson, PhD, Andrew Hsieh, PharmD

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327 Lead Author’s Financial Disclosure: M. Davidson Lead Author’s Financial Disclosure: Nothing to 383 328 is a scientific advisory board member of Abbott, Amgen, disclose. 384 329 385 AstraZeneca, Merck and Sanofi, Regeneron. Study Funding: None. 330 386 Study Funding: Akcea Therapeutics. 331 Background/Synopsis: Randomized trials evaluating 387 332 Background/Synopsis: Familial chylomicronemia eicosapentaenoic acid (EPA) alone have demonstrated positive 388 333 syndrome (FCS) is a rare genetic disorder characterized cardiovascular outcomes. The effect of EPA+ docosahexaenoic 389 334 by a deficiency of lipoprotein lipase leading to extreme acid (DHA) combination on cardiovascular disease remains 390 335 hypertriglyceridemia. While patients’; burden of illness uncertain. 391 336 (BoI) and quality of life (QoL) have been characterized Objective/Purpose: To investigate the efficacy of 392 337 previously in the IN-FOCUS study, there have been no EPA+DHA combination on cardiovascular outcomes. 393 338 systematic efforts to-date comparing the impact to a general Methods: 16 randomized controlled trials (RCTs) of n-3 394 339 population (GP) control group. PUFA including; 200 patients with; 1-year follow-up were 395 340 Objective/Purpose: The Findings and Observations selected using MEDLINE, EMBASE and the CENTRAL 396 341 Captured in Burden of Illness Survey; General Population (inception-November 2019). The primary outcome was cardio- 397 342 Study (FOCUS-GPS) is the first study to independently vascular mortality. The secondary outcomes were major adverse 398 343 measure and compare the burden of illness and quality of cardiovascular events (MACE) (composite as defined in each 399 344 life of patients with FCS against a propensity score- trial), myocardial infarction (MI), stroke, revascularization and 400 345 matched US general population cohort. all-cause mortality. Estimates were reported as random effects 401 346 Methods: FOCUS-GPS was a web survey conducted relative risk (RR) with a 95% confidence interval (CI). The meta 402 347 among FCS patients and the GP. A propensity-score regression analysis of the primary outcome was performed. 403 348 matched (PSM) GP cohort was created using 4 demo- Results: Among 89,221 participants, cardiovascular mortal- 404 349 graphic variables. The survey captured information on ity was significantly reduced by EPA+DHA combination (RR: 405 350 symptoms, comorbidities, disease management, impact on 0.90; 95% CI, 0.84-0.97; P50.01; I2517). Among the sec- 406 351 multiple life dimensions, and PROMIS-10, a validated ondary outcomes, incidence of MI was significantly decreased 407 352 instrument. (RR: 0.89; 95% CI, 0.79-0.99; P50.04; I2544). There was no 408 353 Results: 53 GP respondents and 53 FCS respondents significant reduction of MACE (RR: 0.97; 95% CI, 0.92-1.02; 409 354 were 1:1 PSM-matched for analysis. FCS patients reported P50.20; I2545), all-cause mortality (RR: 0.97; 95% CI, 0.92- 410 355 poorer health on PROMIS-10 scales compared to the GP 1.03; P50.30; I2527), stroke (RR: 1.06; 95% CI, 0.95-1.18; 411 356 cohort. 94% of FCS respondents’; PROMIS-10 physical P50.30; I2523) and revascularization (RR: 0.97; 95% CI, 412 357 health scores were lower than the national mean, versus 0.93-1.01; P50.17; I250). The moment of methods meta 413 358 60% of the GP cohort. 85% of FCS respondents’; PROMIS- regression analysis revealed significant association of cardio- 414 359 10 mental health scores were lower than the national mean vascular mortality reduction with higher percentage of baseline 415 360 versus 57% of the GP cohort. Significantly more FCS male gender, younger population, earlier published and shorter 416 361 respondents experienced lifetime acute pancreatitis epi- duration trials as well as minimum background statin use. 417 362 sodes than the GP cohort (36% vs. 6%; p,0.001). FCS Conclusions: Use of EPA+DHA combination reduces 418 363 respondents reported significantly more annual hospitaliza- cardiovascular mortality and myocardial infarction. 419 364 tions, urgent care and routine doctor visits. FCS signifi- 420 365 cantly impacted employment in 94% of patients, compared 421 366 to 52% of GP respondents (p50.007). 422 367 Conclusions: FCS respondents experience significant 423 368 physical, mental, and employment-related burden and are 424 369 more likely to experience acute medical episodes versus 425 370 their GP counterparts. This study demonstrates FCS; sig- 426 371 nificant impacts, both standalone and compared to a 427 372 matched GP sample. 428 373 429 374 430 375 Omega-3 Fatty Acids 431 376 Hypertriglyceridemia 432 377 433 378 109 115 434 379 Effects of EPA+DHA Combination on Double Heterozygosity of ApoA5 Causing 435 380 Cardiovascular Outcomes: A Meta-Analysis Familial Chylomicronemia Syndrome 436 381 437 382 Hammad Rahman, MD, (Liverpool, NY) James Trippi, MD, (Indianapolis, IN) 438 Tehseen Hammad, Suman Sharma, MD Billie Jones, RN, MSN, Veanna Jones, MA

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439 Lead Author’s Financial Disclosure: Advisory Clinical Applications of Biomarkers, Lipoprotein 495 440 Council - Esperion Speaker - Amgen, Amarin, Sanofi. Testing 496 441 497 442 Study Funding: None. 498 117 443 Background/Synopsis: Familial Chylomicronemia 499 444 Syndrome (FCS) is primarily caused by mutations of The Relationship Between Non-HDL- 500 445 lipoprotein lipase with or without mutations of cofactors. Cholesterol and other Lipid Profile Parameters 501 446 ApoA5 is a cofactor to lipoprotein lipase. Heterozygous in Dyslipidemic Subjects 502 mutations of ApoA5 are a rare (,1%) cause of metabolic 447 Saheed Amusat, Bachelor of Medi, (Maiduguri, Ni) 503 syndrome. 448 Hajarat Asifat, Bachelor of Medi, 504 449 Objective/Purpose: We present the only case found in Lawal Olayemi, MSc Molecular Vi, 505 450 the literature having a double or compound heterozygous Hammed Ojokuku, Bachelor of Medi, 506 451 Apo A5 mutation. The patient displays the phenotype of Mistura Adetunji, Bachelor of Medi, 507 452 FCS. Adeola Adeleke, Bachelor of Medi, 508 453 Methods: This 33 years- old male was referred because Abdulazeez Ibn Abdulazeez, Bachelor of Medi, 509 454 of markedly increased triglycerides and chronic abdominal Hikmat Olanrewaju, Bachelor of Medi, 510 455 pain. He noted his triglycerides remained elevated even on Maryam Muhammad, Bachelor of Medi, 511 456 medications but admitted to only eating fast food. He was Adeola Adedeji, Bachelor of Medi 512 457 unemployed and filed for disability. He had hypertension, 513 458 ADHD, chronic abdominal pain but no diabetes; he took Lead Author’s Financial Disclosure: Nothing to 514 459 atorvastatin, gemfibrozil, lisinopril, prazosin, amlodipine, disclose. 515 460 516 ranitidine, trazadone, quetiapine, buspirone and paroxetine. Study Funding: None. 461 He reported no alcohol or street drug use but did smoke 517 462 Background/Synopsis: Cardiovascular diseases 518 tobacco. He had a history of appendectomy, cholecystec- (CVDs) are the number 1 cause of death globally. Accord- 463 tomy, laminectomy, knee arthroscopy and hernia repair 519 464 ing to the World Health Organization, an estimated 17.9 520 with mesh. Family history noted his father had cardiomy- million people died from CVDs in 2016. Over three 465 opathy and congestive heart failure. Physical exam showed 521 466 quarters of CVD deaths take place in low- and middle- 522 normal except for elevated BMI (30.1). Total cholesterol income countries. People with cardiovascular disease or 467 320, triglycerides 1343, HDL 22, A1C 5.5 and normal liver 523 468 who are at high cardiovascular risk due to the presence of 524 function tests. one or more risk factors such as hypertension, diabetes or 469 Weeks later, he presented to the emergency department 525 470 hyperlipidaemia need early detection of their lipid profile 526 with a recurrence of severe abdominal pain, nausea and for proper management. However, the routine lipid profile 471 vomiting. Exam noted voluntary guarding of the abdomen 527 472 are not directly proportional to CVDs risks from empirical 528 with decreased bowel sounds. Lipase and other labs were perspective. 473 unremarkable. A lipid panel was not drawn but serum 529 Objective/Purpose: This study aims to determine the 474 was reported as lipemic. Abdominal CT showed surgical 530 suitability of non-HDL cholesterol as a dyslipidemia risk 475 scars, a fatty liver and normal pancreas. He improved 531 tool. 476 with analgesics and antiemetics. In further 532 477 communications, he notes persistent episodes of Methods: This study was conducted on the lipid profile 533 478 abdominal pain and nausea. parameters of 231 hyperlipidemic subjects. The profile 534 479 parameters (TC, HDL-C, and TG) were determined using 535 480 Results: A diagnostic genetic test showed double hetero- enzymatic methods while the non-high-density lipoprotein 536 481 zygous ApoA5 variations on Chromosome 11 Exon 4/4 (Non-HDL) cholesterol was extrapolated using Friede- 537 . . 482 c158G A (also known as rs7412) and Exon 2/4 c3A G(a wald’s formula and Non-HDL-C was derived by subtract- 538 483 more common variant known for hypertriglyceridemia), ing HDL-C from total cholesterol (TC) values. For 539 484 both autosomal dominant.1 A very low-fat diet was statistical analysis, a normality test was first conducted to 540 485 recommended with consideration for ApoC3 inhibition determine the distribution of the data. Then, descriptives 541 486 medication when available. were collected to measure central tendencies. Finally, 542 487 Conclusions: FCS is primarily caused by a mutation(s) Pearson’s Correlation was employed to analyze linear 543 488 of lipoprotein lipase with or without a mutation of co- relationships among the variables. All assumptions were 544 489 factors. This patient manifests the hallmarks of FCS with validated at p;0.05. 545 490 high triglycerides / lipemic serum from chylomicrons, Results: The correlation analysis showed that there were 546 491 unresponsiveness to available medications, chronic abdom- significant positive relationships between TC; and HDL-C 547 492 inal pain of low grade pancreatitis, non-alcoholic fatty liver, (r50.26), LDL-C (r50.95), TG (r50.26) and non-HDL 548 493 psychologic disorders, and the inability to maintain cholesterol (r50.95). High-density-lipoprotein cholesterol 549 494 employment because of illness with a double heterozyous showed a significant; negative relationship with TG (r5 550 variation of ApoA5. -0.27), and positive relationship with TC (r50.26).

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551 Interestingly, we found that HDL-C have no correlation therapy - 20 hypo-responders and 31 hyper-responders. 607 552 with LDL-C, and non-HDL-C respectively. The results also Among demographic data, there was no statistical associ- 608 553 showed that LDL-C have a significant positive correlation ation seen in weight (p5 0.35), BMI (p50.13), or age 609 554 with all the parameters except HDL-C. We also found that (p50.76). In the hyper-responder group there was no 610 555 TG positively correlated with TC, LDL-C (r50.14), and difference seen in gender, with 54% men and 46% women. 611 556 non-HDL-cholesterol (r50.36). However, a negative cor- Among the hypo-responder group there was a significant 612 557 relation between TG and HDL-C was observed. Lastly, number of women, with only 30% being male. Among the 613 558 Non-HDL-C was found to have significant positive corre- clinical data reviewed, concurrent lipid lowering therapy 614 559 lations with all the parameters except HDL-C. was noted in 87% of hyper-responders and 50% of hypo- 615 560 Conclusions: The non-HDL cholesterol is significantly responders. Cardiovascular disease was seen among both 616 561 correlated with lipid profile parameters except HDL- hypo 90% and hyper- responders 77%, but Familial 617 562 cholesterol. Therefore, it is suggested that assessment of Hypercholesterolemia was only noted in 10% of hypo- 618 563 the risk and management of cardiovascular diseases should responders and 35% of hyper-responders. 619 564 focus less on HDL-C, but more on non-HDL-cholesterol in Conclusions: There is variability in LDL-C reduction 620 565 conjunction with TC, LDL-C, and TG as an indices for with the use of PCSK9 inhibition therapy, with the greatest 621 566 monitoring treatment. reduction seen in patients on concurrent lipid lowering 622 567 therapy. There was a significant association seen between 623 568 624 Lipid Management in Special Populations LDL lowering response and concurrent heart disease. Women 569 made up the majority of hypo-responders. As more patients 625 570 are prescribed PCSK9i therapy, additional study is warranted 626 571 to predict which patients will benefit the most. 627 572 118 628 573 Variability of Response to PCSK9 Inhibitor 629 574 Therapy Lipid Management in Special Populations 630 575 631 Erica Kindig, MSN, FNP-BC, MS, (Winter Park, FL) 576 121 632 Paul Ziajka, MD, PhD, FNLA 577 Low-Density Lipoprotein-Cholesterol 633 578 Lead Author’s Financial Disclosure: Nothing to Lowering in Patients with a Recent Myocardial 634 579 disclose. Infarction and Subsequent Treatment with 635 580 Evolocumab in Real-World Clinical Practice 636 Study Funding: None. 581 637 582 Background/Synopsis: PCSK-9 inhibitor therapy has Nihar Desai (New Haven, CT) Pin Xiang, Jason Exter, 638 583 revolutionized the treatment of dyslipidemia but recent Mohdhar Habib, Xin Wang, Sasikiran Nunna, Rolin Wade, 639 584 studies have shown a wide range of individual responses. Katherine Mues, Chi-Chang Chen 640 585 For alirocumab the LDL-C lowering response ranged from 641 Lead Author’s Financial Disclosure: Research 586 5% to 90%. For evolocumab the LDL-C lowering response 642 grants from Medtronic, Johnson & Johnson; consulting 587 ranged from 33% to 92%. 643 fees from Amgen Inc, Relypsa, OPKO, scPharmaceuticals, 588 Objective/Purpose: To determine any clinical or de- 644 Cytokinetics. 589 mographic characteristics that might differentiate hypo and 645 590 hyper-responders to PCSK-9 inhibitor therapy. Study Funding: The study was funded by Amgen Inc. 646 591 Methods: Retrospective data was collected from patients Background/Synopsis: Patients with recent myocar- 647 592 of the Florida Lipid Institute on PCSK9 inhibitors who had dial infarction (MI) are at high risk for recurrent events. In 648 593 a pre-PCSK9i baseline lipid panel (on or off other lipid the FOURIER clinical trial, lowering of low-density 649 594 lowering therapy) and a post treatment lipid panel at least 6 lipoprotein cholesterol (LDL-C) with evolocumab in pa- 650 595 weeks after PCSK9i was started. We averaged the LDL-C tients with recent MI resulted in substantial risk reduction. 651 596 lowering and determined the standard deviation for alir- Objective/Purpose: Here, we characterize patients 652 597 ocumab 75mg, alirocumab 150mg, and evolocumab with recent MI who were subsequently treated with 653 598 140mg. We defined hypo-responders as those patients evolocumab and assess LDL-C lowering in a real-world 654 599 who achieved an LDL-C less than the average minus one clinical setting. 655 600 standard deviation, and hyper-responders as those who Methods: This retrospective cohort study used IQVIAs 656 601 achieved an LDL-C greater than the average plus one national medical and pharmacy databases (Longitudinal 657 602 standard deviation for that drug and dose. We then collected Rx/Longitudinal Dx and fully adjudicated claims) linked to 658 603 demographic and clinical data (i.e. gender, age, BMI, Prognos for LDL-C values. Patients with a first fill for 659 604 baseline lipid levels, concurrent medications and concur- evolocumab between 7/1/2015 and 5/31/2019 (index 660 605 rent diseases) from the patient’s medical record. event), hospitalized for MI within 12 months before first 661 606 Results: Of the 170 patient charts reviewed, 30% were evolocumab fill, and with an LDL-C of 70 mg/dL or over 662 identified as above or below average response to PCSK9i (highest LDL-C within 6 months prior to index) were

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663 included. Baseline demographics and clinical characteris- lipoprotein receptor (LDLR) loss-of-function mutations, 719 664 tics were collected during a 1-year pre-index period. Post- leading to elevated LDL-cholesterol (LDL-C) and prema- 720 665 index LDL-C values were assessed for up to 12 months, or ture atherosclerotic cardiovascular disease. Evinacumab, an 721 666 until evolocumab discontinuation (ie, .60-day gap in angiopoietin-like 3 inhibitor, was assessed in a phase 3 722 667 therapy). study (NCT03399786) in HoFH patients. 723 668 Results: Of 102 patients meeting inclusion criteria and Objective/Purpose: We conducted a post-hoc analysis, 724 669 prescribed evolocumab after a recent MI, mean (SD) age evaluating the efficacy and safety of evinacumab in 725 670 was 65 (11) years, 60% were men, 44% were 65 years old difficult-to-treat HoFH patients with little to no LDL- 726 671 or older, and 57% had commercial insurance. Common receptor activity (,2%). 727 672 728 cardiovascular disease related procedures, diagnoses, and Methods: HoFH patients on stable maximally tolerated 673 729 comorbid risk factors included coronary revascularization lipid-lowering therapy (+/-lipoprotein apheresis) were ran- 674 730 (86%), peripheral arterial disease (21%), stroke (12%), domized to intravenous evinacumab 15 mg/kg (N543) or 675 731 diabetes (54%), heart failure (35%), and chronic kidney placebo (N522) every 4 weeks for 24 weeks. All patients 676 732 disease (25%). In the pre-index period, 80% of patients were genotyped. LDL-receptor functionality corresponding 677 733 were on lipid-lowering therapies: 47% on statin alone to the LDLR mutation was reported if in-vitro residual 678 734 (26%, 16%, and 6% on high-, medium-, and low-intensity activity for the mutation was previously assessed (Hobbs et 679 735 statins, respectively), 23% on statin and ezetimibe, and al. Hum Mutat. 1992;1(6):445266). Primary endpoint was 680 736 11% on ezetimibe only. The mean (SD) highest LDL-C LDL-C reduction from baseline to week 24. 681 737 within 6 months prior to index was 147 (41) mg/dL; 14% of Results: Genotype and corresponding LDL-receptor 682 patients had an LDL-C of 190 mg/dL or over. After initial 738 683 functionality characterization determined that 10 patients 739 treatment with evolocumab until discontinuation, 64% and (evinacumab [n58]; placebo [n52]) had mutations with 684 , , 740 50% of patients had an LDL-C of 70 and 55 mg/dL, ,2% LDL-receptor activity. In these patients, mean (stan- 685 , 741 respectively; 72% of patients had an LDL of 70 mg/dL or dard deviation) baseline LDL-C levels were 6.74 (2.6) and 686 at least a 50% reduction in LDL-C. 742 687 6.32 (2.9) mmol/L in evinacumab and placebo groups, 743 Conclusions: In this real-world setting, patients with a 688 respectively, and evinacumab reduced LDL-C by 53.5% at 744 recent MI subsequently treated with evolocumab therapy 689 week 24 vs a 18.8% increase with placebo (least squares 745 had clinically meaningful reductions in LDL-C. Under- 2 690 mean difference 72.3% [standard error: 24.7%]; 746 standing the characteristics of patients with recent MI and 5 691 P 0.005). At week 24 in the overall study population, 747 the ability of evolocumab to reduce LDL-C in the real 692 evinacumab reduced LDL-C by 47.1% vs a 1.9% increase 748 world may be of interest to physicians who treat patients at 2 693 with placebo (least squares mean difference 49.0% 749 high risk for recurrent events. , 694 [standard error: 8.0%]; P 0.0001). Adverse events 750 695 occurred in 2 (10.0%; placebo) and 4 (9.1%; evinacumab) 751 , 696 Pharmacological Control of Lipids and patients with 2% LDL-receptor activity, and 14 (70.0%; 752 . 697 Lipoproteins placebo) and 25 (56.8%; evinacumab) patients with 2% 753 698 LDL-receptor activity. 754 699 124 Conclusions: Evinacumab was generally well-tolerated, 755 providing significant LDL-C reductions even in difficult-to- 700 The Efficacy and Safety of Evinacumab in 756 treat HoFH patients with little to no LDL-receptor activity 701 Homozygous Familial Hypercholesterolemia 757 (,2%). 702 Patients with Little to No Low-Density 758 703 Lipoprotein Receptor Activity 759 704 Management of Statin Intolerance 760 705 Robert Rosenson (New York, NY) Frederick Raal, 761 706 Laurens Reeskamp, John Kastelein, Seth Baum, Shazia Ali, 762 125 707 Poulabi Banerjee, Kuo-Chen Chan, Daniel Gipe, 763 708 Robert Pordy, Daniel Gaudet A Virtual Reality in Practice View: Decreasing 764 709 Cardiovascular Risk for Patients with 765 710 Persistent Hypercholesterolemia 766 711 Lead Author’s Financial Disclosure: Robert Rose- 767 Brianna Hanson, BS, (New York, NY) Lauren Welch, MA 712 nson has received honoraria from Amgen, Kowa, Pfizer, 768 713 and Regeneron; consultancy/advisory board fees from 769 714 Amgen, C5, Corvidia, CVS Caremark, Medicines Com- Lead Author’s Financial Disclosure: Nothing to 770 715 pany, and Regeneron; and research funding from Akcea, disclose 771 716 Amgen, AstraZeneca, Medicines Compan. Study Funding: Supported by an educational grant from 772 717 Study Funding: Regeneron Pharmaceuticals, Inc. Sanofi US and Regeneron Pharmaceuticals. 773 718 Background/Synopsis: Homozygous familial hyper- Background/Synopsis: For four years, Med Learning 774 cholesterolemia (HoFH) is primarily caused by low-density Group (MLG) has weaved virtual reality (VR) and

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775 augmented reality (AR) tools into its educational activities Lipid Management in Special Populations 831 776 to further engage learners, enhance comprehension, 832 777 improve recall, and support practice change. These tools 833 778 are downloadable and promote patient engagement post- 127 834 779 activity. Prevalence and Treatment of Familial 835 780 In 2019, MLG conducted a variety of educational activities Hypercholesterolemia According to the Dutch 836 781 which included VR and AR animations based on the Lipid Clinic Network Score (DLCNS): a 837 782 pathophysiology of hypercholesterolemia and the Retrospective, Single Centered 838 783 mechanism of action of the latest recommended therapies 839 784 to help in reducing the risk of CVD. Post-activity tests and Sanket Gokhale, MD, (Chicago, IL) Noreen Nazir, MD 840 785 evaluations show the importance of advanced continuing 841 786 medical education (CME) VR and AR animations. Lead Author’s Financial Disclosure: Nothing to 842 787 Outcomes from these programs demonstrate how these disclose. 843 788 advanced modalities result in greater knowledge and Study Funding: None. 844 789 845 competency gains, practice improvements, and patient Background/Synopsis: Heterozygous Familial Hyper- 790 846 engagement. cholesterolemia (HeFH) is a relatively common yet under- 791 847 Objective/Purpose: The use of VR and AR in CME reported autosomal dominant disorder (approximately 1/ 792 848 can enhance cardiologists’ understanding of the pathophys- 250 in the United States). HeFH has been associated with 793 849 iology and current and emerging therapies in hypercholes- the development of premature atherosclerotic cardiovascu- 794 850 terolemia care in order to reduce patients’ risk of CVD. lar disease (ASCVD) and necessitates immediate initiation 795 851 Methods: VR and AR tools were integrated into MLG’s of high intensity statin therapy. When genetic testing is 796 852 2019 CVD educational series. At the 2019 annual meetings unavailable, diagnosis of HeFH is made clinically with the 797 853 of ACC, CHW, NLA, DA, NLA, CHE, AHA, and Primed’s Dutch Lipid Clinic Network Score (DLCNS), a point-based 798 854 Cardiology Updates Boston, MLG set up a booth where system that calculates the probability of HeFH based on 799 855 participants wore Oculus headsets to watch VR animations serum low density lipoprotein (LDL), family/personal 800 856 of dyslipidemia and how treatment options work. Partici- history of premature ASCVD, family history of severe 801 857 pants were also able to view the downloadable animations hyperlipidemia, and physical exam. After score calculation, 802 858 from their smart device, prompting continuous learning and patients are stratified into having either unlikely, possible, 803 859 enhanced patient engagement. Pre/posttests, electronic probable, or definite HeFH. 804 860 evaluations, and online surveys were conducted to deter- 805 Objective/Purpose: To estimate the prevalence and 861 mine the importance of these technologies in creating a 806 treatment of probable and definite HeFH based on DLCNS 862 rememberable experience for HCPs, thus improving the 807 within our patient population. 863 patient experience. 808 Methods: We performed a single centered, retrospective 864 809 Results: MLG’s VR and AR tools for this activity observational study in a predominantly urban population. 865 810 reached over 2,000 learners. The use of VR animations in Patients with initial LDL levels greater than 190 mg/dL 866 811 education enhanced HCPs understanding of how therapies presenting at our academic medical center between Jan 1, 867 812 work in a visual manner, leading to improved recall. Pre/ 2013 and Dec 31, 2014 were included. They were then 868 813 posttest results indicate learners improved knowledge and evaluated by the DLCNS and those scoring in the probable 869 814 competence on average 28% and 31%, respectively or definite criteria were assessed for intensity and timing of 870 5 815 (N 2,097). Surveys conducted post-activity illustrate the statin therapy. 871 816 impact of downloadable animations, posters, and AR tools Results: 499 patients were included in our study. Based on 872 817 on improving physician-patient communication as well as DLCNS, 9.8% (n549) of our study population had probable 873 818 physicians’ ability to individualize treatment. These tools HeFH while 1.6% (n58) had definite FH. Of those with 874 819 left 90% and 86% of learners with a better understanding of probable HeFH, 18.8% (n59) were immediately started on a 875 820 pathophysiology and an improved recall of lessons learned, high-intensity statin while 25% (n512) were not started on 876 5 821 respectively (N 1,665). Ultimately, these educational any statin. Additionally, 25% (n52) of those with definite FH 877 822 improvements will benefit 18,383 CVD patients. This is were immediately started on a high-intensity statin while 878 823 an 18% gain in reported practice change compared to 37.5% (n53) were not started on any statin. 879 similar programs MLG conducted without VR/AR the year 824 Conclusions: This study concluded that the prevalence 880 prior. 825 of probable to definite HeFH within an urban patient 881 826 Conclusions: The incorporation of technological tools population is potentially higher than reported in the 882 827 like VR and AR has proved to be an asset to the continuing literature.1 It is concerning that the majority of patients 883 828 education of HCPs treating patients with hypercholester- with probable to definite FH were not started on any statin 884 829 olemia. The ability to use these tools at point-of-care therapy. Given the noted higher prevalence of FH within 885 830 creates a lasting effect on care. our patient population, it is crucial that physicians are 886

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887 educated on the importance of screening high-risk patients 943 888 for HeFH in order to optimize primary prevention of 944 889 premature ASCVD. 945 890 946 891 947 892 Lipid Management Best Practices 948 893 949 894 128 950 895 A Clinical Decision Support Tool for the 951 896 Detection and Treatment of Familial 952 897 Hypercholesterolemia Figure 2 The FH Best Practice Alert (BPA) contains evidence- 953 898 based treatment recommendations, knowledge resources and an 954 899 Hana Bangash, MBBS, (Rochester, MN) actionable FH orderset implemented within the electronic health 955 record for healthcare providers at the point-of-care. 900 Laurie Pencille, CCRP, Joseph Sutton, 956 901 Omar Elsekaily, MD, Justin Gundelach, MS, Methods: A conceptual CDS prototype based on input 957 902 Ozan Dikilitas, MD, Ali Mir, MBBS, Stephen Kopecky, MD, from a diverse group of physicians (Hasnie et al MCP: 958 903 Robert Freimuth, PhD, IQ&O. 2018; 2:103) underwent 2 iterations informed by a 959 904 Pedro Caraballo, MD, Iftikhar Kullo, MD heuristic evaluation and institutional CDS guidelines, 960 905 resulting in an asynchronous in-basket message and a 961 906 962 Lead Author’s Financial Disclosure: Nothing to passive best practice alert (BPA). Both CDS formats were 907 963 disclose. evaluated using a hybrid type 1 effectiveness-implementa- 908 tion framework and a user-centered design process. Over a 964 Study Funding: HL135879 (EHR Strategies to Improve 909 3 month period, primary care physicians and specialists 965 Outcomes in FH); HG06379 (EHR-based Genomic Dis- 910 (n513) participated in qualitative interviews (Table 1), 966 covery and Implementation). 911 usability testing and a survey on implementation outcomes 967 912 Background/Synopsis: Familial hypercholesterolemia (Figure 1). We also measured the number of times the CDS 968 913 (FH) is relatively common, associated with markedly triggered over a 2-month period and documented timelines 969 914 increased risk of coronary heart disease, and yet vastly and barriers to implementation. 970 underdiagnosed. There is need for clinical decision support 915 Analysis of interview transcripts revealed 5 key 971 (CDS) tools to facilitate case detection, improve patient Results: 916 themes: understanding and awareness of FH, usual clinical 972 917 management and promote cascade testing for FH. 973 918 Objective/Purpose: i) Develop an electronic health Table 1 Physician demographic characteristics (n513). 974 919 record (EHR)-based CDS tool to improve detection, 975 920 treatment and control of FH; ii) Assess metrics after Physician Characteristics n (%) 976 921 implementation of CDS; iii) Document timelines and Gender 977 922 barriers encountered. Females 7 (53 8) 978 923 Males 6 (46.2) 979 924 Age 980 925 , 40 years 4 (30.8) 981 926 40-60 years 7 (53 8) 982 . 927 60 years 2 (15.4) 983 928 Race/Ethnicity 984 Non-Hispanic white 10 (76.9) 929 985 Black 1 (7.7) 930 Asian 1 (7.7) 986 931 Hispanic 1 (7.7) 987 932 Specialties 988 933 Community Internal Medicine 3 (23 1) 989 934 Family Medicine 3 (23.1) 990 935 Family Medicine/Obstetrics 1 (7.7) 991 936 Cardiology 5 (33.4) 992 937 Vascular Medicine 1 (7.7) 993 938 Years in Practice 994 939 0-5 3 (23.1) 995 6-10 1 (7.7) 940 996 11-15 2 (15 4) 941 Figure 1 FH clinical decision support (CDS) tool development 16-20 1 (7.7) 997 942 and evaluation using physician feedback at every stage of the More than 20 6 (46 .1) 998 process.

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999 1055 1000 Table 2 Implementation outcome measures and Consolidated Framework for Implementation Research (CFIR) constructs assessed 1056 through survey of primary care physicians and specialist physicians. 1001 1057 1002 Completely 1058 1003 Measures and Constructs Assessed Question Agree/ Agree n(%. Other* n(%) 1059 1004 Acceptability of Intervention This tool meets my approval 11 (64.6) 2 (16.4) 1060 1005 Measure (AIM) This tool is appealing to me 10 (76.9) 3(23.1) 1061 1006 1 like this tool 11 (84.6) 2 (16.4) 1062 1007 1 welcome this tool 12 (92.3) 1 (7.7) 1063 1008 Intervention Approphateness This tool seems fitting 12 (92.3) 1 [7.7) 1064 1009 Measure (1AM) This tool seems suitable 12 (92.3) 1(7.7) 1065 1010 This tool seems applicable 12 (92.3) 1 [7.7) 1066 1011 This tool seems like a oood match 10 (76.9) 3(23.1) 1067 1012 FeGsibilily of Intervention This tool seems implementable 11 (84.6) 2 (15.4) 1068 Measure (FM) This tool seems possible 12 (92.3) 1(7.7) 1013 1069 This tool seems doable 12 (92.3) 1 P.7) 1014 This tool seems easy to use 11 (84.6) 2 (15.4) 1070 1015 Intervention Characteristics 1 trust the quality and validity o( evidence supporting this 12 (92.3) 1 [7.7) 1071 1016 intervention 1072 1017 Implementing this tool is a good option to identify FH patients 11 (84.6) 2 (15.4) 1073 1018 at Mayo 1074 1019 This tool will improve early diagnosis of patients with FH 11 (84.6) 2 (15.4) 1075 1020 Outer Setting This tool meets my needs to provide needed resources to my S (69.2) 4 (30.8) 1076 1021 patients 1077 1022 Inner Setting This tool is appropriate tor ECH clinicians 11 (84.6) 2 (15.4) 1078 1023 This tool frts within my existing workflow 10 (76.9) 3(23.1) 1079 This tool will not increase thetime needed with a patient 4 (30.8) 0 (69.2) 1024 1080 The implementation of this intervention within Mayo is 12 (92.3) 1 [7.7) 1025 important 1081 1026 1 recognize the importance ol implementing this tool into the 13(100) 0 (0.0) 1082 1027 practice 1083 1028 This tool appears easy to access and incorporate into my 10 (76.9) 3(23.1) 1084 1029 workflow 1085 1030 Characteristics of Individuals This is a valuable tool for ECH clinicians 10 (76.9) 3(23.1) 1086 1031 This tool will help me identity and refer or manage FH patients 12 (92.3) 1 [77) 1087 1032 Process It is important to me that the cardiologists embedded in ECH 7 (538) 6 (46.2) 1088 1033 continue to vet this tool 1089 1034 *Other5 (neither agree/disagree+ completely disagree + disagree) FH5 familial hypercholesterolemia; ECH5 employee and community health 1090 1035 1091 1036 1092 1037 1093 1038 workflow, physician preferences and value of CDS tools, Conclusions: i) An implementation science framework 1094 1039 perspectives on patient needs and values and dissemination was useful in developing a CDS tool for the detection and 1095 1040 and implementation. Usability testing yielded recommen- treatment of FH; ii) The number of alerts fired over a 2- 1096 1041 dations on preferred CDS format, placement, content, month period indicated high burden of FH and the potential 1097 1042 frequency and prioritization. Survey analysis revealed that for CDS to increase FH detection; iii) The logistical 1098 1043 84.6% of physicians agreed that the CDS would improve challenges encountered were non-trivial. 1099 1044 early diagnosis of FH and 92.3% agreed that the CDS 1100 1045 would help them identify and refer or manage FH patients Genetics, Gene Therapy and Atherosclerosis 1101 1046 (Table 2). An algorithm to detect ’possible FH’ (LDL-C . 1102 1047 or 5 190 mg/dL in the absence of secondary causes) 129 1103 1048 triggered an ambulatory BPA (Figure 2) and/or an in-basket Modulation of Cardiovascular Risk by 1104 1049 message. Both formats ran in ’silent mode’ for 2 months Monogenic and Polygenic Determinants of 1105 1050 across all Mayo Clinic sites; during this time the ambula- Low-Density Lipoprotein Cholesterol^ 1106 1051 tory BPA triggered 940 times and the in-basket 564 times. 1107 Winner 1052 Development and integration of the CDS for FH took w 4 1108 1053 years due to the need for an iterative design process, Mark Trinder, MSc, (Vancouver, BC) 1109 1054 stakeholder engagement at each stage, multiple institutional Martine Paquette, MSc, Lubomira Cermakova, MSc, 1110 committee approvals and transition to a new EHR system. Matthew Ban, BSc, Robert Hegele, MD,

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1111 G. B. John Mancini, MD, Gordon Francis, MD, 1167 1112 Alexis Baass, MD, MSc, Liam Brunham, MD, PhD 1168 1113 1169 1114 Lead Author’s Financial Disclosure: M.T. is sup- 1170 1115 ported by a Vanier Canada Graduate Scholarship. 1171 1116 Study Funding: This project was by a Sector Improve- 1172 1117 ment Program project from Genome BC. M.T. is supported 1173 1118 by a Vanier Canada Graduate Scholarship. L.R.B. is 1174 1119 supported by a Michael Smith Foundation for Health 1175 1120 Research Scholar Award and is a Canada Research Chair 1176 1121 in Preci. 1177 1122 1178 Background/Synopsis: Familial hypercholesterolemia 1123 1179 (FH) is the most common autosomal dominant genetic 1124 1180 disorder and is caused by pathogenic mutations in the 1125 1181 LDLR, APOB, or PCSK9 genes. FH leads to lifelong 1126 1182 elevations in low-density lipoprotein cholesterol (LDL-C) 1127 1183 and increases the risk of atherosclerotic cardiovascular not have an identified genetic cause. Secondly, in the meta- 1128 1184 disease (ASCVD). However, many individuals with sus- analysis, an elevated LDL-C polygenic score was associ- 1129 1185 pected FH have a polygenic, rather than a monogenic ated with significantly increased risk of ASCVD (hazard 1130 1186 etiology for their condition. It is unclear if the genetic cause ratio [95% confidence interval] 5 1.55 [1.15-2.08], 1131 1187 of hypercholesterolemia alters the risk of ASCVD. p50.004). 1132 1188 1133 Objective/Purpose: Our objectives were to: 1) Conclusions: Our data establish that monogenic FH is 1189 1134 compare the cardiovascular risk of monogenic and poly- associated with a greater risk of ASCVD than polygenic 1190 1135 genic hypercholesterolemia among patients with similar hypercholesterolemia. Furthermore, among individuals with 1191 1136 LDL-C levels, and 2) assess the influence of an LDL-C monogenic FH, polygenic contributions to LDL-C may help 1192 1137 polygenic score on risk of ASCVD among individuals with explain some of the heterogeneity in ASCVD risk. 1193 1138 monogenic FH. 1194 1139 Methods: We used genotyping array and exome Lipid Management in Special Populations 1195 1140 sequencing data to identify individuals with FH or poly- 1196 1141 genic hypercholesterolemia in 48,741 individuals from the 130 1197 . 1142 UK Biobank (weighted LDL-C polygenic score 95th Sociodemographic Variations in Prenatal 1198 1143 percentile using 223-single nucleotide variants). We exam- Cholesterol Screening Among Pregnant 1199 1144 ined the influence of genotype on risk of coronary/carotid Women in the United States: The National 1200 1145 revascularization, myocardial infarction, stoke, and all- Health Interview Survey 2012-2018 1201 1146 cause mortality among the study population, and among 1202 1147 individuals with FH (n5277), polygenic hypercholester- Reed Mszar, MPH, (New Haven, CT) 1203 1148 olemia (n52,379), or undetermined etiology of hypercho- Shiwani Mahajan, MBBS, 1204 1149 lesterolemia (n52,232) that were matched for LDL-C Javier Valero-Elizondo, MD, MPH, 1205 1150 levels measured at study enrollment. Additionally, we Gowtham Grandhi, MD, MPH, Cesar Caraballo, MD, 1206 1151 used a fixed-effect meta-analysis to assess the influence Dipika Gopal, MD, Richard Nemiroff, MD, 1207 1152 of LDL-C polygenic scores on LDL-C levels and ASCVD Jourdan Triebwasser, MD, MA, Daniel Soffer, MD, 1208 1153 risk for individuals with monogenic FH, using data from Jennifer Lewey, MD, MPH, 1209 1154 the British Columbia FH registry (n5275); Nutrition, Khurram Nasir, MD, MPH, MSc 1210 1155 Metabolism and Atherosclerosis Clinic registry (n5552); 1211 1156 and UK Biobank (n5277). Lead Author’s Financial Disclosure: Nothing to 1212 1157 Results: Firstly, we identified 277 individuals from the disclose. 1213 1158 UK Biobank with suspected genetic FH (1 in 176). Study Funding: None. 1214 1159 Individuals with FH were significantly more likely to Background/Synopsis: Atherosclerotic cardiovascular 1215 1160 experience an ASCVD event at an age of 55-years-old or disease (ASCVD) remains a leading cause of death and 1216 1161 younger relative to those without FH (6.14% versus 2.04%: disability among women in the United States with high 1217 1162 p,0.001). Among individuals with comparable levels of cholesterol representing a significant modifiable risk factor 1218 1163 LDL-C, both FH (hazard ratio [95% confidence interval]: that disproportionately affects vulnerable populations. 1219 1164 1.93 [1.32-2.82]; p,0.001) and polygenic hypercholester- Rates of cholesterol screening among reproductive age 1220 1165 olemia (hazard ratio [95% confidence interval]: 1.26 [1.03- women are suboptimal. Considering the higher utilization 1221 1166 1.55]; p50.02) significantly increased the risk of ASCVD of healthcare services during pregnancy and its role as a 1222 relative to individuals with hypercholesterolemia that did significant cardiometabolic stressor, the peripartum period

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1223 1279 1224 Table 1 Weighed proportion and adjusted odds ratios representing sociodemographic factors associated with an absence prenatal 1280 cholesterol screening among pregnant women, from the National Health Interview Survey, 2012 – 2018 1225 1281 1226 N (%) P-Value Adjusted OR (95% CI)† 1282 1227 Study Population 513 (32. 4) 1283 1228 Age Category, y 0.005 1284 1229 18 – 29 307 (36.0) 1.23 (0.90 – 1.69) 1285 1230 30+ 206 (27.8) Reference 1286 1231 Race/ethnicity ,0.0001 1287 1232 White 309 (36.5) 1.93 (1.39 – 2.69) 1288 1233 Non-White 204 (26.6) Reference 1289 1234 Immigration Status 0.273 1290 1235 US-born 421 (33.4) 1.05 (0.66 – 1.66) 1291 1236 Non-US born 91 (28.9) Reference 1292 Education 0.093 1237 1293 Some college or higher 314 (30.6) Reference 1238 HS/GED or less than HS 199 (36.1) 0.94 (0.65 –1.36) 1294 1239 Insurance Status ,0.001 1295 1240 Insured 439 (30.9) Reference 1296 1241 Uninsured 74 (56.1) 2.51 (1.47 – 4.27) 1297 1242 Family Income* 0.023 1298 1243 High 120 (26.8) Reference 1299 1244 Middle 134 (34.4) 1.27 (0.85 – 1.90) 1300 1245 Low 235 (36.3) 1.56 (1.05 – 2.32) 1301 1246 Usual Source of Care ,0.001 1302 1247 Yes 426 (30.0) Reference 1303 No 87 (55.1) 2.38 (1.43 –3.64) 1248 1304 1249 Abbreviations: OR, odds ratio; CI, confidence interval; HS, high school; GED, general education diploma 1305 $ , 1250 *Income classified as high ( 400% of federal poverty level (FPL)), middle (200% to 400% of FPL), and low ( 200% of FPL) 1306 †Adjusted for age, raceyethnicity, immigration /Insurance Status, education, income, and usual source of care. 1251 1307 1252 1308 1253 1309 may represent a unique and currently underutilized oppor- 2.28, 95% CI [1.43 - 3.64]), those with an annual household 1254 1310 tunity to screen for dyslipidemia and assess future cardio- income ,200% of the federal poverty limit (OR 1.56, 95% 1255 1311 vascular risk. CI [1.05 - 2.32]), and women without insurance (OR 2.51, 1256 1312 95% CI [1.47 - 4.27]) had significantly higher odds of lacking 1257 Objective/Purpose: In this study, we examined socio- 1313 prenatal cholesterol screening. 1258 demographic disparities in prenatal cholesterol screening 1314 1259 among pregnant women in the United States. Conclusions: In a national representative sample of 1315 1260 Methods: We used a nationally representative sample of pregnant women in the United States, significant sociodemo- 1316 1261 1,947 pregnant women aged 18-49 years in the United States graphic disparities exist in prenatal screening for high 1317 1262 from the National Health Interview Survey (2012-2018), of cholesterol. These findings highlight a valuable and currently 1318 1263 which 1,517 (78%) reported complete information regarding underutilized opportunity to leverage this period to improve 1319 1264 prenatal cholesterol screening status. Weighted proportions health outcomes in women, reduce disparities in access and 1320 1265 and adjusted logistic regression analysis were conducted for care, and enhance cardiovascular risk assessment. 1321 1266 assessing associations between prenatal screening status and 1322 1267 relevant sociodemographic characteristics including age, Lipid Management Best Practices 1323 1268 race/ethnicity, education, family income, insurance status, 1324 1269 usual source of care, and immigration status. 131 1325 1270 Results: Among 1,517 pregnant women, representing Strategies to Screen for Familial 1326 1271 more than 1.8 million women in the United States, 32.4% Hypercholesterolemia among Primary Care 1327 1272 (95% CI 29.4% - 35.6%; translating to 578,124 pregnant Physicians 1328 1273 women annually) reported no history of prenatal cholesterol 1329 1274 screening. In particular, lower rates of prenatal cholesterol Robert Fishberg, MD, FACC, (Summit, NJ) 1330 1275 screening were observed among non-Hispanic white women Loba Alam, MD, Michael Ngai, MD, Jeffrey Feldman, MD 1331 1276 younger than 30 years of age, uninsured and lower income 1332 1277 women, and those without a usual source of care. After Lead Author’s Financial Disclosure: Nothing to 1333 1278 adjusting for the aforementioned sociodemographic cova- disclose. 1334 riates, pregnant women without a usual source of care (OR Study Funding: None.

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1335 Background/Synopsis: Familial hypercholesterolemia adults, FH should be suspected if the untreated LDL is . 190 mg/ 1391 1336 (FH) is an autosomal dominant disorder involved in low- dl (or the non-HDL cholesterol is . 220 mg/dl, or the total 1392 . 1337 density lipoprotein cholesterol (LDL-c) uptake and meta- cholesterol is 300 mg/dl). FH can be confirmed through 1393 1338 bolism. It occurs in 1:200-250 individuals. If untreated, FH additional patient medical history, family history or physical 1394 exam findings. Current research indicates that although there are 1339 confers a marked increased risk of atherosclerotic cardio- 1395 approximately 600,000 people in the US with FH, less than 10% 1340 vascular disease (ASCVD) and mortality. In the USA, 1396 1341 have been diagnosed with this life- threatening condition. 1397 approximately 5% of all myocardial infarctions (MI)s are Because of a lifelong burden of high cholesterol levels, individuals 1342 1398 caused by FH. A man with FH has a 50% chance of having with FH have a greater than 20-fold increased risk of coronary 1343 an MI by age 50, a woman has a 30% chance by age 60. disease compared to the general population. Importantly, because 1399 1344 Aggressive medical treatment can reduce these odds close FH is inherited in an autosomal dominant pattern, if one person is 1400 1345 to that of the general population. However only 1-10% of diagnosed with FH, his/her family members would also need to be 1401 1346 these cases have been identified in the USA (1). This screened. 1402 1347 underdiagnosis places an immense burden on individuals At the Cardiology Center at Atlantic Health and the Preventive 1403 1348 and the health care system. Atlantic Health System (AHS) Cardiology Clinic (PCC) we have experience in treating FH 1404 1349 is a clinical site for the national Cascade FH Registry, with patients and their family members. If you have concerns your 1405 patient may have FH, we would be delighted to see them in 1350 the goal to identify patients and their families with FH. 1406 consultation. 1351 There are many barriers to screening including financial, 1407 1352 social and legal considerations. One of these barriers is the Thank you, 1408 1353 lack of general awareness to recognize FH among many Robert D Fishberg, MD, FACC 1409 1354 primary care physicians (PCP)s (2). Indeed, in a survey PI – CASCADE FH Registry 1410 1355 among PCPs in Minnesota, only 50% were able to correctly AMG Lipid Workgroup Co-Chair 1411 1356 identify the risk to first degree relatives (3). [email protected] 1412 1357 1413 Objective/Purpose: In this study we used our elec- 1358 1414 tronic health record (EHR), EPIC, to screen for FH by 1359 1415 contacting PCPs. Lipid Management in Special Populations 1360 1416 1361 Methods: Our EHR database consist of 1004 clinicians 1417 132 1362 including 195 PCPs and 404,595 unique patients. We 1418 . Post Coronary Artery Bypass Graft (CABG) 1363 identified approximately 800 patients with LDL 160 1419 Lipid Optimization Trial 1364 mg/dL, out of which we selected 200 patients with possible 1420 or probable FH with LDL ranging 292-190 mg/dL. We 1365 Johanna Ben-Ami, BS, (Hempstead, NY) 1421 1366 contacted their PCPs using an IRB approved standardized 1422 Cascade FH Registry letter electronically. Kristina Grehan, NP, 1367 Alan Hartman, MD, FACS, Guy Mintz, MD, FACC, FNLA 1423 1368 Results: The electronic results generated a conservative 1424 1369 response rate of 6.5% (n513). We contacted each physician 1425 1370 who responded. Each physician demonstrated interest; Lead Author’s Financial Disclosure: Nothing to 1426 1371 however, they uniformly were not familiar in diagnosing disclose. 1427 1372 or treating FH and each requested more information. Study Funding: None. 1428 1373 Conclusions: Despite identifying patients with probable Background/Synopsis: Cholesterol is a major risk 1429 1374 FH, we achieved only 6.5% response rate to our letter in factor for progressive atherosclerosis, a disease process that 1430 1375 Epic. In addition, we found that diagnostic criteria for FH can affect both native and bypass vessels. Lipid lowering 1431 1376 including family history of premature ASCVD, and phys- has been proven to reduce cardiovascular events in post- 1432 1377 ical exam findings of tendon xanthoma and arcus cornealis CABG patients. The 2018 AHA/ACC Cholesterol Guide- 1433 1378 were often poorly documented in the EHR. PCPs are well lines define all post-CABG patients as high risk, or very 1434 1379 positioned to identify FH. In the future, a multipronged high risk depending on comorbidities such as diabetes 1435 1380 approach incorporating clinical decision support systems, mellitus, hypertension, chronic kidney disease and smok- 1436 1381 screening algorithms, and education for physicians and ing. The AHA/ACC guidelines moved away from a 1437 1382 patients is needed to overcome screening barriers. Our cholesterol goal in the high risk group, but continue to 1438 1383 study demonstrates the challenge of using EHR to commu- recommend an LDL-C goal is less than 70 mg/dL in very 1439 1384 nicate with physicians to screen for FH. high risk patients. In order to achieve this goal, maximally 1440 1385 tolerated statin with or without ezetimibe and/or PCSK-9 1441 1386 Primary Care Physician: therapy are recommended. 1442 1387 1443 I am writing to inform you that based on recent laboratory tests your Objective/Purpose: We hypothesized that a lipidolo- 1388 patient *** may be at risk for Familial Hypercholesterolemia (FH). gist would get a higher percentage of post-CABG patients 1444 1389 FH is a genetic condition that occurs in approximately 1 in 500 to LDL-C of ,70mg/dL when compared to community 1445 1390 individuals and affects all race/ethnic groups. FH is characterized physicians consisting of primary care physicians, surgeons 1446 by chronically elevated LDL cholesterol levels in the blood. For and cardiologists. We expect patient not at LDL-C goal to

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1447 be on guideline mandated optimal lipid therapy when demonstration of high remnant lipoprotein cholesterol 1503 1448 managed by a lipidologist. (RLP-C) by serum ultracentrifugation (UC), which is not 1504 1449 Methods: Lipidologist data was obtained by retrospective readily available. The apoB algorithm can identify HLP3 1505 1450 chart review data from 92 patients with ICD-10 code using total cholesterol (TC), triglycerides (TG) and apoB. 1506 1451 presence of aortocoronary bypass graft-Z95.1. This data However, recent data have raised the question whether the 1507 1452 was compared to community data from Nassau county hypertriglyceridemia (hTG) cutoff (133 mg/dl) within the 1508 1453 acquired from the IQVIA lipid disorder data. This data was algorithm is optimal. 1509 1454 generated from health care professional and institutional Objective/Purpose: We analyzed the lipid phenotypes 1510 1455 insurance claims. Patients were stratified into three groups: of those classified as HLP3 by the apoB method at different 1511 1456 LDL-C ,70 mg/dl, 70-99 mg/dl and .100 mg/dl. The TG cutoffs and compared them to UC based HLP3 in order 1512 1457 lipidologist data set was compared to the population to determine the optimal TG cutoff for the apoB algorithm. 1513 1458 1514 parameter with a 1 sample 2-tailed z-test. Lipid lowering Methods: 128,485 UC based lipid profiles in the Very 1459 1515 therapy including statin therapy, with or without the Large Database of Lipids (VLDbL) were analyzed. For 1460 1516 addition of ezetimibe and PCSK-9 inhibitors were also those meeting HLP3 criteria by the apoB method, lipid 1461 1517 evaluated. parameters suggestive of HLP3, in particular RLP-C and 1462 1518 Results: 72% of post-CABG patients cared for by a VLDL-C/TG, were assessed at different TG cutoffs (133 1463 1519 lipidologist were at LDL-C goal of ,70mg/dL significantly mg/dl, 175 mg/dl, 200 mg/dl, 250 mg/dl). Sensitivity (Sn), 1464 1520 different than 42% in Nassau County patients with a history specificity (Sp), and prevalence adjusted bias adjusted 1465 1521 of coronary revascularization, p,.0001. In contrast, pa- kappa (PABAK) of the apoB method at each TG cutoff 1466 1522 tients with a history of coronary revascularization in were calculated against gold standard UC Criteria (VLDL- 1467 1523 community had LDL-C of 70-99 and .100 at 36% and C/TG &; 0.3). 1468 1524 22% respectively, compared to 20% and 6% in the 1469 Results: The median age (IQR) of participants was 57 1525 lipidologist cohort. When under the care of a lipidologist, 1470 years (46-68), with 45% men; 20.1% of participants had 1526 64% of patients with an LDL-C .70 were on optimal lipid 1471 diabetes and 25.5% had hypertension. The median RLP-C 1527 lowering therapy. 1472 for those classified as normal by the apoB method was 22 1528 , 1473 Conclusions: Our data suggests that post-CABG patients (reference normal RLP-C 30 mg/dL). The median RLP-C 1529 1474 benefit from the expertise of a lipidologist. A higher values for apoB defined HLP3 at TG; 133 mg/dL (34 mg/ 1530 $ $ 1475 percentage of patients under the care of a lipidologist dL), TG 175 mg/dL (43 mg/dL), TG 200 mg/dL (50 1531 1476 were at LDL-C goal compared to the community, with the mg/dL), TG; 250 mg/dL (62 mg/dL) were lower than UC 1532 1477 majority of patients not at goal on optimal medical therapy. defined RLP-C (88 mg/dL). The performance of apoB 1533 1478 Further studies are needed to delve into the implications of defined HLP3 as compared with UC defined HLP3 changed 1534 5 5 1479 this improvement on cardiovascular events and mortality. with increasing TG cutoffs of 133 mg/dl (Sn 71%, Sp 1535 5 5 5 1480 98.4%, PABAK 0.97), 175 mg/dl (Sn 49.4%, Sp 1536 5 5 5 1481 99.5%, PABAK 0.99), 200 mg/dl (Sn 36.9%, Sp 1537 5 5 1482 Clinical Applications of Biomarkers, Lipoprotein 99.7%, PABAK 0.99), and 250 mg/dl (Sn 20.4%, Sp 1538 5 5 1483 Testing 99.9%, PABAK 0.99). 1539 1484 Conclusions: The TG cutoff value of 133 mg/dL allows 1540 for high sensitivity and specificity in detection of HLP3. 1485 134 1541 1486 Higher TG cutoffs may identify more severe HLP3 1542 Importance of the Triglyceride Level in the 1487 phenotypes, but with a large loss in sensitivity for HLP3. 1543 Identification of Patients with a Type III 1488 1544 Hyperlipoproteinemia Phenotype using the 1489 1545 ApoB Method 1490 Diabetes, Insulin Resistance and Dyslipidemia 1546 1491 Bibin Varghese, MD, (Baltimore, MD) Jihwan Park, 1547 1492 Aparna Sajja, MD, Adam Brownstein, MD, 1548 135 1493 Vincent Pallazola, MD, Steven Jones, MD, 1549 1494 Allan Sniderman, MD, Seth Martin, MD Cardiovascular Risk Assessment in Patients 1550 1495 with Diabetes Mellitus and Familial 1551 1496 Hypercholesterolemia 1552 1497 Lead Author’s Financial Disclosure: Nothing to 1553 Anandita Agarwala, MD, (Saint Louis, MO) 1498 disclose. 1554 Elena Deych, MS, Aliza Hussain, MD, Zahid Ahmad, MD, 1499 Study Funding: None. 1555 Christie Ballantnye, MD, Anne Goldberg, MD 1500 Background/Synopsis: Hyperlipoproteinemia Type III 1556 1501 (HLP3) is characterized by accumulation of cholesterol and 1557 1502 triglyceride (TG) enriched remnant lipoprotein particles Lead Author’s Financial Disclosure: Nothing to 1558 (RLP). The gold standard for diagnosis of HLP3 requires disclose.

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1559 Study Funding: None. Lead Author’s Financial Disclosure: Nothing to 1615 1560 1616 Background/Synopsis: Individuals with familial hy- disclose. 1561 1617 percholesterolemia (FH) are at high risk for atherosclerotic 1562 Study Funding: This publication was made possible by 1618 cardiovascular disease (ASCVD) due to lifelong exposure 1563 CTSA Grant Number TL1 TR001864 from the National 1619 to elevated levels of low-density-lipoprotein-cholesterol 1564 Center for Advancing Translational Science (NCATS), a 1620 (LDL-C). Diabetes mellitus (DM) is independently associ- 1565 component of the National Institutes of Health (NIH). Its 1621 ated with an increased risk for ASCVD. Despite the 1566 contents are solely the responsibility of the authors and do 1622 widespread prevalence of DM, the combined effects of 1567 not necessarily represent the official view of NIH. 1623 FH and DM on ASCVD risk when they occur concurrently 1568 Background/Synopsis: Lipoprotein(a) (Lp(a)) levels 1624 and the role of DM with regard to ASCVD risk stratifica- 1569 vary by few factors. Lipoproteins are postulated to vary in 1625 tion in the FH population have yet to be explored in a 1570 response to vitamins, minerals, and heavy metals. 1626 quantitative manner. 1571 Objective/Purpose: To evaluate whether serum levels 1627 Objective/Purpose: To characterize the prevalence of 1572 of Lp(a) are associated with vitamins, minerals, and heavy 1628 ASCVD in patients with FH with and without concurrent 1573 metals. 1629 1574 DM and to determine the strongest predictors of ASCVD in 1630 patients with FH. Methods: Cross-sectional analysis using the National 1575 Health and Nutrition Examination Survey III adult cohort. 1631 Methods: The prevalence of DM and ASCVD in 593 1576 We tested the association between Lp(a) with serum 1632 adult patients with FH followed in US-based lipid clinics 1577 vitamins, minerals, and heavy metals levels. We controlled 1633 was assessed retrospectively through a multicenter collab- 1578 for age, sex, race/ethnicity, statin use, hemoglobin A1c, 1634 oration. A multivariate logistic regression model was used 1579 estimated GFR, C-reactive protein, and BMI. Vitamins, 1635 to determine the strongest predictors of ASCVD in patients 1580 minerals, and heavy metals associated with Lp(a) in 1636 with FH. Covariates included age, sex, diabetes mellitus, 1581 multivariate analysis were then tested for association with 1637 hypertension, and current smoking. ASCVD was defined as 1582 LDL-C (calculated via the Martins-Hopkins method and 1638 coronary, peripheral, and cerebrovascular events including 1583 corrected for Lp(a) [LDL-Ccorr 5 LDL-(Lp(a)*0.3)]). In a 1639 angina, myocardial infarction, coronary angioplasty, pe- 1584 sensitivity test, lead and folate were tested as dichotomous 1640 ripheral arterial surgery, claudication, peripheral angio- 1585 variables (, or .5 ug/dL and , or .3 ng/dL, respec- 1641 plasty, transient ischemic attack, stroke and carotid 1586 tively). All analyses were adjusted for sample weights. 1642 1587 endarterectomy. 1643 Results: The median Lp(a) level (n58,661) was 14 mg/ 1588 Results: Baseline characteristics of the 593 adult patients 1644 dL (IQR: 3 to 32). In multivariate analysis Lp(a) was 1589 are shown in table 1. Patients with FH and ASCVD were 1645 positively associated (increase in mg/dL of Lp(a) per unit 1590 older and more likely to have hypertension and DM. Out of 1646 of covariate) with lycopene (0.18 [95% CI: 0.10 to 0.26], 1591 593 adults, 128 (22%) had diabetes and 465 (78%) did not. 1647 p,0.001), lutein (0.14 [95% CI: 0.07 to 0.22], p,0.001), 1592 The prevalence of ASCVD in patients with and without 1648 beta-cryptoxanthin (0.19 [95% CI: 0.08 to 0.30], 1593 diabetes was 44.5% and 24.3% respectively, p ,0.0001. 1649 p50.001), beta-carotene (0.05 [95% CI: 0.02 to 0.09], 1594 The strongest predictors of ASCVD in patients with FH 1650 p50.003), alpha carotene (0.17 [95% CI: 0.07 to 0.29], 1595 were DM, hypertension, and current smoking (table 2). 1651 p50.007), and lead (0.47 [95% CI: 0.13 to 0.80], 1596 Female sex appeared to reduce the odds of ASCVD. 1652 p50.006). Folate associated negatively with Lp(a) (-0.13 1597 There is a significant increase in the 1653 Conclusions: [95% CI: -0.25 to -0.01], p50.04). LDL-Ccorr was 1598 prevalence of ASCVD in diabetic patients with FH compared 1654 associated with all of these factors except for folate 1599 to those with FH alone. In the multivariate logistic regression 1655 (-0.07 [95% CI: -0.25 to 0.11], p50.44). Lead levels .5 1600 model, the strongest predictors of ASCVD in patients with 1656 ug/dL were associated with higher Lp(a) (2.51 mg/dL 1601 FH were DM, hypertension, and current smoking. Increased 1657 [95% CI: 0.18 to 4.84], p50.04), but not LDL-Ccorr (0.43 1602 1658 awareness and aggressive management of modifiable risk mg/dL [95% CI: -2.81 to 3.66], p50.80). Folate levels ,3 1603 factors of DM, HTN, and smoking are crucial for ASCVD 1659 ng/dL were not associated with Lp(a) (-1.53 mg/dL [95% 1604 risk reduction in patients with FH. 1660 CI: -3.45 to 0.38], p50.12) or LDL-Ccorr (0.91 mg/dL 1605 1661 [95% CI -2.15 to 3.97], p50.56). Univariate and multi- 1606 1662 variate results are shown in the table. 1607 Epidemiology of Cardiovascular Disease 1663 1608 Conclusions: In a nationally representative US cohort, 1664 1609 136 Lp(a) was associated with serum levels of multiple fat 1665 1610 Association of Serum Vitamins, Minerals, and soluble vitamins, minerals, and heavy metals. Folate was 1666 1611 Heavy Metals with Lipoprotein(a) the only covariate found to associate with Lp(a) but not 1667 1612 LDL-Ccorr, which has not been previously reported. Lead 1668 1613 Eric Brandt, MD, (New Haven, CT) Daniel Brandt, MPH, toxicity may be associated with higher Lp(a). These results 1669 1614 Nihar Desai, MD, MPH, Erica Spatz, MD, MHS, could be due to multiple comparisons, although warrant 1670 Arya Mani, MD, Khurram Nasir, MD, MPH further investigations.

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1671 Lipid Management Best Practices 1727 1672 1728 1673 1729 137 1674 1730 1675 Early Statin Use and Recurrent Major Adverse 1731 1676 Cardiovascular Events: A Multicenter Study 1732 1677 1733 Kristen Tecson, PhD, (Dallas, TX) Aaron Kluger, MPH, 1678 1734 Andrea Cassidy-Bushrow, PhD, Bin Liu, MPH, 1679 1735 Chad Coleman, MPH, Laney Jones, PharmD, MPH, 1680 1736 Celeena Jefferson, MIT, Jeffrey VanWormer, PhD, 1681 1737 Pin Xiang, PharmD, Modhar Habib, PhD, 1682 1738 Katherine Mues, PhD, Peter McCullough, MD, MPH 1683 1739 1684 1740 1685 Lead Author’s Financial Disclosure: Nothing to less likely to have chronic kidney disease than post-index 1741 1686 disclose. statin non-users. For the first 219 days following an index 1742 1687 Study Funding: Amgen Inc. event, statin therapy was independently associated with a 1743 25.3% decreased risk of MACE (p50.0010). Although statin 1688 Background/Synopsis: Clinical guidelines recom- 1744 use still afforded a net protection after 219 days, the 1689 mend statins for patients with atherosclerotic cardiovascu- 1745 magnitude of this protection was no longer statistically 1690 lar disease (ASCVD), but many remain untreated. The 1746 significant (p50.6537). Of the pre-index statin users, 3274 1691 near-term consequences of statin underutilization following 1747 (84.69%) continued statins following index and 592 1692 ASCVD are not well understood. 1748 1693 (15.31%) discontinued statins. Additionally, of the 4302 1749 Objective/Purpose: To assess the impact of early statin 1694 patients not using statins prior to index, 878 (20.41%) were 1750 use on recurrent cardiovascular (CV) events. 1695 initiated on statins following index and 3424 (79.59%) were 1751 1696 Methods: This study utilized medical records and insur- not. All-cause death was the most substantial driver of the 1752 1697 ance claims data from four health care systems across the MACE risk difference, with 93 (2.24%) post-index statin 1753 1698 United States (Baylor Scott & White, Henry Ford, Geisinger, users dying versus 191 (4.76%) non-users. 1754 1699 and Marshfield Clinic). Eligible adults survived an index CV Conclusions: This study demonstrated a very modest 1755 1700 hospitalization from September 30, 2013 to September 30, increase in statin treatment after an initial ASCVD event, 1756 1701 2014 and were followed up to 1 year. A multivariable with nearly half of patients remaining undertreated. Statin 1757 1702 extended Cox model with robust sandwich estimates was use within 219 days of an ASCVD event was associated 1758 1703 created to investigate the association between post-index with a 25% risk reduction for subsequent MACE, but this 1759 1704 statin use (assessed via prescription fill) and recurrent major effect decreased over time. Statin administration may have 1760 1705 adverse cardiovascular events (MACE) while accounting for the greatest impact in the initial period after ASCVD 1761 1706 clustering, comorbidities, and non-proportional hazards. events. Hence, it is crucial for doctors to prescribe and for 1762 1707 Results: There were 8168 eligible patients; 3866 (47.33%) patients to adhere to this therapy as quickly as possible 1763 1708 filled a statin prescription within 90 days prior to the index following an ASCVD hospitalization. 1764 1709 event and the number of statin users increased to 4152 1765 1710 (50.83%) within 90 days after index. These post-index statin 1766 1711 users were younger, more likely to be male and Caucasian Lipid Management Best Practices 1767 1712 and to have diabetes, hyperlipidemia, and hypertension, but 1768 1713 1769 1714 138 1770 1715 PROMIS Measure Captures Perceived Cognitive 1771 1716 Impairment Associated with Familial 1772 1717 Chylomicronemia Syndrome 1773 1718 1774 Rina Fox, PhD, MPH, (Chicago, IL) John Peipert, PhD, 1719 1775 Montserrat Llonch, MD, MPH, MSc, 1720 1776 Andrew Hsieh, PharmD, 1721 1777 Glenn Phillips, PhD, David Cella, PhD 1722 1778 1723 1779 1724 Lead Author’s Financial Disclosure: Rina S. Fox 1780 1725 completed this work as contracted by Akcea Therapeutics 1781 1726 Study Funding: Funding for this research was provided 1782 to Northwestern University by Akcea Therapeutics.

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1783 Background/Synopsis: Familial Chylomicronemia Lipid Management Best Practices 1839 1784 Syndrome (FCS) is a rare genetic disorder wherein the 1840 1785 1841 body is not able to break down fats appropriately. Living 139 1786 with FCS imposes significant burden on patients, which 1842 1787 Both Cardiologists and Primary Care 1843 in turn can significantly worsen health-related quality of Physicians Lack Awareness in How to 1788 life (HRQOL). Among other concerns, many patients 1844 1789 Recognize and Treat Heterozygous Familial 1845 with FCS report cognitive symptoms, such difficulty Hypercholesterolemia† 1790 concentrating and brain fog, on a daily basis. However, a 1846 1791 detailed understanding of cognitive functioning among Dean Karalis, MD, FNLA, (Philadelphia, PA) 1847 1792 FCS patients has not been ascertained, as legacy patient- Matthew Bang, Robert Block, MD, MPH, FNLA, 1848 1793 reported outcome measures are often not sensitive to Amy Peterson, MD, Nathan Wong, PhD, FNLA 1849 1794 FCSs impact. NIH PROMIS measures, which were 1850 1795 developed to provide a comprehensive HRQOL and 1851 1796 symptom evaluation system for use across conditions, Lead Author’s Financial Disclosure: Regeneron 1852 1797 may be useful for capturing patient-reported cognitive Sanofi consultant / speaker honorarium; Amarin speaker 1853 1798 functioning in FCS patients. honorarium. 1854 1799 Study Funding: Sanofi Regeneron. 1855 1800 Objective/Purpose: To assess the ability of a 1856 PROMIS Cognitive Function measure to detect pa- Background/Synopsis: Heterozygous Familial Hyper- 1801 cholesterolemia (HeFH) is an inherited disorder that leads 1857 1802 tient-perceived cognitive functioning in the FCS 1858 population. to very high LDL-C from birth and premature cardiovas- 1803 cular disease. HeFH is often undiagnosed and undertreated 1859 1804 Methods: Adult FCS patients living in the United States in clinical practice. 1860 (N 5 25) completed a series of patient reported outcome 1805 Objective/Purpose: We sought to compare awareness 1861 measures, including the four-item PROMIS Cognitive 1806 and treatment of HeFH between cardiologists (C) and 1862 Function Short Form v2.0, form 4a (PROMIS CF). The 1807 primary care physicians (PCP). 1863 1808 measure is scored using item response theory and yields a 1864 The National Lipid Association surveyed 500 1809 T-score that has been calibrated so a score of 50 represents Methods: 1865 C and 500 PCP in the United States who prescribe 1810 the mean for the general population, with a standard 1866 medications and have patients with baseline LDL-C . 1811 deviation (SD) of 10. Higher scores indicate better pa- 1867 190 mg/dL. 1812 tient-perceived functioning. 1868 Results: When presented a case of HeFH 57% of C vs 43% 1813 The average score on the PROMIS CF 1869 Results: of PCP made the correct diagnosis (p,0.0001). While 21% 1814 measure (T 5 41.60) was nearly a full SD worse than 1870 of C vs 29% of PCP have never made a diagnosis of HeFH in 1815 that of the general population mean. The marginal 1871 a patient with an LDL-C . 190 mg/dL (p,0.004) with 46% 1816 reliability of this instrument was good at 0.80. One 1872 of C vs 37% of PCP not diagnosing HeFH without a positive 1817 participant (4%) was scored at the lowest possible value 1873 genetic test (p50.16). As an initial step in HeFH 85% of C vs 1818 (floor) and two participants (8%) were scored at the 1874 76% PCP (p50.0019) would prescribe medication (69% of C 1819 highest possible value (ceiling). An independent samples 1875 vs 65% of PCP a high intensity statin; p50.19), while only 1820 t-test demonstrated that when compared to asymptomatic, 1876 7% of C vs 5% of PCP would refer to a lipid specialist 1821 fully-ambulatory participants, those who reported symp- 1877 (p50.05). For additional LDL-C lowering after a statin 65% 1822 toms had significantly worse PROMIS CF scores (M 5 1878 1823 5 5 5 5 of C vs 33% of PCP would prescribe a PCSK9 inhibitor 1879 40.1, SD 8.8; compared to M 49.2, SD 8.1; d , 1824 , (p 0.0001) while 29% of C vs 33% of PCP would choose 1880 1.08, p 0.05). 5 1825 ezetimibe (p 0.19). In HeFH 30% of C vs 53% of PCP have 1881 , 1826 Conclusions: Consistent with expectations, the never prescribed a PSCK9 inhibitor (p 0.0001). The most 1882 1827 PROMIS Cognitive Function Short Form v2.0, form common reasons being cost and lack of experience in 1883 1828 4a captured heightened patient-reported cognitive prescribing one. Cascade screening was routinely recom- 1884 , 1829 impairment by patients with FCS as compared to the mended by 58% of C vs 50% of PCP (p 0.045) and 28% of C 1885 5 1830 general population. The measure captured the broad vs 24% of PCP (p 0.15) would not screen children of an 1886 1831 range of cognitive impairment experienced within the HeFH parent until they are adults. Among C vs PCP (71% of 1887 5 1832 context of FCS, with minimal floor and ceiling effects. vs 69%, p 0.48) would erroneously use a risk calculator in 1888 5 1833 Significant differences between symptomatic and an HeFH patient, (55% vs 53%, p 0.53) reported no access 1889 5 1834 asymptomatic patient groups provided preliminary evi- to a lipid specialist, (32% vs 33%, p 0.76) report no 1890 1835 dence of validity. Results support the sensitivity of the familiarity with the DLCN score, and 67% would treat 1891 1836 PROMIS Cognitive Function measure for use among men vs 57% women with a statin between ages 18 to 29 1892 , 1837 patients with FCS. This measure may be well-suited for (p 0.0001). 1893 1838 monitoring patient-reported cognitive impairment in this Conclusions: C compared to PCP are only somewhat 1894 population. more likely to recognize and treat HeFH patients according

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1895 to guidelines. Many C and PCP do not refer or have access not screen until adulthood, the most common reason cited 1951 1896 to a lipid specialist. There is a need for more education for was lack of familiarity with pediatric cholesterol guidelines 1952 1897 C and PCP in recognizing and treating HeFH, greater (see table). Respondents were most likely to start a statin on 1953 1898 access to lipid specialists, and fewer barriers for PCSK9 a male or female patient with known HeFH between 18 and 1954 1899 inhibitor use. 29 years of age (68% of PCP and 65% of C). 1955 1900 Conclusions: Many PCP and C do not routinely cascade 1956 1901 screen adult relatives of a patient with known HeFH nor 1957 1902 Lipid Management Best Practices screen individuals with a strong family history of premature 1958 1903 ASCVD or high cholesterol. Those who see pediatric 1959 1904 patients are more likely to screen for HeFH but have 1960 140 1905 more concerns about the benefit and safety of treatment. 1961 1906 Primary Care Physician and Cardiologist More education is needed among PCP and C to recognize 1962 1907 Cascade Screening Behaviors and Treatment and treat HeFH and screen family members, particularly 1963 1908 Recommendations for Patients with Familial pediatric family members. 1964 1909 Hypercholesterolemia 1965 1910 1966 1911 Amy Peterson, MD, (Madison, WI) Matthew Bang, 1967 1912 Robert Block, MD, MPH, FNLA, Genetics, Gene Therapy and Atherosclerosis 1968 1913 Nathan Wong, PhD, FNLA, Dean Karalis, MD, FNLA 1969 1914 141 1970 1915 Lead Author’s Financial Disclosure: Nothing to Disclosure of s Genetic Risk Variant to 1971 1916 disclose. Familial Hypercholesterolemia Improves 1972 1917 1973 Study Funding: Sanofi Regeneron. Adherence to Lipid Lowering Therapy 1918 1974 1919 Background/Synopsis: Heterozygous Familial Hyper- Laney Jones, PharmD, MPH, (Danville, PA) 1975 1920 cholesterolemia (HeFH) is an inherited disorder of LDL-C Nan Chen, MS, Dina Hassen, MS, Tracey Klinger, BS, 1976 1921 resulting in early onset atherosclerotic cardiovascular dis- Megan McMinn, MS, Dustin Hartzel, BS, 1977 1922 ease (ASCVD). Guidelines recommend cascade screening David Veenstra, PharmD, PhD, Scott Spencer, MPH, MA, 1978 1923 of potentially affected relatives, starting with children as Susan Snyder, PhD, MBA, Josh Peterson, MD, MPH, 1979 1924 young as two years old and starting statin treatment at 8-10 Victoria Schlieder, MS, Marc Williams, MD, 1980 1925 years old. Jing Hao, MD, PhD, Laura Woods, MPH, 1981 1926 Objective/Purpose: Among cardiologists (C) and Shawn Garbett, MS, Amy Sturm, MS 1982 1927 primary care physicians (PCP), we sought to measure 1983 1928 physicians self-reported compliance with these 1984 Lead Author’s Financial Disclosure: Nothing to 1929 recommendations. 1985 disclose. 1930 Methods: The National Lipid Association surveyed 500 1986 1931 C and 500 PCP in the US who prescribe medications and Study Funding: NIH/NHGRI 5 R01 HG009694. 1987 1932 have patients with baseline LDL-C &; 190 mg/dL. Background/Synopsis: Patient adherence to lipid 1988 1933 Pediatricians were not included, but physicians reported if lowering therapies (LLTs) has been impacted by many 1989 1934 they routinely care for individuals under 18 years. Likert barriers including medication side effects, high cost, and 1990 1935 scales were used to measure likelihood of screening first the necessity for life long use. Review of published 1991 1936 degree family members and age at which cholesterol literature suggests that certain factors may modulate an 1992 1937 screening and statin treatment in patients with FH should individuals’ adherence. 1993 1938 begin. For respondents indicating they would not perform Objective/Purpose: To investigate if the return of a 1994 1939 cholesterol screening in individuals under 18 years, expla- genetic predisposition to familial hypercholesterolemia 1995 1940 nations were sought. (FH) changes an individual’s adherence to LLTs. 1996 1941 Results: Only 54% of respondents indicated they would Methods: A retrospective study on participants who 1997 1942 always recommend cascade screening of potentially received a genomic risk result predisposing to FH through 1998 1943 affected first degree relatives, with no difference between the MyCode Community Health Initiative, had continuous 1999 1944 C or PCP (p50.94). 68% indicated they would begin insurance coverage, and had filled at least one prescription 2000 1945 monitoring LDL-C in individuals with a strong family for a LLT before and after genomic risk result disclosure 2001 1946 history of premature ASCVD or high cholesterol in adult- was conducted. The observation period was from 2 years 2002 1947 hood, most commonly between 18-29 years of age. 74% prior to result receipt to January 16, 2019. Adherence was 2003 1948 would check cholesterol in a child of a patient with known calculated using the accepted metric of proportion of days 2004 1949 HeFH, with physicians who report caring for pediatric covered (PDC). We compared patients’ PDC in pre- and 2005 1950 patients more likely to report screening in childhood post-disclosure periods and in stratified sub-cohorts by age, 2006 (86.9% vs 65.9%, p,0.0001). Among those who would gender, cardiovascular events, and documented statin

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2007 intolerance. Descriptive statistics wereused for patient 2063 2008 characteristics and PDC. Wilcoxon signed rank test was 2064 2009 used to compare statistical differences in PDC pre- and 2065 2010 post-disclosure and Wilcoxon rank sum test for stratified 2066 2011 sub-cohorts. 2067 2012 Results: A total of 18 patients met eligibility criteria and 2068 2013 approximately three-quarters (72%, 13/18) were on LLT for 2069 2014 primary prevention of cardiovascular disease. A third (6/18) 2070 2015 had documented statin intolerance. Most (15/18) had less 2071 2016 than two years of follow-up included in the analysis after 2072 2017 genomic risk result disclosure. There was a statistically 2073 2018 significant improvement in LLT adherence post-disclosure 2074 2019 (Mean(SD), 76.8% (27.5%)) compared to pre-disclosure 2075 2020 (63.9% (30.3%), p50.01). There was no statistical differ- 2076 2021 ence in adherence in the subgroup analysis. Individuals 2077 2022 treated for secondary prevention (n55) had adherence of 2078 2023 49.3% (35.2%) during the entire study period compared to 2079 2024 individuals without cardiovascular events (75.8% (22.0%), 2080 2025 p50.115); and a trend of improved adherence from pre- atherosclerosis and cancer, the two top leading causes of 2081 2026 (44.1% (37.5%)) to post-disclosure (57.0% (35.1%)), sta- mortality worldwide. Moreover, both these conditions share 2082 2027 tistical significance unavailable due to small sample size. common risk factors including obesity, sedentary life style, 2083 2028 Individuals who had documented statin intolerance (n56) diabetes, smoking and hypercholesterolemia. The mecha- 2084 2029 had adherence of 55.3% (34.4%) compared to those without nisms by which common etiological factors initiate or 2085 2030 documented intolerance (75.1% (23.0%), p50.190), and an promote these two diseases remain unclear, but recent 2086 2031 improving trend in adherence from pre- (52.0% (34.4%)) to evidence has shown the presence of extensive cholesterol 2087 2032 post-disclosure (60.0% (35.3%)). crystals (CCs) in cancer tumors similar to atherosclerosis. 2088 2033 2089 Conclusions: Despite a small sample size, the disclosure of Objective/Purpose: The objective of this study was to 2034 2090 a genomic risk result predisposing to FH resulted in signifi- investigate the effect of CCs on altering GJIC in endothelial 2035 2091 cantly increased adherence to LLTs. Future work should cells as a potential link between atherosclerosis and cancer. 2036 2092 investigate the impact on cardiovascular outcomes and sus- Methods: The scrape loading dye transfer (SL/DT) assay 2037 2093 tainability of adherence to LLT over longer time periods. was used to measure intercellular communication in human 2038 2094 umbilical vein endothelial (HUVE) cells. The distance the 2039 2095 dye travelled from the dye-loaded cells was measured using 2040 2096 Pathophysiology of Atherosclerosis ImageJ software (NIH), and GJIC was expressed as a fraction 2041 2097 of control (cells not treated with CCs) +/- standard deviation 2042 2098 142 at the 95% confidence interval. CCs less than 1 micrometer in 2043 2099 The Risk of Cholesterol Crystals on Gap size were prepared by sonication and filtration. HUVE cells 2044 2100 Junction Intercellular Communication in were exposed to CCs (0.125 mg CC/ml media) for 2, 4 and 6 2045 2101 Human Umbilical Vein Endothelial Cells* days and then assayed for GJIC. 2046 2102 2047 Winner Results: CCs significantly decreased GJIC as compared 2103 to the control at 4 and 6 days of exposure respectively (1.00 2048 Levi Fry, BS, (Grand Rapids, MI) 2104 +/- 0.26 vs. 0.19 +/- 0.05 and 0.31 +/- 0.10, p,0.0001) 2049 Heather DeFeijter-Rupp, BS, Brad Upham, PhD, 2105 (Figure). Additionally, cell growth rate of HUVE cells 2050 Abed Janoudi, PhD, Carlo Barnaba, PhD, 2106 cultured with CC-media declined when compared to CC- 2051 Ilce Medina Meza, PhD, George Abela, MD 2107 2052 free media at days 4-5. 2108 2053 Conclusions: CCs significantly reduced GJIC when 2109 Lead Author’s Financial Disclosure: Nothing to 2054 cultured with HUVE cells, suggesting a potential role of 2110 disclose. 2055 CCs in tumorigenesis by interrupting intercellular commu- 2111 2056 Study Funding: 2019 Michigan State University Col- nication through gap junctions, and a potential link between 2112 2057 lege of Human Medicine Oncology Research Scholarship - atherosclerosis and cancer. The presence of a direct 2113 2058 $2,500. relationship between these two diseases would have pro- 2114 2059 Background/Synopsis: Gap junction intercellular found implications including prevention through lifestyle 2115 2060 communication (GJIC) is a critical cellular phenomenon modifications, changes to treatment regimens for cancer, 2116 2061 instrumental in maintaining tissue homeostasis, and the and identification of current and new drugs as well as 2117 2062 alteration of GJIC results in abnormal cell growth that natural products that could be used in the treatment and 2118 contributes to numerous pathologies, including prevention of cancer.

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2119 Other 2175 2120 2176 2121 143 2177 2122 Lipid Abnormalities in Thyroid Dysfunction*,† 2178 2123 Winner 2179 2124 2180 2125 Luiz Franco, MD, (Dallas, TX) Tiwalade Awosanya, MD, 2181 2126 Beverly Huet, MS, Xilong Li, Zahid Ahmad, MD 2182 2127 2183 2128 Lead Author’s Financial Disclosure: Nothing to 2184 2129 disclose. 2185 2130 Study Funding: None. 2186 2131 Background/Synopsis: The relationships between 2187 2132 thyroid hormone levels and low-density lipoprotein-choles- 2188 2133 terol (LDL-C) abnormalities were first described decades 2189 2134 ago when physicians relied on laboratory data from older 2190 2135 assays. From these studies, the association between thyroid 2191 2136 hormone levels and LDL-C was well established. However, 2192 2137 limited data exist assessing these relationships with modern 2193 2138 thyroid assays, and lipid/lipoproteins other than LDL-C are 2194 2139 understudies with regards to their relationship with thyroid 2195 2140 hormone levels. 2196 2141 Objective/Purpose: We hypothesized that thyroid 2197 2142 dysfunction affects all lipids and lipoproteins with substan- 2198 2143 tial variability between patients. 2199 2144 2200 We queried the electronic medical records of a 2145 Methods: 2201 large county hospital in Dallas, TX for all patients who had 2146 2202 thyroid function tests and lipid panels checked on the same 2147 2203 day from 1/1/2013 to 1/1/2018. We stratified test results 2148 2204 into hypothyroid (TSH . 4.5 mcIU/L and Free T4 , 0.8 2149 2205 ng/dL), hyperthyroid (TSH , 0.5 mcIU/L and FT4 . 1.8 2150 2206 ng/dL) and normal thyroid function (0.5 # TSH # 4.5 2151 2207 mcIU/L, 0.8 # FT4 # 1.8 ng/dL). Results consistent with 2152 2208 subclinical hyper- and hypothyroidism were excluded. exception was HLD-C, which was decreased in both sub- 2153 2209 Each group was analyzed for associations with triglycer- groups. See supplemental table and graphs. Additionally, 2154 2210 ides, total cholesterol, high density lipoprotein-cholesterol among the hypothyroid subjects, 8% (n 5 229) had 2155 2211 (HDL-C), non-HDL-C and LDL-C levels. triglycerides levels $ 1000 mg/dL, and 10% (n 5 284) 2156 2212 had LDL-C $ 190 mg/dL without increased triglycerides. 2157 Results: Our query identified 25,290 unique results for 2213 2158 thyroid hormones and lipid panels checked on the same Conclusions: Our results confirm that thyroid dysfunc- 2214 2159 day. Overall, the hypothyroid group displayed the highest tion affects all lipids and lipoproteins: all but HDL-C were 2215 2160 level of cholesterol and triglycerides whereas hyperthy- increased in hypothyroidism and decreased in hyperthy- 2216 2161 roidism was associated with lower level of lipids. The only roidism. Additionally, we found that among hypothyroid 2217 2162 2218 2163 Table 1 Thyroid functions tests and lipid/lipoprotein levels in hypothyroid vs normal vs hyperttiyroid states1 2219 2164 2220 5 5 5 2165 Hypothyroidism (n 1871) Normal (n 12945) Hyperthyroidism (n 782) p value 2221 2166 TSH (mclU/mL) 21.7 (8.7,53.8) 1.8 (1.2,2.6) 0.08 (0.02,0.17) ,0.001 2222 2167 Free T4 (ng/dL) 0.7 (0.5.0.8) 1.2 (1.1,1.3) 2.1 (2,2.7) ,0.001 2223 2168 Hypothyroidism (n 5 1871) Normal (n 5 12945) Hyperthyroidism (n 5 782) p value 2224 2169 Total cholesterol (mg/dL) 215 (181,251) 181 (154,207) 151 (125,184) ,0.001 2225 2170 Triglycerides (mg/dL) 163 (114,227) 123 (87,164) 101 (78,150) ,0.001 2226 2171 LDL-C (mg/dL) 120 (93,153) 99 (78,123) 79 (60,106) ,0.001 2227 2172 Non-HDL-C (mg/dL) 165 (130,198) 128 (103,154) 101 (80,132) ,0.001 2228 2173 HDL-C (mg/dL) 47 (38,62) 49 (40,61) 46 (37,58) ,0.001 2229 2174 1Values represent median (IQR). 2230

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2231 patients, variability may exist in the lipid response to apoB pool size versus control (-20.2%, p50.0003), with no 2287 2232 thyroid hormone. Some patients developed hypertriglycer- change in CRL-LDL PR (-4.7%, p50.7), but hastened 2288 2233 idemia, placing them at risk for pancreatitis, while other CRL-LDL FCR versus control, implying IPE promotes 2289 2234 patients were found to have severe hypercholesterolemia, LDL clearance (+20.2%, p50.0418). 2290 2235 potentially increasing their risk of coronary artery disease. Conclusions: High-dose IPE shrank the TRL apoB pool 2291 2236 Our results reinforce the need to check all hypothyroid in patients with residual hypertriglyceridemia, thus lowering 2292 2237 patients for abnormalities in lipid and lipoproteins. Addi- the prevalence of very low-density lipoprotein (VLDL) 2293 2238 tional work is required to understand why a variability in particles. This is likely because higher EPA exposure slows 2294 2239 lipid response may exist. TRL production, like other omega-3 fatty acids. Beyond 2295 2240 TRL, IPE also shrank the LDL apoB pool, thus lowering the 2296 2241 2297 Omega-3 Fatty Acids prevalence of LDL particles. This apparently results from 2242 high-dose IPE hastening LDL clearance, distinct from other 2298 2243 omega-3 fatty acids. In summary, high-dose IPE likely 2299 2244 144 suppresses atherogenic lipoproteins at both metabolic ends, 2300 2245 Icosapent Ethyl Mitigates Dyslipidemia by by both limiting VLDL production and promoting LDL 2301 2246 Both Hastening LDL Clearance and Slowing clearance. Perhaps these properties contribute to its ability to 2302 2247 Triglyceride-Rich Lipoprotein Production prevent major cardiovascular events. 2303 2248 2304 2249 Richard Dunbar, MD, (Voorhees, NJ) 2305 2250 Christina Copland, PhD, Lisa Jiao, PhD, Pharmacological Control of Lipids and 2306 2251 Robert Wang, PhD, Katy Wong, BS, John Millar, PhD, Lipoproteins 2307 2252 Maria Escobar, BS, 2308 2253 Patty Tarino, PhD, Rebecca Juliano, PhD 2309 145 2254 2310 Contrasting Postprandial Triglyceride 2255 Grants from 2311 Lead Author’s Financial Disclosure: Response of Two Niacin Formulations and 2256 Akcea, Amarin, Arizona Pharmaceuticals, Astra Zeneca, 2312 Regimen To Modify Coronary Heart Disease 2257 Regeneron, UniQure, speakers fees from Akcea, employ- 2313 Risk 2258 ment/stocks from Amarin. 2314 2259 Study Funding: Amarin Pharma, Inc, Bridgewater, NJ. Masako Ueda, MD, (Philadelphia, PA) Harsh Goel, MD, 2315 2260 2316 Background/Synopsis: Icosapent ethyl (IPE) is a Dusanka Lalic, BS, Laura Pollan, BS, 2261 2317 purified ethyl ester form of eicosapentaenoic acid (EPA) Grace Nathanson, BS, Jamila Hoque, BS, 2262 2318 that lowers plasma triglycerides (TGs) and prevents major Maria Escobar, BS, 2263 2319 adverse cardiovascular events (MACE) by an unknown Daniel Rader, MD, Richard Dunbar, MD, MTR 2264 2320 mechanism. 2265 2321 Objective/Purpose: Reveal kinetics of high-dose IPE Lead Author’s Financial Disclosure: Nothing to 2266 disclose. 2322 2267 TG lowering, by assessing TG-rich lipoprotein (TRL) and 2323 Study Funding: None. 2268 cholesterol-rich lipoprotein (CRL) apolipoprotein B (apoB) 2324 2269 pool size changes, plus production (PR) and fractional Background/Synopsis: Triglyceridemia and espe- 2325 2270 catabolic (FCR) rates. cially, postprandial triglyceride (ppTG) elevation raise 2326 2271 Methods: Vascepa to Accelerate Lipoprotein Uptake and coronary heart disease (CHD) risk, and niacin can lower 2327 2272 Elimination (VALUE) Study was a randomized parallel- ppTGs. Dosed thrice daily with meals, immediate-release 2328 2273 arm mechanistic clinical study of IPE effects on lipoprotein niacin (IRNA) and a delayed-release pro-drug lowered 2329 2274 kinetics in statin-treated patients with residual hypertrigly- events in two separate CHD outcomes trials. However, 2330 2275 ceridemia. Patients were randomized to IPE 4 g/d plus dosed once daily at bedtime before the nocturnal fast, 2331 2276 statin (n512) or statin alone (n58) for . 14 weeks. We extended release niacin (ERNA) failed to lower CHD 2332 2277 measured TRL and CRL pool size, PR, and FCR at baseline events beyond a statin in two trials. To lower ppTG and 2333 2278 and on treatment. CHD risk, niacin may require mealtime and/or multiple 2334 2279 Results: Compared to control, high-dose IPE shrank TRL daily dosing to achieve the desired outcome. 2335 2280 apoB pool size (-21.7%, p,0.0001) and slowed TRL FCR Objective/Purpose: To evaluate niacin’s ability to 2336 2281 (-19.4%, p50.0154), ruling out faster clearance shrinking lower ppTG with 2g by single-dose ERNA and multiply- 2337 2282 the TRL pool, with no changes in TRL PR (p50.6). Higher dosed IRNA compared to placebo in patients with/without 2338 2283 serum EPA exposure translated to slower TRL PR, which dyslipidemia. 2339 2284 would explain the smaller TRL pool (-15.4%, p,0.0001 vs Methods: In a random-order double-blinded crossover 2340 2285 lower EPA exposure). CRL-intermediate-density lipopro- study, 26 dyslipidemics and 22 normolipidemics underwent 2341 2286 tein (IDL) pool size, PR, and FCR were stable in both oral fat tolerance tests (OFTTs) with heavy cream (50 g/m2 2342 groups. IPE shrank CRL-low-density lipoprotein (LDL) fat), followed for 12 hours, crossing over to receive

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2343 placebo, ERNA (2g x1) and/or IRNA (0.5g x4 q2h). We for the patient was completed by GBinsight/Otogenetics 2399 2344 assessed ppTGs by incremental peak (mg/dL) and incre- using an Illumina HiSeq panel. 2400 2345 mental area under the curve (incPeak, incAUC 0-12h, mg/ Results: A 54-year-old slim muscular man with severe 2401 2346 dL*h) as well as the entire area under the curve (AUC). hypertriglyceridemia, recurrent AP, hepatosteatosis, and 2402 2347 Results: On placebo, normolipidemics had a ppTG severe insulin resistance/type 2 diabetes mellitus (T2DM) 2403 2348 incPeak of +113 and incAUC +299/AUC 1563. In dyslipi- was diagnosed with FPL. The patient, who originated from 2404 2349 demics ppTG incPeak was +134, incAUC +771/AUC 2035 the Dominican Republic, has persistent hypertriglyceride- 2405 2350 on placebo, and on IRNA ppTG incPeak was +78, incAUC mia and recurrent AP now treated with high intensity statin, 2406 2351 +290 (p50.001 vs placebo)/AUC 1554 (p50.001). Thus, fenofibrate, and high dose non-prescription omega-3 fatty 2407 2352 IRNA effectively normalized ppTGs (p.0.9 vs normolipi- acids resulting in triglycerides that range 250-3000 mg/dL. 2408 2353 demics). On ERNA, ppTG incPeak was +123, incAUC He was diagnosed with T2DM at age 37 and is now treated 2409 2354 +660/AUC 1864 (both p50.20 vs placebo). Contrary to the with metformin, empagliflozin, and high doses of long- 2410 2355 effect of IRNA, ERNA failed to effectively suppress ppTGs acting and meal-time insulin. Hepatosteatosis was present 2411 2356 in dyslipidemics. Moreover, IRNA lowered ppTGs signif- on imaging since at least 2013. We did not recognize any 2412 2357 icantly more than ERNA (both p50.001). secondary characteristics known to cause these metabolic 2413 2358 2414 Conclusions: At a total 2g dose, mealtime-dosed IRNA derangements. He tests negative for HIV, and he drinks 2359 2415 robustly lowered ppTG in dyslipidemics, resembling nor- alcohol on rare occasions. The patient’s 26-year-old 2360 2416 molipidemics’ response. However, a single dose of 2g daughter shares her father’s physical phenotype. Based 2361 2417 ERNA failed to lower ppTG. This suggests that simply re- upon clinical features, he underwent genetic testing, 2362 2418 timing ERNA with meals may not lower ppTG, and revealing a pathogenic mutation in the PPARG gene. 2363 2419 multiple dosing may also be necessary. Our results clearly Conclusions: FPL is a rare disorder that should be 2364 2420 show the importance of pharmacokinetics on effective considered in the setting of hypertriglyceridemia, hepatic 2365 2421 ppTG lowering. Mealtime doses of niacin can reduce steatosis, and poorly controlled DM with insulin resistance 2366 2422 CHD risk by effectively lowering ppTG, but not daily when there are no additional secondary characteristics to 2367 2423 ERNA timed dosing prior to the nocturnal fast. explain the condition. The hallmark feature of the disorder 2368 2424 is an abnormal distribution of subcutaneous fat such that 2369 2425 the extremities appear slim/muscular while there may be 2370 2426 Diabetes, Insulin Resistance and Dyslipidemia increased abdominal (visceral) fat. Genetic testing can be 2371 2427 used to confirm the diagnosis of FPL. There is no specific 2372 2428 146 treatment for FPL beyond management of the various 2373 2429 Familial Partial Lipodystrophy Due to a metabolic derangements. While the great majority of 2374 2430 Mutation in Pparg Resulting in Severe patients with diabetes, hepatosteatosis, and hypertriglycer- 2375 2431 Hypertriglyceridemia, Hepatosteatosis and idemia require weight loss, FPL patients require unique 2376 2432 Insulin Resistance dietary care and may not benefit from weight loss. Family 2377 2433 members may benefit from diagnostic testing. Clinicians 2378 2434 Archna Bajaj, MD, (Philadelphia, PA) should be aware of the potential presence of FPL and best 2379 2435 Gayley Webb, Daniel Soffer, MD care will involve treatment by a Lipid Specialist, Endocri- 2380 2436 nologist and Registered Dietitian/Nutritionist. 2381 2437 Lead Author’s Financial Disclosure: Nothing to 2382 2438 disclose. 2383 Clinical Applications of Biomarkers, Lipoprotein 2439 2384 Study Funding: Genetic testing in this study was Testing 2440 2385 completed complimentary of GBinsight. 2441 2386 Background/Synopsis: We present a 54 year-old man 147 2442 2387 who was referred to Preventive Cardiology because of severe Comparison of Two Methods for Assessing 2443 2388 hypertriglyceridemia and recurrent acute pancreatitis (AP). Small, Dense LDL Cholesterol 2444 2389 His clinical features, including his family history, suggested 2445 2390 the presence of partial lipodystrophy and subsequent genetic Meredith Wilcox, MPH, Indika Edirisinghe, PhD, 2446 2391 testing confirmed the presence of a pathogenic mutation in the Mary Dicklin, PhD, Di Xiao, MS, 2447 2392 PPARG gene consistent with that diagnosis. Recognition of Britt Burton-Freeman, PhD, Kevin Maki, PhD 2448 2393 the phenotype and genetic confirmation of familial partial 2449 2394 lipodystrophy (FPL) is expected to improve medical care for Lead Author’s Financial Disclosure: Meredith 2450 2395 the patient and family members. Wilcox is an employee of Midwest Biomedical Research. 2451 2396 Objective/Purpose: To describe the clinical features Midwest Biomedical Research received research grant 2452 2397 and phenotype of a case of FPL. funding from Almond Board of California for the original 2453 2398 Methods: A review of the electronic health records for study that included the VAP laboratory analyses. Denka 2454 the patient and his daughter was completed. Genetic testing Seiken conducted sdLDL-C te.

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2455 Study Funding: Almond Board of California funded the Study Funding: None. 2511 2456 2512 original study that included the VAP laboratory analyses. Background/Synopsis: Familial hypercholesterolemia 2457 2513 Denka Seiken conducted sdLDL-C testing at no cost. (FH) is characterized by lifelong elevations in low-density 2458 2514 Background/Synopsis: An increased level of small, lipoprotein-cholesterol (LDL-C), Despite being at high risk 2459 2515 dense low-density lipoprotein (sdLDL) particles, or choles- for cardiovascular disease (CVD), not all FH patients 2460 2516 terol (-C) carried by such particles, is associated with develop CVD. The Montreal- FH score is a clinical tool - 2461 2517 coronary artery disease risk. Several methods have been developed from a Canadian cohort of white adult FH 2462 2518 developed to measure sdLDL-C including the density- patients with mutations in low-density lipoprotein receptor 2463 2519 gradient ultracentrifugation vertical auto profile (VAP) (LDLR) - to help predict incident CVD. 2464 2520 assay (Clin Lab Med. 2006;26:787-802) and the Denka 2465 Objective/Purpose: We sought to validate the Mon- 2521 Seiken (DS) two-step enzymatic assay (J Lipid Res. 2466 treal-FH score in an ethnically diverse United States (US) 2522 2003;44:2193-2201), but little is known about how their 2467 based cohort of FH patients. 2523 results compare. 2468 Methods: Through a multicenter collaboration, 593 adult 2524 5 2469 Objective/Purpose: DS sdLDL-C (d 1.044-1.063 g/ patients with FH followed in US-based lipid clinics were 2525 2470 mL) was compared to LDL-C in subfractions 3 and 4 included through retrospective chart review. Since no 2526 2471 measured with VAP in plasma samples from a randomized, consensus diagnostic method exists in the US, patients in 2527 2472 crossover trial that evaluated the effects of consuming our cohort had a heterogeneous means of diagnosis of FH, 2528 2473 almonds vs. carbohydrate-rich control foods on insulin including the use of clinical scores (Dutch Lipid Criteria, 2529 2474 sensitivity and cardiometabolic health markers in 32 sub- Simon Broome, MEDPED, and Gidding’s American Heart 2530 2475 jects with prediabetes (J Am Coll Nutr. 2019; doi.org/ Association criteria) with or without genetic testing. The 2531 2476 10.1080/07315724.2019.1660929). Montreal-FH multivariate logistic regression model was 2532 2477 Methods: Correlation analyses were performed to assess applied to this cohort. Covariates in the Montreal-FH score 2533 2478 the associations between LDL3-C, LDL4-C and LDL3+4-C include age, HDL-C, gender, hypertension, and smoking. 2534 2479 from VAP with DS sdLDL-C. Pearson correlation co- CVD was defined as coronary, peripheral, and cerebrovas- 2535 2480 efficients (r-values) were used to show the strength and cular events including angina, myocardial infarction, cor- 2536 2481 direction of each association. onary angioplasty, peripheral arterial surgery, claudication, 2537 2482 Results: Mean (SEM) baseline values for DS sdLDL-C, peripheral angioplasty, transient ischemic attack, stroke and 2538 2483 LDL3-C, LDL4-C and LDL3+4 -C were 36.2 (3.1), 39.5 carotid endarterectomy. 2539 2484 (3.4), 9.8 (1.5), and 49.3 (3.9) mg/dL, respectively. Neither Results: Baseline characteristics of the 593 adult patients 2540 2485 treatment significantly altered DS sdLDL-C or LDL are shown in table 1. The median Montreal FH score in the 2541 2486 subfraction cholesterol values. Pearson r-values were overall cohort as well as for Whites and Blacks was 28. The 2542 2487 0.662, 0.648, and 0.819 at baseline for DS sdLDL-C with odds ratio for CVD in those with a high Montreal FH score, 2543 2488 LDL3-C, LDL4-C and LDL3+4-C, respectively (p , 0.001 (defined as $21 in the original paper) was 4.6 (95% CI 2.3, 2544 2489 for all). Corresponding correlation coefficients were 0.811, 10.7) in the US-based cohort vs. 8.8 (95% CI 5.8, 13.3) in 2545 2490 0.669, and 0.873 for pooled end-of-treatment, and 0.389, the Canadian validation cohort. Table 2 demonstrates the 2546 2491 0.507, and 0.569 for pooled change from baseline values, application of the Montreal-FH multivariate regression 2547 2492 respectively (all p # 0.001). Results were similar for the model in the US based cohort in comparison to the original 2548 2493 two treatment conditions when analyzed separately. Montreal-FH cohort. Male sex, current smoking, hyperten- 2549 2494 Conclusions: These results show that DS sdLDL-C values sion and low high-density lipoprotein cholesterol (HDL-C) 2550 2495 were generally lower than LDL3+4-C by the VAP method, were significant predictors of incident CVD in multivariate 2551 2496 although values for the methods were strongly correlated. logistic regression. 2552 2497 Conclusions: The Montreal-FH score can be reasonably 2553 2498 applied to an ethnically diverse group of patients with FH 2554 2499 Lipid Management in Special Populations in the US for CVD prediction. 2555 2500 2556 2501 148 Pathophysiology of Atherosclerosis 2557 2502 2558 Validation of the Montreal-FH risk score in a 2503 150 2559 United States based cohort of patients with A Case of Transcatheter Aortic Valve 2504 Familial Hypercholesterolemia 2560 2505 Replacement in a patient with Familial 2561 2506 Anandita Agarwala, MD, (Saint Louis, MO) Hypercholesterolemia 2562 2507 2563 Aliza Hussain, MD, Elena Deych, MS, Zahid Ahmad, MD, Nathan Bekele, MD, (Saint Louis, MO) 2508 2564 Christie Ballantnye, MD, Anne Goldberg, MD Anandita Agarwala, MD, Anne Goldberg, MD 2509 2565 2510 Lead Author’s Financial Disclosure: Nothing to Lead Author’s Financial Disclosure: Nothing to 2566 disclose. disclose.

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2567 Study Funding: None. Objective/Purpose: It is not known whether the health 2623 2568 2624 Background/Synopsis: Familial hypercholesterolemia benefits expected from weight reduction, blood sugar, and 2569 2625 (FH) is an autosomal dominant disorder with a prevalence of triglyceride (TG)-lowering (7) may be offset by a rise in 2570 2626 about 1 in 250 in the general population. One hallmark of FH low-density lipoprotein cholesterol (LDL-C) levels while 2571 2627 is lifelong elevation in low-density lipoprotein cholesterol on a high SFA/high cholesterol KD. Most adherents of 2572 2628 which is a risk factor for cardiovascular disease. Patients with popular diets do not follow the parameters strictly or with 2573 2629 FH are at risk for early-onset atherosclerotic cardiovascular guidance from a registered dietitian nutritionist (RDN). In 2574 2630 disease and can also develop valvular heart disease, partic- addition, some proponents of reduced CHO dieting stress 2575 2631 ularly aortic stenosis. Aortic stenosis can manifest in a severe the value of manipulating the macronutrient content of food 2576 2632 form that poses several surgical challenges involving manip- without respect to potential detriment of some high fat, 2577 2633 ulation of the valve during cross-clamping. high cholesterol food choices (8). It is well-recognized 2578 from clinical trials that a diet high in SFA and cholesterol, 2634 2579 Objective/Purpose: To discuss the use of transcatheter 2635 aortic valve replacement (TAVR) as a means of intervention will result in predictable increases in LDL-C levels (9,10). 2580 We present a case of a young man developing severe 2636 2581 in this specific subset of patients with FH and to explain its 2637 possible utility. hypercholesterolemia on an unsupervised highly-detailed 2582 self-reported KD, with normalization of LDL-C levels after 2638 Methods: n/a. 2583 effective dietary consultation. 2639 2584 Results: We present a case of a 59-year-old man with a 2640 Methods: A 33 yo man who developed severe hypercho- 2585 severe clinical phenotype of heterozygous FH and coronary 2641 lesterolemia while following a KD (,30 gm CHO, 120 gm 2586 artery disease, who developed exertional chest tightness 2642 total fat daily) was referred to lipid clinic. He has no 2587 and shortness of breath. The patient was found to have 2643 clinical atherosclerotic cardiovascular disease, nor does he 2588 severe calcific aortic valve stenosis by echocardiographic 2644 have signs of a severe inherited lipid disorder (e.g. Familial 2589 criteria and cardiac computed tomography. After a multi- 2645 Hypercholesterolemia [FH]). The RDN recommended low- 2590 disciplinary evaluation and discussion of surgical vs. 2646 CHO whole-food, plant-based replacements for high SFA 2591 percutaneous options, the patient underwent TAVR with 2647 and cholesterol foods (he was eating 24 egg yolks per 2592 complete resolution of symptoms. 2648 week) resulting in LDL-C normalization. 2593 Conclusions: Patients with FH may develop severely 2649 Results: On the KD, the patient had a total cholesterol of 2594 calcified aortic valves, which makes achieving safe surgical 2650 483 mg/dL, TG 169 mg/dL, high- density lipoprotein 2595 valve replacement a challenge. TAVR is a safe and effective 2651 cholesterol (HDL-C) 30 mg/dL, and LDL-C 419 mg/dL. 2596 alternative to surgical aortic valve replacement in patients with 2652 2597 After minimally reducing his SFA intake, but significantly 2653 FH and is a viable means for achieving significant symptom- . w 2598 reducing his cholesterol intake from 1000 mg to 300 mg, 2654 atic relief while reducing post-operative all-cause mortality. , 2599 while maintaining CHO intake at 30 gm daily, his lipid 2655 2600 profile improved to the following: TC 206 mg/dL, TG 60 mg/ 2656 2601 Nutrition, Nutrigenomics, Nutraceuticals and dL, HDL-C 70 mg/dL, LDL-C 121 mg/dL (71% reduction). 2657 2602 Exercise Therapies Conclusions: This case demonstrates the occurrence of 2658 2603 severe hypercholesterolemia as a result of extremely high 2659 2604 151 intake of SFA and cholesterol, as well as the important 2660 2605 Ketogenic Diet Causing Severe impact of dietary counseling in susceptible individuals. By 2661 2606 Hypercholesterolemia in Former Athlete incorporating a positive working relationship with a well- 2662 2607 trained RDN, this patient was able to follow his preferred 2663 2608 Cara Smith, MD, (Philadelphia, PA) very-low-CHO diet without compromising lipid control. 2664 2609 Daniel Soffer, MD FNLA, Fran Fran Burke, MS RDN 2665 2610 Pharmacological Control of Lipids and 2666 2611 Lead Author’s Financial Disclosure: Nothing to Lipoproteins 2667 disclose. 2612 152 2668 2613 2669 Study Funding: None. Bempedoic Acid Efficacy and Safety in High 2614 Background/Synopsis: The ketogenic diet (KD) is CVD Risk Patients Treated With or Without 2670 2615 one of the most popular dietary trends in the United States Ezetimibe: Pooled Analysis of 4 Phase 3 2671 2616 (1-6). Individuals who follow a KD may consume high Clinical Trials† 2672 2617 levels of saturated fat (SFA) and cholesterol. We present a 2673 2618 case of a young man who developed severe hypercholes- Alberico Catapano, PhD, MD, (Milan, Italy) 2674 2619 terolemia attributed to extreme intake of SFA and choles- Harold Bays, MD, Maciej Banach, MD, PhD, P. Duell, MD, 2675 2620 terol while on a very-low-carbohydrate (CHO) (,30 gm Ulrich Laufs, MD, PhD, Lawrence Leiter, MD, 2676 2621 CHO per day) KD, which improved with dietary counseling G. B. Mancini, MD, Kausik Ray, MD, MPhil, 2677 2622 and change to very-low-CHO high SFA normal cholesterol Diane MacDougall, MS, 2678 diet. Zhan Ye, PhD, Christie Ballantyne, MD

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2679 Lead Author’s Financial Disclosure: AL Catapano Lead Author’s Financial Disclosure: Kaneka grant 2735 2680 has received research grant(s)/support from Sanofi, Sanofi support; Pfizer grant support: Kaneka consulting fees. 2736 2681 2737 Regeneron, Amgen, Mylan, and Menarini, and has served Study Funding: Sanofi Regeneron. 2682 as a consultant for or received honoraria from Akcea, 2738 2683 Background/Synopsis: Heterozygous familial hyper- 2739 Amgen, Sanofi, Esperion, Kowa, Novartis, Ionis Pharma- cholesterolemia (HeFH) is an inherited disorder that leads 2684 ceuticals, Medco, Mylan. 2740 2685 to very high levels of LDL-C from birth and premature 2741 Study Funding: Esperion funded the research for this 2686 cardiovascular disease. Only 10% of patients with HeFH 2742 study and provided writing support for this abstract. 2687 are diagnosed and appropriate treatment in clinical practice 2743 Medical writing assistance, funded by Esperion, was pro- 2688 is often not performed. 2744 vided by James Bergstrom, PhD and Kelly M. Cameron 2689 Objective/Purpose: Determine physician characteris- 2745 PhD, CMPP, of JB Ashtin. 2690 tics which predict appropriate diagnosis and treatment of 2746 2691 Background/Synopsis: Combination therapy is often patients with HeFH. 2747 2692 required to achieve sufficient low-density lipoprotein choles- Methods: The National Lipid Association surveyed 500 2748 2693 terol (LDL-C) lowering and therapeutic goals in patients with cardiologists (C) and 500 primary care physicians (PCP 2749 2694 hypercholesterolemia. Bempedoic acid is an investigational, ^aV‘‘ not including pediatricians) in the United States 2750 2695 ATP-citrate lyase inhibitor that has demonstrated efficacy who prescribe medications and have patients with base- 2751 2696 when added to background lipid-lowering therapy. line LDL-C $190mg/dL. We built logistic regression 2752 2697 Objective/Purpose: To evaluate the efficacy and safety models by including variables (p-value criteria of 0.15) 2753 2698 of bempedoic acid with or without ezetimibe (EZE) in in stepwise fashion in which the outcomes are: 1) appro- 2754 2699 patients with high CVD risk in a pooled analysis of 4 phase priate treatment of a patient with HeFH and an LDL-C 2755 2700 3 clinical trials. after lifestyle changes of 230mg/dL with a high-dose 2756 2701 Methods: Data were pooled from 4 phase 3 clinical trials in statin; 2) accurate diagnosis of an adult patient with 2757 2702 which patients with hypercholesterolemia were randomized HeFH; and 3) appropriate use of a high dose statin for 2758 2703 2:1 to treatment with bempedoic acid 180 mg or placebo. an adult patient with HeFH and untreated LDL choles- 2759 2704 Background EZE use was permitted (3 studies) or by design (1 terol $190mg/dL, ranked relative to other choices 2760 2705 study). For efficacy assessments, patients were divided into including a low-dose statin, ezetimibe, a PCSK9 inhibi- 2761 2706 those with: (a) atherosclerotic cardiovascular disease and/or tor, and LDL apheresis (see table). Candidate predictors 2762 2707 heterozygous familial hypercholesterolemia receiving back- in the model included, but were not limited to suburban, 2763 2708 ground maximally tolerated statin therapy (ASCVD/HeFH on urban, or rural practice location; familiarity with the 2764 2709 statins pool) and (b) history of statin intolerance (no or low- Simon-Broome and Dutch Lipid Clinic HeFH criteria; 2765 2710 dose statin pool). The primary efficacy endpoint was the and access to a lipid specialist. 2766 2711 percent change from baseline to week 12 in LDL-C. Results: The factors included in the final models 2767 2712 Results: Of the 3623 patients included in the analysis, include: 1) suburban vs. rural practice location being 2768 2713 226 (7.5%) in the ASCVD/HeFH on statins pool and 317 less likely to appropriately recommend high-dose statin 2769 2714 (51.6%) in the statin intolerant pool were receiving for a HeFH patient; 2) incorrectly preferring calcium 2770 2715 background EZE. The treatment effect of bempedoic acid scoring to determine risk in a HeFH patient instead of 2771 2716 was similar in patients with and without background EZE LDL-C and positive genetic testing for HeFH; 3) having 2772 2717 use (P not significant for heterogeneity). The adverse event an approach of monitoring LDL-C starting at age 30-39 vs 2773 2718 profile was similar regardless of background EZE use. age 18-29 being more likely to correctly make an accurate 2774 2719 Conclusions: Bempedoic acid provided significant LDL- diagnosis; 4) those familiar or very familiar with the 2775 2720 C lowering in high CVD risk patients with or without Dutch criteria being more likely to appropriately make a 2776 2721 treatment with background EZE. HeFH diagnosis; 5) those who use genetic testing being 2777 2722 more likely to correctly diagnose someone with HeFH; 2778 2723 and 6) those using no screening tests (genetic testing, 2779 2724 Lipid Management Best Practices family hx of premature CVD or high cholesterol, level of 2780 2725 LDL-C, and Dutch Lipid Clinic or Simon-Broome 2781 2726 2782 155 criteria) being less likely to appropriately make a 2727 diagnosis. 2783 Primary Care Physician and Cardiologist 2728 Conclusions: Physicians with common characteristics 2784 2729 Characteristics Predicting Diagnosis and 2785 Treatment of Patients with Familial are unlikely to correctly diagnosis a patient with HeFH 2730 2786 Hypercholesterolemia and not prescribe a high-dose statin for a patient with 2731 HeFH. Given that patients with HeFH are poorly 2787 2732 Robert Block, MD, MPH, FNLA, (Rochester, NY) diagnosed and treated, leading to premature cardiovas- 2788 2733 Matthew Bang, Nathan Wong, PhD, FNLA, cular disease outcomes, the targeting of particular C and 2789 2734 Amy Peterson, MD, Dean Karalis, MD, FNLA PCP should be considered. 2790

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2791 Hypertriglyceridemia A 17-item instrument was created comprising 4 symptom 2847 2792 items (abdominal pain, physical fatigue, difficulty thinking, 2848 2793 and diarrhea) and 13 items measuring impacts (worry about 2849 2794 157 pancreatitis attack, social activity and planning, dietary 2850 2795 Development of a Novel Patient-Reported restrictions, future health worries, burden to others, 2851 2796 Outcome Measure for Symptoms and Impacts physical activity, depression, judgment by others, 2852 2797 of Familial Chylomicronemia Syndrome financial worries, and productivity). 2853 2798 2854 David Davidson, MD, (Chicago, IL) Conclusions: The content validity of the new FCS 2799 symptom and impacts instrument is supported by qualita- 2855 2800 Michael Stevenson, RPh, PhD, 2856 Montserrat Vera-Llonch, MD, MPH, tive interviews conducted in this study. As such, this 2801 measure has potential to demonstrate benefits of treatment 2857 2802 Andrew Hsieh, Pharm D, T. Brown, PhD, Christina Slota, 2858 PhD, RN, Sheri Fehnel, PhD in the FCS population. Further testing and refinement of the 2803 instrument is ongoing. 2859 2804 2860 2805 2861 Lead Author’s Financial Disclosure: Nothing to Clinical Applications of Biomarkers, Lipoprotein 2806 disclose. 2862 2807 Testing 2863 Study Funding: None. 2808 2864 158 2809 Background/Synopsis: Familial chylomicronemia 2865 2810 syndrome (FCS), a rare genetic disorder characterized by Comparison of the Effect of 2866 2811 high levels of circulating chylomicrons in the blood, can Hypertriglyceridemia on Non-HDL-Cholesterol 2867 2812 have serious and life-threatening consequences, including and Apolipoprotein B as Cardiovascular 2868 *,† 2813 pancreatitis. Findings from the IN-FOCUS survey revealed Disease Risk Markers 2869 2814 symptoms and comorbidities that represent a major burden Winner 2870 for patients with FCS and which considerably impact 2815 Cathy Sun, MD, (Ottawa, ON) Diane Brisson, PhD, 2871 2816 quality of life and activities of daily living. No suitable 2872 patient-reported outcome (PRO) instrument is currently Christopher McCudden, PhD, Julie Shaw, PhD, 2817 Daniel Gaudet, MD, PhD, Teik Ooi, MD 2873 2818 available to evaluate potential benefits of treatment. 2874 2819 Objective/Purpose: This study was initiated to 2875 Lead Author’s Financial Disclosure: Nothing to 2820 develop an FCS-specific PRO measure assessing symptom 2876 disclose. 2821 severity and impacts in a manner consistent with the FDA 2877 2822 PRO guidance for labeling claims. Study Funding: None. 2878 2823 Methods: Concepts included in the new measure were Background/Synopsis: With increasing hypertrigly- 2879 2824 identified from the results of a large cross-sectional burden- ceridemia (HTG), there is progressive abundance of larger 2880 2825 of-illness survey of patients with FCS. Once draft items and less atherogenic triglyceride-rich lipoproteins (TRL), 2881 2826 based on these concepts were generated, in-person and namely, very-low-density lipoproteins (VLDL) and chylo- 2882 2827 telephone interviews were conducted with individuals with microns, and their larger remnants. In HTG, this varying 2883 2828 FCS, both to elicit concepts and cognitively debrief draft TRL composition limits the ability of calculated non-high- 2884 2829 items. Concept elicitation confirmed the concepts of inter- density lipoprotein cholesterol (non-HDLC) to selectively 2885 2830 est and documented their importance and relevance to represent cholesterol from atherogenic lipoproteins. Yet, 2886 2831 patients. Draft items were then debriefed with patients to non-HDLC is widely recommended as a cardiovascular 2887 2832 ensure ease of understanding and response and to identify disease (CVD) risk marker without due consideration to the 2888 2833 items mostly likely to demonstrate change with treatment. presence of HTG. 2889 2834 Item modifications and new items created to address newly Objective/Purpose: We aimed to demonstrate that 2890 2835 identified concepts were debriefed over the course of this serum triglyceride (TG) level has a substantial impact on 2891 2836 iterative interview process. non-HDLC’s ability to represent cholesterol from athero- 2892 2837 Results: Ten interviews were conducted in patients with genic lipoproteins, even though TG is not part of the 2893 2838 FCS. Participant mean age was 53 years; all were white and calculation for non-HDLC. Furthermore, we assessed the 2894 2839 the majority (n 5 7) were female. All participants reported impact of increasing HTG on the concordance and 2895 2840 experiencing severe abdominal pain during acute pancrea- discordance between non-HDLC and apolipoprotein B 2896 2841 titis attacks and the majority (n 5 7) identified abdominal (apoB) as CVD risk markers. 2897 2842 pain as their most bothersome symptom. At least half of the Methods: We have analyzed baseline lipid profile data 2898 2843 participants also reported symptoms of loose bowel move- from 7,492 patients in a Lipid Clinic cohort prior to lipid- 2899 2844 ments/diarrhea, difficulty thinking, physical fatigue, blurred lowering therapy, and 156,311 lipid profiles from The 2900 2845 vision, bloating, and memory difficulties. Participants noted Ottawa Hospital Biochemistry Laboratory. We derived TG- 2901 2846 that these symptoms had a broad impact on their daily lives, interval-specific lipoprotein composition factors (LCF) for 2902 emotional well-being, and social functioning. TRL, which represent the mass ratio of cholesterol to TG in

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2903 TRL. A high LCF indicates TRLs are mainly cholesterol- Objective/Purpose: The 2018 Multisociety Choles- 2959 2904 rich atherogenic remnant lipoproteins, and a low LCF terol Guidelines (8) suggest treatment of individuals with 2960 2905 indicates TRLs are mainly TG-rich larger VLDL and medical therapy should be determined based upon calcu- 2961 2906 chylomicrons, and their larger remnants. lated risk, which can be enhanced by consideration of risk- 2962 2907 In a subset of 4,347 patients in the Lipid Clinic cohort, we enhancing features and atherosclerosis imaging. Prior 2963 2908 analyzed the concordance and discordance between non- guidelines had suggested that high HDL-C was a negative 2964 2909 HDLC and apoB as CVD risk markers in intervals of risk factor. (9) Individuals may have additional idiosyn- 2965 2910 increasing TG. For high CVD risk equivalent range, we cratic characteristics that are undervalued using current 2966 2911 used non-HDLC above 5.7 mmol/L, which corresponds to algorithms and may require a more personalized approach. 2967 2912 w 2968 low-density lipoprotein cholesterol (LDLC) above 5.0 Methods: A 68-year-old Chinese-American woman was 2913 2969 mmol/L (statin-indicated condition), and also corresponds referred for risk-factor management after she suffered a 2914 w 2970 to apoB above 1.4 g/L in epidemiological studies. subacute stroke. Cerebrovascular angiography with 2915 2971 Results: As serum TG increased, there was a progressive computed tomography (CTA) confirmed the presence of 2916 2972 decline in the LCF for TRL. This was shown in both cohorts. two distinct short segments of atherosclerotic severe ste- 2917 2973 In the Biochemistry Laboratory cohort, TG 0.01-1 mmol/L nosis in a distribution consistent with her neurologic 2918 2974 LCF was 0.97, whereas TG 6-7 mmol/L LCF was 0.15. symptoms. In addition to advice on optimizing self-care, 2919 2975 As TG increased, the correlation between apoB and non- we treated her with reduced dose statin and ezetimibe, as 2920 2976 HDLC gradually decreased (TG 0.01-1 mmol/L R^2 was well as anti-platelet therapy. 2921 ^ 2977 0.64; TG 6-7 mmol/L R2 was 0.10). Starting with TG Results: Her risk factors for stroke/ASCVD include her 2922 above 4 mmol/L, mean apoB plateaus in the intermediate 2978 2923 age, high LDL-C, and a family history of stroke in her 2979 CVD risk equivalent range whereas mean non-HDLC father (at 60 years old). Prior to her stroke, her ASCVD risk 2924 enters the high CVD risk equivalent range. 2980 2925 could not be calculated accurately because her total and 2981 Conclusions: As TG increases, non-HDLC gradually 2926 HDL-C were outside the range of the PCE. She had total 2982 includes more cholesterol from larger TRL, which are less 2927 cholesterol 352 mg/dL, low density lipoprotein-cholesterol 2983 atherogenic than LDL and remnant lipoproteins. In mod- 2928 (LDL-C) 179 mg/dL, HDL-C 153 mg/dL, and triglycerides 2984 erate HTG (TG w 4.5-10 mmol/L) and severe HTG (TG 2929 86 mg/dL. Prior treatment with statin therapy was aborted 2985 above 10 mmol/L), there is clinically important discordance 2930 after a brief trial with atorvastatin 10 mg daily due to lower 2986 between mean non-HDLC and mean apoB. 2931 extremity myalgias. 2987 2932 When we met her, she had just completed a 3-month course 2988 of dual anti-platelet therapy and she was tolerating 2933 Lipid Management in Special Populations 2989 2934 rosuvastatin 5 mg every other day and aspirin 81 mg daily. 2990 2935 Her LDL-C had improved to 76 mg/dL prompting initiation 2991 160 2936 of ezetimibe. Atypical chest heaviness prompted subsequent 2992 2937 Case Report: Acute Stroke Due to evaluation with coronary angiography with computed 2993 2938 Cerebrovascular Atherosclerosis in Chinese- tomography (CCTA) and no obstructive disease was 2994 2939 american Woman with Extremely High Level of present, nor was there any calcified coronary atherosclerosis. 2995 2940 High Density Lipoprotein-cholesterol (HDL-C) Conclusions: Clinicians should proceed with caution 2996 2941 and Coronary Artery Calcium Score Equal Zero when interpreting cardiovascular risk based on standard 2997 2942 methods in patients with very high HDL-C levels and 2998 Jan Gong, MD, (Philadelphia, PA) 2943 coronary atherosclerosis imaging may not reflect stroke- 2999 Daniel Soffer, MD FNLA 2944 risk in predisposed individuals. A personalized approach 3000 2945 that includes expanded biochemical/genetic testing and 3001 2946 Lead Author’s Financial Disclosure: Nothing to atherosclerosis imaging should be considered when there 3002 2947 disclose. are confounding features. 3003 2948 Study Funding: None. 3004 2949 Background/Synopsis: We present a 68-year-old Genetics, Gene Therapy and Atherosclerosis 3005 2950 woman who has very high HDL-C (.100 mg/dL) who had 3006 2951 an ischemic stroke attributed to intracranial atherosclerosis 161 3007 2952 and stenosis. She was not taking any cholesterol-lowering Providers Prescribing Behavior for Lipid- 3008 2953 therapy due to the perceived risk-lowering effect of very high lowering Therapy after Receiving Patients 3009 2954 HDL-C and prior side effects. Although HDL-C levels have a Positive Genetic Test for Familial 3010 2955 strong inverse association with atherosclerotic cardiovascu- Hypercholesterolemia† 3011 2956 lar disease (ASCVD) risk in epidemiologic studies, this 3012 2957 relationship is not as robust outside of 2 standard deviations Jing Hao, PhD, MD, (Danville, PA) Nan Chen, MS, 3013 2958 (SDs) from the normal (,30 or .80 mg/dL) and a high level Dina Hassen, MPP, Tracey Klinger, BS, Megan Betts, MS, 3014 does not preclude the presence of ASCVD.(1-7). Dustin Hartzel, BS, David Veenstra, PharmD, PhD,

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3015 Scott Spencer, MPH, MA, Marc Williams, MD, After receiving the genetic result, 60% (64/107) had 3071 3016 Susan Snyder, PhD, MBA, Josh Petersan, MD, MPH, sufficient LDL-C data for analysis. Only 26% (7/27) of 3072 3017 Victoria Schlieder, MS, participants receiving more intensive treatment, 32% (9/28) 3073 3018 Laura Woods, MPH, Laney Jones, PharmD, MPH with no LLT change, and 22% (2/9) not on LLT met their 3074 3019 LDL-C goals. Some individuals in each group (treatment 3075 3020 intensification, no LLT change, and those not on LLT) had 3076 3021 Lead Author’s Financial Disclosure: This project is reductions in their LDL-C levels (Table 1). There were 9 3077 3022 funded by NIH/NHGRI R01HG009694. patients whose most recent post-disclosure LDL-C test was 3078 3023 Study Funding: The project is funded by NIH/NHGRI conducted before the change of their last medication; thus, 3079 3024 R01HG009694. their LDL-C does not reflect the effect of the last 3080 3025 Background/Synopsis: Familial hypercholesterolemia medication. 3081 3026 (FH) is an inherited condition causing significant lifelong Conclusions: Among participants receiving a genetic 3082 3027 elevation in low-density lipoprotein cholesterol (LDL-C) diagnosis of FH, 35% had increased intensity in LLT and 3083 3028 which results in increased risk of premature cardiovascular 35% experienced improvements in their LDL-C level. 3084 3029 disease. The MyCode Initiative is a precision medicine However, after receiving genetic results, more participants 3085 3030 program at Geisinger which discloses medically actionable were not on LLT and about half of the study population 3086 3031 results from exome sequencing including FH. were not monitored making it impossible to know if they 3087 3032 Objective/Purpose: To evaluate providers’ prescribing met their LDL-C goals. Further study is needed, including 3088 3033 behavior for lipid-lowering therapies (LLT) after receiving to control for time trends or have a control group, to better 3089 3034 participants’ positive genetic result for FH. understand the factors impacting treatment. 3090 3035 3091 Methods: We studied a retrospective cohort of MyCode 3036 3092 participants from 2 years prior to the patient receiving a Genetics, Gene Therapy and Atherosclerosis 3037 3093 positive genetic result for FH to January 16, 2019. Patients 3038 3094 health records including LLT prescriptions and LDL-C 3039 162 3095 values were obtained from the electronic health record and 3040 Clinical Limitations of Genotyping-Versus 3096 pharmacy fill data. Descriptive analysis was conducted to 3041 Sequencing-Based Strategies for Familial 3097 demonstrate changes in patients LLT management and † 3042 Hypercholesterolemia 3098 LDL-C level (at goal of either LDL-C less than 100mg/dL 3043 3099 for primary prevention or less than 70mg/dL for secondary Tom Callis, PhD (Boone, NC) 3044 3100 prevention) before and after genetic result disclosure. 3045 3101 Results: We analyzed 107 MyCode patients who received Lead Author’s Financial Disclosure: Tom Callis, 3046 PhD, is an employee and shareholder of Invitae. 3102 3047 positive FH results with a median follow-up time of 14 3103 5 Study Funding: None. 3048 months (range, 3-39). Most (n 87) were already receiving 3104 3049 LLT although 20 were not on LLT prior to disclosure of the Background/Synopsis: Genetic evaluation is recom- 3105 3050 genetic risk. After return of results, 37 patients received mended to improve the diagnosis and management of 3106 3051 more intensive treatment (18 patients added Ezetimibe, 5 familial hypercholesterolemia (FH) in patients and family 3107 3052 patients added a PCSK9 inhitibor), 39 patients had no members. The number of genetic tests is growing rapidly 3108 3053 change in their LLT, and 31 patients were not on LLT at the and includes FDA-authorized direct-to-consumer (DTC) 3109 3054 end of our observation (15 discontinued therapy and 16 tests and hybrid models where consumers order laboratory- 3110 3055 continued existing therapy). developed tests (LDTs) with physician support. Across the 3111 3056 3112 3057 3113 3058 Table 1 LDL-C level change before and after genetic result disclosure 3114 3059 3115 LDL-C level change, Frequency, (perc %) 3060 3116 3061 37 patients who had more 39 patients who had 31 patients who 3117 3062 intensive treatment no change in LLT had no medication 3118 3063 1. Pre & Post at goal 1 (2.7) 5 (12.8) 0 3119 3064 2. Pre at goal, Post not at goal 0 3 (7.7) 0 3120 3065 3. Pre not at goal, Post at goal 6 (16.3) 4 (10.3) 2 (6.5) 3121 3066 4. Pre & Post not at goal, reduction in Post 11 (29.7) 8 (20.5) 6 (19.4) 3122 3067 5. Pre & Post not at goal, increase in Post 4 (10.8) 5 (12.8) 1 (3.2) 3123 6. Pre & Post not at goal, no change in Post 5 (13.5) 3 (7.7) 0 3068 3124 7. Pre NA & Post at goal 0 0 0 3069 8. Pre NA & Post not at goal 3 (8.1) 1 (2.6) 1 (3.2) 3125 3070 9. Post NA 7 (18.9) 10 (25.6) 21 (67.7) 3126

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3127 spectrum of tests, methods vary and the associated clinical challenging. However, due to the emergence of new 3183 3128 limitations are not well-understood by non-specialists nor therapies, clinicians have more tools to individualize 3184 3129 precisely defined among specialists. Recently, a DTC treatment. Despite these advancements, the intensification 3185 3130 screen for FH was offered to the public that reports 24 of lipid-lowering therapy is often not done in a timely 3186 3131 variants in the LDLR and APOB genes out of the more than manner, leading to increased risk for ASCVD events. 3187 3132 2000 known pathogenic or likely pathogenic (P/LP) Objective/Purpose: We sought to determine if real- 3188 3133 variants in these two genes. time patient simulation technology, designed to mimic a 3189 3134 Objective/Purpose: We determine how often screening patient case encounter, could improve clinicians; knowl- 3190 3135 for only the 24 variants would miss other P/LP variants and edge/competence regarding the management of patients 3191 3136 falsely reassure individuals at risk for familial dyslipidemia. with ASCVD and elevated LDL-C. 3192 3137 3193 Methods: We analyzed de-identified data from two Methods: The patient simulation technology, Decision- 3138 3194 cohorts who underwent sequencing and exon-level copy Sim, was incorporated as part of a live symposium, and the 3139 3195 number variant analysis for LDLR, PCSK9, APOB, and changes in competence and knowledge were evaluated 3140 3196 LDLRAP1: 1) An indication-based cohort of 2709 patients using pre-/post-assessment questions. A Chi-Square test 3141 3197 referred by healthcare providers for FH genetic testing, and was used to analyze the percentage of correct responses and 3142 3198 2) a screening cohort of 3481 individuals without a history determine statistical significance (p ,0.05 indicated statis- 3143 3199 of FH undergoing a proactive genetic health screen. We tical significance). Participants; responses to simulation 3144 3200 calculated the fraction of patients with any positive result decision points were also collected and analyzed. 3145 3201 that would have been detected if only the 24 variant DTC 3146 Results: The live activity took place on October 12, 2019. 3202 screen had been used. 3147 A total of 126 health care professionals, among whom 40 3203 3148 Results: The diagnostic yield of the clinical test in the were allied health professionals (PAs, RNs, NPs, PharmDs, 3204 3149 indication cohort was 26.4% (715/2709), including 63 patients CDE/RDs) and 66 were MDs/ DOs , took part in this 3205 3150 with homozygous FH. In contrast, the yield of a DTC screen activity and answered the assessment questions. There was 3206 3151 reporting 24 LDLR and APOB variants in this same cohort was a significant increase in knowledge (21% relative increase 3207 5 3152 8.5% (231/2709). In the screening cohort, 25 individuals had a compared to baseline, p 0.01) and competence (8% 3208 5 3153 P/LP variant in LDLR, PCSK9, or APOB, while only 9 of these relative increase compared to baseline, p 0.03) post- 3209 3154 would be reported by the DTC screen. activity about the efficacy and safety of newer therapies to 3210 3155 Conclusions: These results predict that two-thirds of treat hypercholesterolemia and how to apply them for 3211 3156 individuals with genetically-positive FH would be falsely statin-intolerant or high-risk patients. 82% selected the 3212 3157 reassured by a negative result through a limited genotyping correct treatment decisions in the branching simulation 3213 3158 testing strategy. It is paramount for clinicians to avoid platform, including the intensification of lipid-lowering 3214 3159 interpreting such uninformative results as an all-clear" that therapy in a virtual patient with statin intolerance. Addi- 3215 3160 would preclude patients and at-risk family members from tionally, 46% intend to make changes to practice, with an 3216 3161 receiving appropriate care and monitoring based on their additional 52% indicating that their current practice has 3217 3162 true risk. been reinforced by information received. 3218 3163 Conclusions: Results from this activity indicate that this 3219 3164 simulation format can result in improvements in knowledge 3220 3165 Lipid Management Best Practices and competence, as well as the commitment to change 3221 3166 among learners, which can potentially result in increased 3222 3167 163 awareness about the management of patients with ASCVD 3223 3168 Impact of Simulation-Based CME on Clinicians; and ultimately optimize patient care. 3224 3169 Knowledge and Competence Related to the 3225 3170 Management of Elevated LDL-C 3226 3171 Omega-3 Fatty Acids 3227 3172 Shpetim Karandrea, PhD, (Boca Raton, FL) 3228 3173 Neha Agarwal, PhD, Amanda Jamrogiewicz, CHCP 165 3229 3174 Eicosapentaenoic Acid Maintains Normal 3230 3175 Lead Author’s Financial Disclosure: Nothing to Membrane Cholesterol Distribution under 3231 3176 disclose. Hyperglycemic Conditions unlike a Mixed 3232 3177 Study Funding: Esperion, Sanofi US and Regeneron Omega-3 Fatty Acid Supplement 3233 3178 Pharmaceuticals, and The Medicines Company. 3234 3179 Background/Synopsis: Atherosclerotic vascular dis- Preston Mason, PhD, (Beverly, MA) Samuel Sherratt, BS 3235 3180 ease (ASCVD) is the leading cause of death in the US. 3236 3181 Prevention of adverse cardiovascular events in high-risk Lead Author’s Financial Disclosure: Dr. Mason 3237 3182 patients with elevated LDL-C, associated comorbidities, or acknowledges consulting and research funding from 3238 that have an insufficient response to statin therapy remains Amarin, Novartis, and Pfizer.

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3239 Study Funding: Amarin Pharma Inc., Bridgewater Omega-3 Fatty Acids 3295 3240 Township, NJ 08807, USA. 3296 3241 166 3297 Background/Synopsis: During hyperglycemia, there 3242 Variability in Content of Omega-3 Fatty Acids 3298 is abnormal membrane cholesterol aggregation which has 3243 and other Fatty Acids in Multiple Lots of a 3299 been linked to cholesterol crystal formation and plaque 3244 Widely Used Fish Oil Dietary Supplement 3300 instability. Treatment with prescription, stable eicosapen- 3245 3301 taenoic acid (EPA), an omega-3 fatty acid (O3FA), has been 3246 Preston Mason, PhD, (Beverly, MA) Samuel Sherratt, BS 3302 associated with reduced cardiovascular (CV) risk as 3247 3303 compared to mixed O3FA preparations. Due to its chemical 3248 3304 structure, EPA at a pharmacologic dose may preserve Lead Author’s Financial Disclosure: Dr. Mason 3249 3305 normal cholesterol distribution as compared to a mixed acknowledges consulting and research funding from 3250 3306 O3FA supplement that contains docosahexaenoic acid Amarin, Novartis, and Pfizer. 3251 3307 (DHA). Study Funding: None. 3252 3308 3253 Objective/Purpose: To compare the effects of EPA and Background/Synopsis: Approximately 19 million 3309 3254 mixed O3FA supplement on membrane structure and people in the United States take fish oil dietary supplements 3310 3255 cholesterol crystalline domain formation under conditions (FODS), many for the purpose of treating or preventing 3311 3256 of hyperglycemia and oxidative stress. heart disease. Previous analyses from our laboratory have 3312 3257 Methods: Membrane vesicles were prepared from reported that widely used FODS have significant levels of 3313 3258 dilinoleoylphosphatidylcholine (DLPC) at a cholesterol- oxidized and saturated fatty acids (FA) that could be 3314 3259 to-phospholipid mole ratio of 0.6:1 and treated with harmful to cardiovascular (CV) patients. Clinical CV 3315 3260 pharmacologic levels of EPA or mixed O3FA at a 1:30 outcome trials have failed to show a benefit with FODS 3316 3261 FA mole ratio under conditions of hyperglycemia (200 which may be due to poor quality control and inadequate 3317 3262 mg/dL). Changes in membrane lipid organization and levels of omega-3 fatty acids (O3FAs). 3318 3263 width were measured at time points between 0 and 96 h Objective/Purpose: To measure the FA content of a 3319 3264 using small angle X-ray diffraction approaches and leading (by sales) FODS in multiple lots, including the 3320 3265 correlated with lipid hydroperoxide formation. Cholesterol O3FAs eicosapentaenoic acid (EPA) and docosahexaenoic 3321 3266 domains were identified by the presence of diffraction acid (DHA). 3322 3267 peaks corresponding to a unit cell periodicity or width of Methods: We purchased multiple (three) lots of FODS 3323 3268 34 angstroms. (1.0 g total oil) at a local retail store in the Boston area and 3324 3269 Results: Membranes containing either EPA or the mixed tested FA content and levels using gas chromatography/ 3325 3270 O3FA supplement had a structure characterized by normal mass spectrometry methods. As internal controls, we tested 3326 3271 cholesterol distribution prior to oxidation. Even after 96 h, highly purified (.99%) standards of EPA and DHA. 3327 3272 EPA inhibited the formation of cholesterol domains and Results: In all three lots, the measured amount of total 3328 3273 preserved normal membrane structure with a d-space of 54 O3FA was substantially lower (24 +/- 3%) than the labeled 3329 3274 angstroms. By contrast, the DHA-containing mixed O3FA amount. The total O3FA measured in lots 1-3 were 234, 3330 3275 samples yielded diffraction patterns consistent with a 234, and 220 mg/capsule, respectively, while the advertised 3331 3276 biphasic structure containing prominent cholesterol crys- amount of total O3FA in each lot was 300 mg/capsule. 3332 3277 talline domains and phospholipid bilayer with unit cell There was also significant variability in levels of EPA and 3333 3278 periodicities of 34 angstroms and 49 angstroms, respec- DHA from lot to lot. The amounts of EPA/DHA were 69/ 3334 3279 tively, as early as 48 h. The relative size of the cholesterol 165 mg, 58/176 mg and 119/101 mg in the three lots, 3335 3280 domain peaks increased in the mixed O3FA samples by respectively. All three lots also contained multiple FAs, 3336 3281 818% by 96 h, which also corresponded with a 4 angstrom including 8 different species of saturated fats which 3337 3282 reduction in membrane width. Unlike the mixed O3FA comprised up to 33% of the total weight, and 6 different 3338 3283 supplement, EPA inhibited lipid peroxide formation species of non-O3FA unsaturated fats which comprised up 3339 3284 compared to vehicle. to 26% of the total weight of the capsules. 3340 3285 Conclusions: EPA preserved normal membrane structure Conclusions: Multiple lots of the leading FODS exam- 3341 3286 and cholesterol distribution while reducing lipid oxidation ined in this study had substantially less than the advertised 3342 3287 under conditions of hyperglycemia in a manner that was not amount of O3FA. The FODS also had high levels of 3343 3288 reproduced with a DHA-containing mixed O3FA supple- saturated FAs and other non-O3FAs that exceeded the total 3344 3289 ment. These data indicate a unique hydrocarbon chain amounts of O3FAs. The levels of EPA and DHA varied 3345 3290 length and number of unsaturated fatty acids for EPA that markedly from lot to lot in the FODS. These data indicate 3346 3291 preserves membrane structure and cholesterol distribution that the FODS tested is not an appropriate substitute for 3347 3292 under conditions of hyperglycemia and oxidative stress. prescription EPA for CV patients. 3348 3293 3349 3294 3350

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3351 Omega-3 Fatty Acids highlight the potential physiologic differences between 3407 3352 these long chain omega-3 FAs in reducing oxidative 3408 3353 3409 167 modification of lipoproteins of various sizes, a contributor 3354 to vascular inflammation. 3410 3355 Differential Effects of EPA, DPA, and DHA in 3411 3356 Inhibiting Oxidation of Low-Density 3412 3357 Lipoproteins and Very-Low-Density Omega-3 Fatty Acids 3413 3358 Lipoproteins in Vitro 3414 168 3359 3415 Preston Mason, PhD, (Beverly, MA) Differential Effects of EPA, DHA, and DPA on 3360 Deepak Bhatt, MD, MPH, Samuel Sherratt, BS 3416 3361 Membrane Structure and Stability 3417 3362 Preston Mason, PhD, (Beverly, MA) 3418 3363 Lead Author’s Financial Disclosure: Dr. Mason Deepak Bhatt, MD, MPH, Samuel Sherratt, BS 3419 3364 acknowledges consulting and research funding from 3420 3365 Amain, Novartis, and Pfizer. Lead Author’s Financial Disclosure: Dr. Mason 3421 3366 Study Funding: Matinas Biopharma. acknowledges consulting and research funding from 3422 3367 Background/Synopsis: Omega-3 fatty acids (FAs) Amarin Pharma, Inc., Novartis, and Pfizer. 3423 3368 reduce levels of triglycerides (TGs) but may have addi- Study Funding: Matinas Biopharma, Bedminster, NJ 3424 3369 tional atheroprotective benefits in patient with cardiovas- 07921, USA. 3425 3370 3426 cular risk, including inhibition of lipid oxidation. Low- Background/Synopsis: Our laboratory has previously 3371 3427 density lipoprotein (LDL) oxidation is causally related to demonstrated that eicosapentaenoic acid (EPA, 20:5) and 3372 3428 inflammation and the loss of normal lipid clearance. We docosahexaenoic acid (DHA, 22:6) occupy distinct areas 3373 3429 sought to compare the antioxidant effects of 3 different within the membrane lipid bilayer; DHA has been shown to 3374 3430 long chain omega-3 FAs in isolated human LDL and TG- increase membrane fluidity and support the induction of 3375 3431 rich very-low-density lipoprotein (VLDL). cholesterol crystalline domain formation, while EPA stabi- 3376 3432 To compare the ability of eicosa- lizes the surrounding bulk lipid. The incorporation of 3377 Objective/Purpose: 3433 pentaenoic acid (EPA, 20:5), docosapentaenoic acid (DPA, docosapentaenoeic acid (DPA, 22:5) into membrane lipid 3378 3434 22:5) and docosahexaenoic acid (DHA, 22:6) to interfere bilayers has not been previously described. 3379 3435 with copper-induced oxidation of human LDL and VLDL 3380 Objective/Purpose: To compare the effects of EPA, 3436 in vitro. 3381 DHA, and DPA on membrane structure and stability by 3437 3382 Methods: HumanLDLandVLDLwereisolatedfromthe small angle x-ray scattering (SAXS), including membrane 3438 3383 plasma of healthy subjects and adjusted to a final ApoB width and electron density distribution. 3439 3384 concentration of 100 microgram/mL and 50 microgram/mL Methods: Membrane vesicles composed of 1-palmitoyl-2- 3440 3385 for LDL and VLDL, respectively, in physiologic buffer saline oleoyl-sn-glycero-3 phosphocholine (POPC) and cholesterol at 3441 3386 (PBS) before being incubated with individual FAs (2.5 a 0.3 C/P mole ratio were created with each FA at a 1:10 FA-to- 3442 3387 micromolar) at 37 degrees celcius. Oxidation was initiated phospholipid mole ratio. After shell-drying and removal of 3443 3388 with 20 micromolar copper sulfate (CuSO4) for LDL and 30 residual solvent, desiccated component lipids were resus- 3444 3389 micromolar CuSO4 for VLDL, and measured over time by pended in saline buffer and vortexed to form multilamellar 3445 3390 the formation of malondialdehyde (MDA, a product of vesicles (MLVs), which were oriented by ultracentrifugation 3446 3391 oxidative damage) via UV/Vis spectrophotometry. and underwent SAXS analysis. Membrane structure and FA 3447 3392 Results: In LDL, EPA and DPA provided similar, locations were determined by differences in electron density 3448 3393 sustained inhibition of oxidation; at the 4-hour time point, profiles generated from the diffraction patterns of each mem- 3449 3394 EPA significantly inhibited MDA formation compared with brane preparation, along with membrane widths. 3450 3395 vehicle by 96% (0.50 +/- 0.003 vs 11 +/- 0.3 micromolar, Results: With EPA there was a broad increase in electron 3451 3396 p,0.001) while DPA inhibited MDA formation by 85% density (peak at +/- 12 angstroms from the center of the 3452 3397 (1.7 +/- 0.2 micromolar, p,0.001), while DHA provided a membrane); thus, EPA assumes an extended orientation 3453 3398 lower level of inhibition at 2 hr, and had lost all activity at 4 parallel with the acyl chains of the surrounding phospho- 3454 3399 hr. EPA exhibited the most potent antioxidant activity in lipids. DPA, in contrast, showed an increase in electron 3455 3400 VLDL - 93% (1.7 +/- 0.3 vs 23 +/- 1.2 micromolar, density over an area from +/- 11-20 angstroms from the 3456 3401 p,0.001), followed by DPA - 57% (10 +/- 0.8 micromolar, center of the membrane, centered at about +/- 15 ang- 3457 3402 p,0.001), while DHA’s much weaker antioxidant activity stroms. Thus, DPA appears to interact strongly with the 3458 3403 was again absent at 4 hr. upper membrane hydrocarbon core adjacent to the phos- 3459 3404 Conclusions: Both EPA and DPA significantly reduced pholipid headgroups, and likely assumes more than one 3460 3405 oxidation of LDL and to different extents in VLDL, while conformation. Finally, with DHA, there is a pronounced 3461 3406 DHA rapidly lost activity and showed no inhibition of increase in electron density at +/- 28 angstroms at the 3462 oxidation in either LDL or VLDL by 4 hours. These data phospholipid headgroup/water interface.

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3463 Conclusions: EPA, DPA, and DHA all appear to interact Methods: Data were pooled from 4 phase 3 clinical trials 3519 3464 with distinct portions of the membrane lipid bilayer. Unlike that randomized 3623 patients to treatment with bempedoic 3520 3465 DPA and EPA, DHA appears to have more disruptive acid 180 mg or placebo once daily for 12 to 52 weeks. All 3521 3466 interactions at the phospholipid headgroup of the mem- studies permitted stable background lipid-lowering therapy. 3522 3467 brane, perhaps due to both the longer chain length and one Two studies enrolled patients with ASCVD and/or hetero- 3523 3468 additional double bond. zygous familial hypercholesterolemia (HeFH) who were 3524 3469 receiving background statin therapy; 2 studies enrolled 3525 3470 Pharmacological Control of Lipids and patients with history of statin intolerance. Changes in 3526 3471 Lipoproteins hsCRP are reported from baseline to week 12. 3527 3472 3528 Results: Across each of the 4 phase 3 studies, median 3473 3529 hsCRP was reduced by a range of 18.7% to 32.5%. In the 3474 169 3530 pooled analysis, reduction in hsCRP with bempedoic acid 3475 Factors that Influence Bempedoic Acid- 3531 was greater in patients with baseline values &; 2 mg/L 3476 Mediated Reductions in High-sensitivity C 3532 compared with baseline hsCRP , 2 mg/L and was not 3477 reactive Protein: Analysis of Pooled Patient- 3533 † influenced by background statin intensity (Table). Among 3478 level Data from Phase 3 Clinical Trials 3534 patients with hsCRP; 2 mg/L at baseline, 41.6% in the 3479 3535 Erik Stroes, MD, PhD, (Amsterdam, NL) Harold Bays, MD, ASCVD/HeFH pool (n52010) and 43.3% in the statin 3480 3536 Maciej Banach, MD, PhD, intolerant pool (n5415) randomized to bempedoic acid had 3481 3537 Alberico Catapano, PhD, MD (hc), P. Duell, MD, hsCRP , 2 mg/L at week 12 (P,.001 vs placebo). 3482 3538 Ulrich Laufs, MD, PhD, G. B. Mancini, MD, 3483 Conclusions: Bempedoic acid lowered hsCRP, regard- 3539 Kausik Ray, MD, MPhil, William Sasiela, PhD, 3484 less of the presence or intensity of background statin 3540 Zhan Ye, PhD, Antonio Gotto Jr., MD, DPhil 3485 therapy. The greatest predictor of the degree of hsCRP 3541 3486 reduction was baseline hsCRP level. 3542 3487 Lead Author’s Financial Disclosure: ESG Stroes 3543 3488 has received research grant(s)/support to his institution Diabetes, Insulin Resistance and Dyslipidemia 3544 3489 from Amgen, Sanofi, Resverlogix, and Athera, and has 3545 3490 served as a consultant for Amgen, Sanofi, Esperion, 170 3546 Novartis, and Ionis Pharmaceuticals. 3491 Bempedoic Acid and Glycemic Control: A 3547 3492 Study Funding: Esperion funded the research for this Pooled Analysis of 4 Phase 3 Clinical Trials 3548 3493 study and provided writing support for this abstract. 3549 3494 Medical writing assistance, funded by Esperion, was pro- Lawrence Leiter, MD, (Toronto, ON) 3550 3495 vided by James Bergstrom, PhD, and Kelly M. Cameron Maciej Banach, MD, PhD, 3551 3496 PhD, CMPP, of JB Ashtin. Alberico Catapano, PhD, MD (hc), P. Duell, MD, 3552 3497 Background/Synopsis: Reduced levels of high-sensi- Antonio Gotto Jr., MD, MPhil, Ulrich Laufs, MD, PhD, 3553 3498 tivity C-reactive protein (hsCRP) are associated with lower G. B. Mancini, MD, Kausik Ray, MD, MPhil, 3554 3499 risk of atherosclerotic cardiovascular disease (ASCVD). Jeffrey Hanselman, MS, Zhan Ye, PhD, Harold Bays, MD 3555 3500 Bempedoic acid is an oral ATP-citrate lyase inhibitor for 3556 3501 the treatment of hypercholesterolemia. Prior clinical trial Lead Author’s Financial Disclosure: LA Leiter has 3557 3502 data support bempedoic acid as consistently reducing hsCRP. received research grant(s)/support from Astra Zeneca, 3558 3503 Objective/Purpose: To evaluate the factors influencing Amgen, Kowa, The Medicines Company, and Sanofi/ 3559 3504 bempedoic acid-mediated reductions in hsCRP. Regeneron. He has also served as a consultant for Astra 3560 3505 3561 3506 3562 3507 3563 3508 Median Percent Change in High-sensitivity C-reactive Protein at Week 12 Among Patients Treated with Bempedoic Acid or Placebo 3564 3509 During 4 Phase 3 Clinical Trials, By Baseline hsCRP Level and Background Statin Therapy 3565 3510 Baseline hsCRP $ 2 mg/L Baseline hsCRP , 2 mg/L 3566 3511 n Bempedoic Acid n Placebo n Bempedoic Acid n Placebo 3567 3512 3568 Overall 999 –42.2 (57.3) 497 –15.1 (77.8) 1282 –4.1 (80.8) 651 10.0 (91.2) 3513 3569 Statin intensity 3514 None 207 –46.3 (45.5) 98 –7.9 (63.4) 160 –6.6 (72.1) 82 11.5 (77.7) 3570 3515 Low 106 –40.6 (59.3) 40 –5.0 (68.9) 85 –10.0 (87.1) 48 23.4 (88.9) 3571 3516 Moderate 309 –39.6 (58.7) 182 –16.9 (92.3) 445 –2.3 (80.0) 208 5.2 (82.8) 3572 3517 High 377 –44.0 (60.2) 177 –18.3 (73.9) 592 –3.4 (83.4) 313 10.0 (98.4) 3573 3518 Data are medians (interquartile ranges). hsCRP, high-sensitivity C-reactive protein. 3574

ABS 5.6.0 DTD JACL1584_proof 9 July 2020 5:51 pm 3630 3629 3628 3627 3626 3625 3624 3623 3622 3621 3620 3619 3618 3617 3616 3615 3614 3613 3612 3611 3610 3609 3608 3607 3606 3605 3604 3603 3602 3601 3600 3599 3598 3597 3596 3595 3594 3593 3592 3591 3590 3589 3588 3587 3586 3585 3584 3583 3582 3581 3580 3579 3578 3577 3576 3575 ibts nui eitneadDsiiei 33 Dyslipidemia and Resistance Insulin Diabetes,

Baseline and Week 12 Hemoglobin A1c, Fasting Glucose, and Weight by Baseline Glycemic Status Among Patients Treated with Bempedoic Acid or Placebo During 4 Phase 3 B .. DTD 5.6.0 ABS Clinical Trials Normoglycemiaa Prediabetesb Diabetesc Bempedoic Acid Placebo Bempedoic Acid Placebo Bempedoic Acid Placebo Treatment Group N 5 410 N 5 208 N 5 1259 N 5 609 N 5 755 N 5 380 AL54pof9Jl 0055 pm 5:51 2020 July 9 JACL1584_proof HbA1c, %BL value 5.4 (0.01)0.05 (0.01) 5.4 (0.01)0.03 (0.02) 5.8 (0.01)–0.06 (0.01)d 5.8 (0.01)–0.02 (0.01)d 6.8 (0.04)–0.12 (0.02)e 6.8 (0.05)0.07 (0.03)e Change from BL at 12 weeks Fasting glucose, mg/dLBL value 89.7 (0.3)2.6 (0.4) 90.1 (0.4)1.4 (0.6) 100.3 (0.3)–0.1 (0.3)f 100.0 (0.4)1.4 (0.5)f 130.8 (1.4)0.4 (1.2) 129.7 (1.9)4.1 (2.1) Change from BL at 12 weeks Weight, kgBL value 79.1 (0.7)0.1 (0.1) 80.8 (1.0)0.1 (0.1) 85.2 (0.5)–0.2 (0.1)g 84.3 (0.6)0.2 (0.1)g 90.6 (0.6)–0.4 (0.1) 90.9 (0.9)0.07 (0.2) Change from BL at 12 weeks Values are the mean (6 SE). BL 5 baseline; HbA1c 5 hemoglobin A1c; SE 5 standard error. aPatients not fulfilling the criteria for impaired fasting glucose who did not have diabetes, with diabetes defined as patients with type 1 or type 2 diabetes noted in medical history or HbA1c $6.5% at baseline or $2 values of fasting plasma glucose $126 mg/dL between screening and randomization. bPatients with the term "impaired fasting glucose" noted in medical history, or HbA1c from 5.7% to 6.4% at baseline, or $1 fasting plasma glucose value $100 mg/dL but not more than one $126 mg/dL between screening and randomization. cPatients with type 1 or type 2 diabetes noted in medical history or HbA1c $6.5% at baseline or $2 values of fasting plasma glucose $126 mg/dL between screening and randomization. dP 5 0.0004 for bempedoic acid vs placebo. eP , 0.0001 for bempedoic acid vs placebo. fP 5 0.0099 for bempedoic acid vs placebo. gP 5 0.0076 for bempedoic acid vs placebo. 3686 3685 3684 3683 3682 3681 3680 3679 3678 3677 3676 3675 3674 3673 3672 3671 3670 3669 3668 3667 3666 3665 3664 3663 3662 3661 3660 3659 3658 3657 3656 3655 3654 3653 3652 3651 3650 3649 3648 3647 3646 3645 3644 3643 3642 3641 3640 3639 3638 3637 3636 3635 3634 3633 3632 3631 34 Journal of Clinical Lipidology, Vol -,No-, - 2020

3687 Zeneca, Amgen, Esperion, Kowa, Merck, The Medicines Pathophysiology of Atherosclerosis 3743 3688 Company, and Sanofi/Regeneron. 3744 3689 3745 Study Funding: Clinical trial funding was provided by 171 3690 3746 Esperion Therapeutics, Inc. Authors were given access to Metformin Inhibition of Volume Expansion 3691 the data for the performed analyses. Medical writing 3747 3692 with Cholesterol Crystallization May 3748 assistance, funded by Esperion Therapeutics, Inc., was Contribute to Reducing Plaque Rupture and 3693 provided by James Bergstrom, PhD, and Kelly M Camer 3749 3694 Improved Cardiac Outcomes 3750 Background/Synopsis: Statins have demonstrated the 3695 3751 potential to accelerate the progression from prediabetes to Manel Boumegouas, MD, (Lansing, MI) 3696 3752 diabetes. We evaluated the effect of bempedoic acid, an Brian Grondahl, DO, Levi Fry, Heather De Feijter-Rupp, 3697 3753 oral, ATP-citrate lyase inhibitor that inhibits hepatic Abed Janoudi, PhD, George Abela, MD 3698 3754 cholesterol and fatty acid synthesis and significantly lowers 3699 3755 low-density lipoprotein cholesterol, on glycemic control Lead Author’s Financial Disclosure: Nothing to 3700 3756 and new-onset diabetes in patients with hypercholesterole- disclose. 3701 3757 mia receiving stable lipid-lowering therapy (LLT). 3702 Study Funding: None. 3758 3703 Objective/Purpose: To assess the impact of bempedoic Background/Synopsis: In previous studies we have 3759 3704 acid on measures of glycemic control. demonstrated that cholesterol crystallization is associated 3760 3705 Methods: Data were pooled from 4 randomized, double- with plaque rupture due to volume expansion and the tissue 3761 3706 blind, placebo-controlled, phase 3 trials. Patients with injury by sharp tipped crystals. Metformin is a biguanide 3762 3707 hyperlipidemia were randomized 2:1 to receive bempedoic compound that reduces glucose production by the liver, 3763 3708 acid 180 mg or placebo once daily for 12 to 52 weeks. increases glucose uptake, metabolism in skeletal muscle 3764 3709 Patients were stratified by baseline glycemic status: dia- and has been associated with reduced cardiovascular 3765 3710 betes (patients with &;1 of: history of type 1 or 2 diabetes; events. However, the mechanism for cardiovascular benefits 3766 3711 receiving diabetes medication; HbA1c &;6.5% and/or &;2 has not been elucidated. 3767 3712 fasting glucose values &;126 mg/dL), prediabetes (no Objective/Purpose: Better understanding of the mech- 3768 3713 medical history of diabetes; not receiving diabetes medi- anism of cardiovascular benefits of Metfromin. 3769 3714 cation; and HbA1c of 5.7% to 6.4%, or;1 fasting glucose Methods: To evaluate effects of metformin on cholesterol 3770 3715 value of &;100 mg/dL but not more than 1 value &;126 mg/ crystallization, cholesterol powder (3 g) was melted in 3771 3716 dL), and normoglycemic (patients not fulfilling criteria for graduated cylinders with and without metformin (2 3 mg), 3772 3717 diabetes or prediabetes). Changes in baseline glycemic then allowed to crystallize at 22;C. Differences in volume 3773 3718 status were assessed by analyzing hemoglobin A1c between liquid and crystalline phases were measured. 3774 3719 (HbA1c) and fasting glucose levels through week 12. Crystal morphology was examined by scanning electron 3775 3720 Results: Among 3621 patients (2424 bempedoic acid, 1197 microscopy (SEM). 3776 3721 placebo) included in the analysis (3008 of whom participated Results: In vitro, metformin markedly reduced choles- 3777 3722 in 52-week trials of bempedoic acid), 83.8% were receiving a terol volume expansion during crystallization by 95% 3778 3723 statin with or without other LLTs. The exposure-adjusted compared to control and the effect was dose related 3779 3724 annual event rate of new-onset diabetes was lower for (p,0.001; graph). By SEM, crystal morphology demon- 3780 3725 bempedoic acid vs placebo for patients who were normogly- strated blunting of crystal geometry from rhomboidal plates 3781 3726 cemic at baseline (0.3% vs 0.8%) and for patients with into globular forms with loss of sharp tipped crystal edges 3782 3727 prediabetes at baseline (4.7% vs 5.9%). HbA1c levels at week compared to pointed forms in matched controls. 3783 3728 12 were significantly lower with bempedoic acid treatment 3784 Conclusions: Metformin reduced or eliminated volume 3729 than placebo in patients with diabetes at baseline (mean 3785 expansion during cholesterol crystallization in a dose 3730 placebo-corrected change: -0.19%; nominal P , 0.0001), and 3786 related fashion. Also, crystal morphology was altered to 3731 in patients with prediabetes at baseline (mean placebo- 3787 less traumatic geometrical forms. These altered crystal 3732 corrected change: -0.04%; nominal P 5 0.0004) (Table). 3788 3733 Changes from baseline in fasting glucose levels and in weight 3789 3734 at week 12 in patients with prediabetes at baseline were 3790 3735 significantly lower in the bempedoic acid group compared 3791 3736 with the placebo group (nominal P 5 0.0099 and P 5 0.0076, 3792 3737 respectively). No significant differences in glucose levels and 3793 3738 weight were observed for patients with diabetes or normo- 3794 3739 glycemic patients. 3795 3740 Conclusions: These data suggest that bempedoic acid 3796 3741 does not adversely impact glycemic control when added to 3797 3742 stable background LLT. 3798

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3799 features can potentially prevent tissue injury and may help Lipid Management in Special Populations 3855 3800 explain in part some of the cardiovascular benefits associ- 3856 3801 3857 ated with metformin. 173 3802 3858 3803 Twin Pregnancy Normalizes Triglyceride Level 3859 Nutrition, Nutrigenomics, Nutraceuticals and in Familial Chylomicronemia Syndrome 3804 Exercise Therapies 3860 3805 Pardeep Ratnani, DO, (Park Ridge, IL) 3861 3806 172 Adib Chaus, MD, Alan Brown, MD 3862 3807 Extreme Hypercholesterolemia in 3 Patients 3863 3808 on Very Low Carbohydrate Diets Lead Author’s Financial Disclosure: Nothing to 3864 3809 disclose. 3865 3810 Anna Schaffer, NP-C, (Durham, NC) Study Funding: None. 3866 David D’Alessio, MD, John Guyton, MD 3811 Background/Synopsis: Familial chylomicronemia 3867 3812 syndrome (FCS) is a rare autosomal recessive disorder 3868 3813 Lead Author’s Financial Disclosure: Nothing to characterized most commonly by mutations in the lipopro- 3869 3814 disclose. tein lipase (LPL) enzyme. LPL removes triglycerides (TG) 3870 3815 Study Funding: None. from triglyceride-rich lipoproteins (TRL) and breaks them 3871 3816 Background/Synopsis: Very low carbohydrate (VLC) down into free fatty acids for energy use. Patients with FCS 3872 3817 or ketogenic diets are increasingly popular for weight loss. have severely elevated chylomicrons and hence, severe 3873 3818 The effect of VLC diets on atherosclerotic cardiovascular hypertriglyceridemia which manifests as recurrent pancre- 3874 3819 disease (ASCVD) risk is uncertain. atitis. During pregnancy, TG levels increase to support fetal 3875 3820 3876 Objective/Purpose: To report 3 cases of extreme development. However, in pregnant patients with FCS, TG 3821 3877 hypercholesterolemia following initiation of VLC diets levels are markedly elevated in the blood resulting in 3822 3878 for weight loss. severe, acute pancreatitis with increased risk of mortality 3823 for both the mother and the fetus. 3879 3824 Methods: Between 2015 and 2018 three patients following 3880 To report an interesting case of 3825 VLC diets were referred to lipid specialists at our tertiary care Objective/Purpose: 3881 reduction in TG levels in a patient with FCS during a 2nd 3826 center with total cholesterol exceeding 400 mg/dL. We 3882 and 3rd trimesters of a twin pregnancy. 3827 describe clinical impact and response to treatment. 3883 3828 Results: Case 1. A 49 year-old female presented with Methods: A 37-year-old female diagnosed with FCS at 3884 3829 history of LDL cholesterol (LDL-C) rising from 129 to 446 the age of 3 and managed with a strict low-fat diet. She 3885 3830 mg/dL on VLC diet including 2 eggs daily. On low fat diet started developing recurrent pancreatitis in her early 20s, 3886 3831 LDL-C decreased to 106 mg/dL without lipid medication. requiring multiple hospitalizations per year. She was 3887 3832 She re-initiated VLC diet with LDL-C increase to 369 mg/ managed with TG lowering medications and lifestyle 3888 3833 dL, which resolved with low fat diet resumption. Mild management but with limited response. During one of her 3889 3834 atherosclerotic plaque of 2.2 mm was found in left carotid hospitalizations for pancreatitis, she was found to be 20 3890 3835 bulb. Case 2. 52 year-old male, avid exerciser, had baseline weeks pregnant with a TG level of 3500 mg/dL. Due to 3891 3836 untreated LDL-C 165 mg/dL. On VLC diet he lost 84 lbs over significant concerns for potentially life-threatening pancre- 3892 3837 9 months, but LDL-C rose to 345 mg/dL despite starting atitis and central nervous system complications, she was 3893 3838 atorvastatin 20 mg/day. Due to heaviness felt in both arms started on weekly total plasma exchange (TPE) with 3894 3839 while running, he underwent stress echocardiography with average TG levels of 1340mg/dL and peaked to 6000mg/ 3895 3840 markedly positive results and received drug-eluting stents to dL. She had no subsequent hospitalizations for recurrent 3896 3841 90% left anterior descending and first diagonal lesions. On a pancreatitis and delivered a healthy baby boy. Her TG 3897 , 3842 modified low carbohydrate diet avoiding saturated fat, plus levels remained 1000 mg/dL after discontinuing TPE. 3898 3843 atorvastatin, ezetimibe, and niacin, his LDL-C has decreased Results: At her one-year follow-up, she was found to be 12 3899 3844 to 62 mg/dL. Case 3. A 47 year-old female took pravastatin weeks pregnant with twins and weekly plasma exchanges were 3900 3845 20 mg/day for mild hypercholesterolemia. After starting re-initiated but surprisingly the patient’s TG levels normalized 3901 3846 VLC diet LDL-C rose from 89 mg/dL to a peak level of 596 to 150 mg/dL and the patient did not require any further plasma 3902 3847 mg/dL over 16 months while weight declined 65 lbs. exchange, nor did she have any further hospitalizations for 3903 3848 Apolipoprotein B was 366 mg/dL. 12 months later with pancreatitis during the remainder of her pregnancy. 3904 3849 LDL-C 420 mg/dL, new xanthelasmas were noted. Dietary Conclusions: Twin pregnancy was associated with the 3905 3850 modification has been advised by all providers. normalization of TG levels in our FCS patient and 3906 3851 Conclusions: VLC diets infrequently can lead to extreme reduction in pancreatitis related hospitalizations. We hy- 3907 3852 elevations in LDL-C. Each of our 3 patients had evidence of pothesize that the twin gestations functioned with a 3908 3853 early ASCVD or tissue deposition of cholesterol. Lipid completely normal LPL enzyme processing the mother’s 3909 3854 monitoring should be performed in all patients on VLC diets. elevated TG. This is a novel biochemical mechanism that 3910 Patients may require dietary modification to lower LDL-C. has never been described before.

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3911 Pharmacological Control of Lipids and Methods: Subjects with LDL-C;2.6 and ,4.1 mmol/L 3967 3912 Lipoproteins were enrolled to one of four dose cohorts: evinacumab 3968 3913 subcutaneous (SC) 300 mg single-dose, SC 300 mg once- 3969 3914 175 weekly [QW] for 8 doses, intravenous (IV) 5 mg/kg or 15 3970 3915 Safety, Tolerability, and Pharmacokinetics of mg/kg once every 4 weeks [Q4W] for 2 doses. Each cohort 3971 3916 Evinacumab, an Angiopoietin-Like Protein 3 comprised 24 subjects (12 Japanese, 12 Caucasian), ran- 3972 3917 Inhibitor, in Healthy Japanese and Caucasian domized (3:1) to receive evinacumab or placebo within 3973 3918 Subjects† each ethnic group with a 24-week follow-up. 3974 3919 3975 Results: The safety profile of evinacumab (IV [Table] 3920 Shazia Ali (Tarrytown, NY) Mariko Harada-Shiba, 3976 and SC) in both ethnicities was comparable with placebo, 3921 Daniel Gipe, Evelyn Gasparino, Vladimir Son, 3977 with no serious or severe treatment-emergent adverse 3922 Robert Pordy, Alberico Catapano 3978 events. Pharmacokinetic profiles were comparable between 3923 3979 Japanese and Caucasian subjects across IV and SC groups. 3924 Lead Author’s Financial Disclosure: Shazia Ali is 3980 Mean calculated LDL-C decreased from baseline with both 3925 an employee and shareholder of Regeneron Pharmaceuti- 3981 IV doses, beginning on day 3 up to week 8 (Table). 3926 cals, Inc. 3982 Triglyceride changes observed with evinacumab IV were 3927 Study Funding: Regeneron Pharmaceuticals, Inc. 3983 rapid (seen by day 2) and sustained up to week 8 (Table). 3928 3984 Background/Synopsis: Evinacumab, an angiopoietin- Evinacumab SC doses also reduced levels of LDL-C and 3929 3985 like protein 3 (ANGPTL3) monoclonal antibody, reduced triglycerides, although smaller changes were seen at lower 3930 3986 low-density lipoprotein cholesterol (LDL-C) significantly doses. 3931 in a phase 2 study of patients with homozygous familial 3987 Conclusions: In both ethnicities, evinacumab (IV and 3932 hypercholesterolemia. 3988 3933 SC) was generally well tolerated, exhibiting comparable 3989 Objective/Purpose: In this double-blind phase 1 study pharmacokinetic profiles. Dose-related reductions in LDL- 3934 (NCT03146416), we compared the safety, tolerability, 3990 3935 C and triglycerides were observed with evinacumab in both 3991 pharmacokinetics, and pharmacodynamics of evinacumab ethnic groups. 3936 between healthy Japanese and Caucasian adults. 3992 3937 3993 3938 Table 3994 3939 3995 3940 Evinacumab IV 3996 3941 Placebo 5 mg/kg Q4W 15 mg/kg Q4W 3997 3942 Japanese Caucasian Japanese Caucasian Japanese Caucasian 3998 3943 (n56) (n56) (n59) (n59) (n59) (n59) 3999 3944 4000 Safety data 3945 4001 Number of TEAEs 8 5 3 9 7 8 3946 Subjects with 3 (50.0%) 3 (50.0%) 2 (22.2%) 6 (66.7%) 3 (33.3%) 4 (44.4%) 4002 3947 any TEAE 4003 3948 Subjects with any 0000004004 3949 serious TEAE 4005 3950 Subjects with any 0000004006 3951 severe TEAE 4007 3952 Efficacy data 4008 3953 LDL-C, mean (SD), mmol/L 4009 3954 Baseline 3.2 (0.3) 3.1 (0.9) 3.3 (1.0) 3.1 (0.6) 2.9 (0.5) 3.5 (0.4) 4010 3955 Week 4 3.4 (0.8) 3.1 (0.6) 3.0 (0.9) 2.7 (0.3) 1.8 (0.2) 2.1 (0.3) 4011 % change from 8.7 (28.7) 3.9 (14.9) -7.0 (18.0) -14.4 (14.3) -37.9 (5.6) -38.3 (10.8) 3956 4012 baseline 3957 Week 8 3.3 (0.9) 3.4 (0.6) 2.6 (0.6) 2.6 (0.4) 2.1 (0.4) 2.1 (0.3) 4013 3958 % change from 4.9 (26.8) 13.7 (22.4) -17.7 (15.5) -18.9 (16.5) -28.6 (11.9) -40.2 (9.1) 4014 3959 baseline 4015 3960 Triglycerides, median (Q1:Q3), mmol/L 4016 3961 Baseline 1.1 (0.8:1.5) 1.4 (0.7:2.0) 0.9 (0.7:1.8) 1.5 (1.1:1.6) 0.9 (0.7:1.0) 1.6 (1.3:1.7) 4017 3962 Week 4 1.1 (0.8:1.7) 1.1 (0.8:1.6) 0.7 (0.6:1.0) 1.0 (0.8:1.3) 0.5 (0.5:0.5) 0.6 (0.4:0.7) 4018 3963 % change from 4.2 (-8.5:9.8) -7.0 (-39.7:4.0) -17.5 (-28.6:-5.6) -15.0 (-34.4:-0.7) -51.7 (-55.8-32.7) -59.8 (-73.3:-56.8) 4019 3964 baseline 4020 3965 Week 8 1.7 (1.1:2.3) 1.3 (0.8:1.5) 0.9 (0.7:1.3) 1.0 (0.8:1.0) 0.5 (0.5:0.7) 0.5 (0.5:0.6) 4021 3966 % change from 43.3 (-3.4:72.1) 6.1 (-16.0:12.9) -15.4 (-22.3:-7.8) -32.5 (-37.7:-21.2) -44.7 (-50.0:-33.8) -63.1 (-70.1:-51.9) 4022 baseline LDL-C, low-density lipoprotein cholesterol; Q4W, every 4 weeks; SD, standard deviation; TEAE, treatment-emergent adverse effect

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4023 Omega-3 Fatty Acids related physiological implications (in specific lipoproteins, 4079 4024 or specific lipid moieties such as phospholipid, cholesteryl 4080 4025 176 ester, or triglyceride). These would be interesting next steps 4081 4026 Comparing Eicosapentaenoic Acid Between toward understanding the physiological impacts of EPA by 4082 4027 Plasma and Serum from a Randomized- different delivery methods. In summary, a predictable 4083 4028 Controlled Clinical Trial plasma-serum EPA concentration relationship could help in 4084 4029 cross-study comparisons of measured EPA levels. 4085 4030 Richard Dunbar, MD, (Voorhees, NJ) 4086 4031 4087 Christina Copland, PhD, Lisa Jiao, PhD, Diabetes, Insulin Resistance and Dyslipidemia 4032 Robert Wang, PhD, Katy Wong, BS, John Millar, PhD, 4088 4033 Maria Escobar, BS, 4089 4034 Patty Tarino, PhD, Rebecca Juliano, PhD 177 4090 4035 Discovery of Novel Brown Adipokines that 4091 4036 Lead Author’s Financial Disclosure: Grants from Lower Lipid During Glucose Management 4092 4037 Akcea, Amarin, Arizona Pharmaceuticals, Astra Zeneca, Under Insulin Resistance 4093 4038 Regeneron, UniQure, speakers fees from Akcea, employ- 4094 4039 ment/stocks from Amarin. Nida Tanataweethum, PhD, (Chicago, IL) 4095 Chaeeun Lee, BA, Allyson Trang, BA, Franklin Zhong, BA, 4040 Study Funding: Amarin Pharma, Inc. 4096 4041 Kihwon Kim, MS, 4097 Background/Synopsis: Icosapent ethyl is a pure, 4042 Jhalak Mehta, BA, Abhinav Bhushan, PhD 4098 stable prescription ester of eicosapentaenoic acid (EPA) 4043 4099 which reduced major adverse cardiovascular events in a 4044 4100 recent cardiovascular outcomes trial (REDUCE-IT). Either Lead Author’s Financial Disclosure: Nothing to 4045 4101 plasma or serum can be used to assess EPA exposure. disclose. 4046 4102 However, there are limited studies comparing plasma and Study Funding: P30 DK020595 and the Armor College 4047 4103 serum EPA measurements, with some studies suggesting of Engineering. 4048 4104 similarity whereas others report differences. 4049 Background/Synopsis: The liver is a key insulin 4105 4050 Objective/Purpose: Compare EPA in plasma to serum target tissue for the control of glucose metabolism. In 4106 4051 over a broad range of samples, including fasting/fed and on insulin-resistant disorders such as diabetes, insulin fails to 4107 4052 chronic and/or acute-on-chronic EPA exposure. regulate hepatic glucose production, which leads to 4108 4053 Methods: Mixed effects linear regression was used on elevated circulating glucose concentrations. While 4109 4054 specimens from a randomized, parallel-arm study testing restoring insulin sensitivity is an effective approach to treat 4110 4055 icosapent ethyl effects on lipoprotein kinetics among statin- diabetes, insulin sensitizers increase triglyceride accumu- 4111 4056 treated patients with elevated triglyceride levels in the Vascepa lation. Brown adipose tissue (BAT) has been studied as a 4112 4057 to Accelerate Lipoprotein Uptake and Elimination (VALUE) new target for anti-obesity and type 2 diabetes as BAT 4113 4058 Study. Patients were randomized to icosapent ethyl 4g/ stimulation increases energy expenditure, reduces 4114 4059 d(n512) vs minimal triglyceride management (n58) for adiposity, and improves insulin sensitivity. However, its 4115 4060 .14 weeks. Plasma and serum collected at baseline, follow-up paracrine and endocrine roles on liver remain unclear. 4116 4061 visits, and during an oral fat-tolerance test were assayed for total Objective/Purpose: Our objective was to discover the 4117 4062 EPA by liquid chromatography-tandem mass spectrometry. metabolic interactions between white and brown adipocytes 4118 4063 Results: There was a stable relationship between plasma on hepatic insulin resistance, and in the process discover 4119 4064 and serum EPA across a broad range, 8.2‒410 mg/mL in adipokines that could regulate important metabolic func- 4120 4065 serum (n5165 plasma-serum pairs, pseudo-r5+0.95, tion. Using a novel organ-on-chip construct, we discovered 4121 4066 p,0.0001). Bivariate models adjusting for high-dose novel adipokines that appear to regulate glucose production 4122 4067 EPA, demographics, anthropometrics, and baseline charac- as well as lipid synthesis. 4123 4068 teristics were generally congruent, with a pooled slope of Methods: We developed liver organ-on-chip model using 4124 4069 1.044 (95% CI 0.98‒1.09), suggesting plasma is w4% primary mouse hepatocytes under different states of insulin 4125 4070 higher than serum. Moreover, the slope seldom strayed sensitivity. Adipokines from white/brown adipocytes were 4126 4071 beyond 10% on either side of parity, regardless of fasted/ used as treatments (Figure 1). 4127 4072 fed status (interaction p50.5). Results: Our results demonstrate that brown adipokines 4128 4073 Conclusions: Within these VALUE analyses there was a restored insulin sensitivity and improved glucose produc- 4129 4074 stable relationship between plasma and serum EPA over a tion in IR hepatocytes. This was verified by significantly 4130 4075 broad EPA concentration range, irrespective of meal status, increased expression of Phospho-Akt (Ser473) and reduced 4131 4076 higher/lower exposure, or acute-on-chronic EPA exposure. of glucose production gene markers (G6pc and PEPCK), 4132 4077 These specific experiments did not explore increases in total lowered glucose production, increased glucose uptake, and 4133 4078 EPA levels by delivery methods other than icosapent ethyl, increased glycogen synthesis in treated hepatocytes over IR 4134 EPA exposure-response, or subfractions of EPA and their group (p , 0.05). In addition, brown adipokines suppressed

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4135 Lawrence Leiter, MD, Amy Feng, PhD, 4191 4136 JoAnn Flaim, PhD, Maciej Banach, MD, PhD 4192 4137 4193 4138 Lead Author’s Financial Disclosure: GBJM 4194 4139 received research grant(s)/support from Amgen, AstraZe- 4195 4140 neca, Bayer, Boehringer Ingelheim, Merck, Novo Nordisk, 4196 4141 4197 and Sanofi, and has served as a consultant for these 4142 4198 companies as well as Esperion, Novartis, and Servier. 4143 4199 4144 Study Funding: Esperion Therapeutics, Inc., funded the 4200 research for this study and provided writing support for this 4145 4201 abstract. Medical writing assistance was provided by 4146 4202 Agnella Izzo Matic, PhD, CMPP, and Kelly M Cameron, 4147 4203 Figure 1 Model of the signaling pathways mediating insulin- PhD, CMPP, of JB Ashtin. 4148 4204 dependent regulation of hepatic glucose and lipid metabolism. 4149 Background/Synopsis: Growing evidence supports 4205 4150 hepatic lipogenesis. This was confirmed by significantly treatment of elevated low-density lipoprotein cholesterol 4206 4151 reduced expression of a lipogenesis gene marker (SREPB1) (LDL-C) levels in older patients, especially those at high 4207 4152 and fatty acid uptake in treated hepatocytes over IR group risk for coronary events. Bempedoic acid (BA) is an ATP- 4208 4153 (p , 0.05). In addition, our RNA sequence data showed citrate lyase inhibitor that significantly lowers LDL-C 4209 4154 that brown adipokines significantly lowered expression of levels in adult patients with hypercholesterolemia. 4210 4155 transcripts related to IR (Cd 36 and Nfkbia), type 2 diabetes Objective/Purpose: To report efficacy and safety of 4211 4156 (Kcnj11 and Abcc8), and NAFLD (Plekhs1 and Il1) by at BA treatment in patients with elevated LDL-C stratified by 4212 4157 least 2 fold. Current efforts are focused towards identifying age. 4213 4158 the brown adipokines via mass spectrometry. Methods: Data were pooled from 4 phase 3 randomized 4214 4159 Conclusions: BAT-derived endocrine factors could be a (2:1), double-blind studies that investigated oral BA (180 4215 4160 potential novel targets for unmet needs in type 2 diabetes mg daily) vs placebo for 12 weeks to 52 weeks in adults 4216 4161 and NAFLD treatments. receiving maximally-tolerated statin therapy (including no 4217 4162 statin) and requiring additional LDL-C lowering. Patients 4218 4163 were stratified by age (18 to ,65 years [n51523, 42%], 65 4219 4164 Lipid Management in Special Populations to ,75 years [n51527, 42%], &;75 years [n5571, 16%]). 4220 4165 The primary efficacy endpoint was percent change from 4221 4166 baseline at week 12 in LDL C. Efficacy results were 4222 178 4167 analyzed in cohorts with atherosclerotic cardiovascular 4223 4168 Efficacy and Safety of Bempedoic Acid in disease (ASCVD) and/or heterozygous familial hypercho- 4224 4169 Elderly Patients: Pooled Analyses from Phase lesterolemia (ASCVD/HeFH on statins pool" 4225 3 Trials 4170 Results: n53009) or a history of statin intolerance 4226 4171 4227 G. B. Mancini, MD, (Vancourver, BC) ("statin intolerant pool" 4172 4228 Alberico Catapano, PhD, MD (hc), P. Duell, MD, Conclusions: n5614). Safety assessments included 4173 4229 Anne Goldberg, MD, Ulrich Laufs, MD, PhD, treatment-emergent adverse events (TEAEs)." 4174 4230 4175 4231 4176 4232 4177 Table 1 Change in LDL-C from Baseline to Week 12 in Patients who Received Bempedoic Acid or Placebo in 4 Phase 3 Studies 4233 4178 Age 18 to ,65 years Age 65 to ,75 years Age $75 years 4234 4179 4235 BA Placebo BA Placebo BA Placebo 4180 4236 4181 ASCVD/HeFH on statins pool,N 827 374 800 442 295 162 4237 4182 Mean (SE) % change LDL-C –17.2 (0.8) 1.3 (1.2) –16.6 (0.7) 2.0 (1.1) –15.7 (1.0) 2.6 (1.7) 4238 4183 Mean difference (95% CI), P value –18.4 (–21.3, –15.6), –18.6 (–21.2, –16.1), –18.3 (–22.2, –14.5), 4239 P , 0.001 P , 0.001 P , 0.001 4184 4240 Statin intolerant pool,N 172 84 167 75 60 30 4185 Mean (SE) % change LDL-C –22.8 (1.8) 2.2 (2.0) –24.7 (1.7) –0.9 (1.7) –25.1 (2.3) 5.1 (3.6) 4241 4186 Mean difference (95% CI) –25.0 (–30.3, –19.7), –23.9 (–28.6, –19.2), –30.2 (–38.8, –21.5), 4242 4187 P , 0.001 P , 0.001 P , 0.001 4243 4188 4244 ASCVD, atherosclerotic cardiovascular disease; BA, bempedoic acid; CI, confidence interval; HeFH, heterozygous familial hypercholesterolemia; hsCRP, 4189 high-sensitivity C-reactive protein; ITT, intent-to-treat; LDL-C, low-density lipoprotein cholesterol. 4245 4190 Each efficacy endpoint was analyzed using an ANCOVA model that included treatment, CV risk (ASCVD only; HeFH with or without ASCVD), and baseline 4246 statin intensity (high, moderate, or low) as factors and baseline value as a covariate.

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4247 4303 4248 Table 2 Treatment-emergent Adverse Events in Patients who Received Bempedoic Acid or Placebo in 4 Phase 3 Studies 4304 4249 Aged 18 to ,65 years Aged 65 to ,75 years Aged $75 years 4305 4250 4306 BA Placebo BA Placebo BA Placebo 4251 4307 4252 1049 474 1001 526 374 197 4308 4253 Any TEAE 68.9 (723) 68.6 (325) 76.0 (761) 74.3 (391) 76.7 (287) 77.2 (152) 4309 4254 Serious TEAE 12.6 (132) 12.4 (59) 13.3 (133) 14.1 (74) 20.3 (76) 13.2 (26) 4310 4255 Drug-related TEAE 21.3 (223) 16.9 (80) 26.3 (263) 24.0 (126) 25.9 (97) 18.8 (37) 4311 TEAE leading to drug discontinuation 8.4 (88) 7.4 (35) 12.4 (124) 8.2 (43) 16.3 (61) 7.6 (15) 4256 4312 TEAE with fatal outcome 0.6 (6) 0.4 (2) 0.6 (6) 0.4 (2) 1.9 (7) 0 4257 4313 4258 BA, bempedoic acid; TEAE, treatment-emergent adverse event.Adverse events were coded using Medical Dictionary for Regulatory Activities (MedDRA) 4314 version 20.1. Multiple entries for an individual patient under each adverse event category/preferred term are counted only once. Data are presented as 4259 percent (number), unless otherwise indicated. 4315 4260 4316 4261 4317 4262 Epidemiology of Cardiovascular Disease SCORE (MFHS), that includes 5 clinical variables: age, 4318 4263 sex, HDL-C, hypertension and smoking, has been devel- 4319 4264 179 oped and validated in retrospective cohorts of FH patients. 4320 4265 4321 The Montreal-FH-SCORE Predicts Major Objective/Purpose: The objective of the present study 4266 4322 Adverse Cardiovascular Events in is to verify the clinical usefulness of the MFHS in the 4267 4323 Multinational Cohorts of Familial prediction of future cardiovascular events in a large 4268 4324 Hypercholesterolemia prospective cohort. 4269 4325 4270 Alexis Baass, MD, MSc, (Montreal, QC) Methods: A total of 2434 genetically confirmed adult 4326 4271 Martine Paquette, MSc, Sophie Bernard, MD, PhD, heterozygous FH patients in primary prevention have been 4327 4272 Bertrand Cariou, MD, PhD, Jacques Genest, MD, included in the analysis (26 134 person-year of follow-up). 4328 4273 Robert Hegele, MD, Mark Trinder, MSc, Data from five different prospective cohorts were included 4329 ~ 5 4274 Liam Brunham, MD, PhD, Sophie BAf liard, MD, PhD in the analysis: IRCM (n 482), the FH register from 4330 5 5 4275 British Columbia (n 199), the UK Biobank (n 203), the 4331 5 4276 Robarts Research Institute (n 100) and the FH register 4332 Lead Author’s Financial Disclosure: A.B. received 5 4277 research grants from Akcea, Amgen, Astra Zeneca, the from France (n 1450). 4333 4278 Fondation Leducq, Merck Frosst and Sanofi. He has Results: A total of 190 patients had at least one CVD 4334 4279 participated in clinical research protocols from Acasti event during the follow-up. When patients were divided in 4335 # 4280 Pharma Inc., Akcea, Amgen, Astra Zeneca, Ionis Pharma- two groups according to the MFHS median ( 20 points vs 4336 4281 ceuticals, Inc., The Medicine. . 20 points), the event-free survival probability over 10 4337 4282 Study Funding: This work was supported by The years of follow-up for the 3 major adverse cardiovascular 4338 4283 Fondation Leducq Transatlantic Networks of Excellence events was significantly increased in the group with the 4339 4284 [grant number 13CVD03]. lower value of the MFHS (0.982 +/- 0.005) compared to the 4340 group above the MFHS median (0.964 +/- 0.007) 4285 Due to the important lifelong 4341 Background/Synopsis: (P50.008), with a hazard ratio of 2.25 (1.21-4.16). 4286 LDL cholesterol burden, patients with familial hypercho- 4342 4287 lesterolemia (FH) have a high risk of cardiovascular disease Conclusions: The use of the MFHS by clinicians will allow 4343 4288 (CVD). However, this risk is highly heterogeneous. In a a personalized and optimized medical care of FH patients. 4344 4289 context of precision medicine, it is thus essential to better 4345 4290 stratify the CVD risk in this population. The Montreal-FH- Diabetes, Insulin Resistance and Dyslipidemia 4346 4291 4347 4292 180 4348 4293 BIO89-100, a novel glycoPEGylated FGF21 4349 4294 Analog, Demonstrates Triglyceride Reduction 4350 4295 and Broad Metabolic Effects in Spontaneously 4351 4296 Diabetic Obese Cynomolgus Monkeys 4352 4297 4353 4298 Andrew Pierce, PhD, (San Francisco, CA) 4354 4299 Moti Rosenstock, PhD, 4355 4300 Maya Margalit, MD, Hank Mansbach, MD 4356 4301 4357 4302 Lead Author’s Financial Disclosure: All authors 4358 are employees and stockholders of 89bio, Inc.

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4359 4415 4360 4416 4361 Mean Percentage Change from Baseline to End of Treatment Period 4417 4362 4418 BIO89-100 dose TG (mg/dL) LDL (mg/dL) HDL (mg/dL) ALT (U/L) Glucose (mg/dL) Insulin (mIU/L) Body Weight (kg) 4363 4419 4364 STUDY 1 56 days 4420 4365 baseline (all groups) 253.0 69.8 43.3 154.0 214.5 97.5 8.9 4421 4366 Vehicle QW 22.8% -1.8% 1.2% 52.4% 17.8% 19.2% -1.4% 4422 4367 0.1 mg/kg QW -49.5% -34.3% 38.8% -4.0% -25.1% -35.3% -2.0% 4423 0.3 mg/kg QW -54.6% -26.2% 21.5% -31.7% -34.4% -36.5% -3.0% 4368 4424 1.0 mg/kg QW -78.4% -37.1% 47.2% -26.4% -51.4% -60.7% -9.3% 4369 STUDY 2 28 days 4425 4370 baseline (all groups) 305.0 86.5 38.0 89.8 217.3 76.3 8.4 4426 4371 Vehicle QW 10.8% -6.0% 11 .3% 7.0% -7.0% 25.1% -1.4% 4427 4372 1.0 mg/kg QW -75.7% -52.0% 67.3% 16.1% -57.7% -47.6% -7.6% 4428 4373 1.0 mg/kg Q2W -35.6% -27.3% 9.6% -27.9% -31.5% 9.9% -6.2% 4429 4374 2.0 mg/kg Q2W -52.4% -32.0% 25.0% -35.8% -19.7% -17.1% -9.0% 4430 4375 4431 4376 4432 4377 Study Funding: None. human primates. A Phase 2 clinical trial in patients with 4433 4378 4434 Background/Synopsis: Obesity and its comorbidities, severe hypertriglyceridemia is planned to begin in 2020. 4379 4435 including hyperlipidemia, increase risk for atherosclerotic 4380 4436 cardiovascular disease. FGF21 is an endogenous hormone 4381 Pathophysiology of Atherosclerosis 4437 that regulates lipid and carbohydrate metabolism. FGF21 4382 4438 analogs have previously been shown to have positive effects 4383 181 4439 across a range of metabolic parameters. BIO89-100, a 4384 BIO89-100, a GlycoPEGylated FGF21 Analog, 4440 novel glycoPEGylated FGF21 analog with an extended 4385 Improved Serum Lipids and Extended Half-Life 4441 half-life over native FGF21, has demonstrated substantial 4386 in a Controlled Single Ascending Dose Trial in 4442 improvements in lipid parameters in pre-clinical studies as † 4387 Healthy Subjects 4443 well as in a Phase 1 study in healthy volunteers. A Phase 4388 4444 1b/2a study is ongoing in patients with NASH. 4389 Maya Margalit, MD, (Herzliya, Israel) 4445 4390 Objective/Purpose: Determine the potential of BIO89- Chao-Yin Chen, PhD, Leo Tseng, PhD, 4446 4391 100 to improve lipids and metabolic parameters in obese Moti Rosenstock, PhD, Hank Mansbach, MD 4447 4392 diabetic Cynomolgus monkeys. 4448 Methods: Two studies were conducted in obese diabetic 4393 Lead Author’s Financial Disclosure: Employee of 4449 Cynomolgus monkeys. Study 1 compared BIO89-100 given 4394 89bio, Inc. 4450 4395 weekly to vehicle for 8 weeks (n56 per group). Study 2 4451 Study Funding: None. 4396 compared BIO89-100 given weekly or every other week to 4452 4397 vehicle over 4 weeks (n56 per group). Standard metabolic Background/Synopsis: FGF21 is a non-mitogenic 4453 4398 profile measurements (weight, blood glucose, HbA1C, metabolic hormone that affects energy expenditure and 4454 4399 blood lipids, and ALT. were assessed at pre-determined glucose and lipid metabolism. BIO89-100 is a novel, long- 4455 4400 intervals prior to, during, and after the treatment. acting glycoPEGylated recombinant human FGF21, with 4456 4401 Results: Monkeys treated with BIO89-100 showed robust promising effects on metabolic and liver-related parameters 4457 4402 metabolic improvements over vehicle treated animals (see in mice and monkeys. 4458 4403 supplementary table). BIO89-100 showed significant ef- Objective/Purpose: To evaluate safety and tolerability, 4459 4404 fects on triglycerides with a maximal reduction of 78% and and characterize the pharmacokinetic profile of BIO89-100 4460 4405 76% at doses of 1 mg/kg/QW in Studies 1 and 2 in healthy subjects following ascending single dose. 4461 4406 respectively. BIO89-100 also demonstrated improvements Methods: Fifty-eight healthy subjects were randomized 4462 4407 in other lipids parameters (reduced LDL-C, increased to assess safety, pharmacokinetic, and pharmacodynamics, 4463 4408 HDL-C), metabolic measures (decreased in insulin, blood including serum lipids. Subjects received a single subcu- 4464 4409 glucose) and decreased in ALT. Most improvements were taneous dose of BIO89-100 at 0.45, 1.2, 3, 9.1, 18.2, 39 or 4465 4410 apparent within 4 days of initial treatment and were 78 mg, or placebo, in a 6:2 ratio (7:3 ratio for the 9.1 mg 4466 4411 sustained throughout the treatment period with resolution dose) and were followed for 4 weeks. 4467 4412 back towards baseline values during the washout period. Results: Mean (SD) age and BMI was 39.3 (9.7) years 4468 4413 Conclusions: BIO89-100 is a glycoPEGylated FGF21 and 26.7 (3.1) kg/m2 and 86% were male. Baseline 4469 4414 analog that robustly improved major hallmarks of metabolic characteristics were similar between pooled BIO89-100 4470 disease in two studies of obese spontaneously diabetic non- treated subjects (N543) and pooled placebo (N515).

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4471 BIO89-100 was well tolerated with no deaths, no serious Methods: In a large cohort of 12 434 dyslipidemic 4527 4472 adverse events, nor discontinuations due to AEs. The most patients, 4 891 patients had a mixed dyslipidemia 4528 4473 common treatment-related AEs, .5 2 subjects in the phenotype, characterized by total cholesterol &; 5.2 4529 4474 pooled BIO89-100 group, were injection site reactions and mmol/L (200 mg/dL) and triglycerides (TG) &; 2.0 4530 4475 headache (all mild). No clinically meaningful trends were mmol/L (175 mg/dL)). The APOE genotype or pheno- 4531 4476 observed in laboratories, blood pressure, or anti-drug type as well as the lipoprotein ultracentrifugation results 4532 4477 antibodies. The PK was generally dose proportional with were available for all patients. Among these, we identi- 4533 4478 an average elimination half-life w55-100 hours. fied 188 DBL patients through gold standard criteria: a 4534 4479 Mean baseline lab values were within normal range. At VLDL-C/TG ratio . 0.30 (in mg/dL) and carriers of 4535 4480 single doses of 9.1 mg and higher, BIO89-100 apoE2/E2. 4536 4481 4537 demonstrated significant improvements versus baseline Results: Using the C-statistics, the non-HDL-C/apoB 4482 4538 and versus placebo (post-hoc) on key lipid parameters ratio was found to be the best predictors of DBL 4483 4539 measured 8 and 15 days post dosing. Mean % changes diagnosis (AUC 0.931, 95% CI 0.913-0.949, 4484 4540 versus baseline included reduction in triglycerides (up to P,0.0001). Using a non-HDL-C/apoB cut point of 3.69 4485 4541 51%, compared to placebo reduction of up to 2%) and mmol/g (which is the value that provides the best 4486 4542 LDL-C (up to 37%), and increase in HDL-C (up to 36%). specificity value at a sensitivity of 95%) followed by 4487 4543 Increase in adiponectin (up to 146%) was observed. the presence of apoE2/E2 resulted in a good sensitivity 4488 4544 Conclusions: BIO89-100 at single doses up to 78 mg (94.8%), NPV (99.8%), specificity (99.6%), PPV 4489 4545 was generally safe and well tolerated in healthy subjects (88.5%), accuracy (99.4%) and AUC (0.97 (0.95-0.99)) 4490 4546 and was associated with increased adiponectin and clini- for the prediction of DBL. Previous criteria have been 4491 4547 cally significant improvements in serum triglycerides and proposed for the diagnosis of DBL, but these criteria had 4492 4548 other lipid parameters. The results support further investi- either low sensitivity or low specificity when tested in the 4493 4549 gation of BIO89-100, administered weekly or every-other- present cohort. 4494 week in an ongoing Phase 1b/2a study in patients with 4550 4495 Conclusions: We propose here a 3-step algorithm for the 4551 NASH, and in a planned Phase 2 study in patients with screening and diagnosis of DBL. The first step is to identify 4496 severe hypertriglyceridemia to start in 2020. 4552 4497 patients with mixed dyslipidemia using total cholesterol and 4553 4498 triglycerides cut off. The second step is to identify patients 4554 4499 Clinical Applications of Biomarkers, Lipoprotein with a non-HDL-C/apoB ratio &; 3.69 mmol/g, followed by a 4555 4500 Testing confirmatory test (APOE genotype, lipoprotein ultracentrifu- 4556 4501 gation or electrophoresis) as the third step. The use of this 4557 182 4502 simple algorithm could improve the screening and diagnosis 4558 4503 A Simplified Diagnosis Algorithm for of this rare disease at reasonable costs. 4559 4504 Dysbetalipoproteinemia 4560 4505 Alexis Baass, MD, MSc, (Montreal, QC) David Blank, MD, Lipid Management Best Practices 4561 4506 Martine Paquette, MSc, 4562 4507 Guillaume Par, MD, MSc, Sophie Bernard, MD, PhD 4563 4508 183 4564 4509 Perceptions and Barriers on the Use of PCSK9 4565 Lead Author’s Financial Disclosure: A.B. received 4510 Inhibitors in Heterozygous Familial 4566 research grants from Akcea, Amgen, Astra Zeneca, the 4511 Hypercholesterolemia 4567 Fondation Leducq, Merck Frosst and Sanofi. He has 4512 4568 participated in clinical research protocols from Acasti Matthew Bang (Irvine, CA) Dean Karalis, MD, FNLA, 4513 4569 Pharma Inc., Akcea, Amgen, Astra Zeneca, Ionis Pharma- Robert Block, MD, MPH, FNLA, 4514 4570 ceuticals, Inc., The Medicine. Amy Peterson, MD, Nathan Wong, PhD, FNLA 4515 4571 4516 Study Funding: None. 4572 4517 Background/Synopsis: Dysbetalipoproteinemia (DBL) Lead Author’s Financial Disclosure: Nothing to 4573 4518 is a disease of remnant lipoproteins that occurs when a disclose. 4574 4519 genetic defect of APOE gene is present, combined with the Study Funding: Sanofi Regeneron. 4575 4520 presence of secondary factors such as insulin resistance, Background/Synopsis: Heterozygous familial hyper- 4576 4521 obesity or type 2 diabetes that precipitate the disease. Even if cholesterolemia (HeFH) results in significant elevations in 4577 4522 DBL is associated with a high cardiovascular risk due to the LDL-C and premature atherosclerotic cardiovascular dis- 4578 4523 atherogenicity of remnant particles, there still exists consider- ease (ASCVD). Current guidelines call for the use of high 4579 4524 able level of confusion concerning its diagnosis. intensity statin and ezetimibe followed by PCSK9 inhibitor 4580 4525 Objective/Purpose: The objective of this study is to (PCSK9i) therapy for additional LDL-C lowering. Data are 4581 4526 improve the screening of DBL by proposing a simple sparse, however, regarding physician attitudes, use, and 4582 clinical algorithm. barriers for using PCSK9i in such patients.

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4583 4639 4584 Table Primary Care and Cardiologist Attitudes, Experience, and Barriers Regarding PCSK9i Use 4640 4585 Survey Item Primary Care Cardiologist p-value 4641 4586 4642 Ever Diagnosed pt with LDL-C.5190 mg/dL as HeFH? 71.0% 79.2 % ,0.01 4587 If Yes to Above, Used Genetic Testing to Diagnose 25.6% 23.7% 0.55 4643 4588 Practice has Access to Lipid Specialist 52.6% 55.4% 0.37 4644 4589 Ranking High Intensity Statin as Most Important for 64.8% 68.6% 0.04 4645 4590 HeFH patient with untreated LDL-C .5190 mg/dL 4646 4591 Ranking PCSK9i as Most Important for HeFH Pt on 48.4% 58.2% ,0.01 4647 4592 Maximal Tolerated Statin Needing Add’l LDL-CLowering 4648 4593 Currently has HeFH patient on a PCSK9i 44.2% 68.4% ,0.0001 4649 4594 Likely or Very Likely to Prescribe a PCSK9i in an Adult 66.0% 87.8% ,0.0001 4650 4595 with HeFH on maximum statin Therapy with ASCVD 4651 , 4596 Likely or Very Likely to Prescribe a PCSK9i in an Adult 51.0% 70.2% 0.0001 4652 with HeFH on maximum statin Therapy without 4597 4653 ASCVD 4598 Personally Prescribed a PCSK9i for an Adult Pt with 46.8% 70.4% ,0.0001 4654 4599 HeFH 4655 4600 Encountered Difficulty Prescribing a PCSK9i for 58.1% 50.6% 0.07 4656 4601 aPatient with HeFH (very or extremely difficult) 4657 4602 Most Important Barriers Encountered When Prescribing 34.2% 24.7% ,0.05 4658 4603 a PCSK9i for an Adult Pt with HeFH a) Pre- 4659 4604 authorization process complicatedb) Pre- 4660 4605 authorization process time consumingc) Medicine 4661 4606 too expensived) Get frequent denials from 4662 4607 insurancee) Pt. does not want to take injectable 4663 medicationf) Difficult to document a clinical 4608 4664 diagnosis of HeFH 4609 27.8% 27.8% 4665 4610 12.0% 21.9% ,0.01 4666 4611 12.4% 11.7% 4667 4612 10.7% 9.7% 4668 4613 3.0% 4.3% 4669 4614 4670 4615 4671 4616 4672 4617 4673 Objective/Purpose: We sought to examine physician PCP compared to C (OR50.47, 95% CI50.34-0.64), 4618 4674 attitudes, use, and barriers for using PCSK9i therapy in but more likely in those who correctly diagnosed a 4619 4675 patients with HeFH. patient with LDL-C.5190 mg/dL as HeFH (OR58.3 4620 4676 Methods: We surveyed 1000 physicians (500 primary [5.7-12.1]) or among providers indicating they were 4621 likely to prescribe a PCSK9 in an adult patient with 4677 4622 care providers [PCPs] and 500 cardiologists [Cs]) in the US 4678 regarding their preferred treatments, experience and bar- HeFH on maximal statin needing additional LDL-C 4623 5 4679 riers associated with using PCSK9i. The Chi-square test of lowering either with clinical ASCVD (OR 3.9 [2.5- 4624 6.0]) or without clinical ASCVD (OR51.7 [1.2-2.4]). 4680 4625 proportions compared proportions of PCPs vs. Cs respond- 4681 ing to survey questions. Stepwise logistic regression Those in an urban vs. rural practice location were less 4626 likely (OR50.54 [0.32-0.89]) and overall respondents 4682 4627 examined factors associated with use and difficulty pre- 4683 scribing a PCSK9i. were more likely to face difficulty prescribing a 4628 PCSK9i if they indicated they had ever diagnosed a 4684 Results: Our PCPs were less likely to be in an urban 4629 patient with HeFH (OR54.2 [2.8-6.6] but more likely 4685 practice location and more likely in private practice 4630 to prescribe a PCSK9i in a patient with HeFH with 4686 than the Cs surveyed (p,0.0001). The table below 4631 clinical ASCVD (OR53.0 [2.0-4.6]). 4687 4632 compares PCPs and Cs regarding use, attitudes, and 4688 Conclusions: For patients with HeFH, PCPs compared 4633 barriers regarding PCSK9i. Cs compared to PCPs were 4689 to Cs are less likely to prescribe and consider a PCSK9i 4634 more likely to correctly diagnose a patient with LDL- 4690 important for such patients. Those in an urban practice 4635 C.5190 mg/dL as HeFH, rank a PCSK9i as most 4691 location were less likely to face difficulty prescribing a 4636 important for an HeFH patient needing additional LDL- 4692 PCSK9i. Greater physician education and assistance is 4637 C lowering, as well as prescribing and having a patient 4693 needed to address the gaps in understanding and treatment 4638 on a PCSK9i (table). Stepwise multiple logistic regres- 4694 sion showed prescribing a PCSK9i was less likely by a regarding PCSK9i.

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4695 Diabetes, Insulin Resistance and Dyslipidemia 4751 4696 4752 4697 4753 185 4698 4754 4699 Heterogeneity of Diabetic Dyslipidemia, Data 4755 4700 from the NHANES (2011-2016) 4756 4701 Yanshuang Li, MD PhD, (Nashville, TN) Jiyu Li, MD PhD, 4757 4702 Honglei Li, MD PhD, Li Qin, PhD, Wenliang Song, 4758 4703 Stuart Zarich, MD, Sachin Majumdar, MD 4759 4704 4760 4705 4761 4706 Lead Author’s Financial Disclosure: Nothing to 4762 4707 disclose. 4763 4708 Study Funding: None. 4764 4709 Background/Synopsis: Low high-density lipoprotein 4765 4710 (HDL-C) and high triglycerides (TGs) levels have been 4766 4711 recognized as a characteristic pattern in patients with diabetes. 4767 4712 Low HDL-C and high TGs have both been extensively 4768 4713 recognizedtobeassociatedwithcardiovascularrisk.However, 4769 4714 clinical trials on pharmacological approach to raise HDL-C or 4770 4715 to lower TGs have been mostly negative. Interestingly, in post them have elevated TGs levels, 23.9% of them have low HDL- 4771 4716 hoc analyses of multiple clinical trials, individuals with con- C levels and 8.8% of them have both low HDL-C and elevated 4772 4717 current high TGs and low HDL-C did benefit from therapies, TGs levels. The ratio of LDL-C to Apo B is generally lower in 4773 4718 suggesting the heterogeneity of dyslipidemia patterns. people with diabetes, with the lowest value in the subgroup of 4774 4719 Objective/Purpose: Describe the dyslipidemia patterns concurrent low HDL-C and high TGs group. This suggest this 4775 4720 in people with and without diabetes in the adult US group has the smallest LDL-C particle size, which is most 4776 4721 population. atherogenic. Apo B is generally more concordant with Non- 4777 4722 Methods: Data from National Health and Nutrition HDL-C than LDL-C as previously observed. Interestingly, 4778 4723 Examination Survey (2011-2016) was analyzed. Low Apo B is less concordant with LDL-C in normal TGs people 4779 4724 HDL-C level is defined as 40 mg/dl in male and 50 mg/ especially those without diabetes. Finally, high-sensitivity C- 4780 4725 dl in female adults. High TGs is defined as .150mg/dl. reactive protein (Hs-CRP) levels are found to be elevated in 4781 4726 4782 Results: Surprisingly, about half of the people with diabetes people with low HDL-C levels with and without diabetes but 4727 4783 (49.9%) have both normal TGs and normal HDL-C levels. not in those with elevated TGs. 4728 4784 Approximately one third of the people with diabetes (33.4%) Conclusions: Dyslipidemia patterns are highly hetero- 4729 4785 have elevated TGs levels and one third of them (36.1%) have geneous even in those with diabetes. This explained at least 4730 4786 low HDL-C levels. Only 19.3% of them have both low HDL-C partially of the difficult search for novel therapies in the 4731 4787 and elevated TGs levels. Among people without diabetes, post LDL-C era. Deep phenotyping of sub-groups of 4732 4788 67.5% of them have normal TGs and HDL-C levels, 28.0% of dyslipidemia is warranted to identify higher risk patients 4733 4789 for evaluation non-LDL-C therapies in the future. 4734 4790 4735 4791 4736 4792 4737 4793 4738 4794 4739 4795 4740 4796 4741 4797 4742 4798 4743 4799 4744 4800 4745 4801 4746 4802 4747 4803 4748 4804 4749 4805 4750 4806

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4807 kinetics - are not well understood, especially as they may 4863 4808 vary by chemical form: triglyceride (TG), ethyl esters (EE) 4864 4809 or krill oil (KO, predominantly phospholipids). 4865 4810 Objective/Purpose: The purpose of this study was to 4866 4811 compare the impact of varying doses of EPA+DHA 4867 4812 provided in three chemical forms on the Omega-3 Index 4868 4813 (O3i; erythrocyte EPA+DHA). 4869 4814 4870 Methods: This was a secondary analysis using individual- 4815 4871 level data compiled from 16 placebo controlled clinical 4816 4872 studies with varying doses and durations, and the effects on 4817 4873 the O3i were measured (14 published in Walker et al. Am J 4818 4874 Clin Nutr 2019;110:1034-1040 and 2 unpublished KO 4819 4875 studies). One analysis included the full dataset, and a 4820 4876 restricted analysis was done using studies with similar 4821 4877 dose-ranges of EE, TG and KO. The O3i was determined 4822 4878 by GC-FID at Omegaquant Analytics, Sioux Falls, SD. 4823 4879 Statistical analysis were done in JMP v 15.0.0, SAS institute. 4824 4880 4825 Results: The full dataset included 1639 subjects. Demo- 4881 4826 graphics [median (10-90 percentile)]: Age, 56 (28-75); Male/ 4882 4827 Female, 1172/467; Caucasian, 92%; BMI, 27.9 (22.7-34.3); 4883 5 5 5 4828 chemical form - TG n 219, EE n 1122, and KO n 298; 4884 4829 study duration in weeks, 12 (8-24); dose (mg EPA+DHA/kg 4885 4830 body weight) 4.6 [0 (placebo) - 39]; and O3i at baseline 4.4% 4886 4831 (2.9%-6.9%). Linear regression analysis on the change in O3i 4887 4832 as function of EPA+DHA dose regardless of form was 4888 5 5 4833 CHG_O3I 0.506 + 0.10*DOSE (R2 0.5) However, there 4889 4834 were differences in the dose-response by chemical form in both 4890 4835 the full and restricted datasets. 4891 4836 Full dose range (0-75 mg/kg) Restricted dose range 4892 5 4837 (N 1288, 0-21 mg/kg) 4893 5 5 4838 Ethyl Esters CHG_O3I 0.45 + 0.10*DOSE (R2 0.50) 4894 5 5 4839 CHG_O3I 0.18 + 0.16*DOSE (R2 0.31) 4895 5 5 4840 Triglycerides CHG_O3I 0.55 + 0.15*DOSE (R2 0.58) 4896 5 5 4841 CHG_O3I 0.03 + 0.24*DOSE (R2 0.63) 4897 4842 4898 4843 4899 4844 Omega-3 Fatty Acids 4900 4845 4901 4846 186 4902 4847 Effects of Different Chemical fFrms of EPA and 4903 4848 DHA on the Omega-3 Index: A Meta-Analysis 4904 4849 of 16 Trials 4905 4850 4906 4851 William Harris, PhD, (Sioux Falls, SD) Nils Hoem, PhD 4907 4852 4908 4853 Lead Author’s Financial Disclosure: WSH is the 4909 4854 President of OmegaQuant Analytics, LLC, the laboratory 4910 4855 that performed all of the blood analyses for this study and 4911 4856 that offers the fatty acid analysis services to researchers, 4912 4857 clinicians and consumers. 4913 4858 Study Funding: None. 4914 4859 Background/Synopsis: The long chain omega 3 fatty 4915 4860 4916 acids eicosapentaenoic acid (EPA) and docosahexaenoic Comparison of TG (blue), EE (green) and KO (red) effects on 4861 acid (DHA) have been shown to have protective effects in the Omega-3 Index in the dose-restricted dataset. Dose is ex- 4917 4862 the cardiovascular (CV) system. However, the basic pressed as mg/kg bw, and the change in the Omega-3 Index in 4918 pharmacology - absorption, distribution, elimination absolute percent.

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4919 Krill Oil CHG_O3I 5 -0.08 + 0.32*DOSE (R250.73) across genotypes, symptomatic presentation, disease severity, 4975 4920 CHG_O3I 5 -0.08 + 0.32*DOSE (R250.73). and onset may also vary among individuals with the same 4976 4921 Conclusions: These data suggest that 1) a diminishing mutation, or even family members. The complete burden of 4977 4922 fraction of the EPA+DHA dose appears to be taken up and FPLD due to physical, emotional, and mental impacts is not 4978 4923 incorporated into erythrocyte membranes with increasing fully understood or well documented in the literature. 4979 4924 intakes of both TG and EE, but especially for the latter; and Objective/Purpose: To determine the overall impact of 4980 4925 2) there are clear dose-response differences among the three quality of life FPLD imposes on patients. 4981 4926 4982 forms when similar doses are compared. Further pharmaco- Methods: The REVEAL web-based patient survey was 4927 4983 kinetic studies are needed with larger doses of KO to clarify undertaken to quantify the burden of illness and quality of 4928 4984 the effects of chemical form and dose on the O3i. life from the patient’s perspective. 4929 4985 4930 Results: 37 adult FPLD patients (1 male, 36 female) from 4 4986 4931 countries completed the survey with the majority of patients 4987 5 4932 from the United States (n 30). The median age was 46 years 4988 ^V 4933 (range 25 a ‘‘ 69). Nearly half of patients reported first 4989 4934 noticing FPLD symptoms during teenage years; however, the 4990 4935 median age of diagnosis was 37, with 60% receiving a diag- 4991 4936 nosis between 30 and 50 years. Additionally, 76% of patients 4992 4937 reported being misdiagnosed and patients saw a median of 5 4993 4938 physicians prior to FPLD diagnosis. High triglyceride levels 4994 4939 and diabetes were reported as the most frequent conditions 4995 4940 contributing to the overall burden of FPLD. The most common 4996 4941 reasons for hospitalization were acute pancreatitis and abdom- 4997 4942 inal pain. Hypertriglyceridemia and diabetes due to FPLD were 4998 4943 two of the most reported comorbidities, with 81% and 76% of 4999 4944 patients reporting each respectively. The diet required for 5000 4945 FPLD is challenging to maintain and is a source of stress for pa- 5001 Comparison of TG (blue), EE (green) and KO (red) effects on the tients who face cravings, challenges dining out, and who expe- 4946 Omega-3 Index in the full dataset. Dose is expressed as mg/kg 5002 rience anxiety anticipating that divergence from diet 4947 bw, and the change in the Omega-3 Index in absolute percent. 5003 4948 requirements will result in hospitalization. Other frequent co- 5004 4949 morbidities included hyperlipidemia, insulin resistance, and he- 5005 4950 patic steatosis. Beyond the physical burden, FPLD also impacts 5006 4951 Hypertriglyceridemia patients emotionally and mentally. Eighty-four percent of pa- 5007 4952 tients reported daily anxiety, fear, and worry about their health 5008 due to FPLD. Over 70% also reported worry about their health 4953 187 5009 and quality of life deteriorating with age due to FPLD. Stress 4954 The Impact of Familial Partial Lipodystrophy 5010 andanxietyalsoextendtopatients’families,with70%report- 4955 on Quality of Life from the Patients’ 5011 ing their families have experienced stress due to their FPLD. 4956 Perspective 5012 4957 Conclusions: The physical symptoms and comorbidities of 5013 4958 Elif Oral, MD, (Ann Arbor, MI) Rob Halter, PharmD, FPLD impart substantial burden on patients. However, FPLD 5014 4959 Caroline Crowson, Nandini Hadker, Brant Hubbard, PhD, also exerts considerable emotional and mental burden for 5015 4960 Michael Stevenson, PhD, Louis O’Dea, MD patients due to stress, anxiety and worry regarding their FPLD. 5016 4961 5017 4962 Lipid Management in Special Populations 5018 4963 Lead Author’s Financial Disclosure: Has received 5019 4964 grant support and worked as a scientific advisor to Ionis 188 5020 Pharmaceuticals and Akcea Therapeutics, also receives grant 4965 Effects of Novel Biologics to Treat 5021 support and provides scientific advising for Regeneron 4966 Hypertriglyceridemia in Familial 5022 Pharmaceuticals, Aegerion Pharmaceuticals (now owned 4967 Chylomicronemia Syndrome with Two 5023 by Amryt), recei. 4968 Different Genotypes 5024 4969 Study Funding: This study was funded by Akcea 5025 4970 Therapeutics Inc. Masako Ueda, MD, (Philadelphia, PA) Maria Escobar, BS, 5026 4971 Background/Synopsis: Familial Partial Lipodystrophy Laura Walters, BS, Dusanka Lalic, BS, Robert Hegele, MD, 5027 4972 (FPLD) is a rare genetic disorder characterized by adipose Daniel Rader, MD, Richard Dunbar, MD, MTR 5028 4973 tissue abnormalities and is associated with a variety of 5029 4974 metabolic complications including insulin resistance and high Lead Author’s Financial Disclosure: Nothing to 5030 triglycerides. Phenotypic elements of the disorder can vary disclose.

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5031 Study Funding: None. These very promising results indicate that ANGPTL3 5087 5032 5088 Background/Synopsis: Familial chylomicronemia syn- and apoC-III inhibitors may become effective treatments 5033 5089 drome is a group of rare genetically heterogeneous conditions for FCS beyond the extremely low-fat diet in the future. 5034 5090 with five known causal genes that manifest as severe hyper- 5035 5091 triglyceridemia (HTG) with acute pancreatitis, which can be 5036 5092 life-threatening. Currently, there are no effective FDA- 5037 5093 approved medications to treat HTG in FCS beyond medical Imaging in Atherosclerosis 5038 5094 nutrition therapy with an extremely low-fat diet. Therefore, 5039 5095 there is an urgent need for new therapy for FCS. Since novel 189 5040 5096 biologics mainly suppress known physiologic LPL inhibitors, Low Alpha1/Alpha3 HDL subclass Ratio 5041 5097 their effectiveness may be influenced by FCS genotypes. Predicts Progression of Coronary Plaque 5042 5098 Volumes by Coronary Computed Tomography 5043 Objective/Purpose: To evaluate the response to novel 5099 Angiography (CCTA): EVAPORATE Trial 5044 experimental biologics in patients with FCS due to 5100 5045 lipoprotein lipase (LPL) deficiency and apolipoprotein C- 5101 II (apo-C-II, APOC2) deficiency. Suvasini Lakshmanan, MD, MS, (Torrance, CA) 5046 Deepak Bhatt, MD, MPH, Sajad Hamal, MS, 5102 Methods: Fraternal twins with LPL deficiency and a man 5047 Divya Birudaraju, MBBS, Sebastian Hadeed, 5103 with apoC-II deficiency participated in IRB-approved clinical 5048 Chandana Shekar, MD, John Nelson, MD, 5104 studies investigating the efficacy of ANGPTL3 and APOC3 5049 Matthew Budoff, MD, Sion Roy, MD, 5105 inhibitors in treating HTG. The twin sister and the man with 5050 Lavanya Cherukuri, MBBS, April Kinninger, MPH, 5106 APOC2 deficiency received an experimental ANGPTL3 5051 Suraj Dahal, MD, Andrew Cai, MD, Ilana Golub, BS 5107 5052 inhibitor, while the twin brother received placebo. In a 5108 5053 separate trial, both the twin sister and the man with apoC-II 5109 Lead Author’s Financial Disclosure: Nothing to 5054 deficiency received an experimental APOC3 inhibitor. 5110 disclose. 5055 Results: In ANGPTL3 inhibition trials, the twin sister’s 5111 5056 TG fell w40% from the baseline of 3,020 mg/dL at about Study Funding: None. 5112 5057 15 days post-dose. Her TG remained .25% lower than Background/Synopsis: Low Alpha1 and high Alpha3 5113 5058 baseline for about 140 days. In contrast, on placebo her HDL subclasses are associated with increased risk for 5114 5059 twin brother’s TG showed typical TG fluctuations around cardiovascular disease (CVD) events. Different subpopula- 5115 5060 the baseline of 2,030 mg/dL without appreciable lowering. tions of HDL particles mediate pathogenesis of coronary 5116 5061 Similar to the twin sister, in the man with apoC-II atherosclerosis by multiple pathways. Total Non-Calcified 5117 5062 deficiency TG also fell w50% from a baseline of 3,437 Plaque (TNCP), Low Attenuated Plaque (LAP), and Total 5118 5063 mg/dL at 15 days post-dose, and TG remained .25% lower Plaque (TP) volumes predict adverse cardiovascular 5119 5064 for about 110 days. With doses of an experimental APOC3 outcomes. 5120 5065 inhibitor, TG fell w50% within 10 days of the first dose in Objective/Purpose: To examine the association of 5121 5066 both the twin sister and the man with apoC-II deficiency. baseline alpha1/alpha3 HDL ratio with change in coronary 5122 5067 Conclusions: Our results revealed that both ANGPTL3 plaque burden on CCTA with in patients (n567) enrolled in 5123 5068 and APOC3 inhibitors can effectively lower TG, plausibly the EVAPORATE (Effect of Vascepa on Improving Coro- 5124 5069 by enhancing the residual LPL function. ANGPTL3 nary Atherosclerosis in People with High Triglycerides 5125 5070 disrupts stabilization of LPL homodimers. By inhibiting Taking Statin Therapy) trial. 5126 5071 ANGPTL3, any residual LPL function can be preserved. Methods: Coronary plaque on CCTA was identified and 5127 5072 Alternatively, apoC-III prevents the accessibility of fats to volumes were measured using semi-automated plaque 5128 5073 LPL, and by inhibiting APOC3 there would be no analysis software (Qangio, Medis). HDL subclasses were 5129 5074 hinderance to their interactions. Our findings suggest only quantified using Boston Heart HDL Map test. Multivariate 5130 5075 very small amounts of LPL and apoC-II are necessary for adjusted linear regression was performed to assess the 5131 5076 effective TG-hydrolysis absent an inhibitor. relationship between baseline alpha1/alpha3 HDL ratio 5132 5077 5133 5078 5134 5 5079 Table Lipid Levels Associated with Plaque Volumes: Multivariate Analysis Results Subjects at Baseline (n 67) 5135 5080 Plaque Type tLok Adjusted Lipids logb StdErr P 5136 5081 5137 Fibrous Fatty Volume Alpha1/Alpha3 (0.43) 0.23 0.067 5082 5138 Fibrous Volume (0.32) 0.16 0.045 5083 Low Attenuated Plaque Volume (0.65) 0.30 0.033 5139 5084 TNCP Volume (0.39) 0.17 0.028 5140 5085 Total Plaque Volume (0.35) 0.16 0.030 5141 5086 5142 ^adjusted for Age, Gendet, DV, Hypertension, Past Smoking, Baseline Triglycerides

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5143 and change in coronary plaque between baseline and 9 47% lowering, neither achieving . 50% lowering. Recent 5199 5144 months. clinical trial data showed graded reductions in risk of 5200 5145 Results: Mean (SD) age of participants (n567) was 59 ASCVD down to LDL-C 10-20 mg/dl and overall benefit 5201 5146 (9.9) years and 66% were male. Participants had mean greatest in those ASCVD patients with diabetes or high risk 5202 5147 follow up of 10.8 months. Alpha 1/Alpha3 HDL ratio levels features including recent or multiple MIs, multivessel or 5203 5148 were inversely associated with progression of low attenu- polyvascular disease, which are common in India. Accord- 5204 5149 ated, TNCP and TP volumes, p,0.05 (Table 1). ingly, LAI recommends LDL-C , 50 mg/dl in secondary 5205 5150 5206 Conclusions: This study, for the first time, shows low prevention extreme risk group category A patients (e.g. 5151 5207 baseline alpha 1/alpha 3 HDL ratio in patients on statin those with uncomplicated diabetes, FH, CKD, Lp(a) 5152 . 5208 therapy with residually elevated triglycerides predicts pro- elevation, 3 ASCVD risk factors, and others) with 5153 , 5209 gression of clinically significant coronary plaque volumes optional goal 30 mg/dl. The recommended LDL-C 5154 , 5210 measured by CCTA. This association provides mechanistic goal is 30 mg/dl in extreme risk category B patients 5155 , 5211 evidence for increased CVD events associated with low (e.g. those with recurrent ASCVD despite LDL-C 50 mg/ 5156 5212 alpha1and elevated alpha3 HDL subclasses. dl, diabetes with polyvascular disease, multiple risk factors, 5157 familial hypercholesterolemia). 5213 5158 Conclusions: Aggressive intervention is required to 5214 5159 Lipid Management in Special Populations block the rising tide of early onset ASCVD in Indians 5215 5160 and South Asians, including those living abroad. Control of 5216 5161 190 non-lipid ASCVD risk factors is required as an adjunct to 5217 5162 5218 The Rationale for an LDL-Cholesterol Goal , more aggressive LDL-C lowering to goals of , 50 and , 5163 5219 30 mg/dl: Expert Recommendations From the 30 mg/dl in very high risk and extreme risk patients, 5164 5220 Lipid Association of India respectively. More studies are needed to assess the impact 5165 of these recommendations on ASCVD risk among Indians. 5221 5166 Raman Puri, MD, DM, (New Delhi, India) 5222 5167 Vimal Mehta, MD, DNB, DM, S. S. Iyengar, MD, DM, 5223 5168 Rajeev Agarwal, MD, DM, Sonika Puri, MD, 5224 5169 Devaki Nair, MD, 5225 5170 Nathan Wong, MPH, PhD, P. Barton Duell, MD 5226 5171 5227 5172 Lead Author’s Financial Disclosure: lectures for 5228 5173 Boehringer-Ingelheim, Novartis, Pfizer. 5229 5174 5230 Study Funding: None. 5175 5231 5176 Background/Synopsis: More aggressive LDL-choles- 5232 5177 terol (LDL-C) goals are needed for extreme risk patients in 5233 5178 India. 5234 5179 Objective/Purpose: Rates of atherosclerotic cardio- 5235 5180 vascular disease (ASCVD) events are skyrocketing in India, 5236 5181 with 40% of cases occurring before the age of 40 years and 5237 5182 25% of ASCVD deaths , 40 years. ASCVD in India is 5238 5183 multifactorial, resulting in part from hypertriglyceridemia, 5239 5184 low HDL-C, and metabolic syndrome, but excess LDL-C is 5240 5185 a central causative factor that is undertreated. To address 5241 5186 the epidemic of ASCVD risk, the Lipid Association of 5242 5187 India (LAI) initially proposed an LDL-C goal , 50 mg/dl 5243 5188 in 2016, but subsequent clinical trial data and clinical 5244 5189 experience indicated that this goal is insufficient for 5245 5190 extreme risk patients. 5246 5191 Methods: The LAI conducted a series of 19 meetings 5247 5192 with 162 expert physicians in 13 cities over 11 months to 5248 5193 review existing data and develop revised guidelines for 5249 5194 2020. 5250 5195 Results: The mean LDL-C concentration in the general 5251 5196 population in India approximates 94 mg/dl, which is about 5252 5197 25% lower than levels in Western populations. LDL-C 5253 5198 lowering , 70 mg/dl from an average of 94 mg/dl in India 5254 constitutes only 26% mean lowering and , 50 mg/dl only

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5255 Genetics, Gene Therapy and Atherosclerosis Conclusions: The percentage of positive results on the 5311 5256 expanded pan dyslipidemia gene panel was at 24%. This 5312 5257 192 comprehensive testing allowed for identification of 5 5313 5258 Clinical Utility of Expanded Pan Dyslipidemia additional mutations that would be otherwise missed on a 5314 5259 and Statin-Induced Myopathy Genetic Testing four-gene standard panel. However, the VUS rate was also 5315 5260 high. This would warrant family studies and correlations 5316 5261 Malgorzata Jaremko, PhD, FACMG, FACB, (New York, NY) with clinical/biochemical findings to further classify these 5317 5262 Meghan Miller, MS, CGC, Loba Alam, MD, variants. The incorporation of genetic testing for statin- 5318 5263 Erin Dekanek, MS, CGC, Deborah Gray Briggs, induced myopathy could help to identify patients that may 5319 5264 Michael Jansen, MS, Ari Silver, Maxwell Silver, experience side effects of statin therapy. 5320 5265 Alexander Bisignano, Robert Fishberg, MD, FACC 5321 5266 5322 5267 Lead Author’s Financial Disclosure: This author is Genetics, Gene Therapy and Atherosclerosis 5323 5268 an employee of Phosphorus Inc, and has received compen- 5324 5269 sation from that company. 193 5325 5270 5326 Study Funding: None. Identification of a Novel APOB Mutation in a 5271 5327 Patient with Lifelong Hypercholesterolemia 5272 Background/Synopsis: The diagnostic yield of ge- 5328 netic testing in an evaluation of familial hypercholester- 5273 Meghan Miller, MS, CGC, (New York, NY) Loba Alam, MD, 5329 5274 olemia (FH) and other inherited lipid disorders may depend 5330 on various factors including content of the gene panel, Deborah Gray Briggs, Erin Dekanek, MS, CGC, 5275 Alexander Bisignano, 5331 5276 interpretation of variants of uncertain significance (VUS), 5332 and correlation with clinical and biochemical phenotypes. Malgorzata Jaremko, PhD, FACMG, FACB, 5277 Robert Fishberg, MD, FACC 5333 5278 The standard gene panel consists of four genes (LDLR, 5334 5279 APOB, PCSK9, and LDLRAP1), for which the association 5335 Lead Author’s Financial Disclosure: The author is 5280 with FH has been well established in the literature. How- 5336 an employee of Phosphorus Inc, and has received compen- 5281 ever, availability of expanded gene panels could be useful 5337 sation from that company. 5282 in diagnosis of other monogenic pan dyslipidemias. Addi- 5338 5283 tionally, inclusion of pharmacogenetic markers, such as Study Funding: None. 5339 5284 SLCO1B1, may be useful in predicting statin-related side Background/Synopsis: Familial Hypercholesterole- 5340 5285 effects. mia (FH), in its heterozygous form, is a common genetic 5341 5286 Objective/Purpose: We investigated the positive and disorder occurring in approximately 1:250 individuals and 5342 5287 VUS rates of an expanded pan dyslipidemia panel to is associated with early onset atherosclerosis and coronary 5343 5288 determine its clinical utility. The SLCO1B1 gene was artery disease (CAD). The three main genes associated with 5344 5289 also tested to determine risk of statin-induced FH are LDL, APOB and PCSK9. The risk of coronary 5345 5290 myopathies. disease is thought to increase with elevated LDL, and is 5346 5291 Methods: Next-generation sequencing (NGS) analysis of further modified by genetic predisposition. Individuals with 5347 5292 a 23-gene panel was performed on 68 patients referred for LDL &;190 mg/dl and no genetic mutation were reported to 5348 5293 inherited lipidemia and statin-induced myopathy testing. be at 6-fold higher risk of CAD, which was further 5349 5294 Variants were classified in accordance with ACMG criteria. increased to reach 22-fold if an FH mutation was present 5350 5295 Results: Pathogenic variants were detected in 16 (24%) (1). The higher risk of CAD in carriers of FH mutations has 5351 5296 patients. The average total cholesterol (TC) was 320 mg/dl, been hypothesized by Khera et al. to be a result of a lifelong 5352 5297 LDL-C 237 mg/dl, TAG 162 mg/dl, and Lp(a) 48 nmol/l. A exposure to high LDL levels (1). However, the detection of 5353 5298 positive personal history of Coronary Artery Disease novel variants in any of the FH genes poses additional 5354 5299 (CAD)/Myocardial Infraction (MI) was confirmed in 4 challenges in understanding how the high lifelong LDL 5355 5300 patients, whereas positive family history (CAD, MI or levels will impact the risk of CAD in those individuals. 5356 5301 Coronary Artery Bypass Graft (CABG)) was confirmed in Objective/Purpose: We report a novel APOB missense 5357 5302 10 patients. The most frequent mutation rate was observed variant associated with marked elevation of cholesterol and 5358 5303 in LDLR (8 unique mutations), and APOE genes (2 patients LDL in an individual without any evidence of atheroscle- 5359 5304 with E2/E2, and one patient with E2/E3 genotypes), rosis or coronary disease. 5360 5305 followed by heterozygous variants in APOA5 (c.299delT Methods: 44-year old female with lifelong marked 5361 5306 (p.Leu100fs)), LIPC (c.1214C.T (p.Thr405Met)), hypercholesterolemia and without a family history of heart 5362 5307 ANGPTL3 (c.363_367delCTCAA), and novel mutation in disease undergoes NGS testing for FH. Her most recent 5363 5308 ABCG5 (c.904+1G.C). VUS results were detected in 52 cholesterol is 550 mg/dl and LDL 454mg/dl. Her HDL is 5364 5309 (78%) patients. The risk of statin induced myopathy based 71, triglycerides 81, LDL particle number 3,044 nmol/l, 5365 5310 on SLCO1B1 analysis was identified in 11 (24%) hetero- APO B .240 mg/dl, and Lp(a) 99 nmol/l. She has a 5366 zygous patients. calcium score of zero, a normal stress test and a normal

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5367 carotid ultrasound. She does not have arcus cornealis or pharmacodynamic effects of ARO-APOC3 on healthy 5423 5368 tendon xanthoma. volunteers, severely hypertriglyceridemic patients and 5424 5369 Results: NGS sequencing revealed a rare APOB missense patients with chylomicronemia. 5425 5370 variant in exon 26 (c.11543C.T, p.Ala3848Val), which has Methods: 5 patients with MCM (fasting TG $ 880 mg/ 5426 5371 not been previously associated with FH. The variant is dL at screening) were administered 50 mg of ARO-APOC3 5427 5372 absent from population databases, and it did not occur in subcutaneously on days 1 and 29. Measurements of 5428 5373 995 individuals tested for FH internally. In silico functional therapeutic responses included plasma APOC3 and TGs. 5429 5374 5430 algorithms (PolyPhen/SIFT) predicted it to be damaging. Results: Mean (range) baseline fasting TGs were 3086 5375 5431 No family segregation was performed. mg/dL (1346 6 4818 mg/dL (n55)). Currently available 5376 5432 Conclusions: We have presented a woman with lifelong follow-up data after the first dose ranges from 0-43 days for 5377 5433 elevated LDL and an APOB missense variant without APOC3 and from 0-71 days for TGs. For patients with at 5378 5434 discernible atherosclerosis or CAD. Although the LDL is least 29 days of follow-up (n53), mean maximum reduc- 5379 5435 markedly elevated, this variant does not appear to confer tion of APOC3 was 97% (92-99%), associated with a mean 5380 5436 the same risk that would have been predicted by Khera’s maximum reduction in TGs of 95% (94-95%). The most 5381 5437 hypothesis. Therefore, further studies are required to frequent adverse events in those on drug include upper 5382 5438 determine the impact of novel variants in any of the FH respiratory infection, AEs at the venipuncture site (swelling 5383 5439 genes on risk of CAD. or bruising) and injection site AEs, generally mild for all. 5384 5440 Tolerability for ARO-APOC3 in 47 normal volunteers and 5385 5441 patients on drug has been good with no reported drug- 5386 5442 Pharmacological Control of Lipids and related serious or severe AEs. 5387 Lipoproteins 5443 5388 Conclusions: Preliminary results indicate that ARO- 5444 5389 APOC3 can produce deep reductions in APOC3 which 5445 5390 194 lead to TG reductions below thresholds associated with 5446 5391 First Results of RNA Interference Against pancreatitis risk in MCM with good tolerability. Using 5447 5392 Apolipoprotein C3 as a Treatment for RNAi to silence expression of APOC3 appears promising 5448 5393 Chylomicronemia for treating patients with MCM. Expanded results will be 5449 5394 available at time of presentation. 5450 Peter Clifton, BBS, B Med Sci P, (Adelaide, AU) 5395 5451 David Sullivan, John Baker, MB ChB FRCPA FRA, 5396 5452 Christian Schwabe, MD, Susan Thackwray, MD, 5397 Genetics, Gene Therapy and Atherosclerosis 5453 Russell Scott, BMedSc MB ChB(Ot), 5398 5454 James Hamilton, MD MBA, Bruce Given, MD, 5399 195 5455 Javier San Martin, MD, Stacey Melquist, PhD, 5400 GBinsight Comprehensive Dyslipidemia 5456 Gerald Watts, DSc, PhD, DM, FR, Ira Goldberg, MD, 5401 Genetic Analysis Demonstrates High 5457 Daniel Gaudet, Josh Knowles, MD PHD, 5402 Concordance Between Clinical Diagnosis and 5458 Rob Hegele, MD FRCPC, Christie Ballantyne, MD 5403 Genetic Findings 5459 5404 5460 5405 Mendel Roth, PhD, (San Diego, CA) Carter, MA, PhD, 5461 5406 Lead Author’s Financial Disclosure: Arrowhead Liyang Xiong, PhD, Jun Cui, MS, Li Shen, PhD 5462 5407 Pharmaceuticals, AROAPOC31001 PI. 5463 5408 Study Funding: Arrowhead Pharmaceuticals funded this Lead Author’s Financial Disclosure: Iaman 5464 5409 study. employee of and have equity in GB Healthwatch. 5465 5410 Background/Synopsis: Plasma triglyceride (TGs) Study Funding: None. 5466 5411 levels $ 1,000 mg/dL cause an increased risk of acute Background/Synopsis: The genetic architecture of 5467 5412 pancreatitis. Genetic studies indicate that individuals with dyslipidemias and atherosclerotic cardiovascular disease 5468 5413 apolipoprotein C-3 (APOC3) loss-of-function mutations (ASCVD) is complex, which includes both rare, large- 5469 5414 have low TGs and reduced cardiovascular risk. RNA effect size, and common, low-to-moderate effect size, 5470 5415 interference (RNAi) has been effective at producing deep genetic variants. The precise combination of genetic 5471 5416 and durable knockdown (KD) of APOC3 in healthy variants and the different pathways impacted uniquely 5472 5417 volunteers (presented at AHA 2019) with good tolerability. contribute to patients’ clinical presentations. The GBinsight 5473 5418 We report initial results of an RNAi molecule (ARO- Comprehensive Dyslipidemia panel was developed to 5474 5419 APOC3) designed to KD APOC3 in patients with multi- reflect the monogenic and polygenic etiologies of dyslipi- 5475 5420 factorial chylomicronemia (MCM). demias and ASCVD risk. 5476 5421 5477 Objective/Purpose: The AROAPOC31001 study eval- Objective/Purpose: To present validation data on 5422 5478 uates the safety, tolerability, pharmacokinetics and dyslipidemia patients analyzed by GBinsight.

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5479 Methods: The validation cohort consisted of 376 samples Study Funding: None. 5535 5480 5536 submitted to GBinsight services with at least one ICD-10 Background/Synopsis: APOE is a central mediator of 5481 5537 code related to dyslipidemia or ASCVD from lipid clinics lipid metabolism and as such, genetic variation in APOE 5482 5538 around the United States. The samples were then subcate- underlies several lipid-related disorders and influences 5483 5539 gorized based on the ICD10 codes: Familial hypercholes- atherosclerotic cardiovascular disease (ASCVD) risk. 5484 5540 terolemia (FH; E78.0, E78.01, and Z82.49), Comprehensive genetic analysis of patients with hyperlip- 5485 5541 Hypertriglyceridemia (HTG; E78.1, E78.3, and E88.1) or idemias promises improved diagnostic, prognostic and 5486 5542 elevated LP(a) (E78.41, Z83.430). GB developed the precision therapies that improves outcomes and reduces 5487 5543 bioinformatic analytical pipeline that includes polygenic adverse events. 5488 risk scores (PRS) using the R software package. 5544 5489 Objective/Purpose: To describe the contribution of 5545 Results: (1). For FH codes, 37% have at least one 5490 APOE-related disorders and to highlight how genetic 5546 pathogenic variant: 82% in LDLR (4% of these were 5491 analysis can help to more precisely identify them. 5547 copy number variants), 6% in APOB, 2% in LDLRAP1, 0% 5492 Methods: We have developed the GBinsight Compre- 5548 in PCSK9, and 10% in APOE. 46% of FH patients without 5493 hensive Dyslipidemia Panel and sequenced patients from 5549 a pathogenic mutation have a high PRS for hypercholes- 5494 clinicians across the US. This panel uses next-generation, 5550 terolemia or combined hyperlipidemia. The combined 5495 short-read, sequencing (NGS) performed in a CLIA lab. 5551 positive identification rate for FH is 82%. (2). For HTG, 5496 Results: Among 34 cases (see table for full list) with a 5552 30% have one or more pathogenic mutations in a known 5497 definite or likely APOE cause, 6 were identified with E2/ 5553 causal gene: APOA5, APOC2, APOE, GPIHBP1, LMF1, 5498 E2. Type 3 hyperlipoproteinemia is canonically caused by 5554 LPL or PPRAG. Variants in LPL accounted for the greatest 5499 homozygosity for the E2 allele. But only 10-20% of E2/E2 5555 proportion amongst these genes. 42% without a pathogenic 5500 individuals will be affected. E2 is a loss-of-function variant 5556 mutation have a high PRS. (3). For elevated Lp(a), the 5501 with minimal binding to the LDL receptor. 2 of 6 with E2/ 5557 positive genetic identification rate is 84%. (4). For ASCVD 5502 E2 were referred for combined hyperlipidemia. Another 5558 only (without co-presence of hyperlipidemia) ICD-10 5503 referred for familial hypercholesterolemia (FH) with pe- 5559 codes, 68% have high genetic risk for elevated Lp(a). 5504 ripheral artery disease had E2/E2+Arg168His 5560 64% have a rare variant in one or more reverse cholesterol 5505 (rs376170967). The other 3 were referred for hypolipide- 5561 transport genes (ABCA1, APOA1, LCAT or SCARB1). 5506 mia; 2 with premature CHD. Four heterozygous cases of 5562 One patient has a CBS mutation related to 5507 the Arg163Cys (rs769455) variant were identified; this 5563 hyperhomocysteinemia. 5508 variant has been reported to cause type 3 hyperlipoprotei- 5564 5509 Conclusions: GBinsight results are highly concordant nemia. Three of these were referred for type 2 diabetes and 5565 5510 with clinical diagnoses. Patients with pathogenic mutations 1 with combined hyperlipidemia. One patient, referred for 5566 5511 in APOE genes were frequently misdiagnosed as FH. The type 3 hyperlipoproteinemia, was compound heterozygous 5567 5512 results presented is consistent with the collective published for the Arg163Cys variant and the Glu31Lys-Arg163Cys 5568 5513 accounting of the relative proportion of FH and FHTG haplotype (also known as APOE4-Philadelphia). One pa- 5569 5514 having both monogenic and polygenic causes. High LP(a) tient referred for combined hyperlipidemia and type 2 5570 5515 is genetically determined and the GBinsight results reflect diabetes had the E4-Arg269Gly (rs267606661) haplotype. 5571 5516 this. High LP(a) and defects in reverse cholesterol transport Four cases were identified with the rare haplotype called 5572 5517 pathways are important causes of ASCVD. Comprehensive APOE4(-)-Freiburg that were referred for FH. One case 5573 5518 genetic analysis can uncover the precise cause of dyslipi- referred for premature CHD was identified to have the 5574 5519 demias and ASCVD, opening the path for targeted Gly145Asp (rs267606664)-Arg176Cys (E2) haplotype 5575 5520 therapies. (AKA APOE-E1). Two cases within the same family 5576 5521 referred for premature CHD had a novel APOE variant, 5577 5522 Genetics, Gene Therapy and Atherosclerosis Gln141Arg. This variant introduces another positively 5578 5523 charged amino acid within the canonical LDL receptor 5579 5524 196 binding region of APOE. Fifteen cases of E4/E4 were 5580 referred for FH or polygenic FH. 5525 Genetic Analysis Identifies APOE-Opathies 5581 5526 that Mask Other Dyslipidemias Conclusions: Genetic variations within the APOE gene 5582 5527 are an underappreciated cause of dyslipidemia and 5583 5528 Mendel Roth, PhD, (San Diego, CA) Megan Kalwick, BSc, ASCVD. Sequencing of APOE can identify the precise 5584 5529 Carter Ma, PhD, Liyang Xiong, PhD, Li Shen, PhD causes of lipid disorders and targeted therapies may be 5585 5530 initiated. Special care is required when sequencing the 5586 5531 Lead Author’s Financial Disclosure: Employee and APOE gene as most commercial kits are unable to sequence 5587 5532 own equity in GB Healthwatch. parts of APOE due to its heavy GC-rich composition. 5588 5533 5589 5534 5590

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5591 5647 5592 Table 1 List of APOE variants identified and the given reason for referral for genetic testing 5648 5593 Number Clinical indication (provided by 5649 5594 of cases APOE Variant(s) referring physician) Comments 5650 5595 1 E2/E2 (Arg176Cys) + Familial hypercholesterolemia, 5651 5596 Arg168His (rs376170967), Peripheral artery disease 5652 5597 heterozygous 5653 5598 2 E2/E2 (Arg176Cys) Combined hyperlipidemia 1 is heterozygous for a very rare LEPR 5654 5599 (leptin receptor) genetic variant with 5655 5600 a BMI540 5656 5601 3 E2/E2 (Arg176Cys) Hypolipidemia. 2 with premature CHD 5657 5602 4 Arg163Cys (rs769455), heterozygous Combined hyperlipidemia, type 2 5658 5603 diabetes 5659 5604 1 Glu31Lys (rs201672011) Type 3 hyperlipidemia The Glu31Lys-Arg163Cys haplotype has 5660 -Arg163Cs (rs76945, homozygous) been referred to as APOE4- 5605 5661 Philadelphia 5606 1 Arg269Gly (rs267606661) – Combined hyperlipidemia, type 2 5662 5607 Cys130Arg (E4) haplotype diabetes 5663 5608 4 Leu46Pro (rs769452) Familial hypercholesterolemia This haplotype has been referred to as 5664 5609 - Cys130Arg (E4) haplotype APOE4(-)- Freiburg). Literature is 5665 5610 mixed about its pathogenicity 5666 5611 1 Gly145Asp (rs267606664) Premature CHD This haplotype has been referred to as 5667 5612 -Arg176Cys (E2) haplotype APOE-E1 5668 5613 2 Gln141Arg, heterozygous Familial hypercholesterolemia, Novel variant found within the LDL 5669 5614 Premature CHD receptor family binding motif. Adds 5670 5615 positive charge (Arginine) 5671 15 E4/E4 (Cys130Arg) Hypercholesterolemia (FH or polygenic 5616 5672 FH) 5617 5673 5618 5674 5619 5675 Epidemiology of Cardiovascular Disease Background/Synopsis: Small experimental studies 5620 5676 have suggested that moderate alcohol consumption in- 5621 5677 creases HDL cholesterol (HDL-C) levels and cholesterol 5622 197 5678 efflux (CEC), a main anti-atherosclerotic HDL function. 5623 Elucidating the Link Between Alcohol and HDL 5679 However, it is unknown at a population level whether 5624 Metabolism in the Multiethnic Dallas Heart 5680 alcohol intake impacts CEC. 5625 Study 5681 5626 Objective/Purpose: This study aims to understand the 5682 5627 Rohit Badia, BS, (Dallas, TX) degree towhich alcohol intake is associated with various HDL 5683 5628 Colby Ayers, MS, Anand Rohatgi, MD markers in a large, multiethnic population cohort, the Dallas 5684 5629 Heart Study (DHS), and whether alcohol modifies the link 5685 Lead Author’s Financial Disclosure: Nothing to 5630 between HDL markers and cardiovascular disease (CVD). 5686 disclose. 5631 Methods: Participants of the DHS were included if they 5687 5632 Study Funding: None. had self-reported alcohol intake and CEC measurements 5688 5633 5689 5634 Table 1 Standardized beta estimates derived from separate regression models that reflect the change in each HDL parameter with 5690 5635 change in self-reported alcohol intake after adjustment. 5691 5636 5692 Alcohol Current Drinkers 5637 5693 Standardized Consumption by Grams Compared with Light DrinkersCompared 5638 Beta Estimates Per Week Non- Drinkers with Moderate Drinkers 5694 5639 5695 5640 HDL-C 0.201* 0.068** -0.180* 5696 5641 HDL-P 0.200* 0.137* -0.231* 5697 HDL-Size 0.103* -0.001 -0.079* 5642 5698 ApoAI 0.226* 0.095* -0.165* 5643 CEC 0.071** -0.025 -0.125** 5699 5644 5700 5645 The relationships between alcohol categories and HDL measures were adjusted for confounders like age, sex, race, diabetes, blood pressure, BMI, waist 5701 circumference, physical activity, smoking, socioeconomic status, and atherogenic lipid levels. 5646 *p , 0.0001 5702 **p , 0.05

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5703 (N52,919). Alcohol intake was analyzed continuously overall rates of lipid screening among women of childbearing 5759 5704 (grams/week) and as an ordered categorical variable (never, age in order to improve rates of early detection, treatment, and 5760 5705 past, light, moderate, heavy, and binge drinkers). The cascade screening among patients with severe hyperlipidemia 5761 5706 moderate drinking group was the referent group for all with the ultimate goal of improving cardiovascular outcomes 5762 5707 analysis as it is the upper limit for alcohol consumption as among women and families at risk. Our objective is to assess 5763 5708 delineated by the American Heart Association. HDL-C, the feasibility and outcomes of implementing an algorithm of 5764 5709 CEC, HDL particle number (HDL-P), HDL particle size routine lipid screening and follow-up as standard of OB 5765 5710 (HDL-Size), and ApoAI were the primary HDL measures. preventive care for pregnant women. 5766 5711 Results: After adjustment for confounding variables, Methods: We have assembled an interdisciplinary team 5767 5712 increasing continuous measure of alcohol intake was asso- of lipid specialists, cardiologists, and maternal fetal med- 5768 5713 ciated with increased levels of all HDL markers. Current icine specialists. We propose the following methods: 5769 5714 drinkers had marginally increased HDL-C, HDL-P, and 5770 1. Assess screening rates among a racially diverse pa- 5715 ApoAI levels when compared with non-drinkers. Moreover, 5771 tient population by querying the electronic health record 5716 as compared to moderate drinkers, light drinkers had 5772 (EHR) and administering patient surveys among preg- 5717 decreased levels of the HDL markers (Table 1). Additional 5773 nant women receiving prenatal care at UPHS; 5718 analysis revealed that alcohol consumption does not modify 5774 2. Survey OB patients and providers regarding barriers 5719 the relationship between HDL markers and CVD events. 5775 5720 to routine lipid screening during early pregnancy; and 5776 Conclusions: In a large, multiethnic cohort, increased 5721 3. Testing the feasibility of implementing routine lipid 5777 alcohol intake was associated with improved levels of 5722 screening during prenatal care as part of an integrated 5778 multiple markers of HDL metabolism. However, the asso- 5723 care model utilizing existing care pathways that does 5779 ciation of HDL markers with CVD risk is not affected by 5724 not burden the OB team. 5780 alcohol consumption in this low risk cohort. 5725 5781 Results: Our early results reveal very low rates of lipid 5726 5782 screening prior to pregnancy. The roll-out of the OB 5727 Lipid Management in Special Populations 5783 provider survey is planned for March 2020. We plan to 5728 5784 198 design a feasibility pilot of routine lipid screening as part of 5729 5785 first trimester prenatal blood work with appropriate re- 5730 Improving Identification and Treatment of 5786 ferrals to primary care and/or preventive cardiology clinic 5731 Primary and Secondary Hyperlipidemia for 5787 based on predetermined thresholds of abnormal lipid results 5732 Young Women at a Large Health System 5788 by the end of 2020. The outcomes of this pilot will include 5733 5789 Jennifer Lewey, MD, (Philadelphia, PA) patient and provider acceptability and patient follow-up. 5734 5790 Richard Nemiroff, MD, Daniel Soffer, MD 5735 Conclusions: There is a need to develop an interdisci- 5791 5736 plinary research and clinical program to gradually intro- 5792 5737 Lead Author’s Financial Disclosure: Nothing to duce opportunistic lipid screening as part of routine 5793 5738 disclose. prenatal care and to facilitate appropriate follow-up care 5794 5739 Study Funding: None. among women of childbearing age. 5795 5740 Background/Synopsis: Familial hypercholesterolemia 5796 5741 (FH) is a major cause of atherosclerotic cardiovascular Genetics, Gene Therapy and Atherosclerosis 5797 5742 disease and a majority of individuals with this condition go 5798 5743 undiagnosed and undertreated. Pregnant women have 199 5799 5744 frequent contact with the healthcare system and identifica- Assessment of the JACC 2018 5800 5745 tion of severe dyslipidemia during pregnancy may improve Recommendations for Genetic Testing for 5801 5746 screening of affected offspring. However, rates of lipid Familial Hypercholesterolemia: A Tertiary Care 5802 5747 screening among women of childbearing years are subop- Center’s Experience 5803 5748 timal. The prenatal care visit and first trimester may be an 5804 5749 optimal time to provide FH screening, before significant Emily Brown (Baltimore, MD) Kathleen Byrne, CRNP, 5805 5750 changes in lipid metabolism occur. Routine lipid testing is Dorothy Davis, RN, Marios Arvanitis, MD, 5806 5751 not offered as part of standard obstetric (OB) care due to a Thorsten Leucker, MD, PhD, 5807 5752 variety of factors including absence of national guidelines, Steven Jones, MD, Seth Martin, MD, MHS 5808 5753 contraindication to most pharmacotherapy options, 5809 5754 competing demands on the OB team, and difficulty with Lead Author’s Financial Disclosure: Emily is a 5810 5755 access to care by primary care and specialists. consultant for My Gene Counsel. 5811 5756 Objective/Purpose: The Women’s Lipid screening In Study Funding: None. 5812 5757 Pregnancy Improves Diagnosis (Women-LIPID) Program at Background/Synopsis: Familial hypercholesterolemia 5813 5758 the University of Pennsylvania Health System (UPHS) pro- (FH) is a hereditary condition characterized by elevated 5814 poses to examine a novel care delivery model to improve LDL-C from birth leading to premature coronary disease.

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5815 Early diagnosis and treatment is key, and genetic testing is an Lead Author’s Financial Disclosure: Nothing to 5871 5816 important diagnostic tool. In 2018 the Journal of American disclose. 5872 5817 5873 College of Cardiology (JACC) Scientific Expert Panel Study Funding: None. 5818 published a consensus statement concerning the utilization 5874 5819 of genetic testing for FH. The recommendations established Background/Synopsis: Lipoprotein (a) [Lp(a)] is 5875 5820 two subgroups for recommending genetic testing: those composed of a LDL particle and apolipoprotein (a) 5876 5821 where the testing should be offered and individuals where [apo(a)], which is bound to apolipoprotein B of LDL. 5877 5822 genetic testing may be considered. The translation of these Unlike LDL-C, Lp(a) levels are thought to be completely 5878 5823 recommendations to clinical practice has yet to be evaluated. genetically determined, unaffected by an individual’s 5879 lifestyle. In addition, the structure of Lp(a) is highly 5824 Objective/Purpose: To assess the JACC 2018 expert 5880 heterogeneous as a result of several different genetically 5825 panel recommendations in referral lipidology practice. 5881 5826 determined isoforms of apo(a). 5882 Methods: We retrospectively reviewed patients seen in our 5827 Current recommendations state elevation of Lp(a) is 5883 clinic at Johns Hopkins Hospital between January 2015 and 5828 observed in 1:5 of the population and evidence supports a 5884 January 2020. Inclusion criteria required patients to have 5829 causative and independent relationship between elevated 5885 undergone genetic testing for FH as the proband. Patients with 5830 Lp(a) and cardiovascular disease (CVD). 5886 a secondary cause of hyperlipidemia were excluded. Genetic 5831 While elevated Lp(a) is thought to be a common and 5887 testing included analysis of four genes (LDLR, PCSK9, 5832 independent contributor to the development of CVD, no 5888 APOB, and LDLRAP1). Variants were classified according to 5833 treatment currently lowers Lp(a) to levels that cause an 5889 the 2015 American College of Medical Genetics guidelines. 5834 observable reduction of risk and measurement rates are 5890 5835 Results: We identified 188 probands referred to our clinic for typically low. As a result, measurement methodology and 5891 5836 evaluation for FH. Four individuals were omitted due to reference ranges are not standardized. 5892 secondary causes of hypercholesterolemia. Of the 184 in- 5837 Objective/Purpose: We have reviewed Lp(a) measure- 5893 dividuals included, 104 (56%) met the JACC recommendations 5838 ments in patients from January 2014 - October 2019. 5894 5839 for offering genetic testing. An additional 19 (10%) individuals 5895 met the recommendations for considering genetic testing. The Methods: Cook Children’s Medical Center has a pediat- 5840 ric lipid clinic, focused on the prevention and reduction of 5896 5841 remaining 61 individuals didnt meet the recommendations. 5897 Altogether, 51 (28%) individuals were determined to have a cardiovascular risk factors. Lp(a) is frequently measured in 5842 patients seen in our clinic. Analysis of initial and repeat 5898 5843 pathogenic or likely pathogenic genetic variant. The majority 5899 5 measurements are reported. 5844 of individuals (n 45) met JACC Expert Panel 5900 5845 recommendations. Two additional individuals met the Results: From January 2014 - October 2019, 525 5901 5846 genetic testing may be considered category. Four measurements were reported, including 65 patients with 5902 5847 individuals didnt meet the recommendations. In the repeat measurements. 5903 5848 subgroup where genetic testing should be offered, a Fifty one (51%) percent of children with Lp(a) measurements 5904 5849 number needed to test was 2.3 individuals. This number were male, with an average population age of 12.5 years. 5905 5850 needed to test was 2.6 when the population was expanded to Average Lp(a) was 51 nmol/L (Table 1). 5906 5851 include everyone who met criteria. The yield in our entire As Lp(a) increased, we observed an increase in TC and LDL- 5907 5 5 5852 cohort resulted in a number needed to test of 3.6 individuals. C(r 0.2 and 0.27, respectively), and a decrease in TG (r 5908 5853 Conclusions: Applying the JACC recommendations to -0.22); however these trends were not statistically significant. 5909 5854 our patient cohort resulted in a high yield with a number In contrast to published recommendations on Lp(a), of the 5910 5855 needed to test of about two if the individual met criteria for 65 patients with repeat measurements of Lp(a), statistically 5911 , 5856 offering genetic testing. However, even when testing was significant variation (p .05) was observed between the 1st 5912 5857 expanded to the subgroup of individuals where it may be and 2nd measurement (28.6 nmol/L; 27% absolute change). 5913 5858 considered, four individuals with positive results still were (Tables 2, 3). However, such a change is unlikely to be of 5914 5859 missed. Therefore, genetic testing should be considered on clinical significance unless it affects risk stratification. 5915 5860 a case by case basis in patients not meeting the JACC Conclusions: In our population, Lp(a) does not appear to 5916 5861 Expert Panel selection criteria. be associated with standard lipid and lipoprotein measure- 5917 5862 ments. We observed, however, that repeat measurements of 5918 5863 Clinical Applications of Biomarkers, Lipoprotein Lp(a) appear to be highly variable, potentially interfering 5919 5864 Testing with accurate risk assessment. 5920 5865 Lp(a) is known to be an independent risk factor for the 5921 5866 200 development of CVD; however, the clinical utility of 5922 5867 Use and Variability of Lipoprotein (a) in a measurement of Lp(a) in children is currently unknown. 5923 5868 Pediatric Lipid Clinic Future analysis will include retrospective data through 5924 5869 January 2020 to further explore the variation in repeated 5925 5870 Luke Hamilton, MS, (Fort Worth, TX) Lp(a) measurements,and the association of Lp(a) with apoB 5926 Alejandro de la Torre, MD, Don Wilson, MD measurements.

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5927 Pharmacological Control of Lipids and therapy, received 100 mg ( n56), 200 mg (n56) or 300 mg 5983 5928 Lipoproteins (n54). Mean max reductions in LDL-C were between 39- 5984 5929 42% at all doses. Mean max reductions in ANGPTL3 were 5985 5930 201 79% for 100 mg dose, 88% for 200 and 90% at 300 mg. 6 5986 5931 Reduced Expression of Angiopoietin-Like patients with TGs .300 mg/dL received 200 mg ARO- 5987 5932 Protein 3 via RNA Interference with ARO- ANG3 which reduced mean max ANGPTL3 by 83%. 5988 5933 ANG3 Produces Prolonged Reductions in LDL-C Baseline TGs (range) in this cohort were 1019 mg/dL 5989 5934 and Triglycerides in Dyslipidemic Patients (186-3011 mg/dL) on day 1) at baseline with mean max 5990 5935 reduction of 79%. Effects have been durable in all cohorts. 5991 5936 Gerald Watts, DSc, PhD, DM, FR, (Perth, AU) Most common adverse events have been headache, injec- 5992 5937 Patrick Gladding, MB ChB FRACP, tion site AEs and upper respiratory infections, all mild. 5993 5938 Christian Schwabe, MD, Conclusions: ARO-ANG3 produces deep and durable 5994 5939 Russell Scott, BMedSc MB ChB(Ot, Peter Clifton, MD, reductions in plasma ANGPTL3, TGs and LDL-C in 5995 5940 David Sullivan, MBBS MD FRACP FR, patients already on standard medical therapy (e.g. statins). 5996 5941 John Baker, MB ChB FRCPA FRA, The ability to simultaneously lower both LDL-C and TGs 5997 5942 James Hamilton, MD MBA, Bruce Given, MD, may have clinical utility in broad patient populations with 5998 5943 Stacey Melquist, PhD, Javier San Martin, MD, CVD secondary to elevated LDL-C despite standard 5999 5944 Josh Knowles, MD PHD, Ira Goldberg, MD, therapy and/or elevated TRLs (e.g. mixed dyslipidemia). 6000 5945 Daniel Gaudet, MD, PhD, 6001 5946 Rob Hegele, MD FRCPC, Christie Ballantyne, MD 6002 5947 Other 6003 5948 Lead Author’s Financial Disclosure: Arrowhead 6004 5949 6005 Pharmaceuticals, PI for AROANG1001. 202 5950 6006 Study Funding: This study was funded by Arrowhead 5951 Lipid Lowering Treatment Patterns and Risk of 6007 Pharmaceuticals. 5952 Subsequent Cardiovascular Outcomes Among 6008 5953 Background/Synopsis: Elevated LDL-C and elevated Patients Initially Rejected for pcsk9 Inhibitor 6009 5954 triglyceride rich lipoproteins (TRLs) are independent risk Therapy 6010 5955 factors for cardiovascular (CV) disease. Inherited defi- 6011 Nihar Desai, MD, MPH, (New Haven, CT) 5956 ciency of angiopoietin-like protein 3 (ANGPTL3) is 6012 Pallavi Rane, PhD, Sasikiran Nunna, PhD, 5957 associated with low LDL-C, TGs, VLDL-C and reduced 6013 Chi-Chang Chen, PhD, Jason Exter, PharmD, 5958 CV risk with no described adverse phenotype. ARO-ANG3 6014 Mohdhar Habib, PhD, 5959 is a RNA interference drug designed to silence expression 6015 Zifan Zhou, PhD, Rolin Wade, RPh, MS 5960 of hepatic ANGPTL3. In the AROANG1001 study, single 6016 5961 doses of ARO-ANG3 were shown to simultaneously reduce 6017 Lead Author’s Financial Disclosure: Research 5962 ANGPTL3, TGs, VLDL and LDL-C in healthy volunteers 6018 grants from Medtronic, Johnson and Johnson; consulting 5963 (presented at AHA 2019). Reported here are effects of 6019 fees from Amgen Inc., Relypsa, OPKO, SC Pharmaceuti- 5964 ARO-ANG3 in patients with LDL-C not at goal despite 6020 cals, Cytokinetics. 5965 standard therapy and also in patients with high TGs. 6021 5966 Objective/Purpose: The AROANG1001 study evalu- Study Funding: This study was funded by Amgen Inc. 6022 5967 ates the safety, tolerability, pharmacokinetics and pharma- Background/Synopsis: PCSK9is requests are often 6023 5968 codynamic effects of ARO-ANG3 on healthy volunteers, subject to initial payer rejection, which sometimes may 6024 5969 patients with hypertriglyceridemia, patients with dyslipide- lead to negative consequences in patients such as gaps in 6025 5970 mia despite standard therapy and patients with heterozy- therapy and risk of cardiovascular events (CVE). 6026 5971 gous familial hypercholesterolemia. Objective/Purpose: We describe patterns of lipid 6027 5972 Methods: Doses of 100, 200 or 300 mg of ARO-ANG3 lowering therapy (LLT), low density lipoprotein cholesterol 6028 5973 are administered on days 1 and 29 subcutaneously to (LDL-C) levels, and risks of acute CVE in the 12-months 6029 5974 patients with LDL-C .70 mg/dL despite standard therapy, following an initial PCSK9i request rejection. 6030 5975 patients with treated heterozygous familial hypercholester- Methods: We identified patients with a prescription 6031 5976 olemia (HeFH), and patients with fasting TGs .300 mg/dL request and a rejected claim status for PCSK9i from 01/ 6032 5977 at screening. Parameters measured include plasma 2016-06/2019 (index period) in the linked IQVIA LAAD/ 6033 5978 ANGPTL3, LDL-C, and TGs over time. P+/LRx-Prognos lab databases. Patients were indexed to 6034 5979 Results: Patients on statins with LDL-C . 70 mg/dL their first PCSK9i rejection date and were included if they 6035 5980 (n56) received 200 mg of ARO-ANG3 with resultant mean had continuous enrolment for at least 12-months pre-index, 6036 5981 max reduction in LDL-C from 96.2 mg/dL at baseline to and 1-month post-index. Patients were censored from the 6037 5982 62.0 mg/dL (-39%), with mean max reduction in LDL-C and CVE analysis if they subsequently initiated 6038 ANGPTL3 of 91%. HeFH patients, also all on standard PCSK9i post-index.

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6039 Results: A total of 7,089 patients (mean age 58, 56.8% highlighting the unmet need for population-level identifi- 6095 6040 males, 93.5% commercially insured) with a rejected cation and management of FH in healthcare delivery 6096 6041 PCSK9i claim were identified. LDL-C data was available systems. 6097 6042 for only 1,067 patients. Most of the rejected requests were Objective/Purpose: To describe our initial experience 6098 6043 written by primary care physicians (45.4%). In the 12- implementing a program for population- level identification 6099 6044 months pre-index, 56.7% patients had documented athero- and management of Familial Hypercholesterolemia in a 6100 6045 sclerotic cardiovascular disease or familial hypercholester- large diverse integrated health care delivery system. 6101 6046 6102 olemia, 11.4% had an acute CVE, and 76.5% had at least Methods: MEDPED criteria to diagnose FH in the 6047 6103 one high-risk comorbidities such as diabetes, hypertension, general population were utilized to screen 1.6 million 6048 6104 chronic kidney disease, heart failure, and hemodialysis. Kaiser Permanente Northern California patients aged 6049 6105 Overall, 67.9% patients were on LLT including statins and/ ,560 with at least one LDL value from 1993-2017 to 6050 6106 or ezetimibe, and 7.7% patients were on prescription identify patients with a high likelihood of FH. Patients 6051 6107 antiplatelet medication during this period. Mean(SD) 6 identified by the algorithm were evaluated in a specialty 6052 6108 month pre-index LDL-C was 145(56)mg/dL, with 91.6% clinic (N 5 100 to date). Cascade and genetic testing were 6053 6109 patients at an elevated LDL-C (&;70mg/dL). At 12-months offered to all patients. 6054 6110 post-index, 21.8% patients initiated non-PCSK9i LLT and Results: MEDPED criteria identified 7,145 patients for 6055 7.8% either intensified or augmented their non-PCSK9i 6111 6056 an overall prevalence of 0.45% (1:222), consistent with FH 6112 LLT. An additional 25.7% were eventually approved and general-population prevalence estimates (1:225). Preva- 6057 initiated PCSK9is during this period. Despite initiating or 6113 6058 lence was similar across all age groups. 93/100 (93%; 6114 intensifying non-PCSK9i LLT post-index, the mean(SD) 6- 95% CI: 86% to 97%) patients evaluated were diagnosed 6059 month post-index LDL-C was only reduced to 127.2(56.7) 6115 6060 with FH of whom only 5% had been previously diagnosed. 6116 mg/dL in these patients, with 84.6% patients still at an The majority were young (30% , age 30, 67% , age 45). 6061 elevated LDL-C. At 12-months post-index, the overall 6117 6062 48% were not on lipid-lowering therapy; none were on 6118 acute CVE rate per 100 patient years was 3.59 (including , 6063 combination therapy or had achieved a LDL goal 100 mg/ 6119 myocardial infarction (MI), ischemic stroke (IS), and dL. 6 patients at time of initial clinic evaluation presented 6064 unstable angina hospitalization). The mean(SD) time to 6120 6065 with high grade or unstable angina requiring revasculari- 6121 first acute CVE in the post-index period were 152 (101) and zation with PCI or CABG. 82 patients accepted genetic 6066 158 (116) days for MI and IS, respectively. 6122 6067 testing and 55 (67%; 95% CI: 56% to 77%) had pathogenic 6123 Conclusions: The initial rejections and delays in 6068 mutations. To date, cascade testing identified 20 additional 6124 approval for PCSK9i requests appears to leave many 6069 cases. After clinic evaluation, all eligible patients were 6125 patients with inadequate LDL-C control and an increased 6070 started on high-dose, high potency statin and ezetimibe 6126 risk of acute CVE. Collaboration between payers and 6071 combination lipid lowering therapy. 6127 clinicians to re-evaluate current utilization management 6072 Conclusions: MEDPED criteria were effective for 6128 criteria and processes for PCSK9i is warranted. 6073 identifying FH in this cohort of 1.6 million patients, 6129 6074 yielding an identification rate mirroring the frequency of 6130 6075 Lipid Management in Special Populations FH in the general population. Of those evaluated, FH was 6131 6076 vastly underdiagnosed and undertreated: Following clinical 6132 evaluation, lipid-lowering therapy was optimized in all 6077 203 6133 6078 medication-eligible patients. Taken together, this approach 6134 Identification and Management of Familial 6079 was highly effective for population-level identification and 6135 Hypercholesterolemia in an Integrated Health 6080 management of patients with FH, including young adults, 6136 Care Delivery System 6081 and may serve as a model for other healthcare systems to 6137 6082 Richard Birnbaum, MD, (San Leandro, CA) improve the recognition and management of FH. 6138 6083 Brandon Horton, MPH, 6139 6084 Leslie Manace Brenman, MD, MPhil, Genetics, Gene Therapy and Atherosclerosis 6140 6085 Brian Macapinlac, PharmD, 6141 6086 Samuel Gidding, MD, Andrew Avins, MD, MPH 6142 6087 204 6143 6088 Non-Responders to Treatment with PCSK9 6144 Lead Author’s Financial Disclosure: Nothing to 6089 Inhibitors: a Tale of Two FH Patients 6145 disclose. 6090 6146 6091 Study Funding: None. Laney Jones, PharmD, MPH (Danville, PA) 6147 6092 Background/Synopsis: Untreated, Familial Hypercho- 6148 6093 lesterolemia (FH) confers a 20x increased risk for prema- Lead Author’s Financial Disclosure: Nothing to 6149 6094 ture CAD. However, in the U.S. and worldwide, FH is disclose. 6150 poorly recognized (,5% diagnosed) and undertreated, Study Funding: None.

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6151 6207 6152 Table 1 6208 6153 Evolocumab 6209 6154 Baseline, off treatment 6 weeks of Rosuvastatin + Ezetimibe Evolocumab 140 mg (3 doses) 140mg (6 doses) 6210 6155 Case 1 LDL, mg/dL 251 199 (-20%) 251 (+26%) 230 (-8%) 6211 6156 Lp(a), nmol/L , 10 6212 6157 Genetic Testing Heterozygous LDLR c.1055G.A (known as Mexico 2 mutation, found exclusively in Mexican population, 6213 6158 with reported 15-30% LDLR activity) 6214 6159 Case 2 LDL, mg/dL 459 394 (-14%) 322 (-18%) pending 6215 6160 Lp(a), nmol/L 61 6216 6161 Genetic Testing Heterozygous LDLR c.2389G.A (originally detected in Iberian Peninsula but eventually identified 6217 6162 in Italy and named FH-Monfalcone). LDLR functionality is not determined. 6218 6163 6219 6164 Background/Synopsis: PCSK9 binds LDL receptor response to therapy. Supplementing genetic databases 6220 6165 (LDLR), initiating its degradation. PCSK9 inhibitors with information on observed response to PCSK9i treat- 6221 6166 (PCSK9i) bind and inactivate plasma PCSK9, thus ment, could help to gain insight into the therapeutic 6222 6167 increasing the LDLR lifespan and LDL-C clearance. effectiveness of PCSK9 inhibitors depending on the muta- 6223 6168 Therefore, functioning LDLRs are necessary for PCSK9i tion class. Development of LDL-C lowering agents through 6224 6169 action. Non-response to PCSK9i is expected with lack of LDLR-independent mechanisms is essential in patients 6225 6170 LDLR activity. with impaired LDLR function. 6226 6171 6227 Objective/Purpose: To describe 2 cases of heterozy- 6172 6228 gous FH due to LDLR mutation with no response to Genetics, Gene Therapy and Atherosclerosis 6173 6229 PCSK9i. 6174 6230 6175 Methods: CASE 1. A 38-year-old Mexican male with 205 6231 6176 HIV on HART since 2006, referred to lipid disorders clinic Genetic Testing in Patients with High 6232 6177 for LDL-C levels in 230-270 mg/dL range despite lipid- Lipoprotein(a): Experience from the UCSD 6233 6178 lowering therapy. FH was diagnosed based on DUTCH Lipoprotein(a) Specialty Clinic 6234 6179 Criteria (9 points). Treatment with rosuvastatin 40 mg and 6235 6180 ezetimibe 10 mg resulted in 20% reduction in LDL-C. Elizabeth Epstein, MD, (San Diego, CA) 6236 6181 Eventually PCSK9i was added with no improvement in Michael Wilkinson, MD, Mendel Roth, PhD, Carter Ma, 6237 6182 LDL-C (Table 1). To rule out faulty injection technique or Calvin Yeang, MD, PhD;, Jessica Zhang, 6238 6183 noncompliance, the following three PCSK9i injections Bruno Cotter, MD, Sotirios Tsimikas, MD 6239 6184 were delivered under direct observation of a nurse practi- 6240 Lead Author’s Financial Disclosure: Nothing to 6185 tioner. Despite patient’s compliance, LDL-C reduction 6241 disclose. 6186 remained non-satisfactory. Genetic testing revealed LDLR 6242 6187 mutation, found exclusively in Mexican population and was Study Funding: None. 6243 6188 consistent with heterozygous FH. Background/Synopsis: Lipoprotein(a) (Lp(a)) is an 6244 6189 CASE 2. A 53-year-old Mexican female with history of inherited and likely causal risk factor for cardiovascular 6245 6190 hypercholesterolemia and severe 3-vessel CAD, referred disease (CVD) and aortic stenosis. LPA variants 6246 6191 for statin intolerance due to myalgia. Despite the maximum rs10455872 and rs3798220 are present in w15% and 6247 6192 tolerated statin (rosuvastatin 10 mg) + ezetimibe, her LDL- w3% of Caucasians, respectively, and are associated with 6248 6193 C reduction was suboptimal. PCSK9i was initiated with elevated Lp(a) levels. Genetic testing in clinical practice is 6249 6194 insignificant response (see table 1). Genetic testing emerging as a tool for personalizing risk assessment and 6250 6195 confirmed heterozygous FH due to LDLR mutation that treatment decisions. 6251 6196 was originally detected in Eastern Spain. Objective/Purpose: To explore the role of genetic 6252 6197 Results: We describe two cases of no response to PCSK9i testing for LPA SNPs and other genetic mutations in 6253 6198 in Hispanic patients with genetically confirmed heterozy- patients with elevated Lp(a). 6254 6199 gous FH due to LDLR mutations. Both mutations are Methods: In the UC San Diego Lipoprotein(a) Specialty 6255 6200 defined as pathogenic in University College London (UCL) Clinic, next-generation DNA sequencing was performed 6256 6201 LDLR variant database and not expected to result in absent using the GBinsight Comprehensive Dyslipidemia Panel 6257 6202 LDLR activity. Neither one is linked to no-response to (GB Lifesciences, San Diego, CA, USA) in 26 patients with 6258 6203 lipid-lowering therapy. Lp(a) ./5 50 mg/dL, evaluating 327 exons and selected 6259 6204 Conclusions: Genetic heterogeneity in FH with variable single-nucleotide polymorphisms (SNPs) in 129 genes 6260 6205 LDLR functionality can explain unusual cases of non- known or suspected to be associated with CVD. Known 6261 6206 response to PCSK9i. Preferably, genetic testing should be LPA SNPs and high impact variants in other genes 6262 accompanied by LDLR functionality testing to predict associated with lipid abnormalities were reported as

ABS 5.6.0 DTD JACL1584_proof 9 July 2020 5:51 pm 6318 6317 6316 6315 6314 6313 6312 6311 6310 6309 6308 6307 6306 6305 6304 6303 6302 6301 6300 6299 6298 6297 6296 6295 6294 6293 6292 6291 6290 6289 6288 6287 6286 6285 6284 6283 6282 6281 6280 6279 6278 6277 6276 6275 6274 6273 6272 6271 6270 6269 6268 6267 6266 6265 6264 6263 eeis eeTeayadAhrslrss57 Atherosclerosis and Therapy Gene Genetics, Table UC San Diego Lipoprotein(a) Specialty Clinic Genetic & Clinical Data for Patients with Lipoprotein(a) ./5 50 mg/dL Highest LPA SNP? LPA SNP(s) vs. History of History of Aortic Patient # Age Sex Race/Ethnicity Lp(a) (mg/dL) (yes/no) Other Pertinent Genetic Findings Other Variant Genes History of CAD CVA/TIA/PAD Stenosis or Sclerosis 6 69 F European 360* yes rs10455872 APOE No No Yes 14 60 M European 278 yes rs10455872 APOA4, APOA5, APOE, Yes (PCI) No Yes LDLR, SVEP1, ZPR1 rs3798220 45 55 F European 263 yes rs10455872 ABCA6, ABCG8 No No Yes rs3798220 rs186696265 2 40 M European 249 yes rs10455872 APOE No No No

B .. DTD 5.6.0 ABS 4 55 F European 225 yes rs10455872 Yes (PCI) No No 57 66 M European 145* yes rs3798220 APOA5, APOE (2), ZPR1 Yes (CAC 5 673) No No rs186696265 29 66 M European 135* yes rs3798220 APOB Yes (CAC 5 2509) No No rs186696265

AL54pof9Jl 0055 pm 5:51 2020 July 9 JACL1584_proof 51 51 M European 128 yes rs10455872 No No No rs41272112 34 77 M European 114 yes rs10455872 APOE, LDLR, ZPR1 No No Yes 16 75 M European 109 yes rs3798220 Yes (CAC 5 1039) No Yes 27 57 F European 106 yes rs10455872 APOE, ABCA1, LMF1, ZPR1 No No No 60 62 M European 90 yes rs3798220 APOE Yes (PCI) No No rs186696265 7 74 M European 66 yes rs10455872 APOA4, APOE, ZPR1, APOA5 Yes (PCI) No Yes 21 33 F East Asian 56 yes rs3798220 LDLR, STAP1, ZPR1 No No No 15 81 F Middle Eastern 187 no APOE, SVEP1 Yes (PCI) No Yes 64 49 M European 180 no APOA5, STAP1, ZPR1 No No No 33 58 F European 137 no PPARG, ABCA1 No No No 3 47 M European 124 no ZPR1 Yes (CABG) No No 19 72 M European 119 no Yes (PCI, CABG) Yes (CVA) No 9 48 M Hispanic/Latino 102 no APOE, ABCA6 No No No 11 56 F European 99 no No No No 5 70 F Middle Eastern 93 no Identified a heterozygous likely LDLRAP, LMF1 Yes (PCI, CABG) No Yes pathogenic variant in LDLRAP1 18 66 F European 68 no APOE e4 homozygous APOB, APOE No No No 26 72 F European 58 no ANGPTL4, APOB, ZPR1 Yes (CABG) No No 20 71 F European 54 no Compound heterozygous LDLR, HNF1A, ZPR1 Yes (PCI, CABG) No Yes LDLR variants 10 63 F European 50 no LDLR, ANGPTL4 No No No Lp(a), lipoprotein(a), SNP, single nucleotide polymorphism, CAD, coronary artery disease, CVA, cerebrovascular accident, TIA, transient ischemic attack, PAD, peripheral arterial disease, CAC, coronary artery calcium score (Agatston units), PCI, percutaneous coronary intervention, CABG, coronary artery bypass grafting *Lp(a) value converted to mg/dL from nmol/L using conversion factor of 2.4 6374 6373 6372 6371 6370 6369 6368 6367 6366 6365 6364 6363 6362 6361 6360 6359 6358 6357 6356 6355 6354 6353 6352 6351 6350 6349 6348 6347 6346 6345 6344 6343 6342 6341 6340 6339 6338 6337 6336 6335 6334 6333 6332 6331 6330 6329 6328 6327 6326 6325 6324 6323 6322 6321 6320 6319 58 Journal of Clinical Lipidology, Vol -,No-, - 2020

6375 pathogenic/likely pathogenic. Given non-normality, Lp(a) Lead Author’s Financial Disclosure: Nothing to 6431 6376 values were compared using a Mann-Whitney U test. disclose. 6432 6377 6433 Results: Among the 26 patients (mean age 61 yrs, 50% Study Funding: Amgen. 6378 women),14(53.8%)hadLPASNPsthathavebeenshowntobe 6434 6379 Background/Synopsis: Cardiovascular disease is the 6435 associated with elevated Lp(a): rs10455872 (minor allele leading cause of morbidity and mortality in patients with 6380 frequency (MAF) 2.2%) occurred in 9 patients (34.6%), and 6436 6381 chronic kidney disease (CKD). Evidence-based practice 6437 rs3798220 (MAF 5.1%) occurred in 7 patients (26.9%). Two guidelines recommend high intensity statins (ACC/AHA 6382 patients (7.7%) had both rs10455872 and rs3798220 LPA 6438 6383 Multisociety Guidelines) or statins without or with ezeti- 6439 SNPs. LPA SNP rs41272112 (MAF 2.2%) was present in 1 mibe (KDIGO Guidelines) in patients with CKD to 6384 patient (3.8%), and rs186696265 (MAF 0.3%) was present in 4 6440 6385 decrease the risk of atherosclerotic cardiovascular events 6441 patients (15.4%). Thus, 12 patients (46.2%) with elevated Lp(a) (ASCVD). 6386 had no known LPA SNPs. Three of those 12 patients had other 6442 Objective/Purpose: We sought to evaluate changes in 6387 potential genetic explanations for elevated Lp(a) (compound 6443 the use of evidence-based lipid-lowering therapies (LLT) in 6388 heterozygote LDLR, APOE e4 homozygote, and a heterozy- 6444 patients with CKD and ASCVD over time. 6389 gous likely pathogenic variant in LDLRAP1) (Table). Patients 6445 6390 with elevated Lp(a) and at least 1 LPAvariant had Lp(a) 166 +/- Methods: In the GOULD registry, we examined the use 6446 6391 92 mg/dL (mean+/-SD) (131.5, 106.75-243 mg/dL (median, of different classes of LLT in 5,006 ASCVD patients with 6447 5 6392 IQR)), and those with elevated Lp(a) but without an LPAvariant an LDL-C &; 70mg/dL (n 4,452) or those on a PCSK9i 6448 5 6393 had Lp(a) 105.9 +/- 46 mg/dL (mean+/-SD) (100.5, 65.5- (n 554) at 119 centers across the US. Patients were 6449 6394 127.25 mg/dL (median, IQR) (p50.08)). categorized by renal function based on estimated glomer- 6450 6395 ular filtration rates (eGFR) at baseline. Utilization of LLT 6451 Conclusions: Real-world testing for LPA SNPs in a 6396 was measured via chart review and surveys at the initiation 6452 referral Lp(a) specialty practice demonstrates genetic 6397 of the study and again at 1 year. 6453 associations of elevated Lp(a) in approximately half of 6398 , 6454 the patients, which is substantially higher than the general Results: Among the 870 patients with eGFR 60 mL/ 6399 6455 population. However, a significant proportion of patients min/1.73m2 with follow-up data through 12 months, 14.8% 6400 6456 have no known LPA SNPs despite highly elevated Lp(a), had intensification of LLT during follow-up and 7.2% were 6401 6457 suggesting they harbor small apo(a) isoforms. The role of de-escalated (table 1). The greatest percentage of intensi- 6402 6458 genetic testing at the bedside in such patients is evolving. A fication was seen in the LDL-C &;100 cohort at 21%, while 6403 6459 dedicated Lp(a) specialty clinic may allow optimal evalu- the greatest de-escalation was seen in the PCSK-9i cohort 6404 6460 ation and management of patients with elevated Lp(a). at 15.9%. There was no significant difference in LLT 6405 change across the eGFR groups. 6461 6406 In patients with eGFR ,60 mL/min/1.73m2 in the LDL-C 6462 6407 Lipid Management Best Practices cohorts, there was a statistically significant decrease in 6463 6408 206 LDL-C at 1 year from baseline (mean -13.6 mg/dL, 6464 6409 , 6465 Use of Lipid-Lowering Therapies in Patients p 0.0001). The change was not significant in the 6410 5 6466 with CKD and ASCVD: A 1-Year Update From PCSK9i cohort (mean -10.8 mg/dL, p 0.07). 6411 6467 GOULD* While there were modest increases in overall usage of high 6412 intensity statin (40.8% vs 38.6%), ezetimibe (12.6% vs 6468 6413 Winner 10.6%), and statin plus ezetimibe (8.2% vs 6.0%) in 6469 6414 Aleesha Shaik, MD, MPH, (New York, NY) patients with eGFR,60 mL/min/1.73m2 at 1-year 6470 6415 Christopher Cannon, MD, Yuyin Liu, PhD, compared to baseline, these changes were not significant 6471 6416 Katherine Mues, PhD, MPH, Shushama Alam, PharmD, (p.0.05 for each). Similar to at baseline, among patients in 6472 6417 James de Lemos, MD, Deepak Bhatt, MD, MPH, the LDL-C cohort, use of statins (p50.27) and use of 6473 6418 Christie Ballantyne, MD, ezetimibe (p50.13) were not significantly different among 6474 6419 Mikhail Kosiborod, MD, Robert Rosenson, MD the eGFR groups. High intensity statins continue to be 6475 6420 6476 6421 6477 6422 Table 1 Changes in LLT among the cohorts in subjects with baseline eGFR ,30 and 30 - ,60 mL/min/1.73m2 over 12 months 6478 6423 6479 6424 Intensification of therapy De-escalation of therapy 6480 6425 Baseline eGFR Baseline eGFR Baseline eGFR Baseline eGFR 6481 6426 ,30 mL/min/1.73m2 30 - ,60 mL/min/1.73m2 ,30 mL/min/1.73m2 30 - ,60 mL/min/1.73m2 6482 6427 6483 PCSK9i Cohort 0% (0/7) 8.0% (8/100) 14.3% (1/7) 16.0% (16/100) 6428 6484 LDL-C 70-99 mg/dL Cohort 16.2% (6/37) 11.7% (47/403) 13.5% (5/37) 4.5% (18/403) 6429 LDL-C $100 mg/dL Cohort 21.4% (6/28) 21.0% (62/295) 7.1% (2/28) 7.1% (21/295) 6485 6430 Total 14.8% (129/870) 7.2% (63/870) 6486

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6487 underutilized in women (37.1%) compared to men (44.0%) disease and metastasis were found to have significantly 6543 6488 with baseline eGFR ,60 mL/min/1.73m2 (p50.038). higher expression detected by WB in CCs treated cells 6544 6489 Conclusions: This national survey demonstrates that use compared to untreated cells (Figure 2). 6545 6490 of high intensity statin and ezetimibe therapy in ASCVD Conclusions: These findings offer significant novel in- 6546 6491 patients does not differ by CKD status. Furthermore, sights into the mechanism by which CCs contributes to the 6547 6492 despite evidence-based recommendations, there have not increased activation of VEGF that can increase BC growth 6548 6493 been significant improvements in the use of optimal LLT and aggressiveness and potentially atherosclerosis as well. 6549 6494 since baseline. As a result, the proportion of patients with 6550 6495 CKD and ASCVD receiving optimal guideline-recommen- 6551 6496 ded risk reduction medications remains low. 6552 6497 6553 6498 6554 6499 Pathophysiology of Atherosclerosis 6555 6500 207 6556 6501 6557 The Association Between Cancer and 6502 6558 Atherosclerosis: Cholesterol Crystal Induced 6503 6559 Neovascularization in Breast Cancer 6504 6560 6505 George Abela, MD, (East Lansing, MI) 6561 6506 Venkat Katkoori, PhD, Harvey Bumpers, MD 6562 6507 6563 6508 Lead Author’s Financial Disclosure: Speaker for 6564 6509 Amgen and Kowa Pharmaceuticals. 6565 6510 6566 Study Funding: None. 6511 6567 6512 Background/Synopsis: Atherosclerosis and cancer are 6568 6513 common diseases of the aging population and these two 6569 6514 diseases share similar risk factors including obesity, 6570 6515 elevated cholesterol, sedentary lifestyle and others. 6571 6516 Recently we have demonstrated that cholesterol crystals 6572 6517 (CCs) are abundant in solid tumors including breast cancer 6573 6518 (BC) as known to be present in atherosclerosis. Angiogen- 6574 6519 esis and neovascularization have been shown to be critical 6575 6520 for growth of both atherosclerotic plaque and solid cancers. 6576 6521 This process is driven primarily by activation of vascular 6577 6522 endothelial growth factor [VEGF] as the signaling mech- 6578 6523 anism. However, the molecular mechanisms by which CCs 6579 6524 impacts tumor progression of BC remain unclear. 6580 6525 Objective/Purpose: In order to investigate the effects Pharmacological Control of Lipids and 6581 6526 of CCs on angiogenesis we evaluated vascular endothelial Lipoproteins 6582 6527 growth factor [VEGF] on signaling mechanisms and 6583 208 6528 associated markers of cancer stemness on progression of 6584 6529 BC. An Approach to PCSK9-inhibitor Non- 6585 6530 Methods: BC cell line (MDA-MB231) was cultured with Responders- A Case Series 6586 6531 varying degrees of CCs to select for increasing expression 6587 Sasha De Jesus, MD, (New York, NY) 6532 of VEGF (a marker for angiogenesis), CD44 and Ubiquityl- 6588 James Underberg, MD, FACPM, FNLA, 6533 Histone H2B [Ub-H2B] (markers for cancer stemness) 6589 Bruce Gordon, MD, Lisa Hudgins, MD, 6534 phenotypes. Western blot (WB) and Immunofluorescence 6590 Rachel Nahrwold, NP, Eugenia Gianos, MD, FACC, FNLA 6535 (IF) analyses were performed on lysates of BC cell line to 6591 6536 assess the effect of CCs on the signaling pathways that 6592 6537 promote BC progression. Lead Author’s Financial Disclosure: Nothing to 6593 disclose. 6538 Results: The present study revealed that CCs treated BC 6594 6539 cell line have increased expression of VEGF signature Study Funding: None. 6595 6540 indicative of angiogenesis. Immunofluorescence analysis Background/Synopsis: Hyporesponse to PCSK9-i has 6596 6541 confirmed that CCs treated cells displayed increased been noted in major landmark trials(1,2) with w0.5% of 6597 6542 expression of VEGF (Figure 1). Furthermore, the expres- patients having no significant reduction in the calculated 6598 sion of CD44, and Ub-H2B that correlates with advanced low density lipoprotein cholesterol (LDL-C) (LDL-C

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6599 decrease &;15%) and w11% having an LDL-C decrease 6655 6600 &;25% in a real world study(3). The mechanisms, however, 6656 6601 remain elusive. 6657 T 6602 Objective/Purpose: To review clinical cases with a 6658 6603 less than expected LDL-C lowering while on PCSK9-i in 6659 6604 order to develop a clinical algorithm for the work-up of 6660 6605 such patients. 6661 6606 6662 ezetimibe 10mg, and LDL apheresis every 2 weeks ezetimibe intolerant ezetimibe intolerant ezetimibe intolerant Methods: Five patients from several lipid clinics in NYC 6607 6663 were noted to have a small or absent LDL-C response to 6608 6664 PCSK9-i. Four had no significant LDL-C lowering after at least 6609 6665 3 doses (patients 1-4), while one had 50% LDL-C reduction 6610 6666 after 1 year but subsequent return to her pre-medication LDL-C 6611 6667 level after 18months of treatment (patient 5).

6612 Lp(a) change % Other treatments 6668 6613 Results: ***Please refer to attached image for table with 6669 6614 results. 6670 6615 Conclusions: Various factors can influence response to 6671 PCSK9-i. The first to rule out is non-adherence and poor 6616 Lp(a) after treatment nmol/L 6672 6617 injection technique. All of these patients were thought to be 6673 6618 adherent and to have good injection technique. Second, a 6674 6619 diagnosis of homozygous (Ho) FH with very low LDL 6675 10 NA NAreceptor None- statins activity and and expected poor response to a PCSK9 Lp (a) at baseline nmol/L 6620 , 6676 6621 inhibitor(3)(patient 2) can be differentiated from (He) FH 6677 6622 (patient 3) by DNA sequencing. Third, high levels of 6678 6623 lipoprotein-a (Lpa) co-measured with the LDL-C, such as 6679 6624 in patients 2-4, may result in a less than expected LDL 6680 6625 lowering, since PCSK9-i lowers Lp(a) by only 15-20%. 6681 LDL-C change % -48.0 -2.4 6626 Fourth, as illustrated by our patient who initially responded 6682 6627 and then failed to respond, tachyphylaxis should be 6683 6628 considered. To our knowledge, this response pattern has 6684 6629 not been described with PCSK9-i; however, it is seen with 6685 6630 other monoclonal antibody therapies. Fifth, for those with 6686 244 at 18 mo. HoFH or severe HeFH, Evolocumab 420mg every 2 weeks LDL-C after treatment mg/dL 6631 479 401 Not calculated 311 NA NA None- statins and 6687 6632 has been reported to be effective and can considered(5). 6688 6633 Lastly, trial of the alternate PCSK-9-i could be considered 6689 6634 although we did not observe a better outcome with this 6690 6635 approach. In these instances, PCSK9 levels could be 6691 6636 measured to confirm that the monoclonal antibody engages 6692 range 6637 350 out of its target and the PCSK9 thereby remains in the circulation 6693 LDL-C at baseline mg/dL 239 192 208 -19.7 -13.0 17 nmol/L 12 nmol/L -29.4% Pravastatin 20mg . 201 191 211 -4.9 +4.9 210 216 179 +2.9 -14.8 None- statins and 6638 and its clearance is delayed(4). Although anti-drug anti- 6694 6639 bodies might theoretically lead to a less than optimal 6695 6640 response, their presence in patients in landmark trials was 6696 6641 not noted to correlate with non-response(2,6). 6697 Alirocumab Evolocumab 6642 Alirocumab 6698 Alirocumab Evolucumab -250 120 at 1 yr.: 6643 Lipid Management Best Practices 6699

6644 T p.P52SS. receptor defective 6700 6645 . 6701 209 6646 6702 6647 Lipid Screening Patterns in an Urban 6703 6648 Population 6704 6649 Dipika Gopal, MD, (Philadelphia, PA) Reed Mszar, BS, 6705 FH" 6650 criteria} 6706 Y. P.R595W; c.1576C

A, p.cys352tyr, receptor defective Daniel Soffer, MD, Srinivas Denduluri, PhD, . 6651 . Richard Nemiroff, MD, 6707 6652 Jennifer Lewey, MD, MPH, Tierney Ann, MS 6708

6653 c.1783C 6709 *c.1055 G 6654 Ô Lead Author’s Financial Disclosure: Nothing to 6710 Patient No FH status PCSK9-i 1 No FH mutation Evolocumab 2 Homozygous FH* Evolucumab 339 393 +17.8 237 179 -24.5 Atorvastatin 40mg 3 Compound heterozygous 4 FH (Dutch criteria) Evolocumab 5 Probable FH (Dutch disclose.

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6711 6767 6712 Table 1 Demographics 6768 6713 Screened (n53720) Not Screened (n510,032) 6769 6714 6770 Age (years) 13 (0.3) 546 (5.4) 6715 ,20 3677 (98.8) 9467 (94.4) 6771 6716 20-44 30 (0.8) 19 (0.2) 6772 6717 45 6773 6718 Gestational Age (weeks) 38.663.1 38.662.9 6774 6719 Race 1451 (39.4) 4823 (48.7) 6775 6720 Black 1839 (50) 4048 (40.9) 6776 6721 White 231 (6.3) 602 (6.1) 6777 6722 Asian 159 (4.3) 434 (4.4) 6778 6723 Other 6779 6724 Hypertension 362 (9.7) 449 (4.5) 6780 Diabetes 132 (3.6) 95 (0.9) 6725 6781 Coronary Artery Disease 13 (0.3) 24 (0.2) 6726 Heart Failure 31 (0.8) 34 (0.3) 6782 6727 Chronic Kidney Disease 19 (0.5) 7 (0.1) 6783 6728 Gestational Hypertension 235 (6.3) 542 (5.4) 6784 6729 Preeclampsia 775 (20.8) 1508 (15.0) 6785 6730 Gestational Diabetes 135 (3.6) 152 (1.5) 6786 6731 Polycystic Ovarian Syndrome 280 (7.5) 194 (1.9) 6787 6732 6788 6733 6789 6734 6790 Study Funding: None. Conclusions: In a population eligible for standard of 6735 6791 care lipid screening, actual screening rates were very low. 6736 Background/Synopsis: It is estimated that one in four 6792 While a majority of women have internal medicine and 6737 women will die of cardiovascular disease and hyperlipid- 6793 family medicine as their primary care, a significant portion 6738 emia remains a significant modifiable risk factor. Three 6794 of women have Ob/Gyn as their primary care doctor and 6739 major associations recommend that women undergo lipid 6795 there remains substantial room for improvement in 6740 screening starting at age 20 years. Currently, surveys show 6796 screening rates in this population. 6741 that only half of women of reproductive age undergo 6797 6742 screening despite presence of cardiovascular risk factors. 6798 6743 The lack of lipid screening represents a significant missed Other 6799 6744 opportunity to identify women at a young age who are at 6800 future risk of cardiovascular disease. 6745 210 6801 Objective/Purpose: Our aim is to examine screening 6746 Nonalcoholic Fatty Liver Disease in Children 6802 patterns stratified by primary care provider type for 6747 and Adolescent with Overweight and Obesity: 6803 hyperlipidemia at a large academic medical center in effort 6748 a Retrospective Cohort Study 6804 6749 to identify incidence of lipid screening in this population 6805 6750 and factors associated with screening. Julie St-Pierre, MD PhD FAHA FRCP, (Montreal, QC) 6806 6751 Methods: A retrospective analysis was performed using Maude Sirois, RN, Genevieve Paquin, Reg Dietician, 6807 6752 the EPIC electronic medical record (EMR) on 58,921 women Marylin Robert, MD MSc, Elisa Jean Baptiste, MSc 6808 6753 between 2008 and 2017 who gave birth at one of two 6809 6754 university affiliated hospitals and who received primary care 6810 6755 within the health system. Demographics, comorbidities, and Lead Author’s Financial Disclosure: Nothing to 6811 6756 primary care physician (PCP) information was aggregated. disclose. 6812 6757 The primary outcome was presence of lipid screening at any Study Funding: None. 6813 6758 point in time in the EMR prior to the delivery date. Background/Synopsis: The rising epidemic of child- 6814 6759 Results: Of 13,752 women with a primary care physician hood obesity and its co-morbidities is of growing concern. 6815 6760 in our health system, mean age was 28 +/- 6 years (Table 1). Overweight and obese children are at increased risk for 6816 6761 PCP types included internal medicine (45%), family med- nonalcoholic fatty liver disease (NAFLD). This risk is 6817 6762 icine (43%), obstetrics/gynecology (OB/Gyn) (12%). Over- higher in the setting of other cardiometabolic risk factors, 6818 6763 all, 3,720 women (27%) had lipid screening performed such as insulin resistance, dyslipidemia, central adiposity, 6819 6764 prior to their delivery date. Women with an internal and ethnicities (1). In order to detect NAFLD in the early 6820 6765 medicine PCP had the highest screening rate (36.7%). course of the disease, before advanced fibrosis develops, 6821 6766 Only 24.1% of women with family medicine PCPs and and ensure adequate clinical management, screening is 6822 1.9% of women with OB/Gyn PCPs received screening. important, the North American Society of Pediatric

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6823 Gastroenterology, Hepatology and Nutrition (NASPGHAN) syndrome and lower social and school determinants. Not 6879 6824 published new clinical guidelines for the diagnosis of only pediatric NAFLD was previously associated with 6880 6825 NAFDL in 2017 (1). increased morbidity and mortality, but data have also 6881 6826 Objective/Purpose: The objective of the current study demonstrated a lower quality of life among obese children 6882 6827 was to evaluate the prevalence of NAFLD among obese and with NAFLD (1). Education in primary care givers related to 6883 6828 overweight children and adolescents referred in a 2nd line ALT newest NASPGHAN cutoffs should also be emphasized 6884 6829 pediatric multidisciplinary obesity clinic at their first in order not to delay its clinical management and prevent 6885 6830 appointment according to the new NASPGHAN NAFLD cardiometabolic complications. 6886 6831 6887 guidelines and to better understand social-school determi- (1) Vos MB et al. J Pediatr Gastroenterol Nutr. 2017 6832 nants associated with this condition. 6888 6833 Feb;64(2):319-334. doi: 10.1097/MPG.000000000 6889 Methods: We have looked, retrospectively, at the initial 6834 0001482. 6890 blood tests performed among 278 overweight and obese 6835 6891 patients (body mass index above 85th percentile or 97th 6836 Enhancing Adherence, Compliance to Therapies 6892 percentile for age and sex ) aged 2 to 18 years, between 6837 6893 July 2017 and April 2019. Sixty percent (60%) of our urban 212 6838 6894 cohort is represented by 1st and 2nd generation immigrants. 6839 Physician Characteristics and Attitudes 6895 NAFLD was defined as an alanine aminotransferase (ALT) 6840 towards Lipid-Lowering Treatment and 6896 value above 22 U/L for girls and 26 U/L for boys, without 6841 Variability in Implementation of Guidelines: 6897 other hepatic conditions, using cutoffs from the newest 6842 Insights from the Getting to an ImprOved 6898 NASPGHAN clinical guidelines. The elevated ALT group 6843 Understanding of Low-Density Lipoprotein- 6899 was compared to the normal ALT group. Pediatric over- 6844 Cholesterol and Dyslipidemia Management 6900 weight and obese patients were referred by general 6845 (GOULD) Reg 6901 practitioners or community pediatricians. Social and school 6846 6902 determinants were also assessed by validated question- Mahmoud Al Rifai (Houston, TX) Mikhail Kosiborod, MD, 6847 6903 naires and filled with the family by a clinical nurse. James de Lemos, MD, Robert Rosenson, MD, 6848 6904 Analyses were performed by a biostatistician. Yuyin Liu, MD, Katherine Mues, PhD MPH, 6849 6905 Results: Two hundred and seventy eight (278) medical Shushama Alam, PharmD, Deepak Bhatt, MD MPH, 6850 Christopher Cannon, MD, Christie Ballantyne, MD 6906 6851 files were revised and 117 (42%) shown an ALT elevation. 6907 6852 No difference was observed between girls and boys (p 6908 50,818). Fifty-six percent (56%) of the NAFLD group Lead Author’s Financial Disclosure: Nothing to 6853 disclose. 6909 6854 patients were 1st and 2nd generation immigrants. The 6910 Study Funding: None. 6855 prevalence of hyperinsulinemia was significantly higher 6911 6856 among the NALFD group (56,4%) in comparison to the Background/Synopsis: To understand the variability 6912 5 6857 control group (36,6%) (p 0,004) with significantly higher in use of lipid-lowering therapy (LLT) in patients with 6913 6858 level of fasting insulin concentrations (167,3 pmol/L versus ASCVD, we conducted a clinician survey within the 6914 6859 102,9 pmol/L, respectively). In addition, in the NAFLD GOULD program. 6915 6860 group, the mean triglycerides concentrations were higher (p Objective/Purpose: A better understanding of clinician- 6916 5 6861 0,004) compared to the control group (123,9 mg/dL specific factors underlying LLT prescription may help improve 6917 6862 versus 97.3 mg/dL). Interestingly, screen time per day was adherence to cholesterol guideline recommendations. 6918 6863 much higher among FAFLD children and adolescents, with Methods: We used data from the GOULD Registry, 6919 6864 a higher proportion of them being treated for attention which includes patients &;18 years with established 6920 6865 deficit hyperactivity disorder and were also showing a ASCVD who were enrolled into 3 cohorts: 1) currently 6921 6866 higher level of school-learning difficulties. Of interest, the on proprotein convertase subtilisin/kexin type 9 inhibitor 6922 6867 abnormal ALT new cutoffs from NASPGHAN were not (PCSK9i), or not on PCSK9i with 2) low-density lipopro- 6923 6868 identified by primary care givers. tein cholesterol (LDL-C) 70-99 mg/dL, or 3) LDL-C;100 6924 6869 Conclusions: With an overall increased prevalence of mg/dL. We included non-PCSK9i cohorts, which were 6925 6870 obesity and metabolic syndrome among children and divided into 4 quartiles based on percentage of patients at 6926 6871 adolescents, screening for NAFLD in high-risk populations each site at goal LDL-C (,70 mg/dL). One physician per 6927 6872 and better understand the social determinants associated with site was surveyed regarding his or her attitudes and beliefs 6928 6873 this condition is of great interest. The newest ALT cutoff towards LDL-C goals, statins and PCSK9i. 6929 6874 values from NASPGHAN seemed more prone to identify Results: Achievement of LDL-C of ,70 mg/dL varied 6930 6875 high-risk children in our pediatric obese and overweight widely ranging from 7.8% in Q1 to 50.5% in Q4. 6931 6876 cohort in which hyperinsulinemia and hypertriglyceridemia Physicians in leading sites were more often cardiologists 6932 6877 were also impaired. The very high proportion of NAFLD (69% vs. 14%) and practiced in hospital-based settings 6933 6878 (42%) in our cohort of obese and overweight children and (28% vs. 4%). They were more likely to spend more time 6934 adolescents was associated with makers of the metabolic (&;20 minutes) during regular follow-up visit of patients

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6935 6991 6936 Table Physician characteristics by quartiles of low-density lipoprotein cholesterol goal achievement at 12 months* 6992 6937 Sites in Sites in Sites in Sites in 6993 6938 1st quartile 2nd quartile 3rd quartile 4th quartile p-value 6994 6939 % of patients with LDL-C , 70 mg/dl 7.8 6 7.1 20.0 6 2.0 28.3 6 3.0 50.5 6 18.7 ,.001 6995 6940 at 12 months (mean 6 SD) 6996 6941 % on combination therapy [any 21.6 6 16.2 27.5 6 15.6 34.7 6 16.9 41.8 6 23.7 ,.001 6997 6942 statin + nonstatin combo] (mean 6 SD) 6998 6943 Cardiology practice type 14.3% 48.3% 50.0% 69.0% ,0.001 6999 6944 Spend 20 minutes or more on a regular 21.4% 24.1% 17.9% 44.8% 0.006 7000 6945 follow-up visit with a patient with ASCVD 7001 6946 Hospital-based site 3.6% 6.9% 21.4% 27.6% 0.030 7002 6947 Medical record type 0.007 7003 6948 Paper 35.7% 44.8% 10.7% 13.8% 7004 Electronic 64.3% 55.2% 89.3% 86.2% 6949 7005 No change to LLT for patients with very 28.6% 41.4% 42.9% 82.8% 0.018 6950 low LDL-C 7006 6951 % on PCSK9 inhibitors (mean 6 SD) 4.6619.0 2.163.5 1.764.8 10.5612.1 0.016 7007 6952 % on nonstatin (any) as monotherapy 3.5% 3.5% 3.2% 10.2% 0.002 7008 6953 Nonfamiliarity with PCSK9i [1–10 scale] 3.9 6 3.1 4.1 6 3.2 2.1 6 1.7 1.8 6 1.4 ,0.001 7009 6954 (mean 6 SD) 7010 6955 Importance of injectable delivery method 4.9 6 2.7 4.1 6 2.6 3.4 6 2.5 2.8 6 2.0 0.009 7011 6956 in decision not to prescribe PCSK9i 7012 6957 [1–10 scale] (mean 6 SD) 7013 6958 Ever prescribed a PCSK9i 57.1% 69.0% 82.1% 93.1% 0.039 7014 6959 Abbreviations: ASCVD 5 atherosclerotic cardiovascular disease; LDL-C 5 low-density lipoprotein cholesterol; LLT 5 lipid-lowering therapy; PCSK9i 5 7015 6960 proprotein convertase subtilisin/kexin type 9 inhibitor 7016 , 6961 *Patients with LDL-C 70 mg/dL 7017 6962 7018 6963 7019 6964 with ASCVD (45% vs. 21%) and maintain patients on their Lead Author’s Financial Disclosure: Nothing to 7020 6965 current LLT if they had very low LDL-C (83% vs. 29%). disclose. 7021 6966 Furthermore, they were more likely to prescribe combina- Study Funding: None. 7022 tion therapy (41% vs. 22%), use nonstatin as monotherapy 6967 Background/Synopsis: Severe elevation in triglycer- 7023 (10% vs. 4%), have prescribed a PCSK9i (93% vs 57%) 6968 ides can cause pancreatitis and triglyceride (TG) rich 7024 and be less concerned about injectable delivery method 6969 lipoproteins are likely causal risk factors for atherosclerotic 7025 (2.8% vs 4.9%) (Table). 6970 cardiovascular disease (ASCVD) based on epidemiologic and 7026 , 6971 Conclusions: The achievement of LDL-C levels of 70 Mendelian randomization studies. Moreover, genetic linkage 7027 6972 mg/dL varied widely in different sites and was associated studies have provided novel targets for therapy against 7028 6973 with provider specialty, practice setting, time allocation per hypertriglyceridemia. While hypertriglyceridemia is often a 7029 6974 patient, electronic medical record use and the use of polygenic disease, genetic testing has potential to affect 7030 6975 combination therapy. The decision to prescribe statins or clinical decision making, particularly given the emergence of 7031 6976 other nonstatin LLT such as PCSK9i may be subjective and targeted therapies for Apolipoprotein CIII and ANGPTL4. 7032 6977 can vary for each physician. Our findings suggest that 7033 Objective/Purpose: The aim of this pilot study is to 6978 clinical care delivery models that encourage greater 7034 evaluate the clinical utility of genetic testing in a lipid 6979 clinician emphasis on prevention in high-risk patients 7035 clinic for patients with hypertriglyceridemia. 6980 may result in a higher likelihood of achieving optimal 7036 6981 guideline-recommended LDL-C goals. Methods: In collaboration with GBinsight, we conducted 7037 6982 a pilot study of 72 patients who had genetic testing. Patients 7038 6983 Genetics, Gene Therapy and Atherosclerosis presented to lipid clinic from January 2018 to February 7039 2020 and provided informed consent and saliva samples. 6984 213 7040 Monogenic variants were reported as pathogenic/likely 6985 Genetic Testing for Hypertriglyceridemia– 7041 pathogenic, variants of unknown significance, likely 6986 Experience From a Single Center Lipid Clinic* 7042 6987 benign/benign in accordance to American College of 7043 6988 Winner Medical Genetics recommendations. Polygenic risk scores 7044 6989 Trevor Hadley, B.S, (Houston, TX) Aliza Hussain, MD, were also calculated for each individual. 7045 6990 Carter Ma, PhD, Mendel Roth, PhD, Results: During the study period, 26 patients with a history 7046 Christie Ballantyne, MD of hypertriglyceridemia underwent genetic testing. All but 6

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7047 7103 7048 Table 1 Genetic Variants and Polygenic Risk Scores in Patients with Hypertriglyceridemia 7104 7049 Patient Race Polygenic Risk Variant Zygosity Classification 7105 7050 7106 1 Hispanic/Latino 98 LPL(c.95 3A.G(p.Asn318Ser))* Heterozygous VUS-Likely Pathogenic 7051 APOA5(c.5 6C.G(p.Ser19Trp)) Heterozygous Strong Risk Factor 7107 7052 APOE(E4(p.Cys130Arg)) Heterozygous Strong Risk Factor 7108 7053 APOE(E2(p.Arg17 6Cys)) Heterozygous Strong Risk Factor 7109 7054 ZPR1(c.*724C.G) Heterozygous Strong Risk Factor 7110 7055 2 South Asian 98 ABCA1(c.1913G.A(p.Arg63 8Gln)) Heterozygous VUS-Likely Pathogenic 7111 7056 LPL(c.929G.A(p.Cys310Tyr)) Homozygous VUS 7112 7057 3 European 90 CREB3L3(c.7 31 7 3 2insG(p.Lys244Glufs)) Heterozygous VUS-Likely pathogenic 7113 7058 CREB3 L3(c.7 38A.T(p.Lys246Asn)) Heterozygous VUS-Likely pathogenic 7114 . 7059 LMF1(c.1052G A (p.Arg3 51Gln)) Heterozygous Strong Risk factor 7115 . 7060 ZPR1(c.*724C G) Heterozygous Risk factor 7116 4 European 94 APOA5(c.5 6C.G(p.Ser19Trp)) Homozygous Strong Risk Factor 7061 7117 5 European 2 n/a n/a n/a 7062 6 East Asian 7 APOE (E4 (p.Cys130Arg) ) Heterozygous Strong Risk Factor 7118 7063 7 South Asian 84 ABCA7(c.274G.T(p.Gly9 2Trp)) Heterozygous VUS 7119 7064 APOE(E4 (p.Cys130Arg)) Heterozygous Strong Risk Factor 7120 7065 POMC(c.706C.G(p.Arg2 3 6Gly)) Heterozygous VUS-Likely Strong Risk Factor 7121 7066 PPARG(c.6 2 5G.T(p.Ala237Ser)) Heterozygous VUS-Likely Pathogenic 7122 7067 8 European 99 LPL (644G.A(p.Gly215Glu) Heterozygous Pathogenic 7123 7068 PPARG (c.551G.A(p.Arg184Gln) Heterozygous VUS-Likely Pathogenic 7124 7069 9 European 85 APOA5 (c.56C.G(p.Ser19Trp)) Heterozygous Strong Risk Factor 7125 7070 PPARA (c.484C.G(p.Leu162Val)) Heterozygous Strong Risk Factor 7126 . 7071 10 Middle Eastern 96 LMF1 (c.1317C G(p.Tyr439Ter)) Homozygous Pathongenic 7127 LPA (c.42 6 2G.A(p.Arg1421Gln)) Heterozygous VUS 7072 7128 11 Middle Eastern 96 GPIHBP1 (c.230G.A(p.Cys77Tyr)) Homozygous VUS-Likely Pathogenic 7073 12 Middle Eastern 91 APOA5 (c.553G.T(p.Gly185Cys)) Heterozygous VUS-Likely Pathogenic 7129 7074 CD300LG (c.244C.T(p.Arg82Cys)) Heterozygous Risk Factor 7130 7075 13 Hispanic/Latino 44 APOA5 (c.56C.G(p.Ser19Trp)) Heterozygous Strong Risk Factor 7131 7076 APOE (E4 (p.Cys130Arg)) Heterozygous Strong Risk Factor 7132 7077 LPA (c.5 67 3A.G(p.Ile1891Met)) Heterozygous Strong Risk Factor 7133 7078 14 European 100 APOA5 (c.56C.G(p.Ser19Trp)) Heterozygous Strong Risk Factor 7134 7079 APOA4 (c.37G.A(p.Val 13Met)) Heterozygous VUS 7135 7080 LPA (c.3947+467T.C) Heterozygous Strong Risk Factor 7136 7081 15 European 63 APOE (E2 (p.Arg176Cys) ) Heterozygous Strong Risk Factor 7137 . 7082 LPA (c.42 6 2G A(p.Arg1421Gln)) Heterozygous VUS 7138 ZPR1 (c.*72 4C.G) Heterozygous Risk Factor 7083 7139 16 European 34 ZPR1 (c.*724C.G) Heterozygous Risk factor 7084 17 Middle Eastern 43 ZPR1 (c.*724C.G) Heterozygous Risk Factor 7140 7085 18 European 34 APOE (E2 (p.Arg176Cys) ) Heterozygous Strong Risk Factor 7141 7086 19 Hispani c 91 LMF1 (c.8 37C.A(p.Phe279Leu)) Heterozygous VUS 7142 7087 LPA (c.5 67 3A.G(p.Ile1891Met)) Heterozygous Strong Risk Factor 7143 7088 20 East Asian 96 LPL (c.249+1G.A) Heterozygous Pathogenic 7144 7089 ZPR1 (c.*72 4C.G) Heterozygous Risk factor 7145 7090 21 Caucasian 81 APOE (E2 (p.Arg176Cys) ) Heterozygous Strong Risk Factor 7146 7091 LPL (c.106G.A(p.Asp36Asn)) Heterozygous Strong Risk Factor 7147 7092 22 European 41 APOE (E4 (p.Cys130Arg) ) Heterozygous Strong Risk Factor 7148 . 7093 POMC (c.641A G(p.Glu214Gly)) Heterozygous VUS-Likely Strong Risk Factor 7149 CD300LG (c.244C.T(p.Arg82Cys)) Heterozygous Risk Factor 7094 7150 PPARA (c.484C.G(p.Leu162 Val)) Heterozygous Strong Risk Factor 7095 23 Hispanic/Latino 99 LIPA (c.894G.A(p.Gln2985)) Heterozygous Pathogenic 7151 7096 APOA5 (c.56C.G(p.Ser19Trp)) Heterozygous Strong Risk Factor 7152 7097 APOE (E4 (p.Cys130Arg) ) Heterozygous Strong Risk Factor 7153 7098 LIPI (c.164G.A(p.Cys55Tyr)) Heterozygous VUS-Likely Pathogenic 7154 7099 LMF1 (c.1091G.A(p.Arg3 64Gln)) Heterozygous VUS 7155 7100 24 N/A GCKR (c.307G.A(p.Val 103Met)) Heterozygous VUS-Likely Pathogenic 7156 7101 99 APOA5 (c.56C.G(p.Ser19Trp)) Heterozygous Strong Risk Factor 7157 7102 LMF1 (c.1685C.G(p.Pro562Arg)) Heterozygous VUS-Likely Pathogenic 7158 (continued on next page)

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7159 (continued) 7215 7160 7216 Patient Race Polygenic Risk Variant Zygosity Classification 7161 7217 7162 25 South Asian 90 LPL (c.9 29G.A(p.Cys310Tyr)) Heterozygous Likely Pathogenic 7218 . 7163 26 European 100 APOA5 (c.56C G(p.Ser19Trp)) Heterozygous Strong Risk Factor 7219 7164 CREB3L3 (c.7 3 2dup(p.Lys245GlufsTer130)) Heterozygous VUS-Likely Pathogenic 7220 CREB3L3 (c.7 38 A.T( p. Lys2 46Asn)) Heterozygous VUS-Likely Pathogenic 7165 7221 7166 7222 7167 7223 7168 7224 of the patients have documented TG . 500mg/dL. Of these 7169 Conclusions: Genetic testing in patients with hyper- 7225 26 patients, 4 had pathogenic variants, 13 had a variant of 7170 triglyceridemia, especially in those with a history of 7226 unknown significance (VUS) classified as likely pathogenic, 7171 pancreatitis, has a high yield for pathogenic variants and 7227 25 had at least one variant of probable association with 7172 variants of unknown significance classified as likely 7228 clinical phenotype, and 15 had a polygenic risk score for 7173 pathogenic. Further research in this area can help to 7229 hypertriglyceridemia . 90%. The prevalence of diabetes 7174 identify individuals who may benefit from additional 7230 was 38% and the prevalence of pancreatitis was 50%. The 7175 novel therapy targeting APOC3 and ANGPTL4. Larger 7231 mean (standard deviation) for relevant clinical data were: 7176 studies are needed which include various ethnic groups, 7232 highest documented TG 2129 (2008), high-density lipopro- 7177 especially South Asians, as previous recommendations 7233 tein (HDL) cholesterol 28 (13), non-HDL cholesterol 236 7178 may have underestimated the benefit of routine genetic 7234 (132). Genotypic data per individual are presented in Table 1. 7179 testing. 7235 7180 7236 7181 7237 7182 7238 7183 7239 7184 7240 7185 7241 7186 7242 7187 7243 7188 7244 7189 7245 7190 7246 7191 7247 7192 7248 7193 7249 7194 7250 7195 7251 7196 7252 7197 7253 7198 7254 7199 7255 7200 7256 7201 7257 7202 7258 7203 7259 7204 7260 7205 7261 7206 7262 7207 7263 7208 7264 7209 7265 7210 7266 7211 7267 7212 7268 7213 7269 7214 7270

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