JACC: HEART FAILURE VOL.4,NO.5,2016

ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 2213-1779/$36.00

PUBLISHED BY ELSEVIER http://dx.doi.org/10.1016/j.jchf.2016.02.016

Neprilysin Inhibition in the Time of Precision Medicine*

Arthur M. Feldman, MD, PHD

he recent results of the PARADIGM-HF trial Time of Cholera is a quintessential example of that T (Prospective Comparison of ARNI with ACEI genre (3). Magic realism mixes elements of fantasy to Determine Impact on Global Mortality into otherwise realistic or common settings. As phy- and Morbidity in Heart Failure) showing that the sicians, we must however look at the results combination of the (NEP) inhibitor sacubi- of PARADIGM-HF from a realistic and scientific tril (sac) and the angiotensin receptor antagonist perspective based on the elements that we have (ARB) valsartan (sacubitril/valsartan [sac/val]; used to judge all HF therapies: 1) the pre-clinical Entresto, Novartis) decreased the risk of death from data; 2) the design and results of all relevant clinical cardiovascular cause or first hospitalization for heart trials; and 3) associated risks – both observed and failure (HF) while modestly reducing the risk of death theoretical. from 19.8% to 17.0% (hazard ratio: 0.84) when compared with the angiotensin-converting PRE-CLINICAL CARDIAC DATA inhibitor (ACEi) enalapril engendered considerable interest among cardiologist and HF specialists (1).In NEP is a plasma membrane that is a JACC: Heart Failure this issue of ,Dr.MiltonPacker member of the family. Widely posits that since “the PARADIGM-HF trial has expressed in mammalian tissues, NEP is the prin- demonstrated the need to inhibit NEP, we should ciple mechanism for degradation of the natriuretic do so as early as possible and not delay until we peptides. However, NEP is not precise in its actions— have achieved target doses of a conventional inhib- hydrolyzing numerous other peptides including ” itor of the renin-angiotensin system (2).Heuses angiotensin I, angiotensin II, endothelin-1, kinins, LoveintheTimeofCholera the allegory of the novel adrenomedullin, opiod peptides, enkephalin, gastrin, fi to make the point that physicians are having dif - and amyloid beta (Ab). culty breaking from their long-standing comfort in Most of what we know about the role of NEP usinganACEiasapivotaltherapyforpatients inhibition in the heart and vasculature comes from with HF and reduced ejection fraction (HFrEF). classical pharmacologic studies begun 2 decades ago Written by the Nobel laureate Gabriel García Már- showing that NEP inhibition alone resulted in an Love in the Time of Cholera quez, describes how increase in natriuretic peptides but also in periph- Florentino Ariza meets and falls in love with Fer- eral vasoconstriction (4). When compared with pla- mina Daza, only to have his advances spurned until cebo, the combination of a NEP inhibitor (NEPi) with fate brings them together over 50 years later, albeit an ACEi (omapatrilat) (5,6) or the combination of a with a less than happy ending. This is an interesting NEPi with an ARB (valsartan) decreased maladaptive allegory to use because Márquez is universally cardiac remodeling (7). Omapatrilat was more recognized as one of the most preeminent effective at preventing changes in left ventricular “ members of a literary movement known as magic geometry and premature mortality in Syrian hamster ” “ ” Love in the realism ( marvelous realism )and cardiomyopathy then was captopril (8). By contrast, in rats with chronic HF, omapatrilat did not result in benefit as compared with captopril (9,10). Similarly, sac/val had no effect on left ventricular remodeling *Editorials published in JACC: Heart Failure reflect the views of the or hemodynamic indices including cardiac output, JACC: Heart Failure authors and do not necessarily represent the views of stroke work, or dP/dt when compared with val in the or the American College of Cardiology. same model: there was however a significant in- From the Department of Medicine, Lewis Katz School of Medicine at crease in ejection fraction (11).Thus,thepre-clinical Temple University, Philadelphia, Pennsylvania. Dr. Feldman has reported that he has no relationships relevant to the contents of this paper to data does not consistently demonstrate robust disclose. beneficial effects of NEP inhibition when combined 410 Feldman JACC:HEARTFAILUREVOL.4,NO.5,2016 Neprilysin Inhibition in the Time of Precision Medicine MAY 2016:409– 14

with an ACEi or an ARB in comparison with an ACE for worsening HF (p < –0.027) and there was a 13% or ARB alone. reductioninHFadmissions(p< 0.025) and an 11% reduction in cardiovascular admissions (p < 0.023) CLINICAL EFFECTS OF NEP INHIBITION IN HF (16).Furthermore,wedemonstratedthatinpatients with HF, only a high dose of an ACEi diminished the Studies begun 2 decades ago also demonstrated negative impact of the presence of an ACE deletion that NEP inhibition alone did not have salutary allele (ACE-D or ACE-DD) that is associated with effectsinpatientswithHF(12). In addition, a phase II increasedACEactivityandanincreasedriskofHF- study comparing omapatrilat with lisinopril failed to related events (17). Studies that failed to show a show a difference in the primary endpoint of exercise decrease in blood pressure with a high dose of an performance (13). Omapatrilat also failed to meet its ACEi or an ARB as compared with a low dose did not primary endpoint of death or hospitalization in the show any difference in outcomes between the 5,770-patient phase III OVERTURE (Omapatrilat 2groups(18,19). Versus Enalapril Randomized Trial of Utility in There were other factors in the design of the trial Reducing Events) trial and was associated with a that make translation to patient care challenging. For 2-fold increase in angioedema—leading the sponsor to example, a run-in with enalapril preceded the run-in discontinue its development. Investigators posited with sac/val. The intent of the run-in period was to that ARBs might be less likely than ACEis to interfere ensure that the maximum benefit from sac/val could with bradykinin metabolism; thus, the combination be achieved by selecting for patients who would most of a NEPi and an ARB became a more attractive choice likely tolerate the target doses of both medications; for further development. however, this design precludes physicians from The PARADIGM-HF trial was the first large phase III understanding the true tolerance to sac/val. In study of a NEPi/ARB to meet its primary endpoint; particular, this selection bias may have resulted in an however, the design of the trial raises important under-representation of angioedema. With only 2 questions. First, the PARADIGM-HF trial compared an doses evaluated in the trial physicians will face a optimal (titrated) dose of val/sac with a fixed dose of second therapeutic conundrum: if patients do not enalapril (10 mg twice a day): a dose of enalapril reach their target dose of sac/val or if they require that is below the maximum dose recommended by down-titration of sac/val because of hypotension, the American College of Cardiology/American Heart would a prudent approach be to switch patients to Association Practice Guidelines (10 to 20 mg twice a their prior dose of an ACEi or an ARB? In fact, 18% of day) (14). That this dose of enalapril may have been sac/val patients developed symptomatic hypoten- inadequate in the PARADIGM trial is demonstrated by sion. Similarly, because pre-specified subgroup the finding that blood pressure was significantly analysis suggested that sac/val was no better than lower after treatment with sac/val than after treat- enalapril in treating patients with New York Heart ment with enalapril (1). Association functional class III/IV symptoms, should Blood pressure is an important metric because patients who progress to worsening symptoms while “high-dose ACE” inhibitors proved more effective on therapy be switched to an ACEi, an agent known than “low-dose ACE” inhibitors when the high-dose to benefit patients with severe disease (20).Despite ACEi lowered blood pressure more than did the low- an overwhelming percentage of patients having an dose ACEi but not when the 2 doses had the same ejection fraction #35%, only 15% of patients enrolled blood pressure response. For example, the ATLAS in the trial had received an implantable cardioverter- (Assessment of Treatment with Lisinopril and Sur- defibrillator (a Class 1A recommendation) and only vival) trial showed only an 8% nonsignificant 7% of patients had received cardiac resynchroniza- decrease in mortality with high dose ACEi compared tion therapy—raising the possibility that mortality with low-dose ACEi; however, there was a 12% lower rates might have been lower and the effect of drug risk of death or hospitalization for any reason (p ¼ therapy less evident had more patients been 0.002), 24% fewer hospitalizations for HF (p ¼ 0.002) receiving what is considered appropriate therapy in and systolic blood pressure decreased by 4.4 mm Hg the United States (14).Sac/valsignificantly increased more in the high-dose group (p < 0.001) (15).Konstam the ratio of urine albumin to creatinine when et al. (16) found similar outcomes in the HEAAL (Ef- compared with enalapril, a difference that could fects of high-dose versus low-dose losartan on clinical reflect worsening renovascular disease. Finally, it outcomes in patients with heart failure) trial: high- should be noted that treatment with sac/val can also dose lisinopril as compared with low-dose lisinopril impair monitoring of chronic HF patients with B-type met the primary endpoint of death or admission natriuretic testing (21). JACC:HEARTFAILUREVOL.4,NO.5,2016 Feldman 411 MAY 2016:409– 14 Neprilysin Inhibition in the Time of Precision Medicine

OFF-TARGET EFFECTS The brain is not the only organ in which altered Ab homeostasis can cause disease (39).Ab is present in When NEPis were first developed 20 years ago, the drusen, extracellular deposits in the subretinal area off-target effects of a new drug could only be ascer- oftheeyethatareassociatedwithAMD,themost tained once that drug was synthesized and even then common cause of legal blindness in the United States the experimental designs were often challenging. in individuals older than 50 years of age (40).More Today, in the era of proteomics, metabolomics, and recent studies have shown that: 1) mice lacking NEP pharmacogenomics, molecular genetics can be used develop degeneration of the retinal pigment epithe- to rapidly overexpress or knock down selected pro- lial cells and subretinal deposits that are similar to teins in a tissue-dependent manner resulting in in- those in AMD in humans (39);2)senescentmicehave formation being available from translational research higher retinal levels of Ab due to a decrease in the well before the results of large multicenter clinical expression of NEP and an increase in Ab synthesis trials become available. These studies have raised the (41,42); and 3) injection of a recombinant form of the theoretical risk that inhibition of NEP could increase NEP catalytic domain into the vitreous decreased levels of Ab in the brain and in the eye leading to the ocular Ab levels in models of retinal degeneration development of symptomatic Alzheimer’sdisease (43). Taken together, these studies have led investi- (AD) or age-related macular degeneration (AMD), gators to suggest that overexpression of NEP via gene respectively (22–25). therapy is a promising therapeutic approach for both Ab homeostasis is regulated by a balance between AD and AMD (32). Ab production through sequential cleavage of the The PARADIGM-HF trial investigators addressed Ab precursor by secretases and either the potential adverse effects of NEP inhibition on removal of Ab from the central nervous system (CNS) the CNS (1). They pointed out that: there are by transport and perfusion mechanisms or by pro- redundant systems for NEP degradation and removal teolytic degradation (23).ThatanincreaseinAb in and therefore inhibition of NEP alone would not the brain is associated with the development of AD is influence Ab in the CNS; a study in cynomolgus shown by the finding that: 1) accumulation of Ab in monkeys showed increased levels of the Ab oligo- genetically engineered mice results in a neurologic mers in the cerebrospinal fluid without an increase phenotype that mimics AD (26,27);2)genemutations in levels of Ab in the brain; a 2-week study in in humans that increase Ab production cause healthy volunteers showed normal levels of Ab1-42 autosomal-dominant AD, whereas genetic variants and Ab1-40butanincreaseinAb1-38; and PARA- that reduce Ab production protect against the DIGM-HF trial investigators did not report adverse development of AD; and 3) Ab oligomers are neuro- events associated with cognition, memory loss or toxic and are major precipitants of the Ab cascade dementia. These arguments are not convincing: NEP (26). Interestingly, HF itself has been identified as a is generally regarded as playing a critical role in Ab risk factor for the development of cognitive degradation (23); a characteristic feature of early dysfunction that may be attributable to decreased (asymptomatic) AD is disruption of the blood brain cerebral blood flow and/or alterations in molecules barrier and increased permeability thus abrogating that are involved in Ab metabolism (28–31). the value of studies in normal volunteers or young There is also strong evidence that modulation of monkeyswithnormalblood-brainbarriers;andolder the activity of NEP in the brain plays a critical role in patients with HF are at high risk for alterations the pathogenesis of AD: 1) overexpression of NEP is in blood-brain barrier permeability due to age, sufficient to ameliorate AD in transgenic models of neurovascular disease, hypertension, diabetes, high AD (32); 2) NEP levels are low in regions of the brain cholesterol, or a family history of AD (44,45). that are vulnerable to AD pathology but normal in Furthermore, patients with early AD have leakiness areas not affected by AD (33,34);3)disruptionofthe of the blood-brain barrier due to the vascular pro- NEP gene causes an elevation in the levels of Ab in cesses that are pathognomonic of AD (46). Vodovar the mouse brain (35); 4) NEP levels decline with age et al. (47) posited that because most patients with in areas of the brain most affected by AD; 5) genetic HF are elderly, the risk of developing AD is limited mutations in the NEP gene or in the APP gene have by their shortened lifespan; however, the patients in been associated with increased risk of AD (36,37); whom sac/val appeared to be most effective in the and 6) aging is associated with decreased levels of PARADIGM-HF trial were those with the best NEP and increased Ab deposition and aggregation prognosis. in those areas of the brain that are most affected by Finally, the fact that neither patients nor the AD (38). members of the study team reported changes in 412 Feldman JACC:HEARTFAILUREVOL.4,NO.5,2016 Neprilysin Inhibition in the Time of Precision Medicine MAY 2016:409– 14

cognitive function as an adverse event is also not change in medication, those with worsening disease reassuring. An early diagnostic finding in AD is a on current therapy, and those in whom a pro- decrement in executive function that can only be nounced decrease in blood pressure could be toler- diagnosedwithspecific cognitive testing and is often ated (49). not noted by patients or their spouses. Similarly, patients can have early signs of AMD without noticing CONCLUSIONS changes in their vision, particularly if drusen or fluid accumulation occurs outside of the macula or is too The PARADIGM-HF trial was an ambitious study that small to influence vision. has provided important information regarding the While the theoretical risks associated with val/sac potential benefits of the combination of NEP inhibi- have not been widely discussed the AD risk has not tion and blockade of the angiotensin II receptor in gone without recognition by regulatory authorities. patients with relatively mild HF due to reduced The Office Director Decisional Memo (NDA 207620) ejection fraction. Nonetheless, an important lesson noted that: “the unanswered questions are whether that we have learned from drug development in HF sacubitril causes subtle CNS toxicity in the short over the past 4 decades is that the results from one term, or more severe toxicity in the longer term. trial provide information that is only informative These are salient questions, given that approxi- about the specific group of patients enrolled in that mately 50% of patients with HF will survive longer trial. Important areas of equipoise still exist and than 5 years” (48). Because of these concerns, the provide opportunities for additional and important Food and Drug Administration is requiring the trials despite the mortality benefitdemonstratedin sponsor to conduct a “multicenter, randomized, the PARADIGM-HF trial. For example, is sac/val safe double-blind, active-controlled trial to evaluate the and effective in patients with New York Heart Asso- effects of Entresto compared to valsartan on cogni- ciation functional class III/IV symptoms, lower tive function as assessed by a comprehensive resting blood pressure, and a higher use of implant- neurocognitive battery and [positron emission to- able cardioverter-defibrillators and resynchronization mography] imaging in patients with chronic heart devices? A study in a population with a higher failure with preserved ejection fraction” (48). severity of disease will provide information as to Unfortunately, the sponsor is not required to make whether sac/val is equally effective at lower doses the information from the trial available until 2022—a since patients with lower blood pressures are far less time period that could place a large number of pa- likely to tolerate the doses of sac/val used in the tients at risk before definitive data regarding safety PARADIGM-HFtrial.Anotherasyetunanswered is available. Because patients with heart failure with question is whether sac/val is beneficial in patients preserved ejection fraction have a different pheno- with left ventricular dysfunction post-myocardial type, a lower incidence of coronary disease and a infarction? It will also be important to know different prognosis, it is unclear whether evaluation whether patients who can no longer tolerate the dose of patients with HFpEF will approximate the poten- of sac/val used in the PARADIGM-HF trial should have tial effects in HFrEF. Unfortunately, the regulatory their dose reduced or should they be returned to their authorities have not recognized the theoretical risk pre-sac/val dose of an ACEi or an ARB? Only through of AMD with an NEPi and therefore there are no additional and well-designed clinical trials will phy- admonitions regarding evaluations of the potential sicians be able to know how best to use sac/val in the effects of sac/val on vision. treatment of the wide spectrum of phenotypes seen It should be noted that there are also adverse in patients with HF. economic consequences of treatment with sac/val In view of the theoretical risks associated with NEP for individuals who must pay for their own medi- inhibition and the devastating effects that AD or AMD cine. With a wholesale acquisition cost of $4,560 per canhaveonHFpatientsandtheirfamilies,anyfuture year, at least 8 times that of enalapril, physicians studies in patients with HFrEF should include thor- must weigh the risk-benefitratiofortheuseofsac/ ough, appropriate and serial assessment of cognitive val in each patient since it is far better for a patient and ophthalmic changes using diagnostic criteria to fill their prescription for an ACEi then to defer defined by consensus panels of AD neurologists therapy with a new agent because they cannot afford (cognitive testing including assessment of executive it (40). In fact, the California Technology Assessment function and either cerebrospinal fluid chemistry or Forum recommended that sac/val prescribing be positron emission tomography scanning) (50) and restricted to cardiologists and its use be prioritized retinal specialists (optical coherence tomography) toyoungerpatientswhoaremoreabletotoleratea (51). While recognizing that HF itself is a risk factor JACC:HEARTFAILUREVOL.4,NO.5,2016 Feldman 413 MAY 2016:409– 14 Neprilysin Inhibition in the Time of Precision Medicine

for the development of AD, physicians should be however, it can only reach that goal through addi- prudent in using sac/val in patients at high risk for AD tional studies that provide valid information about or AMD with particular care in patients with docu- thepreciseuseofthedruganditspotentialrisksin mented early forms of AD or AMD or with a family real-world settings. history of AD or AMD until more data is available. Finally, patients and their family members should be REPRINT REQUESTS AND CORRESPONDENCE: Dr. informed of the theoretical risks of cognitive and/or Arthur M. Feldman, Department of Medicine, Lewis visual dysfunction associated with NEP inhibition so Katz School of Medicine at Temple University, Suite that any cognitive or visual changes can be recog- C942, Parkinson Pavilion, 3401 North Broad Street, nized as early as possible. Sac/val may well provide a Philadelphia, Pennsylvania 19140. E-mail: arthur. new paradigm for the treatment of HF patients; [email protected].

REFERENCES

1. McMurray JJ, Packer M, Desai AS, et al. fraction in streptozotocin-induced diabetic mice. (CONSENSUS). The CONSENSUS Trial Study Angiotensin-neprilysin inhibition versus enalapril in Eur J Heart Fail 2016; Jan 7 [Epub ahead of print]. Group. N Engl J Med 1987;316:1429–35. heart failure. N Engl J Med 2014;371:993–1004. 12. Kentsch M, Otter W, Drummer C, Notges A, 21. Mair J, Lindahl B, Giannitsis E, et al. Will 2. Packer M. Love of ACE inhibitors in the time of Gerzer R, Muller-Esch G. Neutral endopeptidase sacubitril-valsartan diminish the clinical utility of cholera. J Am Coll Cardiol HF 2016;4:403–8. 24.11 inhibition may not exhibit beneficial hae- B-type natriuretic peptide testing in acute cardiac modynamic effects in patients with congestive care? Eur Heart J Acute Cardiovasc Care 2016; Jan 3. Flores A. Magical realism in Spanish American heart failure. Eur J Clin Pharmacol 1996;51: 12 [Epub ahead of print]. fiction. Hispania 1955;38:187–92. – 269 72. 22. Feldman AM, Haller JA, DeKosky ST. Valsartan/ 4. Fitzpatrick MA, Rademaker MT, Charles CJ, 13. sacubitril for heart failure: reconciling disparities et al. Acute hemodynamic, hormonal, and renal Rouleau JL, Pfeffer MA, Stewart DJ, et al. between preclinical and clinical investigations. effects of neutral endopeptidase inhibition in Comparison of vasopeptidase inhibitor, omapa- JAMA 2016;315:25–6. ovine heart failure. J Cardiovasc Pharmacol 1992; trilat, and lisinopril on exercise tolerance and 19:635–40. morbidity in patients with heart failure: IMPRESS 23. Nalivaeva NN, Belyaev ND, Kerridge C, – randomised trial. Lancet 2000;356:615 20. Turner AJ. Amyloid-clearing and their 5. Abassi ZA, Yahia A, Zeid S, et al. Cardiac and 14. epigenetic regulation as a therapeutic target in renal effects of omapatrilat, a vasopeptidase in- Yancy CW, Jessup M, Bozkurt B, et al. 2013 Alzheimer’s disease. Front Aging Neurosci 2014;6: hibitor, in rats with experimental congestive heart ACCF/AHA guideline for the management of heart 235. failure. Am J Physiol Heart Circ Physiol 2005;288: failure: a report of the American College of Car- H722–8. diology Foundation/American Heart Association 24. Iwata N, Higuchi M, Saido TC. Metabolism of Task Force on Practice Guidelines. J Am Coll Car- amyloid-beta peptide and Alzheimer’s disease. 6. Maki T, Nasa Y, Tanonaka K, Takahashi M, diol 2013;62:e147–239. Pharmacol Ther 2005;108:129–48. Takeo S. Direct inhibition of neutral endopeptidase 15. in vasopeptidase inhibitor-mediated amelioration Packer M, Poole-Wilson PA, Armstrong PW, 25. Iwata N, Tsubuki S, Takaki Y, et al. Identifica- of cardiac remodeling in rats with chronic heart et al. Comparative effects of low and high doses of tion of the major Abeta1-42-degrading catabolic failure. Mol Biochem 2003;254:265–73. the angiotensin-converting , lisi- pathway in brain parenchyma: suppression leads nopril, on morbidity and mortality in chronic heart to biochemical and pathological deposition. Nat 7. von Lueder TG, Wang BH, Kompa AR, et al. failure. ATLAS Study Group. Circulation 1999;100: Med 2000;6:143–50. Angiotensin receptor neprilysin inhibitor LCZ696 – 2312 8. 26. attenuates cardiac remodeling and dysfunction Baranello RJ, Bharani KL, Padmaraju V, et al. after myocardial infarction by reducing cardiac 16. Konstam MA, Neaton JD, Dickstein K, et al. Amyloid-beta protein clearance and degradation ’ fibrosis and hypertrophy. Circ Heart Fail 2015;8: Effects of high-dose versus low-dose losartan on (ABCD) pathways and their role in Alzheimer s – 71–8. clinical outcomes in patients with heart failure disease. Curr Alzheimer Res 2015;12:32 46. (HEAAL study): a randomised, double-blind trial. 27. 8. Trippodo NC, Fox M, Monticello TM, Krohn M, Bracke A, Avchalumov Y, et al. Lancet 2009;374:1840–8. Panchal BC, Asaad MM. Vasopeptidase inhibition Accumulation of murine amyloid-beta mimics ’ with omapatrilat improves cardiac geometry and 17. McNamara DM, Holubkov R, Postava L, et al. early Alzheimer s disease. Brain 2015;138: – survival in cardiomyopathic hamsters more than Pharmacogenetic interactions between angiotensin- 2370 82. does ACE inhibition with captopril. J Cardiovasc converting enzyme inhibitor therapy and the 28. de Toledo Ferraz Alves TC, Ferreira LK, Pharmacol 1999;34:782–90. angiotensin-converting enzyme deletion poly- Wajngarten M, Busatto GF. Cardiac disorders as morphism in patients with congestive heart failure. ’ 9. Lapointe N, Blais C Jr., Adam A, et al. Com- risk factors for Alzheimer s disease. J Alzheimers J Am Coll Cardiol 2004;44:2019–26. – parison of the effects of an angiotensin- Dis 2010;20:749 63. converting enzyme inhibitor and a vasopeptidase 18. Nanas JN, Alexopoulos G, Anastasiou-Nana MI, 29. Jefferson AL, Himali JJ, Au R, et al. Relation of inhibitor after myocardial infarction in the rat. et al. Outcome of patients with congestive heart left ventricular ejection fraction to cognitive aging J Am Coll Cardiol 2002;39:1692–8. failure treated with standard versus high doses of (from the Framingham Heart Study). Am J Cardiol enalapril: a multicenter study. High Enalapril Dose 2011;108:1346–51. 10. Lapointe N, Tsoporis JN, Parker TG, et al. Study Group. J Am Coll Cardiol 2000;36:2090–5. Comparative effects of a vasopeptidase inhibitor 30. Jefferson AL, Himali JJ, Beiser AS, et al. Cardiac vs. an angiotensin converting enzyme inhibitor on 19. Tang WH, Vagelos RH, Yee YG, et al. Neuro- index is associated with brain aging: the Framing- cardiomyocyte apoptosis in rats with heart failure. hormonal and clinical responses to high- versus ham Heart Study. Circulation 2010;122:690–7. Mol Cell Biochem 2003;254:235–45. low-dose enalapril therapy in chronic heart failure. 31. Qiu C, Winblad B, Marengoni A, Klarin I, J Am Coll Cardiol 2002;39:70–8. 11. Suematsu Y, Miura SI, Goto M, et al. LCZ696, Fastbom J, Fratiglioni L. Heart failure and risk of an angiotensin receptor-neprilysin inhibitor, im- 20. Effects of enalapril on mortality in severe dementia and Alzheimer disease: a population- proves cardiac function with the attenuation of congestive heart failure. Results of the Coopera- based cohort study. Arch Intern Med 2006;166: fibrosis in heart failure with reduced ejection tive North Scandinavian Enalapril Survival Study 1003–8. 414 Feldman JACC:HEARTFAILUREVOL.4,NO.5,2016 Neprilysin Inhibition in the Time of Precision Medicine MAY 2016:409– 14

32. Li Y, Wang J, Zhang S, Liu Z. Neprilysin gene 39. Ohno-Matsui K. Parallel findings in age- 47. Vodovar N, Paquet C, Mebazaa A, Launay JM, transfer: A promising therapeutic approach for related macular degeneration and Alzheimer’s Hugon J, Cohen-Solal A. Neprilysin, cardiovascu- Alzheimer’s disease. J Neurosci Res 2015;93: disease. Prog Retin Eye Res 2011;30:217–38. lar, and Alzheimer’s diseases: the therapeutic 1325–9. split? Eur Heart J 2015;36:902–5. 40. Anderson DH, Talaga KC, Rivest AJ, Barron E, 33. Carpentier M, Robitaille Y, DesGroseillers L, Hageman GS, Johnson LV. Characterization of beta 48. U.S. Food and Drug Administration. New Drug Boileau G, Marcinkiewicz M. Declining expression amyloid assemblies in drusen: the deposits asso- Application Approval Letter. 2015. Available at: of neprilysin in Alzheimer disease vasculature: ciated with aging and age-related macular http://www.accessdata.fda.gov/drugsatfda_docs/ possible involvement in cerebral amyloid angi- degeneration. Exp Eye Res 2004;78:243–56. appletter/2015/207620Orig1s000ltr.pdf. Accessed November 30, 2015. opathy. J Neuropathol Exp Neurol 2002;61: 41. He Y, Zhao H, Su G. Ginsenoside Rg1 decreases – 849 56. neurofibrillary tangles accumulation in retina by 49. Ollendorf DA, Sandhu AT, Pearson SD. Sacu- 34. Yasojima K, McGeer EG, McGeer PL. Relation- regulating activities of neprilysin and PKA in retinal bitril-valsartan for the treatment of heart failure ship between beta amyloid peptide generating cells ofADmice model.J Mol Neurosci 2014;52:101–6. effectiveness and value. JAMA Internal Medicine 2016;175:249–50. molecules and neprilysin in Alzheimer disease and 42. Wang J, Ohno-Matsui K, Morita I. Elevated – normal brain. Brain Res 2001;919:115 21. amyloid beta production in senescent retinal 50. Albert MS, DeKosky ST, Dickson D, et al. The 35. Huang SM, Mouri A, Kokubo H, et al. Neprily- pigment epithelium, a possible mechanism of diagnosis of mild cognitive impairment due to ’ sin-sensitive synapse-associated amyloid-beta subretinal deposition of amyloid beta in age- Alzheimer s disease: recommendations from the peptide oligomers impair neuronal plasticity and related macular degeneration. Biochem Biophys National Institute on Aging-Alzheimer’s Associa- cognitive function. J Biol Chem 2006;281: Res Commun 2012;423:73–8. tion workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011;7: 17941–51. 43. Parthasarathy R, Chow KM, Derafshi Z, et al. 270–9. 36. Betts V, Leissring MA, Dolios G, Wang R, Reduction of amyloid-beta levels in mouse eye 51. Selkoe DJ, Walsh DM. Aggregation and catabolism tissues by intra-vitreally delivered neprilysin. Exp American Academy of Opthalmology. AAO – of disease-associated intra-Abeta mutations: Eye Res 2015;138:134 44. Retina/Vitreous PPP Panel, Hoskins Center for Quality Eye Care. Age-Related Macular Degenera- reduced proteolysis of AbetaA21G by neprilysin. 44. Deane R, Zlokovic BV. Role of the blood-brain tion PPP. 2015. Available at: http://www.aao.org/ Neurobiol Dis 2008;31:442–50. barrier in the pathogenesis of Alzheimer’s disease. preferred-practice-pattern/age-related-macular- 37. Curr Alzheimer Res 2007;4:191–7. Wood LS, Pickering EH, McHale D, degeneration-ppp-2015. Accessed November 15, 45. Dechairo BM. Association between neprilysin Ujiie M, Dickstein DL, Carlow DA, Jefferies WA. 2015. polymorphisms and sporadic Alzheimer’s disease. Blood-brain barrier permeability precedes senile Neurosci Lett 2007;427:103–6. plaque formation in an Alzheimer disease model. Microcirculation 2003;10:463–70. 38. Iwata N, Takaki Y, Fukami S, Tsubuki S, Saido TC. Region-specific reduction of A beta- 46. Erickson MA, Banks WA. Blood-brain barrier KEY WORDS age-related macular degrading endopeptidase, neprilysin, in mouse dysfunction as a cause and consequence of Alz- degeneration, Alzheimer’s disease, angiotensin- hippocampus upon aging. J Neurosci Res 2002;70: heimer’s disease. J Cereb Blood Flow Metab 2013; converting enzyme inhibitor, heart failure, 493–500. 33:1500–13. neprilysin