Andrew E. Schneider, MD,​a Bryan C. Cannon, MD,a​ Jonathan N. Johnson, MD,a​ LeftMichael J. Ackerman, Axis MD, PhD, Deviationa,​ ​b,​c Philip L. Wackel, MDa in Children Without Previously Known Heart Disease BACKGROUND: abstract

Left axis deviation (LAD) discovered in children via electrocardiogram (ECG) is uncommon but can be associated with heart disease (HD). The optimal diagnostic approach in a seemingly healthy child with LAD is unclear. We sought to better stratify which patients METHODS: with LAD but without previously known HD may warrant additional workup.≥ − A retrospective chart review was performed to identify patients 1 to <18 years of age with LAD (QRS frontal plane axis 0 to 90) on an ECG between January 2002 and RESULTS: n December 2014. Patients with known HD before their initial ECG were excluded. ± − ± ° Overall, 296 patients were identified ( = 181 [61%] male; mean age: 10.8 4.6 years; mean QRS axis: 24 22 ). An echocardiogram was performed in 158 (53%) n − − ° patients, with 24 (15%) having HD. Compared with those with an echocardiogram but P ≤− ° P without HD ( = 134), patients with HD had a more negativeP mean QRS axis ( 42 vs 27 ; = .002) and were more likely to have a QRSP axis 42 (58% vs 26%; = .003), ECG chamber enlargement or hypertrophy (38% vs 5%; < .0001), and abnormal cardiac CONCLUSIONS: physical examination findings (75% vs 8%; < .0001). LAD discovered in isolation in the asymptomatic pediatric patient may not necessitate further cardiovascular investigation. Clinicians should consider obtaining ≤− ° an echocardiogram in patients with LAD and ECG cardiac chamber enlargement or hypertrophy, a QRS axis 42 , and/or the presence of abnormal cardiac physical examination findings. aDivision of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, bDivision of Heart Wh’ownat s Kn on This Subject: Left axis Rhythm Services, Department of Cardiovascular Diseases, and cDepartment of Molecular Pharmacology deviation (LAD) is associated with particular forms and Experimental Therapeutics and Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, of cardiac pathology in children, with many cases Rochester, Minnesota identified during infancy. The prevalence of heart Dr Schneider conceptualized and designed the study, performed data collection, analysis, and disease (HD) in asymptomatic children with LAD is interpretation, and reviewed and revised the manuscript; Dr Wackel conceptualized and designed unknown, and the additional workup required is the study and reviewed and revised the manuscript; Drs Ackerman, Johnson, and Cannon unclear. critically analyzed the collected data and reviewed and revised the manuscript; and all authors What This Study Adds: We identify risk factors approved the final manuscript as submitted. that make the presence of HD more likely in children DOI: https://​doi.​org/​10.​1542/​peds.​2017-​1970 with LAD but without previously known HD. These Accepted for publication Dec 5, 2017 risk factors aid physicians in determining which Address correspondence to Philip L. Wackel, MD, Mayo Clinic, 200 First St SW, Gonda 6, Rochester, patients may require further workup if LAD is MN 55905. E-mail: [email protected] detected incidentally. PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2018 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: Other than those already listed under Potential Conflict of Interest, the other authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: No external funding. To cite: Schneider AE, Cannon BC, Johnson JN, et al. Left Axis Deviation in Children Without Previously Known Heart Disease. Pediatrics. 2018;141(3):e20171970

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 141, number 3, March 2018:e20171970 Article TABLE 1 Patient Demographics and ECG QRS Axis Total Cohort (n = 296) Echocardiogram No Echocardiogram P Physicians caring for children (n = 158) (n = 138) may obtain an electrocardiogram Age, y 10.8 ± 4.6 (1–17) 10.2 ± 4.9 (1–17) 11.4 ± 4.3 (1–17) .02 (ECG) for any number of reasons Male sex, n (%) 181 (61) 97 (61) 84 (61) .99 during the life of a child. When an QRS axis, degrees −24.2 ± 21.6 −29.0 ± 22.6 −18.7 ± 19 <.0001 abnormal QRS axis is noted, this Follow-up, y 3.9 ± 3.7 4.6 ± 3.8 3.2 ± 3.5 .001 may implicate underlying congenital Continuous variables are expressed as mean values followed by the SD and interquartile range. The remaining are heart disease (CHD). Age-based numerical values followed by a percentage. pediatric normative values for the mean frontal plane QRS axis 1have been established previously. Left axis deviation (LAD) occurs when ECG were excluded from this study, and outcomes. In a subset of patients the summation of ventricular as were patients with left bundle in whom HD was discovered, we electrical forces results in a mean branch block, paced ventricular also reviewed the type of HD present frontal plane QRS vector that is more rhythm, LAD occurring in the context and the indication for the ECG. This negative than normative values, of wide complex , and protocol was approved by the Mayo arriving via a counterclockwise loop LAD occurring after orthotopic heart Clinic Institutional Review Board. transplant. In patients with more ± in the vectorcardiogram. LAD is a Continuous variables were expressed than 1 ECG revealing LAD, the initial relatively uncommon finding in the as a mean SD and ordinal variables ECG revealing LAD was used for ’ t ’ pediatric population but one that as total number and percentage. analysis. has been associated with specific Student s test or 2-tailed Fisher s forms of cardiac pathology, namely 2 Standard 12- or 15-lead ECGs exact test were performed to the following: ,​ 3 were obtained at the discretion of compare continuousP and ordinal atrioventricular septal defects,​ and ≤ 4,5​ the ordering provider caring for values between groups, respectively, Wolff-Parkinson-White syndrome. each individual patient. Reported as appropriate. A value .05 was LAD in an infant is highly suspicious mean fontal plane QRS values were deemed statistically significant. All for CHD, and an echocardiogram calculated automatically by the MUSE data analyses were performed by is generally warranted, but there Cardiology Information System (GE using JMP (SAS Institute, Inc, is a paucity of literature in which Healthcare, Chicago, IL). ECGs were Cary, NC). the implications of LAD in the read by a pediatric cardiologist using Results asymptomatic child outside of age-based normative QRS axis values infancy have been outlined. This 1 reported by Davignon et al. LAD lack of data could result in over- or ≤ ≥− ° ± – was defined in our study as a QRS Overall, 296 patients (mean age: underuse of further testing to exclude axis 0 and 90 . Transthoracic 10.8 4.6 years; range: 1 17 years; heart disease (HD). Furthermore, echocardiograms (TTEs) were 181 male [61%]) met inclusion the prevalence of previously obtained at the discretion of the criteria for our study (Table 1). The unrecognized HD in this patient − ± ° provider caring for each individual mean frontal plane QRS axis for this population is uncertain, making it ± patient because screening group was 24 22 with a mean difficult to know if further workup is echocardiograms are not performed follow-up duration of 3.9 3.7 years. warranted. In this study, we aimed universally at our institution for An echocardiogram was performed to better stratify which children with children with newly diagnosed in 158 (53%) patients (Table 1). LAD but without previously known LAD. TTEs were performed at Mayo Compared with the 138 patients HD may warrant further cardiac Clinic during the study period and without an echocardiogram, these workup. P were conducted on commercially patients were significantly younger in − Methods available cardiac ultrasound systems age (10.2 vs 11.4 years; = .02), had − ° P by employing an established CHD a more negative QRS axis ( 29.0 vs protocol. P 18.7 ; < .0001), and had a longer ’ follow-up period (4.6 vs 3.2 years; A retrospective review of Mayo We subsequently examined = .001). Because we were unable to Clinic s electronic medical record demographic variables, the ≥ verify the presence or absence of HD was performed to identify all mean frontal plane QRS axis, ECG in those without a TTE, our subset patients 1 to <18 years of age evidence of cardiac enlargement analysis was focused on patients who who had ECG evidence of LAD from or chamber hypertrophy, cardiac received a TTE. January 2002 to December 2014. physical examination findings, Patients with known HD (including echocardiographic findings (when Of the 158 patients who were LAD- channelopathies) before their initial available), patient follow-up duration, positive who had a TTE, 24 (15%) Downloaded from www.aappublications.org/news by guest on September 30, 2021 2 Schneider et al TABLE 2 HD Subtypes Diagnosed in Children With LAD but Without Previously Known HD (n = 24) Identified HD Subtypes (n = 24) ASD, secundum (4) DCM (4) HCM (4) Partial atrioventricular septal defect (4) Bicuspid (1) Congenitally corrected transposition of the great arteries (1) Traumatic flail (1) Left ventricular noncompaction (1) Mitral stenosis (1) MVP (1) RCM (1) VSD, membranous (1)

patients were determined to have some form of HD (Table 2). Detected n FIGURE 1 forms of HD included secundum Mean frontal plane QRS axis (degrees) in patients with HD compared with those without. atrialn septal defect (ASD) ( = 4), dilated cardiomyopathyn (DCM) ( = 4), hypertrophicn cardiomyopathy n (HCM) ( = 4), partial atrioventricular Compared with those with a TTE but .0001) (Table 3). The NPV in this case no HD ( = 134), patients with HD had was 98%, with a sensitivity of 92%. canal defect ( = 4), and 1 instance − − ° P of each of the following: bicuspid a significantly more negative mean There was no statistical difference aortic valve, congenitally corrected QRS axis ( 41.9 vs 26.7 ; = .002) between groupsP of patients with just (Fig 1). Although patients with HD 1 positive variable (38% HD versus transposition of the great arteries, ≤− ° P left ventricular noncompaction were more likely to have a mean QRS 31% without;P = .6). Patients with 2 cardiomyopathy, axis 30 (67% vs 39%; = .01), positive variables (29% HD versus 3% a receiver operating characteristic without; = .0002) were significantly stenosis, (MVP), ≤− ° more likely to have HD (specificity: restrictive cardiomyopathy (RCM), curve suggested that a mean QRS axis 97%; PPV: 64%; relative risk [RR]: membranous ventricular septal 42 may provide enhanced patient discrimination. Patients with HD were 9.8; odds ratio [OR]: 13.4), as were defect (VSD), and flail tricuspid valve ≤− ° P significantly more likely to have a patients with all 3 positive variables leaflet (traumatic). Indications for P ’ mean QRS axis 42 (58% vs 26%; (25% HD versus 1% without; < the original ECG as documented by n = .003) (sensitivity: 58%; specificity: .0001) (specificity: 99%; PPV: 88%; the patient s care provider included n 74%; positive predictive value [PPV]: RR: 33.5; OR: 44.3). murmur ( = 10), and/or n 29%; negative predictive value tachycardia ( = 3), screening The mean follow-up duration for n [NPV]: 91%), evidence of cardiac patients with HD was significantly for familial HCM ( = 3), dyspnea P P chamber enlargement or hypertrophy longer than in those without HD (6.5 vs ( = 2), and 1 instance of each of the n on an ECG (38% vs 5%; < .0001) 4.3 years; = .006). However, 77% following: chest pain, renal failure, ≥ (sensitivity: 38%; specificity: 95%; ( = 103) of the patients without HD scleroderma, stroke, syncope, PPV: 56%; NPV: 89%), and abnormal were followed for 1 year, and none of and trauma. Abnormal cardiac cardiac examination findingsP as these patients subsequentlyn developed physical examination findings were documented by the physician caring HD or died of a cardiac cause. Likewise, documented in 18 (75%) patients for them (75% vs 8%; < .0001) none of the patients ( = 138) without ± with HD. Specific heart defects that (sensitivity: 75%; specificity: 92%; a TTE subsequently developed HD or were detected on TTE in patients PPV: 62%; NPV: 95%) (Fig 2). Patients ≤− ° died of a cardiac cause in 3.2 3.5 without a concomitantly documented who had none of these 3 variables years of follow-up. Two (9%) patients physical examination abnormality present (axis 42 , ECG enlargement within the HD patient subset died of included bicuspid aortic valve, or hypertrophy, or abnormal cardiacP cardiac causes during follow-up. One secundum ASD, DCM, HCM, MVP, and examination) were unlikely to have patient with RCM died of sudden RCM (1 patient each). HD (8% HD versus 65% without; < cardiac death at the age of 16 after Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 141, number 3, March 2018 3 5,8,​ 9​ VSDs,​ ‍ ‍ disruption of the5,10​ left anterior11 bundle branch,​ ‍ and natural aging. LAD may also be a normal variant in a small subset of children who seemingly experience a benign

clinical course on the6, basis12​ of short- term follow-up data. ‍ Out of 158 patients with LAD and a TTE in our study, 24 (15%) patients had some form of HD. Four of the identified patients had partial atrioventricular canal defects, in which LAD is expected secondary to displacement of the

A-V node posteriorly3 and His bundle inferiorly. Although LAD has been

described in patients with both13 primum and secundum ASDs and

congenitally corrected14 transposition of the great arteries,​ it is not classically associated with the other defects FIGURE 2 Comparison of the following selected variables between patients with HD and those without: that were appreciated in our study. abnormal cardiac physical examination findings, electrocardiographic evidence of cardiac chamber LAD in these patients may reflect a enlargement or hypertrophy, and a mean QRS axis ≤−42°. normal, coincidental variant given that anatomically the conduction system TABLE 3 Statistical Analysis of Variable Positivity in Patients With HD Compared With Those Without should not be disrupted or displaced from the usual position. No. HD No HD P Sensitivity, Specificity, PPV, NPV, RR OR Positive (n = (n = 134), % % % % Variables 24), % % Three objective clinical features were 0 8 65 <.0001 92 65 32 98 0.13 0.01 identified as being discriminators 1 38 31 .64 38 69 18 86 1.2 1.3 of patients with HD compared ≤− ° 2 29 3 .0002 29 97 64 88 9.8 13.4 with those without: degree of LAD 3 25 1 <.0001 25 99 86 88 33.5 44.3 ( 42 ), presence of ECG chamber Assessed variables include the following: (1) abnormal cardiac physical examination findings, (2) electrocardiographic enlargement or hypertrophy, evidence of cardiac chamber enlargement or hypertrophy, and (3) mean QRS axis 42 . ≤− ° and abnormal cardiac physical examination findings. The latter 2 variables were the most sensitive receiving an orthotopic heart on an individual basis if the clinical discriminators of HD when taken on transplant. The second patient scenario is suggestive of a child with their own. However, the presence had HCM and died of a cardiac previously unrecognized HD or simply of any 1 variable found in isolation, statistically, did not predict the Ddysrhythmiaiscussion at 21 years of age. a variant of normal. Objective data discriminating these 2 groups are existence of HD in patients with LAD (PPV: 18%; RR: 1.2). Patients with a lacking. Therefore, we evaluated a combination of any 2 or all 3 positive cohort of children without previously The incidence of LAD in the pediatric variables were 10 to 33 times more recognized HD who had LAD identified population has not been– well likely to have HD, and additional on an ECG at our institution. Ultimately, established, but previous5 7 estimates cardiovascular workup would be we determined that LAD found in range from 1% to 2%. ‍‍ Patients warranted based on these data. with LAD and clinically significant HD isolation may be a variant of normal, Conversely, patients with none of the are often identified during infancy. but in certain patients, specific risk 3 aforementioned positive variables LAD discovered incidentally in the factors may suggest unidentified HD. were extremely unlikely to have otherwise healthy child outside of Across the spectrum of ages, LAD HD, and additional cardiovascular infancy is less common, and the may result from multiple etiologies, workup may not be of benefit. prevalence of HD in this patient including2 the following: tricuspid 3 population is unknown. Pediatricians atresia,​ atrioventricular septal defects,4,5​ ​ Two patients with HD had none of and cardiologists alike must determine Wolff-Parkinson-White syndrome,​ ‍ the 3 positive variables. One of the Downloaded from www.aappublications.org/news by guest on September 30, 2021 4 Schneider et al patients was being screened for arrhythmia or sudden cardiac death, obtaining the ECG was not always palpitations and was found to have so additional cardiovascular workup known. Patients were also selected to DCM, whereas the other was found to or referral is likely unnecessary in the have ECGs and echocardiograms on have asymptomatic HCM after being absence of additional cardiovascular the basis of the suspicion of disease screened for familial HCM. The single risk factors or other clinical concerns. from the physicians caring for them. An patient without HD but who tested 13 ascertainment bias was also present positive for all 3 variables was a 3-year- As previously stated, Ravi et al because we did not prove or disprove concluded that the next most cost- old with an innocent murmur who met then presence of HD in those patients right criteria effective step in the evaluation of with LAD and no echocardiogram − ° on the basis of S-wave depth in lead V6, patients with recognized LAD would ( = 138), so they were not included with a QRS axis of 53 . Nevertheless, be referral to a pediatric cardiologist in our analysis of variables. Secondary the most compelling conclusion from who may be more judicious in to these aforementioned reasons, and our data is that patients with no determining if an echocardiogram is in conjunction with the fact that we positive variables are unlikely to have required. They did not, however, take excluded all patients with known HD HD (NPV: 98%). into account additional identifiable from our study, our data should not risk factors (as we did) that may be interpreted as an estimate of LAD 13 place the patient at an increased risk A previous study by Ravi et al prevalenceConclusions in children. revealed that consultation with a for structural HD, thus increasing pediatric cardiologist was the most the pretest probability of the echocardiogram. With our data, we cost-effective initial step in further ≥ LAD discovered in isolation in the evaluation of patients with LAD. suggest that a child with LAD and any concomitant combination of 2 asymptomatic pediatric patient may Echocardiograms were found to only ≤− ° not necessitate further cardiovascular be cost-effective in patients with positive variables (degree of LAD [ 42 ], presence of ECG chamber investigation, particularly if no LAD in the presence of abnormal additional findings are present. cardiovascular physical examination enlargement or hypertrophy, and abnormal cardiac physical Clinicians should consider obtaining findings. In our study, the presence or an echocardiogram in patients with absence of abnormal cardiovascular examination findings) would benefit from an echocardiogram to rule LAD who exhibit at least 2 of these examination findings was based on 3 variables: (1) abnormal cardiac documentation from any provider out the presence of structural HD, particularly in the context of abnormal physical examination findings, (2) who saw the patient and ordered ECG cardiac chamber enlargement or the ECG, many of whom were not physical examination findings. The ≤− ° decision to obtain the echocardiogram hypertrophy, and/or (3) a QRS axis pediatric cardiologists. The following 42 . 6 cardiovascular abnormalities were first or refer directly to a pediatric not identified or suspected on the cardiologist and then get an echocardiogram will vary depending basis of the documented clinical Abbreviations examination: bicuspid aortic valve, on multiple factors, including access ’ secundum ASD, DCM, HCM, MVP, to testing and/or care and the comfort and RCM. It s possible that some level of the provider following up on ASD: atrial septal defect of these lesions could have been the results. If a referral is made first, CHD: congenital heart disease detected by a provider more adept cardiologists should use their clinical DCM: dilated cardiomyopathy at detecting subtle nuances of the judgment regarding the need for an ECG: electrocardiogram cardiac examination. However, echocardiogram in patients with LAD, HCM: hypertrophic despite these patients with HD having although an echocardiogram should ≥ cardiomyopathy no detected physical examination be strongly considered in patients HD: heart disease abnormalities, the NPV of having with 2 positive variables. LAD: left axis deviation none of the 3 identified variables Our study was limited by a small MVP: mitral valve prolapse was still high (98%). Therefore, with sample size, although to our NPV: negative predictive value these data we suggest that it may not knowledge, this study represents OR: odds ratio be absolutely necessary to have a the largest of its kind in the medical PPV: positive predictive value pediatric cardiologist examine each literature. Other limitations included RCM: restrictive cardiomyopathy patient with LAD to determine if an selection bias because all patients RR: relative risk echocardiogram is justified. It should presented to our medical center TTE: transthoracic also be noted that LAD in and of itself under the assumption that some type echocardiogram has not been shown to predispose of medical problem was present, VSD: ventricular septal defect an individual to life-threatening although the exact indication for Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 141, number 3, March 2018 5 POTENTIAL CONFLICT OF INTEREST: Dr Ackerman is a consultant for Audentes Therapeutics, Boston Scientific, Gilead Sciences, Invitae, Medtronic, MyoKardia, and St. Jude Medical. Dr Ackerman and Mayo Clinic have a potential equity and/or royalty relationship with AliveCor, Blue Ox Health, and StemoniX. However, none of these entities have participated in this study in any way; the other authors have indicated they have no potential conflicts of interest to disclose.

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