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Introduction:Left ventricular systolic dysfunction (LVSD, LV ejection fraction (LVEF) <50), occurs in ~8% of adults with hypertrophic cardiomyopathy (HCM) and is associated with poor prognosis. However, the incidence and prognosis of LVSD in pediatric patients with HCM (<18 years old) is poorly understood.Methods:Patients in SHaRe with pediatric HCM were included. Time-to-event analyses were performed to estimate 1) cumulative incidence of LVSD in pediatric vs adult HCM (Kaplan Meier), 2) predictors of incident LVSD in pediatric HCM (Cox-proportional hazards) and 3) a composite outcome of all-cause mortality, heart transplant and left ventricular assist device implant in pediatric HCM.Results:In total, 1296 pediatric HCM patients (34% females, median 12.2 years at diagnosis, median 8.3 years follow-up) were included. LVSD occurred in 155 (12%) of patients with 29% (n=45) having LVSD at the first SHaRe visit and 22% (n=34) developing LVSD <18 years old. At 5-year follow-up, the cumulative incidence of LVSD was 9% [8-11%]. Predictors of incident pediatric LVSD included HCM before age 12 (HR 2.0 [1.3-3.0]), female sex (HR 0.49 [0.32-0.77]), P/LP variants in thick filament genes (HR 2.6 [1.1-4.2], multiple P/LP variants (HR 9.1 [CI 2.9-29.1]) and baseline LVEF (HR 0.63 [0.58-0.68], per 5 %-points increase). Pediatric HCM was associated with higher rate of LVSD compared to adult-onset HCM (n=6428, median HCM at age 49 years, median follow-up of 7.1 years), p=0.05 (Figure 1). The composite endpoint occurred in 41% (n= 63/155) of children with HCM and subsequent LVSD. In patients with LVSD, female sex (HR 2.44 [1.41-4.17]) and baseline LVEF <35% (HR 4.0 [2.4-6.9]) were independently associated with the composite outcome.Conclusion:Females were less likely to develop LVSD but more likely to have adverse outcomes once they do. Clinical outcomes are adverse, and greater recognition of and surveillance for LVSD in pediatric HCM are warranted.

Introduction:Mavacamten, a selective inhibitor of cardiac myosin, improved symptoms and exercise capacity (pVO2) in adults with obstructive hypertrophic cardiomyopathy (oHCM) (EXPLORER-HCM; NCT03470545). Improvements in pVO2were observed regardless of whether patients were receiving beta-blockers (BB), but were greater in those not receiving BB. To examine whether BB lessen the effect of mavacamten on other parameters such as function, echocardiographic parameters, biomarkers and symptoms further sub-group analyses of EXPLORER-HCM and the mavacamten long-term extension (MAVA-LTE; NCT03723655) studies were conducted.Methods:In the phase 3, placebo-controlled EXPLORER-HCM trial, randomization was stratified by BB usage, and pre-specified sub-group analyses were performed. MAVA-LTE is an ongoing study evaluating long-term mavacamten dosing in patients with HCM who completed EXPLORER-HCM or MAVERICK. Sub-group analyses by BB usage for the same endpoints, if available, were performed post hoc including only patients with oHCM.Results:Results are shown in the Table. In EXPLORER-HCM, the majority of patients not taking BB received non-dihydropyridine calcium channel blockers (mavacamten [25/29 patients] or placebo [17/33]); this trend continued in MAVA-LTE. In EXPLORER-HCM, the mean change from baseline in pVO2was lower in the sub-group using BB (1.1 ml/kg/min) vs not using BB (2.2 ml/kg/min), while the heart rate-independent parameter, VE/VCO2slope (ventilatory efficiency), improved similarly in both groups (-2.4 vs -2.7). Improvements in symptoms (NYHA Class, KCCQ-CSS), LVOT gradients, LAVI, and biomarkers (NT-proBNP and cTnI) were similar between subgroups across both studies.Conclusion:In EXPLORER-HCM, the reduced effect of mavacamten on pVO2 in BB users is likely due to the effect of BB on heart rate response during exercise. Mavacamten benefits were observed across a range of clinically meaningful parameters regardless of BB use.

Introduction:Pressure overload from hypertension (HTN) is an important cause of left ventricular hypertrophy (LVH) in the general population, however its impact on disease expression in hypertrophic cardiomyopathy (HCM), and differences based on the presence/absence of a sarcomeric gene variant are not well characterized.Hypothesis:HTN is associated with more prominent manifestations of HCM.Methods:Genotyped HCM patients in the Sarcomeric Human Cardiomyopathy Registry were designated SARC+ ((likely) pathogenic sarcomeric variant present) or SARC- and categorized as having HTN (≥140/90 mmHg) or normal blood pressure (nonHTN; <140/90 mmHg). Heart failure (HF; LVEF<35%, NYHA III-IV, transplant/LVAD), ventricular arrhythmias (VA; sudden death, resuscitated arrest, appropriate ICD discharge), atrial fibrillation (AF), and an overall composite (HF, VA, AF, death) were assessed by Kaplan-Meier analysis and logistic regression.Results:Of 1706 patients (62% male), 445 (26%) had HTN. Median follow up was 4.2 years. SARC+ nonHTN patients were youngest and SARC- HTN patients oldest (p<0.001; Table). Obstructive physiology was most common in SARC- HTN. SARC+ nonHTN patients had the greatest wall thickness, although absolute differences were minimal (Table). HTN was associated with HF and the overall composite outcome, but not VA or AF (Figure). On multivariable analysis, HTN predicted the HF composite (OR 1.59 [95% CI 1.07-2.26], p=0.02), especially in SARC+ patients (OR 2.34 [95% 1.33-4.11], p=0.003).Conclusions:HTN is associated with worse HF outcomes in HCM, especially among SARC+ patients, but has minimal impact on the degree of cardiac remodeling.

Introduction:Genetic hypertrophic cardiomyopathy (HCM) is an autosomal dominant inherited condition primarily due to pathogenic variants in sarcomere genes, often with marked clinical variability. We hypothesized that this variability may, in part, be due to additive effects from low penetrance sarcomere variants that would otherwise be dismissed due to high population prevalence.Methods:Low-penetrance HCM-associated sarcomere gene variants were identified by meeting a threshold for enrichment in HCM (ascertained from the Sarcomeric Human Cardiomyopathy Registry, SHaRe) versus the general population (ascertained from the Genome Aggregation Database, gnomAD), defined by an odds ratio (OR) >5, and a population prevalence greater than the most common autosomal dominant pathogenic HCM variant, MYBPC3R502W (4x10-5). Clinical variables and time-event analyses were performed from SHaRe .Results:A total of 507 unique sarcomere gene variants were present in 6384 individuals with genetic testing. Ten putative low-penetrance variants were identified in the genes MYBPC3(N=2), TNNT2(N=1), TNNI3(N=2), and MYH7(N=5) with a combined OR of 12.7 (range 5.8 - 28.4). These variants had a population prevalence of 4.02x10-5to 3.5x10-4. Family members of low-penetrance variant carriers were less likely to have HCM (35/171, 20%) than those of MYBPC3R502W carriers (44/113, 39%, p<0.005). Age of diagnosis was older in patients with isolated low-penetrance variants than those with pathogenic variants (42 ± 19 vs 37 ± 18, p=0.005). Composite adverse events were less likely in patients with isolated low-penetrance variants than typical pathogenic sarcomere variants, but the risk was additive with both present (see Figure).Conclusions:A subset of low-penetrance sarcomere gene variants are tolerated in the general population at higher than expected proportions for HCM and may exert an additive pathogenic effect. These findings support an oligogenic risk model of HCM.

Introduction:Safety of vigorous exercise for individuals with appropriately-treated HCM remains debated. Physical activity practices in this population have not been described. The objective of this report is to describe physical activity pattern in HCM patients. Long term follow up which is ongoing will determine safety of vigorous exercise.Methods:The NIH-funded LIVE-HCM study prospectively enrolled individuals age 8-60 years with clinically overt HCM or patients with a positive genetic test for sarcomeric HCM. Participants (or parents, for children) answered surveys describing activity patterns. Vigorous exercise was defined as > 6 METS for > 60 hours per year. Clinical and demographic data were derived from medical record review.Results:Among 1798 participants, 745 (41%) reported exercising vigorously, including 296 competitive athletes, with 59 at high-school or college varsity level, 770 (43%) were exercising at moderate, and 283 (16%) at low levels. Of those working, 6% described jobs more active than walking, including 16 in protective services, and 11 in sports/coaching. Clinical/demographic data including imaging characteristics and treatments, are shown in Table, and were mostly similar amongst the exercise-groups.Conclusions:Many patients with HCM are engaged in vigorous exercise including competitive athletics. Prospective follow-up of this cohort is ongoing. Comparison of arrhythmic outcomes outcomes in vigorous exercisers vs moderate/low level exercisers will help determine the safety of exercise in HCM patients.