Joseph W. Rossano

BACKGROUND: Dilated cardiomyopathy (DCM) frequently presents with heart failure in children. Whether a genetic cause of DCM is associated with disease severity or eventual outcome in pediatric DCM is unclear. METHODS: A multiinstitutional prospective pediatric cohort study (0–18 years) with nonsyndromic DCM was undertaken from 2013 to 2016. A panel of 37 cardiomyopathy-associated genes was interrogated by exome sequencing with analysis for pathogenic or likely pathogenic (LP) variants. Clinical severity and outcomes of death, cardiac transplant, and continuing left ventricular dysfunction versus echocardiographic normalization were assessed. RESULTS: A total of 279 DCM probands (47% male) with a median (interquartile range) age at diagnosis of 1.6 (0.4–10.4) years were enrolled. Median follow-up was 1.1 (0.2–4.0) years. Gene variants designated as pathogenic/LP were identified in 18 of the 37 genes evaluated, and of all positive variants, TTN (17%), TNNT2 (15%), MYH7 (15%), RBM20 (9%), and LMNA (8%) were most frequently implicated. Only 19% of the overall cohort yielded an identifiable genetic cause, without any difference between ancestries. Children >12 years old had the highest genetic yield at 34% ( P P =0.09) toward greater echo normalization, was noted in those without a pathogenic/LP variant by 10 years after diagnosis. CONCLUSIONS: A genetic cause was detected in a minority of children and was not associated with the phenotypic severity of DCM at diagnosis. Echocardiographic normalization of left ventricular function over time was noted more frequently in patients who did not have an identified pathogenic/LP variant.

Background: Patients with pediatric heart failure (HF) face significant morbidity and death. However, there are limited data describing neighborhood characteristics in pediatric patients with HF or exploring the relationship of these factors to resource use and clinical outcomes. We used the Child Opportunity Index 3.0 (COI), a composite index of community resources pertinent to child health, to describe neighborhood characteristics for children with HF and identify its associations with in‐hospital death. Methods: This retrospective cohort study used the Pediatric Health Information System, a national administrative database of tertiary care pediatric hospitals. Inpatient encounters between January 2014 and December 2024 for pediatric patients (aged International Classification of Diseases ( ICD ) codes. The primary exposure of interest was the COI, and the primary outcome of interest was in‐hospital death. Mixed logistic regression models were estimated, unadjusted and adjusted for administrative sex, age, race, and primary payor. Results: Our cohort consisted of index HF admissions in 7060 patients. Half of the cohort was in either the very low (n=2034 [29%]) or low (n=1521 [22%]) COI quintile. After adjustment, patients with a very high COI were less likely to experience in‐hospital death than those living in very low COI neighborhoods (odds ratio, 0.73 [95% CI, 0.54–0.99]; P =0.048). Conclusions: A substantial proportion of children admitted with HF have limited neighborhood resources. Those with higher neighborhood resources are more likely to survive to discharge, emphasizing the relationship between environmental factors and clinical outcomes in pediatric HF.

Background: Obesity is associated with adverse outcomes in overt hypertrophic cardiomyopathy, but the prevalence and impact of elevated body mass index (BMI) in early‐stage hypertrophic cardiomyopathy is uncertain. Methods: In this post hoc analysis of the randomized VANISH (Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy) trial, participants were categorized according to baseline BMI (nonelevated or elevated [≥85th percentile if age 2 if age ≥18 years]). Exercise capacity (peak oxygen uptake [milliliters per kilogram per minute]) and cardiac imaging parameters were evaluated by baseline BMI and 2‐year change in BMI. Results: Among 171 (96%) participants (mean age, 23±10 years; 39% female sex; 97% White), 82 (48%) had nonelevated BMI and 89 (52%) had an elevated BMI. After covariate adjustment, higher baseline BMI was associated with lower peak oxygen uptake; lower left ventricular systolic and diastolic function; higher left ventricular mass; and higher atrial, ventricular, and extracellular volumes. Similarly, greater 2‐year increases in BMI were associated with greater declines in peak oxygen uptake and greater increases in left ventricular mass. Participants with elevated BMI were more likely to develop late gadolinium enhancement over 2 years (adjusted odds ratio, 3.6 [95% CI, 1.1–11.9]; P =0.033). Valsartan appeared to modestly attenuate 2‐year increases in body weight versus placebo (adjusted mean difference, −3.1% [95% CI, −6.2 to −0.1%]; P =0.042). Baseline BMI did not appear to modify the effect of valsartan on cardiac remodeling ( P _interaction =0.96). Conclusions: Elevated BMI was common and associated with greater hypertrophic, eccentric, and fibrotic remodeling in early‐stage hypertrophic cardiomyopathy. Two‐year increases in BMI were associated with greater phenotypic progression. These findings suggest prevention and treatment of elevated BMI may attenuate hypertrophic cardiomyopathy progression. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01912534.

BACKGROUND: Conflicting evidence exists about whether sarcomeric hypertrophic cardiomyopathy (HCM) caused by genes encoding thin filament proteins ( TNNT2, TNNI3, ACTC, TPM1 , TNNC1 ; thin filament HCM) has a distinct clinical presentation and natural history from disease caused by the more commonly involved thick filament genes ( MYH7 , MYBPC3 , MYL2 , MYL3 ; thick filament HCM). METHODS: Retrospective analysis of the Sarcomeric Human Cardiomyopathy Registry. RESULTS: Four hundred eighty-eight patients with thin filament HCM were compared with 3494 patients with thick filament HCM. After controlling for age at diagnosis, sex, and proband status, thin filament HCM was associated with a higher risk of composite ventricular arrhythmias (hazard ratio, 1.48 [95% CI, 1.09–2.01]), cardiac arrest (hazard ratio, 2.02 [95% CI, 1.33–3.06]), and heart transplant or left ventricular assist device implantation (hazard ratio, 2.18 [95% CI, 1.3–3.65]). Younger age at diagnosis was associated with an increased risk for the ventricular arrhythmia composite outcome in thin and thick filament HCM (hazard ratio, 0.93 [95% CI, 0.91–0.94]; hazard ratio, 0.93 [95% CI, 0.93–0.94]; age reported as 5-year increment). Within specific thin filament genes, an increased risk of arrhythmic events or heart transplant/left ventricular assist device implantation was evident for variants in TNNT2 amino acids 92 to 94 (odds ratio versus other TNNT2 variants; odds ratio, 3.02 [95% CI, 1.17–7.49]) and TNNI3 amino acids 191 to 210 (odds ratio versus other TNNI3 variants; odds ratio, 3.5 [95% CI, 1.58–8.02]). CONCLUSIONS: Thin filament HCM seems to carry a higher risk for ventricular arrhythmias and advanced heart failure compared with thick filament HCM. Integrating gene-level and intragene-level information may improve risk stratification in patients with HCM.

BACKGROUND: Titin truncating variants ( TTN tv) represent the most common genotype underlying dilated cardiomyopathy but are also detected in the general population, exhibiting incomplete penetrance and marked phenotypic variability. This heterogeneity complicates clinical interpretation and risk stratification. Emerging molecular evidence suggests that truncating location within the gene may influence disease mechanisms. We aimed to investigate whether TTNt v location also affects clinical phenotype and prognosis. METHODS: We established an international multicenter registry of phenotypically affected carriers of pathogenic or likely pathogenic TTN tv. Patients were classified into 3 groups: A-band, Z/I-band, and M-band. A case-control study assessed the enrichment of TTN tv across regions. The primary outcome was a composite of all-cause mortality and heart transplantation. Secondary outcomes included: (1) sudden cardiac death or major ventricular arrhythmias and (2) heart failure-related death/heart transplantation/left ventricular assist device implantation. RESULTS: The study included 467 patients (81% probands, 73% men, median age 47 years, 81% dilated cardiomyopathy phenotype). Most carried TTN tv in the A-band (80% versus 15% Z/I-band and 5% M-band). All groups showed enrichment compared with GnomAD, with greater Bayesian-estimated penetrance for A-band variants. Over a median follow-up of 83 months, the primary end point was similar across groups. However, the risk of sudden cardiac death/major ventricular arrhythmias was significantly higher in M-band carriers (45% M-band versus 23% Z/I-band versus 12% A-band; P =0.001), especially as the first disease manifestation. Band location independently predicted sudden cardiac death/major ventricular arrhythmias risk, whereas left ventricular ejection fraction was predictive only in A- and Z/I-band groups. CONCLUSIONS: TTN tv are differently enriched across the gene in patients with dilated cardiomyopathy/non-dilated left ventricular cardiomyopathy. Penetrance and risk of sudden cardiac death/major ventricular arrhythmias differ according to variant location, supporting the TTN truncation site as a parameter that should be considered for personalized risk stratification in TTN cardiomyopathy.

BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia in dilated cardiomyopathy (DCM) and is associated with adverse outcomes. However, the genetic determinants of AF risk and its prognostic significance across genotyped DCM subtypes remain unknown. METHODS: In this observational cohort study, we analyzed 3117 genotyped patients with DCM from the SHaRe (Sarcomeric Human Cardiomyopathy Registry). AF prevalence, incidence, and clinical characteristics were assessed by genotype. Patients were classified as genotype-positive [G(+)] if they had a pathogenic or likely pathogenic variant in a DCM-associated gene, and genotype-negative [G(−)] if genetic testing was negative. Factors associated with incident AF were evaluated using Cox regression. AF was modeled as a time-dependent variable to evaluate associations with clinical outcomes. RESULTS: Among 3117 genotyped patients with DCM (mean age, 48±15 years; 39% were female; and 35% were G[+]), 12.3% (n=384) had prevalent AF. Of 2491 patients without prevalent AF and with follow-up, 312 (12.5%) developed AF during a median of 4.5 years (interquartile range, 1.6–9.0). Among 2851 patients with follow-up, cumulative AF prevalence was 23.6%. LMNA had the highest AF incidence (7.6/100 patient-years) and cumulative AF prevalence (56.7%) and was the only genotype independently associated with incident AF compared with that in G(−) patients (hazard ratio, 5.52 [95% CI, 3.84–7.95]; P TTN had an AF incidence of 2.1 per 100 patient-years and cumulative AF prevalence of 24.4%, comparable to that in G(−) patients. Older age, male sex, and prior heart failure hospitalization were also independently associated with incident AF. AF was independently associated with a higher risk of the composite clinical outcome (hazard ratio, 1.58 [95% CI, 1.29–1.94]; P LMNA was associated with an increased risk of incident AF. AF onset was independently associated with adverse outcomes, supporting genotype-guided AF surveillance and management in DCM.

Background: One in 5 children with a ventricular assist device (VAD) remains on the device for >6 months. However, there are sparse outcomes data. We sought to characterize preimplant characteristics, survival, and frequency of adverse events. Methods: Patients aged 6 months. Compared with those supported ≤6 months, those supported >6 months were older (11.2 [5.0–15.2] versus 4.9 [0.6–13.4] years; P P =0.029) and implantable continuous devices (68.3% versus 33.6%; P 6 months, most undergo transplant; however, 20.3% remain on support at 2 years. Further study of morbidity and quality of life is needed.