Sonia F. Epstein

In adults with hypertrophic cardiomyopathy (HCM), left ventricular outflow tract (LVOT) obstruction on exercise stress echocardiography (ESE) and reduced left atrial (LA) strain increase heart failure and cardiac outcome risk. However, limited pediatric data exist. We evaluated the association of exercise-induced LVOT obstruction and LA strain with cardiac events in young HCM patients. Patients who underwent ESE (n = 114, 32%F, median = 17 yrs) from 2014–2022 at a single center were stratified by LVOT gradients: Group 1 (n = 44, rest/exercise gradients < 30mmHg); Group 2 (n = 41, rest < 30mmHg; exercise ≥ 30mmHg); Group 3 (n = 29, rest/exercise ≥ 30mmHg). LA reservoir (LASr), conduit (LAScd), and contractile strain were analyzed with TOMTEC AutoStrain LA. Composite cardiac event included: heart failure, non-sustained/sustained ventricular tachycardia, cardiac syncope, heart transplantation, and HCM-related death. At follow-up (median = 2.0 years), there was a greater hazard of the composite event in Group 3 vs. 2 (hazard-ratio [HR] = 4.97, p = 0.013). Severe events were rare and largely observed in Group 3. Increased HR was seen in Group 2 vs. 1 but the difference was not significant. Adjusting for LVOT gradient (Group 3), lower LASr or LAScd or increased LA stiffness (E/e’ to LASr ratio) were associated with composite event (HR LASr = 1.57; LAScd = 1.70; LA stiffness = 1.31; all p < 0.01). Concordance indices were similar for these three strain/stiffness models (0.81–0.82) and higher than in models including LVOT group with traditional diastolic indices (LA volume index or E/e’; c-index = 0.76). In one of the largest pediatric HCM cohorts undergoing ESE, reduced LA strain demonstrated greater incremental value to LVOT gradient than traditional diastolic indices when evaluating association with cardiac events.

Heart failure is a multifaceted syndrome contributing significantly to mortality and hospitalization rates among the global population1. One of the prevalent causes of heart failure is ischemic heart disease (IHD), often caused by a blockage in a coronary artery, ultimately leading to the loss of myocardial tissue and contractile force2. The impact of this ischemic ambiance on the cardiomyocyte genome and transcriptome has not been thoroughly studied. During normal aging, cardiomyocytes progressively accumulate somatic mutations faster than many dividing cells, suggesting that internal and external factors specific to cardiomyocytes might influence this accumulation3. In this study, we analyzed single-cell whole-genome and transcriptome data from the left ventricle of 5 individuals with IHD and 10 healthy control individuals. We found that somatic DNA alterations significantly increase in IHD cardiomyocytes, with distinct mutational patterns indicating a disrupted DNA repair system and a cytotoxic environment, potentially associated with increased inflammatory response in the myocardium and a compensatory anti-inflammatory response in IHD. An in vitro iPS-derived hypoxic cardiomyocyte mutational profile indicates similar mutational spectra. Transcriptomic analysis revealed increased expression of EGR1, FOS, and collagen genes in ischemic heart cardiomyocytes, leading to a more fibrotic heart. The aberrant accumulation of DNA alterations and changes in transcriptional patterns in the ischemic heart cardiomyocytes provide insight into the development of IHD.