Genotype-Specific Remodeling in Hypertrophic Cardiomyopathy Revealed by Deep Learning-Based 3D Volumetric Imaging

All articles of this category (opens in new window) Background: Hypertrophic cardiomyopathy (HCM) is a common genetic cardiac disorder marked by left ventricular (LV) hypertrophy, myocyte disarray, and extracellular matrix (ECM) expansion. While cardiomyocyte (CM) hypertrophy is considered a hallmark of HCM, its morphologic assessment has been limited by conventional 2D histology. This study aimed to characterize genotype-dependent differences in structural remodeling at the cellular and extracellular level. Methods: We analyzed interventricular septal tissue from 24 patients undergoing surgical myectomy for obstructive HCM [MYH7 ( n = 8), MYBPC3 ( n = 7), sarcomere-negative (SARC–, n = 9)] and 11 nonfailing donor hearts. In parallel, disease progression was studied in a MYH7 R403Q pig model (WT: n = 14, R403Q: n = 16) across ages 2 to 13 months. High-resolution 3D confocal microscopy and deep learning-based image analysis enabled quantification of CM volume, eccentricity (width-length ratio), cellular alignment, and extracellular volume. We used multiple linear regression models to determine the relative contributions of CM and ECM remodeling to LV wall thickness in both human and porcine hearts. Results: Volumetric analysis of > 13,000 CMs showed that MYH7 and MYBPC3 HCM samples exhibited pronounced concentric hypertrophy and disarray, with MYH7 showing the most severe changes. In contrast, SARC—CMs had volumes comparable to controls. Increased LV wall thickness in MYH7 and MYBPC3 was driven by equal expansion of CM and ECM volume, whereas SARC cases showed predominant ECM remodeling. In R403Q pigs, changes in CM morphology closely mirrored findings in human HCM: increased CM volume was primarily driven by increased width rather than length, indicating concentric growth. Early fibrotic remodeling preceded CM hypertrophy, suggesting that ECM expansion is an early and independent contributor to disease. Conclusion: Using an advanced 3D volumetric imaging pipeline in human and pig HCM hearts, we identified distinct genotype-specific patterns of CM and ECM remodeling. These findings highlight mechanistic differences across HCM subtypes and underscore the importance of genotype-informed classification to guide future diagnostics and therapies. Publication History Article published online: 17 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany