A scalable segment-based in vivo platform for precision modeling of dilated and hypertrophic cardiomyopathies in Drosophila

Cardiomyopathies are major causes of heart failure and sudden cardiac death, yet the functional consequences of many disease-associated genes and variants remain poorly defined. Here, we establish a scalable, segment-based in vivo platform in Drosophila for quantitative cardiac phenotyping and precision modeling of cardiomyopathy subtypes. By integrating established cardiac imaging approaches into a standardized framework, termed Segmental Cardiac Output and Performance Evaluation (SCOPE), we systematically compared cardiac function across abdominal heart segments. This analysis identified segment A3 as the dominant pumping region, exhibiting the largest systolic and diastolic diameters, highest fractional shortening, and greatest cardiac output, thereby providing an optimal and reproducible site for functional assessment. Leveraging this platform, we generated genetically defined models of dilated and hypertrophic cardiomyopathy through heart-specific knockdown of LamC and bt , homologs of human LMNA and MYBPC3 , respectively. LamC silencing produced hallmark features of dilated cardiomyopathy, including chamber dilation, cardiomyocyte loss, reduced contractility, and decreased cardiac output. In contrast, bt silencing induced hypertrophic remodeling characterized by increased heart wall thickness and impaired cardiac performance. These models recapitulate key structural and functional characteristics of human cardiomyopathy subtypes. Together, this work establishes a scalable in vivo platform for segment-resolved cardiac phenotyping that enables precise modeling of cardiomyopathy, systematic functional validation of candidate genes and variants, and future discovery of genetic and pharmacologic modifiers.