Computational Models Show Afterload Dominates Cardiac Function, and Functional Remodeling Increases Anatomical Dependency
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Hypertrophic cardiomyopathy (HCM) is a heterogeneous condition characterized by myocardial hypertrophy and impaired cardiac function. Beyond anatomical differences, functional remodeling of myocardial material properties contributes to symptoms, disease progression, and variability in treatment response. However, it is not clear how these properties interact to determine cardiac performance and response to treatment. We quantified how cardiac anatomy variability, HCM-related functional remodeling, and pharmacological treatment influence the importance of biophysical mechanisms that govern cardiac function. We built five four-chamber electromechanical heart models representing previously defined anatomical clusters. We performed global sensitivity analyses on 46 parameters across 32 functional outputs. We repeated this process 18 times to model different types of functional remodeling and two times to model pharmacological treatments (mavacamten and aficamten). Across all representative HCM anatomical phenotypes, sensitivity profiles were broadly preserved. Ventricular afterload was the dominant determinant of ventricular hemodynamic outputs, explaining up to 69% of output variance. Simulated functional remodeling led to scenario-specific shifts in parameter importance, with changes in explained variance of up to 56% relative to baseline. The modeling of pharmacological treatments led to modest but targeted changes, with aficamten producing larger effects than mavacamten. Notably, in the left ventricular outflow tract obstruction anatomy, the presence of aficamten increased the importance of ventricular stiffness on left ventricular ejection fraction. This suggests that in patients with high stiffness and this specific anatomy, aficamten may have a reduced beneficial effect on ejection performance compared to other morphologies. Across major anatomical phenotypes of hypertrophic cardiomyopathy, cardiac performance was governed by a conserved, load-sensitive physiological pattern reflecting ventricular–arterial coupling. Functional remodeling and pharmacological therapy induced mechanism-specific shifts in physiology. This framework provides a quantitative approach to integrating anatomical and functional biomarkers to explain variability in symptoms, anticipate treatment response, and guide individualized therapy titration in HCM.
