Introduction: Hypertrophic cardiomyopathy (HCM) is a heritable cardiac disease characterized by hyper-contractility, impaired filling, and exertional intolerance. The molecular basis for this pathophysiology remain poorly understood, hindering the development of targeted and more effective therapies. Therefore, in vivo and ex vivo studies were performed in a novel large-animal model of HCM to determine the association between induced myofilament abnormalities and the in vivo clinical phenotype.
Methods: Young (3 month old) Yucatan mini-pigs with a heterozygous knock-in of the R403Q MYH7 mutation and age-matched wildtype (WT) herd-mates were studied. Ex vivo biomechanical studies in fibers as well as in vivo imaging (MRI) and invasive hemodynamics were performed. Twitch mechanics (ex vivo), as well as load-independent systolic and diastolic function (via LV pressure-volume relationships), and cardiac reserve (during dobutamine challenges, 10 ug/kg/min IV) were assessed.
Results: Muscle fibers from mutant pigs showed increased Ca2+ sensitivity with decreased cooperativity, favoring enhanced inotropy. Concordant with these observations, mutant pigs showed hyper-contractility in vivo as indicated by both load-dependent and independent inotropic indices (e.g., LVEF: +23 ± 8% and PRSW: +31 ± 5%, vs. WT). Mutants also exhibited diastolic impairments with markedly elevated LV end-diastolic filling pressures (25 ± 4 mmHg) and stiffer ventricles. Despite enhanced inotropy at baseline, mutant pigs had limited cardiac reserve, characterized by a blunted β-adrenergic recruitment of systolic and diastolic function (e.g., dP/dtmin: -42 ± 12% and PRSW: -48 ± 5% vs. WT).
Conclusions:MYH7 R403Q mutant mini-pigs showed myofilament abnormalities ex vivo and a corresponding hyper-contractile phenotype in vivo. Mutant animals also had limited cardiac reserve and elevated filling pressures, a potential mechanism for exertional intolerance in patients. This translational dataset strengthens the mechanistic link between in vivo HCM phenotypes, biophysical twitch mechanics, and sarcomere-mutations while supporting the hypothesis that myofilament-targeted therapies could provide benefit to HCM patients.