HFpEF animal models display differences in myofibril mechanics.

Abstract

Heart Failure with preserved Ejection Fraction (HFpEF) is a complex, multi-organ disease historically defined by cardiac aberrations including diastolic dysfunction with normal resting systolic function and depressed systolic reserve, hypertrophy, and impaired relaxation. Though diastolic dysfunction is a hallmark of HFpEF, it is unknown whether organ-level deficiencies in relaxation persist down to the myofibrils, the contractile organelles within cells. Here, we performed mechanics analysis on cardiac myofibrils from three common HFpEF animal models to assess potential differences in myofibrillar force and relaxation kinetics, independent of higher-order deficits associated with the disease. The Göttingen minipig (GM) HFpEF model recapitulates the spectrum of human HFpEF multiorgan pathophysiology, including severe diastolic dysfunction, myocardial hypertrophy, fibrosis, and pulmonary and systemic hypertension. We found that GM-HFpEF myofibrils produced significantly less maximal force versus controls, with no change in either the slow or fast relaxation phases. Therefore, impaired myofibril relaxation likely does not contribute to the diastolic dysfunction in this model. Another model assessed was the Zucker spontaneously hypertensive heart failure F1 (ZSF1) rat, which exhibits elevated E/e′, insulin resistance, elevated end-diastolic pressure, and preserved ejection fraction. Our preliminary data indicate that ZSF1 myofibrils produce normal maximal force, but have a slower initial rate of relaxation compared to controls. These data suggest that impaired myofibril relaxation may contribute to diastolic dysfunction in the ZSF1 model. Moreover, the distinct responses of myofibrils from these models appear to recapitulate cell-level behavior in human cardiomyocytes isolated from patients with different HFpEF subphenotypes. Therefore, certain animal models may mimic unique HFpEF characteristics at the cellular and/or myofibril levels and be better-suited for investigating specific aspects of this extremely complex syndrome, and aid in the design of effective pharmacological or device-based treatments.