Changes in Cardiac and Vascular Contractile Protein in a Rat Model of Heart Failure with Preserved Ejection Fraction

Abstract

Heart failure is classified as heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF). Although several therapies have been demonstrated to improve outcomes in patients with HFrEF, none benefit patients with HFpEF. The molecular mechanism that results in HFpEF is unknown and has been impacted by the lack of animal models, and thus, we tested the hypothesis that metabolic and hypertensive stress would result in a rat model of HFpEF. Fischer 344 rats (6mo old) were fed a high fat diet and L‐NAME in the drinking water for 4‐weeks. Invasive and noninvasive hemodynamics demonstrate that the treated animals develop HFpEF; treated animals (n=7) vs controls (n=6) have normal systolic function with LV hypertrophy (20.7±0.4mm v 27.6±2.1mm, p<0.05) and diastolic abnormalities including a decrease in both E (79.4±3.6cm/s v 64.2±3.4cm/s, p=0.003) and dP/dtmin (‐7600±1100mmHg/s v ‐5600±1400mmHg/s, p=0.015), a steeper EDPVR (0.1±1.1mmHg/μl v 3.6±1.7mmHg/μl, p=0.042) and a slower time constant of relaxation (τ; 11±1ms v 16±2ms, p=0.029), as well as edema of the liver and lungs. Compared to controls, in cardiac muscle of HFpEF rats, there is no difference (p>0.05) in the expression and/or phosphorylation of TnI or MyBPC. However, the expression of SERCA2 (p=0.021) and phosphorylation of phospholamban (p=0.046) are reduced, which would be expected to decrease the rate of SR Ca2+ reuptake and slow relaxation. In both the aorta and tertiary mesenteric vessels of HFpEF rats, the expression of nonmuscle myosin was significantly higher and the expression of the leucine zipper positive isoform of myosin light chain phosphatase was reduced, which should increase vascular tone and decrease the sensitivity of the vasculature to NO mediated vasodilatation. This study represents the first rat model of HFpEF and our results define a molecular mechanism that would contribute to both diastolic dysfunction and vascular abnormalities that characterize this disease. This rat HFpEF model could be used in future studies designed to delineate the mechanism(s) that produce the cardiac and vascular abnormalities that produce HFpEF and identify novel targets for rational drug design.