Cardiomyocyte Functional Etiology in Heart Failure With Preserved Ejection Fraction Is Distinctive—A New Preclinical Model

Abstract

Background Among the growing numbers of patients with heart failure, up to one half have heart failure with preserved ejection fraction ( HF p EF ). The lack of effective treatments for HF p EF is a substantial and escalating unmet clinical need—and the lack of HF p EF ‐specific animal models represents a major preclinical barrier in advancing understanding of HF p EF . As established treatments for heart failure with reduced ejection fraction ( HF r EF ) have proven ineffective for HF p EF , the contention that the intrinsic cardiomyocyte phenotype is distinct in these 2 conditions requires consideration. Our goal was to validate and characterize a new rodent model of HF p EF , undertaking longitudinal investigations to delineate the associated cardiac and cardiomyocyte pathophysiology. Methods and Results The selectively inbred Hypertrophic Heart Rat (HHR) strain exhibits adult cardiac enlargement (without hypertension) and premature death (40% mortality at 50 weeks) compared to its control strain, the normal heart rat. Hypertrophy was characterized in vivo by maintained systolic parameters (ejection fraction at 85%–90% control) with marked diastolic dysfunction (increased E/E′). Surprisingly, HHR cardiomyocytes were hypercontractile, exhibiting high Ca 2+ operational levels and markedly increased L‐type Ca 2+ channel current. In HHR , prominent regions of reparative fibrosis in the left ventricle free wall adjacent to the interventricular septum were observed. Conclusions Thus, the cardiomyocyte remodeling process in the etiology of this HF p EF model contrasts dramatically with the suppressed Ca 2+ cycling state that typifies heart failure with reduced ejection fraction. These findings may explain clinical observations, that treatments considered appropriate for heart failure with reduced ejection fraction are of little benefit for HF p EF —and suggest a basis for new therapeutic strategies.