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

• DOI: 10.1161/jaha.117.007451
• Publication Date: 2018-06-01T09:20:47Z
• Authors: Claire L. Curl; Vennetia R. Danes; James R. Bell; Antonia J. A. Raa...; Wendy T. K. Ip; Chanchal Chandram...; Tristan W. Harding; Enzo R. Porrello; Jeffrey R. Erickson; Fadi J. Charchar; Andrew R. Kompa; Amanda J. Edgley; David J. Crossman; Christian Soeller; Kimberley M. Mellor; Jonathan M. Kalman; Stephen B. Harrap; Lea M. D. Delbridge
• Keywords: Interventricular septum; Hypertensive heart disease

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