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Cardiomyocyte Functional Etiology in Heart Failure With Preserved Ejection Fraction Is Distinctive-A New Preclinical
Claire L Curl1, Vennetia R Danes1, James R Bell1
1Department of Physiology, University of Melbourne, Victoria, Australia.
Journal of the American Heart Association
|June 3, 2018
Summary
A new Hypertrophic Heart Rat (HHR) model exhibits heart failure with preserved ejection fraction (HFpEF) characteristics, including diastolic dysfunction and hypercontractile cardiomyocytes, distinct from heart failure with reduced ejection fraction (HFrEF). This model offers insights into HFpEF pathophysiology and potential therapeutic strategies.
Area of Science:
- Cardiology
- Physiology
- Animal Models
Background:
- Heart failure with preserved ejection fraction (HFpEF) affects a significant patient population, yet lacks effective treatments.
- Existing treatments for heart failure with reduced ejection fraction (HFrEF) are ineffective for HFpEF, highlighting distinct underlying pathologies.
- A lack of HFpEF-specific animal models impedes research and the development of targeted therapies.
Purpose of the Study:
- To validate and characterize a novel rodent model for studying heart failure with preserved ejection fraction (HFpEF).
- To investigate the cardiac and cardiomyocyte pathophysiology associated with HFpEF using longitudinal studies.
- To explore the distinct cellular mechanisms differentiating HFpEF from HFrEF.
Main Methods:
- Utilized a selectively inbred Hypertrophic Heart Rat (HHR) strain and a control normal heart rat strain.
- Conducted in vivo characterization of cardiac function, including systolic and diastolic parameters (ejection fraction, E/E').
- Analyzed cardiomyocyte properties, focusing on calcium (Ca2+) handling and L-type Ca2+ channel currents, alongside histological examination for fibrosis.
Main Results:
- The HHR strain displayed adult cardiac enlargement and premature mortality without hypertension.
- In vivo assessments revealed maintained systolic function (ejection fraction) but marked diastolic dysfunction (increased E/E') in HHR rats.
- HHR cardiomyocytes were hypercontractile with elevated Ca2+ levels and increased L-type Ca2+ channel current, alongside localized fibrosis in the left ventricle.
Conclusions:
- The HHR rat serves as a valid preclinical model for HFpEF, exhibiting distinct cardiomyocyte remodeling with enhanced Ca2+ cycling.
- This contrasts with the suppressed Ca2+ handling observed in heart failure with reduced ejection fraction (HFrEF) models.
- Findings provide a rationale for the inefficacy of HFrEF treatments in HFpEF and suggest avenues for novel therapeutic strategies.
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