A Feline HFpEF Model with Pulmonary Hypertension and Compromised Pulmonary Function

Markus Wallner,Steven R Houser,Remus M Berretta,Marla R Wolfson,Jichuan Wu,Sandy T Baker,Deborah M Eaton,Eric A Feldsott,Heiner Post,Mark A Oyama,Sadia Mohsin,Thomas E Sharp,Giulia Borghetti,Dirk Von Lewinski

doi:10.1038/s41598-017-15851-2

Abstract

Heart Failure with preserved Ejection Fraction (HFpEF) represents a major public health problem. The causative mechanisms are multifactorial and there are no effective treatments for HFpEF, partially attributable to the lack of well-established HFpEF animal models. We established a feline HFpEF model induced by slow-progressive pressure overload. Male domestic short hair cats (n = 20), underwent either sham procedures (n = 8) or aortic constriction (n = 12) with a customized pre-shaped band. Pulmonary function, gas exchange, and invasive hemodynamics were measured at 4-months post-banding. In banded cats, echocardiography at 4-months revealed concentric left ventricular (LV) hypertrophy, left atrial (LA) enlargement and dysfunction, and LV diastolic dysfunction with preserved systolic function, which subsequently led to elevated LV end-diastolic pressures and pulmonary hypertension. Furthermore, LV diastolic dysfunction was associated with increased LV fibrosis, cardiomyocyte hypertrophy, elevated NT-proBNP plasma levels, fluid and protein loss in pulmonary interstitium, impaired lung expansion, and alveolar-capillary membrane thickening. We report for the first time in HFpEF perivascular fluid cuff formation around extra-alveolar vessels with decreased respiratory compliance. Ultimately, these cardiopulmonary abnormalities resulted in impaired oxygenation. Our findings support the idea that this model can be used for testing novel therapeutic strategies to treat the ever growing HFpEF population.

Highlights

heart failure (HF) is classified into three main categories, HF with reduced ejection fraction (HFrEF), HF with mid-range ejection fraction (HFmrEF), or HF with preserved ejection fraction (HFpEF)[4]
While rodent Heart Failure with preserved Ejection Fraction (HFpEF) models have contributed to our understanding of underlying mechanisms of left ventricular (LV) diastolic dysfunction, rodents have inherent limitations due to their size, cardiac structure and function that preclude comprehensive hemodynamic assessments that can be performed in large mammalians and humans
The present experiments showed that slow-progressive pressure overload of the LV caused LV concentric hypertrophy, diastolic dysfunction with elevated LV filling pressures, and left atrial (LA) dilation with reduced LA systolic function

Summary

Introduction

HF is classified into three main categories, HF with reduced ejection fraction (HFrEF), HF with mid-range ejection fraction (HFmrEF), or HF with preserved ejection fraction (HFpEF)[4]. The aim of this study was to characterize a feline model of slow-progressive pressure overload to determine if it has critical structural and functional cardiac phenotypic features of HFpEF, and for the first time determine if this model has a HFpEF pulmonary phenotype that includes changes in lung mechanics, gas exchange and hemodynamics. These studies should reveal new mechanistic insights into the development of pulmonary impairment due to elevated left-sided filling pressures and establish this as a suitable model for studying HFpEF mechanisms and testing new therapeutics

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