Genomic, Proteomic, and Metabolic Comparisons of Small Animal Models of Heart Failure With Preserved Ejection Fraction: A Tale of Mice, Rats, and Cats

Abstract

Heart failure with preserved ejection fraction (HFpEF) remains a medical anomaly that baffles researchers and physicians alike. The overall phenotypical changes of diastolic function and left ventricular hypertrophy observed in HFpEF are definable; however, the metabolic and molecular alterations that ultimately produce these changes are not well established. Comorbidities such as obesity, hypertension, and diabetes, as well as general aging, play crucial roles in its development and progression. Various animal models have recently been developed to better understand the pathophysiological and metabolic developments in HFpEF and to illuminate novel avenues for pharmacotherapy. These models include multi-hit rodents and feline aortic constriction animals. Recently, genomic, proteomic, and metabolomic approaches have been used to define altered signaling pathways in the heart associated with HFpEF, including those involved in inflammation, cGMP-related, Ca²⁺ handling, mitochondrial respiration, and the unfolded protein response in endoplasmic reticulum stress. This article aims to present an overview of what has been learnt by these studies, focusing mainly on the findings in common while highlighting unresolved issues. The knowledge gained from these research models will not simply be of benefit for treating HFpEF but will undoubtedly provide new insights into the mechanisms by which the heart deals with external stresses and how the processes involved can fail.

Keywords: cardiac remodeling; diastolic dysfunction; endoplasmic reticulum stress; metabolomics; preclinical model; proteomics; transcriptomics.

Figure 1. Comparisons among heart failure with preserved ejection fraction models for mechanisms linked to diastolic dysfunction.

Prominent among these are increased fibrosis and altered titin isoform expression and/or posttranslational modifications. Reduced NO/cGMP/PKG signaling, which has antifibrotic and antihypertrophic actions and also affects titin phosphorylation, may be linked to enhanced NOS2/iNOS expression. The latter may affect Ca²⁺ handling, which is linked as well to unfolded protein response/endoplasmic reticulum stress and mitochondrial dysfunction. ~ indicates not prominent/involved or conflicting reports. AC indicates aortic constriction; AIU, aldosterone‐infused uninephrectomy; cGMP, cyclic guanosine monophosphate; ER, endoplasmic reticulum; iNOS, inducible nitric oxide synthase; IRE1α, inositol requiring transmembrane kinase endoribonuclease 1α; NO, nitric oxide; NOS2, nitric oxide synthase 2; PKG, protein kinase G; and UPR, unfolded protein response.

Figure 2. Small animal models are beginning to identify key cellular events in the progression of adverse cardiac remodeling linked to diastolic dysfunction in heart failure with preserved ejection fraction.

A key initiating factor is thought to be microvascular inflammation, an event linked to diastolic dysfunction or impaired contractile relaxation by 2 means: via increased fibrosis and by impairing normal NO/cGMP/PKG signaling and altering titin phosphorylation. In addition, the upregulation of iNOS leads to an impaired unfolded protein response, resulting from impaired IRE1α (inositol requiring transmembrane kinase endoribonuclease 1α) splicing activity and diminished Xpb1s levels, in cardiomyocytes that are subjected to endoplasmic reticulum stress attributable to hypertrophic pressures. Exacerbation of endoplasmic reticulum stress leads to oxidative stress, mitochondrial dysfunction, and impaired Ca²⁺ handling that can feedback to worsen diastolic function. Some content is adapted from Servier Medical Art (https://smart.servier.com/) under the terms of the Creative Commons Attributions 3.0 Unported License. AIU, aldosterone‐infused uninephrectomy; cGMP, cyclic guanosine monophosphate; ER, endoplasmic reticulum; iNOS, inducible nitric oxide synthase; NO, nitric oxide; NOS2, nitric oxide synthase 2; PKG, protein kinase G; and UPR, unfolded protein response.