Heart Failure With Preserved Ejection Fraction: Heterogeneous Syndrome, Diverse Preclinical Models

Abstract

Heart failure with preserved ejection fraction (HFpEF) represents one of the greatest challenges facing cardiovascular medicine today. Despite being the most common form of heart failure worldwide, there has been limited success in developing therapeutics for this syndrome. This is largely due to our incomplete understanding of the biology driving its systemic pathophysiology and the heterogeneity of clinical phenotypes, which are increasingly being recognized as distinct HFpEF phenogroups. Development of efficacious therapeutics fundamentally relies on robust preclinical models that not only faithfully recapitulate key features of the clinical syndrome but also enable rigorous investigation of putative mechanisms of disease in the context of clinically relevant phenotypes. In this review, we propose a preclinical research strategy that is conceptually grounded in model diversification and aims to better align with our evolving understanding of the heterogeneity of clinical HFpEF. Although heterogeneity is often viewed as a major obstacle in preclinical HFpEF research, we challenge this notion and argue that embracing it may be the key to demystifying its pathobiology. Here, we first provide an overarching guideline for developing HFpEF models through a stepwise approach of comprehensive cardiac and extra-cardiac phenotyping. We then present an overview of currently available models, focused on the 3 leading phenogroups, which are primarily based on aging, cardiometabolic stress, and chronic hypertension. We discuss how well these models reflect their clinically relevant phenogroup and highlight some of the more recent mechanistic insights they are providing into the complex pathophysiology underlying HFpEF.

Keywords: aging; animal models; atrial fibrillation; blood pressure; edema; heart failure; obesity.

Figure 1:. A stepwise phenotype-based approach to developing HFpEF models.

HFpEF is a clinical syndrome with complex systemic pathophysiology that includes functional impairments in both cardiac and extra-cardiac tissues. Developing reliable animal models of HFpEF requires that investigators rigorously assess and validate multiple clinically relevant phenotypes, starting with the hallmark features of HF, congestion and exercise intolerance (1^st panel). Next, preserved left ventricular ejection fraction, a defining feature of HFpEF, should be confirmed (2^nd panel). Additional cardiac and extra-cardiac phenotyping should then be assessed, and tailored to the specific phenogroup, being modeled (3^rd and 4^th panels). The illustration was made using images from smart.servier.com. Illustration credit: Ben Smith

Figure 2:. Animal models of the aging, cardiometabolic, and hypertension-associated HFpEF phenogroups.

Advanced age, metabolic syndrome, and chronic hypertension represent the dominant comorbidities contributing to HFpEF pathogenesis. The Venn diagram displays animal models that are relatively unique to these primary HFpEF phenogroups, along with newer multi-hit strategies being used to integrate these primary comorbidities in model development. Recent mechanistic insights into the underlying pathobiology of these phenogroups, and HFpEF in general, that have been derived from these models are displayed. Blue = age-associated HFpEF. Green = cardiometabolic HFpEF. Gray = hypertension-associated HFpEF. Orange = multi-hit, integrated HFpEF. The illustration was made using images from smart.servier.com. Illustration credit: Ben Smith.

Figure 3:. SAUNA model of hypertension-associated HFpEF.

The SAUNA model using a combination of SAlty drinking water, Unilateral Nephrectomy, and chronic Aldosterone to induce a model of hypertension-associated HFpEF in rodents. The schematic displays some of the key cardiac and extra-cardiac (e.g. chronic kidney disease) observed in this model. Recent mechanistic work in this model has implicated inflammation, endo-MT, and titin modifications as underlying pathogenic processes in the pathophysiology of hypertension-associated HFpEF. The illustration was made using images from smart.servier.com.