Clinical Phenotypes of Heart Failure With Preserved Ejection Fraction to Select Preclinical Animal Models

Abstract

At least one-half of the growing heart failure population consists of heart failure with preserved ejection fraction (HFpEF). The limited therapeutic options, the complexity of the syndrome, and many related comorbidities emphasize the need for adequate experimental animal models to study the etiology of HFpEF, as well as its comorbidities and pathophysiological changes. The strengths and weaknesses of available animal models have been reviewed extensively with the general consensus that a "1-size-fits-all" model does not exist, because no uniform HFpEF patient exists. In fact, HFpEF patients have been categorized into HFpEF phenogroups based on comorbidities and symptoms. In this review, we therefore study which animal model is best suited to study the different phenogroups-to improve model selection and refinement of animal research. Based on the published data, we extrapolated human HFpEF phenogroups into 3 animal phenogroups (containing small and large animals) based on reports and definitions of the authors: animal models with high (cardiac) age (phenogroup aging); animal models focusing on hypertension and kidney dysfunction (phenogroup hypertension/kidney failure); and models with hypertension, obesity, and type 2 diabetes mellitus (phenogroup cardiometabolic syndrome). We subsequently evaluated characteristics of HFpEF, such as left ventricular diastolic dysfunction parameters, systemic inflammation, cardiac fibrosis, and sex-specificity in the different models. Finally, we scored these parameters concluded how to best apply these models. Based on our findings, we propose an easy-to-use classification for future animal research based on clinical phenogroups of interest.

Keywords: ANGII, angiotensin II; BNP, brain natriuretic peptide; DOCA, deoxycorticosterone acetate; DahlSS, Dahl salt sensitive; HF, heart failure; HFD, high-fat diet; HFHS, high fat, high sugar; HFpEF; HFpEF, heart failure with preserved ejection fraction; HHR, hypertrophic heart rat; IVRT, isovolumetric relaxation time; L-NAME, Nω-nitrol-arginine methyl ester; LV, left ventricle/ventricular; LVDD; LVDD, left ventricular diastolic dysfunction; LVEDP, left ventricular end-diastolic pressure; LVEF, left ventricular ejection fraction; PO, pressure overload; T2DM, type 2 diabetes mellitus; ZSF1, Zucker fatty and spontaneously hypertensive; animal models; heart failure with preserved ejection fraction; left ventricular diastolic dysfunction; phenogroups.

Graphical abstract

Figure 1

Inclusion and Exclusion Criteria to Define Preclinical Animal Models for HFpEF Inclusion criteria are heart failure symptoms, presentation with parameters of LVDD, and inflammation/fibrosis. Exclusion criteria were systolic dysfunction and a reduced ejection fraction. Because most studies do not report symptoms of heart failure, most animal models are extended LVDD models. HFpEF = heart failure with preserved ejection fraction; LVDD = left ventricular diastolic dysfunction.

Figure 2

Classification and Scoring of Animal Models of Heart Failure With Preserved Ejection Fraction Schematic overview of small and large animal models, visualizing the presence or absence of comorbidities, systemic inflammation, cardiac fibrosis, and left ventricular diastolic dysfunction (LVDD) parameters, using color coding. Phenogroup aging contains the senescence-accelerated mouse prone 8 mouse (SAMP8), as well as the Fischer 344 rat, the hypertrophic heart rat (HHR), and the old hypertensive dog (OHT). Phenogroup hypertension/kidney dysfunction consists of the left ventricular pressure overload pig (LVPO), the pressure overload cat (PO), the angiotensin II mouse (ANGII), the Dahl salt-sensitive rat (DahlSS), the Nω-nitrol-arginine methyl ester mouse (L-NAME), the subtotal nephrectomy rat (SNX), and the deoxycorticosterone acetate rat (DOCA). Phenogroup cardiometabolic syndrome consists of the Zucker diabetic fatty rat (ZDF), the obese mouse (ob/ob), the diabetic mouse (db/db), the high-fat-high-sugar mouse (HFHS), the old high-fat diet + angiotensin II mouse (Old HFD+ANGII), the high-fat-high-sugar pig (HFHS), the Dahl salt sensitive/obese rat (DahlSS/obese), the Zucker fatty and spontaneously hypertensive rat (ZSF1/obese), the Nω-nitrol-arginine methyl ester + high fat diet mouse (L-NAME+HFD), the deoxycorticosterone acetate/angiotensin II/Western diet pig (DOCA/ANGII/WD), the hypertensive, hypercholesterolemia, diabetes mellitus pig (HT/HC/DM), the Western diet/aortic block pig (WD/AB), the diabetic + angiotensin II mouse (db/db+ANGII), and the deoxycorticosterone acetate/Western diet pig (DOCA/WD). Color coding shows whether certain parameters are present and used to score: dark green 2 points, light green 1 point, yellow 0 points, light green −1 point, and dark red −2 points. Sex differences were not included in scoring. EDPVR = end-diastolic pressure volume relationship; IVRT = isovolumetric relaxation time; LVEDP = left ventricular end-diastolic pressure; LVEF = left ventricular ejection fraction; Ms = mouse; P = pig; PUV = peak untwist velocity; T2DM = type 2 diabetes mellitus (T2DM).

Central Illustration

Selection-Guide for Animals Models of HFpEF Based on Clinical Phenogroups A tool to help selection of suitable animal models for underlying phenogroups based on their scoring explained in this paper. Three phenogroups were translated from applicable clinical phenogroups into preclinical animal models: aging, hypertension/kidney failure, and cardiometabolic syndrome. Colors represent different model animals (from small on the left to big on the right). The higher a model is on the scale, the more suitable it is to mimic the phenogroup. AB = aortic block pig; ANG II = angiotensin II; DahlSS = Dahl salt sensitive; db/db = diabetic mouse; DOCA = deoxycorticosterone acetate rat; HFD = high fat diet mouse; HFHS = high-fat, high-sugar pig; HHR = hypertrophic heart rat; HT/HC/DM = hypertensive; hypercholesterolemia diabetes mellitus pig; L-NAME = Nω-nitrol-argininemethyl ester; LVPO = left ventricular pressure overload; ob/ob = obese mouse; OHT = old hypertensive dog; PO = pressure overload; SAMP8 = senescence-accelerated mouse prone 8 mouse; SNX = subtotal nephrectomy rat; WD = Western Diet pig; ZSF1 = Zucker fatty and spontaneously hypertensive.