Table 4.

Examples of animal models that mimic disease characteristics of HFpEF patients

Experimental model	Species	Pathological features	Strengths and limitations of model	Score as HFpEF model (− to +++)
Diabetes and obesity model	db/db (leptin deficient) and ob/ob (leptin receptor-deficient) mice61–63	Hypertrophy, diastolic dysfunction	Strength: mimics the HFpEF metabolic signature Limitation: confounding, adverse effects from altered leptin signalling	+
	Obese Zucker rats64	Hypertrophy, fibrosis, diastolic dysfunction	Strength: mimics the HFpEF metabolic signature Limitation: rarely used in HFpEF studies; possibly confounding effects due to altered leptin receptor	+/++
	ZDF (Zucker Diabetic Fatty) rats65	Hypertrophy, diastolic dysfunction		+/++
	Otsuka Long-Evans Tokushima Fatty rats66	Hypertrophy, diastolic dysfunction	Strength: mimics the HFpEF metabolic signature Limitation: mainly a type II diabetes model; rarely used in HFpEF studies	++
Hypertension models	Deocycoticosterone acetate-salt hypertensive mice67	Hypertension, diastolic dysfunction	Strength: mimics hypertension-mediated effects, in particular hypertrophy Limitation: lacks comorbidities and the metabolic HFpEF signature; rodents can develop LV dilatation later in life, which is rarely seen in HFpEF patients	−/+
	Dahl Salt-sensitive rats68	Hypertension, eccentric or concentric hypertrophy, and systolic and/or diastolic dysfunction dependening on age-dependent timing of high-salt diet		−/+
	Bilateral renal wrapping in dogs69	Hypertension, hypertrophy, fibrosis, diastolic dysfunction		−/+
	Deocycoticosterone acetate combined with a Western diet in pigs70	Hypertension, hypertrophy, impaired relaxation	Strength: combines hypertension and metabolic dysregulation Limitation: role of diabetes and obesity not addressed; no fibrosis	+
Hormones	Low dose angiotensin II in mice71	Diastolic dysfunction	Strength: diastolic dysfunction in the absence of hypertrophy Limitation: lacks comobidities and the metabolic HFpEF signature; no clear role of angiotensin II in HFpEF pathophysiology	−
Hypertrophy	Inbred Hypertrophic Heart in rats72	Hypertrophy, diastolic dysfunction	Strength: hypertrophy, diastolic dysfunction and preserved systolic function in the absence of hypertension Limitation: lacks comobidities and the metabolic HFpEF signature	−/+
Aortic constriction or banding	Mice with mild and severe transverse aortic constriction73	Hypertrophy, fibrosis, diastolic and systolic dysfunction	Strength: studies on myocardial remodelling, in particular cardiac hypertrophy and fibrosis In large animal models: studies on the effect of cardiac hypertrophy on coronary perfusion Limitation: lacks co-mobidities and the metabolic HFpEF signature	−/+
	Rats with aortic banding74	Hypertrophy, diastolic dysfunction
	LV pressure overload by an implantable stent or inflatable aortic cuff in pigs75,76 or cats77	Hypertrophy, fibrosis, impaired relaxation, symptoms of heart failure
	Dogs with aortic banding78	Hypertrophy
Ageing models	Physiologic or accelerated ageing in mice79,80	Hypertrophy, fibrosis, diastolic dysfunction	Strength: captures age-related changes Limitation: lacks comobidities and the metabolic HFpEF signature	+
	Fischer F344 rats81
Cardiometabolic syndrome models	Dahl Salt-sensitive-Obese rats65	Diabetes, hypertension, hypertrophy, fibrosis, diastolic dysfunction	Strength: mimics human metabolic syndrome Limitation: rarely used in HFpEF studies	++
	ZSF1: ZDFxSHHF (spontaneously hypertensive heart failure)-hybrid rats82,83	Diabetes, hypertension, obese at older age, hypertrophy, fibrosis, diastolic dysfunction	Strength: mimics most HFpEF characteristics seen in humans, incuding exercise intolerance; well established as a HFpEF model Limitation: no identical genotype in control group (ZSF1-lean)	++/+++
	L-NAME plus high-fat diet in mice84	Hypertrophy, fibrosis, diastolic dysfunction	Strength: mimics most HFpEF characteristics seen in humans Limitation: no obvious LV stiffness increase found	++/+++
	Pigs with streptozotocin-induced diabetes, high-fat diet, and hypertension caused by renal artery embolization85	Hypertrophy, fibrosis, diastolic dysfunction	Strength: combines hypertension and metabolic dysregulation Limitation: role of obesity not addressed; no evidence of exercise intolerance	++

Abbreviations: VICs, valvular interstitial cells; CAVD, calcification aortic valve disease.