Table 4:

Animal Models of PH-HFpEF

	Experimental PH-HFpEF models/Comorbidities and disease modifiers	Type of animal species	Advantages	Limitations
Single-hit models	Aortic banding	Mouse Rat Cat Pig	•Reliable and commonly used model for examining cardiac factors without interference from additional comorbidities •Disease phenotypes have been extensively characterized	•The acute increase in afterload does not reflect the pathophysiology of human HFpEF •Prolonged banding (after ~4weeks) leads to LV dilation and systolic heart failure (HFrEF)
	Leptin-deficient ob/ob mouse	Mouse	•No surgery or additional treatment is needed	•Incomplete characterization of PH-HFpEF in this model
	High-fat diet (HFD)	Mouse	•Can be combined with specific genetic manipulations	•Not all mouse strains develop HFD-induced PH-HFpEF •Mild PH-HFpEF phenotypes in susceptible mouse strains
Multi-hit models	Supra-coronary banding + HFD + olanzapine	Rat	•Recapitulate many features of human disease •Permits omics analyses of specific vessel types	•Exercise intolerance, kidney dysfunction and skeletal muscle abnormalities have not been reported
	SU5416 + obese ZSF1 rat	Rat	•Recapitulate many of the key features of human disease, including comorbidities, systemic alterations, physical inactivity, and exercise intolerance •Reproducible •Develop exercise-induced PH-HFpEF during treadmill training	•Relatively expensive •Female obese ZSF1 rats are resistant to the development of hyperglycemia and proteinuria
Large-Animal Model	Banding of pulmonary veins	Pig	•Recapitulates global vascular remodeling observed in humans	•Requires advanced surgical expertise •May not model the effect of comorbidities on pulmonary hypertension (e.g., systemic hypertension)