Experimental animal models of coronary microvascular dysfunction

Abstract

Coronary microvascular dysfunction (CMD) is commonly present in patients with metabolic derangements and is increasingly recognized as an important contributor to myocardial ischaemia, both in the presence and absence of epicardial coronary atherosclerosis. The latter condition is termed 'ischaemia and no obstructive coronary artery disease' (INOCA). Notwithstanding the high prevalence of INOCA, effective treatment remains elusive. Although to date there is no animal model for INOCA, animal models of CMD, one of the hallmarks of INOCA, offer excellent test models for enhancing our understanding of the pathophysiology of CMD and for investigating novel therapies. This article presents an overview of currently available experimental models of CMD-with an emphasis on metabolic derangements as risk factors-in dogs, swine, rabbits, rats, and mice. In all available animal models, metabolic derangements are most often induced by a high-fat diet (HFD) and/or diabetes mellitus via injection of alloxan or streptozotocin, but there is also a wide variety of spontaneous as well as transgenic animal models which develop metabolic derangements. Depending on the number, severity, and duration of exposure to risk factors-all these animal models show perturbations in coronary microvascular (endothelial) function and structure, similar to what has been observed in patients with INOCA and comorbid conditions. The use of these animal models will be instrumental in identifying novel therapeutic targets and for the subsequent development and testing of novel therapeutic interventions to combat ischaemic heart disease, the number one cause of death worldwide.

Keywords: Animal model; Coronary microvascular dysfunction; Endothelial dysfunction; INOCA; Metabolic derangements.

Figure 1

Relation between HR and LVMBF at rest and during exercise in dogs, swine, rats, mice, and humans. For awake rabbits only a single resting measurement is available.^aThere are no measurements available in awake mice. Note that the regression line is based on the human data points. Adapted with permission from Duncker et al. HR, heart rate; LVMBF, left ventricular myocardial blood flow.

Figure 2

Animal models for CMD in the presence of metabolic derangement: large and small animal models for CMD, either spontaneous, inducible, or inbred/engineered for the development of metabolic risk factors have been employed to study the mechanisms leading to CMD. Alterations in microcirculatory endothelial function leading to a disturbed vasodilator/vasoconstrictor balance as well as structural modifications both at the arteriolar and capillary level have been described, mimicking the human pathology including reduced basal and maximal coronary perfusion and myocardial ischaemia. apoE, apolipoprotein E; CBF, coronary blood flow; CCK-1R, cholecystokinin-1 receptor; CFR, coronary flow reserve; CKD, chronic kidney disease; ET-1, endothelin-1; HFD, high-fat diet; LDLR, low-density lipoprotein receptor; LEPR, leptin receptor; NO, nitric oxide; RAAS, renin–angiotensin–aldosterone system; ROS, reactive oxygen species. Right-sided panel presents the mechanisms of CMD which have been recapitulated in at least one animal model/species (black), which have been investigated but were not found to be present (black ↔) or which have not been investigated (grey) in the various species.