Abstract
Comorbidities of ischemic heart disease, including diabetes mellitus (DM), hypercholesterolemia (HC) and chronic kidney disease (CKD), are associated with coronary microvascular dysfunction (CMD). Increasing evidence suggests that CMD may contribute to myocardial ‘Ischemia and No Obstructive Coronary Artery disease’ (INOCA). In the present study, we tested the hypothesis that CMD results in perturbations in myocardial perfusion and oxygen delivery using a novel swine model with multiple comorbidities. DM (streptozotocin), HC (high-fat diet) and CKD (renal embolization) were induced in 10 female swine (DM + HC + CKD), while 12 healthy female swine on a normal diet served as controls (Normal). After 5 months, at a time when coronary atherosclerosis was still negligible, myocardial perfusion, metabolism, and function were studied at rest and during treadmill exercise. DM + HC + CKD animals showed hyperglycemia, hypercholesterolemia, and impaired kidney function. During exercise, DM + HC + CKD swine demonstrated perturbations in myocardial blood flow and oxygen delivery, necessitating a higher myocardial oxygen extraction—achieved despite reduced capillary density—resulting in lower coronary venous oxygen levels. Moreover, myocardial efficiency was lower, requiring higher oxygen consumption for a given level of myocardial work. These perturbations in myocardial oxygen balance were associated with lower myocardial lactate consumption, stroke volume, and LVdP/dtmax, suggestive of myocardial ischemia and dysfunction. Further analyses showed a reduction in adenosine-recruitable coronary flow reserve, but this was exclusively the result of an increase in basal coronary blood flow, while maximal coronary flow per gram of myocardium was maintained; the latter was consistent with the unchanged arteriolar wall/lumen ratio, arteriolar density and peri-arteriolar collagen content. However, isolated small arteries displayed selective blunting of endothelium-dependent vasodilation in response to bradykinin in DM + HC + CKD swine, suggesting that changes in coronary microvascular function rather than in structure contributed to the perturbations in myocardial oxygen delivery. In conclusion, common comorbidities in swine result in CMD, in the absence of appreciable atherosclerosis, which is severe enough to produce perturbations in myocardial oxygen balance, particularly during exercise, resembling key features of INOCA.
Highlights
Common comorbidities of cardiovascular disease, including diabetes mellitus (DM), hypercholesterolemia (HC) and chronic kidney disease (CKD), are well-known risk factors for the development of coronary artery disease of both large epicardial arteries and smaller coronary arteries [8, 13, 18, 31]
There was no difference in aspartate aminotransferase (ASAT) plasma levels between groups, while alanine aminotransferase (ALAT) levels even decreased in DM + HC + CKD compared to normal diet served as controls (Normal) swine
Kidney weights were not different from Normal swine, renal dysfunction was present in DM + HC + CKD swine reflected in increased creatinine plasma levels and a significantly impaired glomerular filtration rate (GFR), as measured by inulin clearance, increased histological scores of tubulointerstitial injury, and glomerular sclerosis
Summary
Common comorbidities of cardiovascular disease, including diabetes mellitus (DM), hypercholesterolemia (HC) and chronic kidney disease (CKD), are well-known risk factors for the development of coronary artery disease of both large epicardial arteries and smaller coronary arteries [8, 13, 18, 31]. The mechanisms underlying INOCA remain incompletely understood, there is increasing evidence that CMD, in particular impaired endothelium-dependent vasodilation, plays an important role [2, 10, 13, 66] In agreement with these clinical observations, experimental data obtained in swine chronically exposed to multiple comorbidities, demonstrate endothelial dysfunction of isolated small coronary arteries studied in vitro, in the absence of obstructive CAD [54, 57, 63]. Whether these perturbations in coronary microvascular endothelial function translate into impaired myocardial perfusion and oxygen delivery in vivo, i.e., result in INOCA, was not assessed in these studies. Swine were chronically instrumented after 5-months of exposure to DM + HC + CKD, to allow the assessment of systemic and coronary hemodynamics as well as myocardial metabolism and function in the awake state, at rest and during treadmill exercise
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