Early experimental hypertension preserves the myocardial microvasculature but aggravates cardiac injury distal to chronic coronary artery obstruction

Abstract

Coronary artery disease is a leading cause of death. Hypertension (HT) increases the incidence of cardiac events, but its effect on cardiac adaptation to coexisting coronary artery stenosis (CAS) is unclear. We hypothesized that concurrent HT modulates microvascular function in chronic CAS and aggravates microvascular remodeling and myocardial injury. Four groups of pigs ( n = 6 each) were studied: normal, CAS, HT, and CAS+HT. CAS and HT were induced by placing local irritant coils in the left circumflex coronary artery and renal artery, respectively. Six weeks later multidetector computerized tomography (CT) was used to assess systolic and diastolic function, microvascular permeability, myocardial perfusion, and responses to adenosine in the “area at risk.” Microvascular architecture, inflammation, and fibrosis were then explored in cardiac tissue. Basal myocardial perfusion was similarly decreased in CAS and CAS+HT, but its response to adenosine was significantly more attenuated in CAS. Microvascular permeability in CAS+HT was greater than in CAS and was accompanied by amplified myocardial inflammation, fibrosis, and microvascular remodeling, as well as cardiac systolic and diastolic dysfunction. On the other hand, compared with normal, micro-CT-derived microvascular (20–200 μm) transmural density decreased in CAS but not in HT or CAS+HT. We conclude that the coexistence of early renovascular HT exacerbated myocardial fibrosis and vascular remodeling distal to CAS. These changes were not mediated by loss of myocardial microvessels, which were relatively preserved, but possibly by exacerbated myocardial inflammation and fibrosis. HT modulates cardiac adaptive responses to CAS and bears cardiac functional consequences.

Regulation of Coronary Blood Flow in Health and Ischemic Heart Disease

“…52 These findings support the concepts that endothelial dysfunction contributes to microvascular dysfunction distal to a stenosis, and does so via alterations in the control of vascular tone as well as through structural changes in microvessel diameter 5 and densities. 51 These findings indicate that a chronic epicardial stenosis may not only limit flow reserve by increasing proximal artery resistance, but also by producing microvascular dysfunction. This explains, at least in part, the observation that many patients with a significant coronary artery stenosis show an exaggerated reduction in coronary flow reserve for the level of stenosis severity.…”

“…In contrast, there is evidence that a chronic coronary artery stenosis, not only results in myocardial and interstitial, 6,50 but also in structural and functional microvascular alterations distal to the stenotic artery. Thus, arteriolar inward remodeling 5 and rarefaction 51 have been reported, as well as increased vasoconstrictor responses to endothelin (due to a loss of ET B -mediated vasodilation) and blunting of myogenic responses. 52 These findings support the concepts that endothelial dysfunction contributes to microvascular dysfunction distal to a stenosis, and does so via alterations in the control of vascular tone as well as through structural changes in microvessel diameter 5 and densities.…”

Transition From Obesity to Metabolic Syndrome Is Associated With Altered Myocardial Autophagy and Apoptosis

“…21 MDCT studies performed 2 days after MRI evaluated cardiac structure and function, as shown previously. 22 LV muscle mass, systolic function, early (E) and late (A) LV filling rates were calculated, as well as myocardial perfusion and MV permeability index before and during adenosine infusion, as we described. 20, 22, 23 Intra-abdominal adipose tissue measured using MDCT was expressed as volume and fraction.…”

“…22, 24, 25 Microvessels were classified using Analyze™ as small (diameters 20–200 µm), medium (201–300 µm), or large (301–500 µm). See Supplemental data for detail.…”

“…22 Staining in 10 random fields was quantified and expressed as fraction of surface area or of total cells stained with DAPI.…”