Coronary microvascular dysfunction after long-term diabetes and hypercholesterolemia

Abstract

Coronary microvascular dysfunction (CMD) has been proposed as an important component of diabetes mellitus (DM)- and hypercholesterolemia-associated coronary artery disease (CAD). Previously we observed that 2.5 mo of DM and high-fat diet (HFD) in swine blunted bradykinin (BK)-induced vasodilation and attenuated endothelin (ET)-1-mediated vasoconstriction. Here we studied the progression of CMD after 15 mo in the same animal model of CAD. Ten male swine were fed a HFD in the absence (HFD, n = 5) or presence of streptozotocin-induced DM (DM + HFD, n = 5). Responses of small (∼300-μm-diameter) coronary arteries to BK, ET-1, and the nitric oxide (NO) donor S-nitroso-N-acetylpenicillamine were examined in vitro and compared with those of healthy (Normal) swine (n = 12). Blood glucose was elevated in DM + HFD (17.6 ± 4.5 mmol/l) compared with HFD (5.1 ± 0.4 mmol/l) and Normal (5.8 ± 0.6 mmol/l) swine, while cholesterol was markedly elevated in DM + HFD (16.8 ± 1.7 mmol/l) and HFD (18.1 ± 2.6 mmol/l) compared with Normal (2.1 ± 0.2 mmol/l) swine (all P < 0.05). Small coronary arteries showed early atherosclerotic plaques in HFD and DM + HFD swine. Surprisingly, DM + HFD and HFD swine maintained BK responsiveness compared with Normal swine due to an increase in NO availability relative to endothelium-derived hyperpolarizing factors. However, ET-1 responsiveness was greater in HFD and DM + HFD than Normal swine (both P < 0.05), resulting mainly from ET receptor-mediated vasoconstriction. Moreover, the calculated vascular stiffness coefficient was higher in DM + HFD and HFD than Normal swine (both P < 0.05). In conclusion, 15 mo of DM + HFD, as well as HFD alone, resulted in CMD. Although the overall vasodilation to BK was unperturbed, the relative contributions of NO and endothelium-derived hyperpolarizing factor pathways were altered. Moreover, the vasoconstrictor response to ET-1 was enhanced, involving the ET receptors. In conjunction with our previous study, these findings highlight the time dependence of the phenotype of CMD.

Crocin Improves the Endothelial Function Regulated by Kca3.1 Through ERK and Akt Signaling Pathways

“…EDHF requires triggering by the hyperpolarization of endothelium to be activated. Some papers have reported on the significance of EDHF to endothelium-dependent relaxation which is compromised due to endothelial dysfunction in streptozotocin (STZ)-induced rats [17, 21, 22]. As we have known, KCa3.1 mediates the hyperpolarization of endothelium, and is considered to be critical in initializing EDHF–dilator responses in endothelium-dependent relaxation [18, 23, 24].…”

Myocardial first pass perfusion assessed by cardiac magnetic resonance and coronary microvascular dysfunction in women with angina and no obstructive coronary artery disease

“…The in-and exclusion criteria in the iPOWER study is previously published (18)(19)(20). Further exclusion criteria for the CMR sub-study were contraindication for CMR and diabetes due to the known potential microvascular dysfunction caused by impaired glycemic control (21). Baseline assessment included clinical and demographic data from interview, charts and the regional CAG database.…”

“…The median CFVR from the TTDE examination was 2.3 (1.8;2.7) and the median MBFR from the PET examination was 2.7 (2.2;3.1); the two were correlated (p<0.001, R=0.44), though not closely. Median time (IQR) between the TTDE and PET examination was 18 (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) days. Using a cut-off to define CMD of 2.0 by TTDE and 2.5 by PET, 25 (38%) and 21 (39%), respectively, had CMD.…”

Early detection of left ventricular diastolic dysfunction using conventional and speckle tracking echocardiography in a large animal model of metabolic dysfunction

“…Diabetes was induced with intravenous (ear catheter) injections of streptozotocin (25 mg/kg/day) over 3 days (total dose 75 mg/kg). One week after diabetes induction, a high fat diet (25% of saturated fats and 1% of cholesterol) was gradually introduced for diabetic pigs, whereas control pigs continued on a normal chow diet [ 27 ]. Pigs were group-housed (a total of 9 pigs at the same time) with a separate individual ad libitum access to food for 1 h/meal, twice daily for the entire 3-month study duration.…”