Short-term exercise training prevents micro- and macrovascular disease following coronary stenting

Abstract

The purpose of this study was to determine the effects of exercise on coronary blood flow and macrovascular atherosclerosis in response to stent deployment. Male Yucatan swine were placed on a control diet (C); on a high-fat/cholesterol diet (hypercholesterolemic; H); or on a high-fat/cholesterol diet and aerobically exercise trained (HX) starting after 36 wk on the diet. All pigs underwent coronary angiography and intravascular ultrasound (IVUS) guided placement of a bare metal stent in the circumflex coronary artery after 40 wk on diets and 3 wk later pigs underwent repeat angiography and IVUS and coronary blood flow (CBF) measurement. Average peak velocity (APV) was measured under basal conditions and in response to intracoronary application of the endothelium-independent vasodilator adenosine and the endothelium-dependent vasodilator bradykinin. There was a similar approximately 8-fold increase in total cholesterol in H and HX compared with control. Baseline CBF was increased above control and H in HX (P<0.05). At all doses adenosine-induced CBF was impaired in H, but preserved in HX. Similarly, bradykinin-induced CBF was impaired in H vs. control, yet was potentiated in HX. Microvessel density was decreased in H and preserved in HX vs. control. Native atheroma in HX was lower relative to H and control, while in-stent stenosis in HX was not different from H. Hyperlipidemia-induced microvascular dysfunction after stent deployment may be a result of reduction in microvessel density. This is the first report that short-term exercise training near the time of stenting prevents stent-induced microvascular dysfunction and attenuates native atheroma independent of changes in plasma cholesterol in this porcine model.

Fig. 1.

Schematic representation showing placement of coronary stent, positioning of intravascular ultrasound (IVUS) and flow wire in the circumflex artery, and IVUS images. A: for coronary blood flow (CBF) determinations, IVUS and flow wire (thin line in CFX) information were collected from a position in the circumflex (CFX) artery proximal to the coronary stent. The full length of the circumflex artery was interrogated with IVUS at stent placement and 3 wk later. The nonstented left anterior descending (LAD) artery was interrogated with IVUS only at the time the animal was euthanized, and the right coronary (RC) was not interrogated. B: representative IVUS image of coronary artery with minimal atherosclerosis. Arrows indicate location of lumen and artifact caused by IVUS catheter. C: image indicating percent degree atheroma calculation. This artery shows 300 degrees of atheroma (wall coverage) of a thin (<0.3 mm) layer of intimal thickening. Degrees of atheroma for an interrogated artery were summed and divided by (360°/mm × length of vessel in mm). This was multiplied by 100 to yield % degrees atheroma to normalize for different lengths of arteries (10).

Fig. 2.

Baseline CBF and response to vasodilators. A: summary data illustrating baseline coronary blood flow was greater in swine placed on a high-fat/cholesterol diet and aerobically exercise trained (HX) vs. those on a high-fat/cholesterol diet (H) and those on a control diet (C). B: summary data demonstrating bradykinin-induced CBF was impaired in H and potentiated in HX relative to C at all doses. C: summary data demonstrating adenosine-induced CBF impairment is prevented with exercise training. *P < 0.05 relative to C; #P < 0.05 relative to both C and H.

Fig. 3.

Percent stenosis in areas 5 and 10 mm proximal to stented section was significantly greater in H animals compared with control and HX. A: represents a diagram of the circumflex artery and relative location of the stented section and the sections proximal to the stent. B: representative image of the method used to calculate intima and media areas in histological section. Arrowheads indicate location of some stent struts and arrows indicate artery luminal border. Internal and external elastic laminas and neointima are identified. C: representative images of each histological section. Stented sections of the circumflex artery were stained with Verhoeff-van-Gieson stain to accentuate the internal and external elastic lamina. Areas of neointima and lumen were quantified to calculate percent stenosis values. D: summary data for the % stenosis determined at the location 5 mm proximal to the stent (peri-stent CAD). *P < 0.05, H vs. C and HX. E: summary data for the % stenosis obtained from histological analysis within the stent. There were no significant differences across groups within the stent.

Fig. 4.

Coronary microvessel density after stenting was significantly less in the H animals vs. control (P < 0.05). Left ventricular sections obtained from each animal were preserved in formalin and stained with an antibody for α-smooth muscle actin to identify arteriolar microvessels. A–C: representative section of left ventricular tissue from a C, H, and HX animal. Asterisk (*) indicates areas of cardiac muscle; arrow indicates coronary microvessels. D: summary data for the microvessel density obtained from immunohistochemical analysis in the myocardium. *P < 0.05 vs. C and HX.