Effect of Diltiazem on Myocardial and Microvascular Stunning in Open Chest Dog

Lim, Do Sun; Kim, Byung Hoe; Kim, Hyun Chul; Lee, Seong Jin; Park, Sang Won; Ahn, Jeong Cheon; Song, Woo Hyuk; Park, Chang Gyu; Kim, Young Hoon; Seo, Hong Seog; Shim, Wan Joo; Oh, Dong Joo; Ro, Young Moo

Abstract

BACKGROUND
Post-ischemic myocardial dysfunction (myocardial stunning) is known to be associated with low reflow phenomenon or the reduction of coronary vasodilatory reserve. However, it remains controversial whether a relationship between myocardial stunning and post-ischemic impairment of coronary flow reserve exists. With increased influx of calcium into myocardial cells precipitated by ischemia and reperfusion known to be involved not only in the progression of myocardial tissue damage but also in the pathogenesis of post-ischemic myocardial dysfunction and impaired coronary vasodilatory reserve, it has been hypothesized that calcium channel blockers exert protective effects on post-ischemic myocardial dysfunction and microvascular dysfunction. PURPOSE: To investigate the effects of diltiazem, a calcium channel blocker, on post-ischemic myocardial dysfunction and coronary vasodilatory reserve, vehicle or diltiazem was administered before brief coronary artery occlusion in open chest dogs. Peak coronary flow and myocardial contractile function were measured after intracoronary infusion of endothelium-dependent vasodilator acetylcholine and endothelium-independent vasodilator adenosine. The parameters measured before and after reperfusion in control dogs and diltiazem-treated dogs were compared. METHOD: Open chest dogs (n-17) underwent 20 minutes occlusion of left circumflex artery followed by reperfusion for 60 minutes:the subjects were divided into two groups (n-10 in control group and n-7 in diltiazem group). Diltiazem dogs received diltiazem (0.2 mg/kg) intravenuously 15 minutes before coronary occlusion. Control dogs received vehicle-a saline solution. Coronary blood flow was measured with electromagnetic flow probe. Coronary flow reserve was determined by peak coronary flow after intracoronary infusion of acetylcholine (ACH, 0.01ug/kg) and adenosine (ADE, 1.5 mg/kg):it was also determined by reactive hyperemia (RH) measured after coronary occlusion for 20 seconds at baseline and 30 and 60 minutes after reperfusion. Segmental left ventricular function was assessed by 2-D echocardiography at the level of mid-papillary muscle, and changes of left ventricular function was expressed as % change of myocardial thickening and % change of endocardial thickening.
RESULTS
Peak coronary flow and minimal coronary vascular resistance with ACH, ADE and RH were maintained at 30 and 60 minutes after reperfusion in the diltiazem group, but those in the control group were significantly impaired. There was no difference in reduction of % change of peak flow with ACH in both groups (p-0.44), but the reduction of % change of peak flow with ADE was attenuated in the diltiazem group when compared with the control group (p-0.03) 60 minutes after reperfusion. Total myocardial thickening and endocardial wall motion at 30 and 60 minutes after reperfusion were significantly reduced than those assessed before coronary occlusion in both groups, but the endocardial wall motion was less depressed in the diltiazem group than that in the control group. There was no correlation between % change of peak flow in response to ACH and to ADE and % change of myocardial thickening:there was also no correlation between % change of endocardial wall motion in the control group and % change of myocardial thickening in the diltiazem group. There was however good correlation between % change of peak flow and % change of endocardial wall motion in the diltiazem group.
CONCLUSION
The findings that changes in peak coronary flow and minimal coronary vascular resistance do not correlate with the change in myocardial contractile function in the dog model with reperfusion after 20 minutes coronary occlusion suggest that microvascular and myocardial stunning develop independent of each other. The protective effect of diltiazem on impaired coronary flow reserve and contractile dysfunction following reperfusion after brief ischemia also suggests that calcium overloading plays a role in the pathogenesis of microvascular stunning as well as myocardial stunning.