The effect of homocysteine-lowering therapy on vascular endothelial function and myocardial ischemic burden in coronary patients with hyperhomocysteinemia

This study was performed to determine whether homocysteine-lowering therapy (HLT) improves endothelium-dependent vasodilation and whether this results in a reduction in myocardial ischemic burden in patients with coronary artery disease. Sixteen male patients (plasma homocysteine levels >15 μmol/L) on a waiting list for routine coronary angioplasty (PTCA) of a focal stenosis at least 70% in the left anterior descending artery were studied. Patients were randomized to receive HLT (n=9, 0.4 mg of folic acid, 2 mg of vitamin B6, and 6 μg of vitamin B12) or placebo (n=7) until the time of PTCA (mean 4.8±0.9 weeks). At baseline and after four weeks of HLT, brachial artery vasomotion was assessed noninvasively and exercise T1-201 scintigraphy was performed in each patient. Myocardial ischemic burden was defined as maximal perfusion defect and redistribution gradient of perfusion abnormality on the polar map display. All patients had a follow-up angiogram at the time of PTCA. Plasma homocysteine levels were significantly reduced by HLT compared with baseline (21.2±5 vs. 11.8±3.1 μmol/L; p<0.008) whereas placebo had no effect (19.9±5 vs. 20.2±7 ±mol/L; p=NS). HLT produced a marked improvement in endothelium dependent, flow-mediated dilation, from 3.8±1.3% to 9.2±2.2 (p<0.0001). There was no significant change in flow-mediated dilation with placebo (3.7±1.3% vs. 3.8±1.6%; p=NS). Endothelium-independent, nitroglycerin-induced dilation was similar in the HLT (12.3±2.4% vs. 13.1±1.9%; p=NS) and placebo (13.2±2.2% vs. 12.9±2.8%; p=NS) groups compared with baseline. HLT resulted in significant reductions in maximal perfusion defect, from 52±21% to 42±17% (p=0.004) and in redistribution gradient, from 24.8±13% to 16.7±8% (p=0.006) whereas placebo did not. The severity of stenosis was not different between the initial and follow-up angiograms in HLT (81±9% vs. 82±11%; p=NS) and placebo (79±8% vs. 80±9%; p=NS) groups. In addition, the degree of reduction in plasma homocysteine level was negatively correlated with endothelium dependent vasodilation (r=-0.63, p=0.05). Improvement in endothelium dependent vasodilation was also negatively correlated with maximal perfusion defect (r=-0.65, p=0.05) and redistribution gradient (r=-0.67, p=0.04). In conclusion, lowering plasma homocysteine levels with HLT improves endothelium-dependent vasodilation and this may result in a reduction in exercise-induced myocardial ischemia in coronary patients with hyperhomocysteinemia.