Kunihisa Miwa

Circadian variation of exercise capacity in patients with Prinzmetal's variant angina: role of exercise-induced coronary arterial spasm.

Thirteen patients with Prinzmetals variant angina performed treadmill exercise tests in the early morning in the afternoon of the same day. The attacks with ST elevation were induced repeatedly in all 13 patients in the early morning, but in only two patients in the afternoon. Propranolol did not suppress the exercise-induced attacks in all 13 patients. Diltiazem suppressed the attacks in all 13 patients phentolamine in eight of the nine patients. Coronary arteriograms demonstrated that spasm occluding completely or almost completely the large coronary artery supplying the area of myocardium showing ST elevation appeared during the attacks disappeared along with the attacks after nitroglycerin administration in all four patients in whom the attacks were induced by arm exercise in the catheterization laboratory. We conclude that there is circadian variation of exercise capacity in patients with Prinzmetals variant angina caused by coronary arterial spasm induced by exercise in the early morning but not in the afternoon.

Coronary arterial spasm and Prinzmetal's variant form of angina induced by hyperventilation and Tris-buffer infusion.

SUMMARY Vigorous hyperventilation was induced for five minutes immediately after a five-minute infusion of 100 ml of Tris-buffer (pH 10) in nine patients with Prinzmetals variant angina. In eight of the patients, chest pain with ischemic changes in the electrocardiogram occurred during this procedure or within five minutes after it ended. Coronary arterial spasm appeared after the procedure and disappeared after the administration of nitroglycerin in all four patients in whom coronary cinearteriography was performed. This was evident both before and after the procedure and after sublingual administration of nitroglycerin (0.6 mg). The oral administration of 90 mg of diltiazem, a calcium antagonistic drug, two hours before, completely suppressed the attack induced by the procedure in all of the five patients who received this drug. We conclude that hyperventilation plus Tris-buffer infusion induces coronary arterial spasm and anginal attack in patients with Prinzmetals variant angina and that diltiazem suppresses these reactions.

Exertional angina pectoris caused by coronary arterial spasm: Effects of various drugs

In four patients with exertional angina induced by arm exercise, coronary arteriograms taken before, during and after the attack demonstrated that spasm appeared in the large coronary artery supplying the area of myocardium shown to be ischemic in the electrocardiogram during the attack. The spasm disappeared with subsidence of the attack after administration of nitroglycerin. Anginal attacks induced by treadmill exercise were not suppressed by propranolol, 60 mg orally, in two of the four patients. However, such attacks were suppressed in all patients by oral administration of diltiazem (90 mg, four patients) or nifedipine (20 mg, three patients) or intramuscular injection of phentolamine (0.2 mg/kg body weight, three patients). It is concluded that coronary arterial spasm can be induced by exercise and can cause exertional angina in some patients. Diltiazem and nifedipine, calcium antagonistic drugs, prevent spasm.

Inhibition of Human Low-Density Lipoprotein Oxidation by Flavonoids in Red Wine and Grape Juice

In the presence of red wine or grape juice, low-density lipoprotein was significantly resistant to oxidation; the biological activity of flavonoids, but not ethanol or nonflavonoid phenolic compounds, appeared to contribute to the antioxidant properties of red wine and grape juice. A significant antioxidant activity was also confirmed in low-density lipoprotein from humans after ingesting red wine but not grape juice, suggesting that flavonoids in red wine can be absorbed from the intestine more efficiently than those in grape juice.

Vitamin E Deficiency in Variant Angina

BACKGROUND Oxidative modification of LDL has been suggested to increase coronary vasoreactivity to agonists. A deficiency of vitamin E, a major antioxidant, may be related to the occurrence of coronary artery spasm. METHODS AND RESULTS Vitamin E levels were determined with the use of high-performance liquid chromatography in normolipidemic subjects, including 29 patients with active variant angina (group 1), 13 patients with inactive stage of variant angina without anginal attacks during the past 6 months (group 2), 32 patients with a significant (>75%) organic coronary stenosis and stable effort angina (group 3), and 30 patients without coronary artery disease (group 4). Total lipid levels in blood were calculated as total cholesterol plus triglyceride levels. The plasma alpha-tocopherol levels as well as alpha-tocopherol/lipids were significantly lower in group 1 than in groups 2 through 4. Also, the plasma gamma-tocopherol levels were significantly lower in group 1 than in groups 2 through 4. The vitamin E levels were not significantly different between group 1 patients with and those without a significant organic stenosis. In group 1, both alpha- and gamma-tocopherol levels were significantly elevated after a > or = 6-month angina-free period. The alpha-tocopherol levels in the LDL fraction were significantly lower in group 1 than in group 4. Plasma alpha-tocopherol levels were significantly correlated with those in the LDL fractions. In 6 patients of group 1 still having anginal attacks while receiving calcium channel blockers, the addition of vitamin E acetate (300 mg/d) significantly elevated plasma alpha-tocopherol levels and inhibited the occurrence of angina. CONCLUSIONS Plasma vitamin E levels were significantly lower in patients with active variant angina than in subjects without coronary spasm, suggesting an association between vitamin E deficiency and coronary artery spasm.

Soluble E-selectin, ICAM-1 and VCAM-1 levels in systemic and coronary circulation in patients with variant angina

OBJECTIVE The purpose of this study was to assess whether the plasma levels of soluble adhesion molecules including E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are elevated in patients with variant angina and whether they are released in the coronary circulation. METHODS Antecubital venous plasma samples were collected from 33 patients with variant angina, 22 patients with stable effort angina and 20 control subjects. Samples were also collected from the aortic root (AO) and the coronary sinus (CS) in 18 patients with variant angina before and after left coronary spasm induced by intracoronary injection of acetylcholine. The soluble adhesion molecules were assayed by enzyme immunoassay. RESULTS Antecubital venous plasma soluble E-selectin (P < .05), ICAM-1 (P < .01) and VCAM-1 (NS) levels were higher in the variant angina group than in the control group, respectively. The plasma soluble ICAM-1 level was also higher (P < .01) in the variant angina group than in the stable effort angina group. In the variant angina group, both soluble ICAM-1 (P < .05) and VCAM-1 (P < .01) levels were significantly lower in CS than AO at baseline. In contrast, after the spasm the plasma soluble ICAM-1 level was (P < .05) higher in CS than AO and the CS-AO differences of soluble ICAM-1 (P < .05) and VCAM-1 (P < .05) increased as compared with the baseline, respectively. These values were remained unchanged in the stable effort angina group after rapid atrial pacing and in the control group after administration of acetylcholine. CONCLUSIONS Circulating plasma levels of both soluble E-selectin and ICAM-1 were elevated in patients with variant angina, indicating an association of an inflammatory reaction with coronary spasm. Both soluble ICAM-1 and VCAM-1 appeared to be trapped in the coronary circulation at baseline and released into the coronary circulation following coronary spasm and reperfusion in the patients.

Significance of preinfarction angina for preservation of left ventricular function in acute myocardial infarction.

The effect of preinfarction angina on the preservation of left ventricular function was evaluated with the use of cineventriculography in 37 patients who had either total or subtotal occlusion of the proximal left anterior descending coronary artery during the convalescent period of myocardial infarction. In 15 patients who had preinfarction angina more than 1 week before the onset of acute myocardial infarction (group A), the global left ventricular ejection fraction was 54 +/- 3% (SEM) and regional wall motion in the infarct area was 10 +/- 3%. In 10 patients who had preinfarction angina occurred within 1 week before the onset of acute myocardial infarction (group B), the left ventricular ejection fraction and regional wall motion in the infarct area were 42 +/- 3% and 1 +/- 2%, respectively. In 12 patients without preinfarction angina (group C), the left ventricular ejection fraction and regional wall motion in the infarct area were 38 +/- 3% and -1 +/- 2%, respectively. In groups B and C, both the left ventricular ejection fraction and regional wall motion in the infarct area were lower than those in group A (p less than 0.05). The collateral circulation at the onset of acute myocardial infarction was better in group A compared with groups B and C (p less than 0.05). Thus the collateral circulation, promoted by repetitive anginal episodes indicative of myocardial ischemia, causes the preservation of myocardial function.

Alterations of autonomic nervous activity preceding nocturnal variant angina: Sympathetic augmentation with parasympathetic impairment ☆ ☆☆ ★

BACKGROUND Autonomic nervous discharge has been implicated in the pathogenesis of coronary artery spasm. METHODS Cardiac autonomic nervous activities were evaluated from the power of the low-frequency and the high-frequency spectral components of heart rate variability with Holter monitoring in 18 patients with nocturnal variant angina. Samples during the first 512 seconds of each 10-minute period from 60 minutes before to immediately before an anginal attack occurring during the night or at dawn (2:00 to 7:00 AM) were analyzed by fast Fourier transformation. RESULTS The R-R interval during the 10- to 0-minute period was significantly shorter than those during the other 10-minute periods. The coefficient of variance of the high-frequency component (0.15 to 0.40 Hz) (CVHF) from the 10- to 0-minute period was not significantly different from the other 10-minute periods. However, both the coefficient of variance of the low-frequency component (0.04 to 0.15 Hz) (CVLF) and the ratio of CVLF and CVHF (CVLF/CVHF) were significantly greater during the 10- to 0-minute period than those during the 30- to 20-minute period, respectively. A significant nighttime fluctuation in the spectral components of heart rate variability with a peak in the CVHF and a nadir in both the CVLF and CVLF/CVHF observed in the control group was blunted in the patients during the attack-free periods while they were medicated with calcium entry blockers. CONCLUSION Sympathovagal imbalance, sympathetic activation without parasympathetic augmentation, enhanced in the early morning may play an important role in the genesis of coronary artery spasm in patients with nocturnal variant angina.

Recent insights into the mechanisms, predisposing factors, and racial differences of coronary vasospasm

Coronary vasospasm is currently considered to be an exaggerated contractile nonspecific response of the vascular smooth muscle in the large coronary artery to various agonists or stimulation, that is established after the process of inflammation and fibrocellular proliferation. Endothelial dysfunction with reduced nitric oxide bioavailability has been reported in angiographically normal coronary arteries in Japanese patients with coronary spastic angina. Recently, several interesting findings concerning the exact mechanism of calcium hypersensitivity of spastic vascular smooth muscle have been reported. In animal models with coro-nary spasm Rho-kinase is upregulated at the spastic site and plays a key role in inducing vascular smooth muscle hypercontraction by inhibiting myosin light chain phosphatase, resulting in enhancement of its phosphorylation. Also, oxidative stress has been given attention as an important mediator of the spastic conversion of vascular smooth muscle cell “phenotype.” The incidence of coronary spastic angina in the Japanese population is reported to be remarkably high compared with that in Caucasians. Clinical and pathophysiological differences between Japanese and Caucasian patients with respect to coronary vasospasm are characterized by a lower prevalence of fixed coronary artery stenoses and diffuse coronary hyperreactivity in the Japanese patients. Recently, several distinct characteristics have been recognized to be associated with coronary vasospasm in studies analyzing data obtained from Japanese patients. In the present review, we will discuss our point of view on the mechanisms and predisposing factors in coronary vasospasm. Predisposing factors include smoking, lipid metabolic disorders, and gene expression, all of which may be interrelated issues.

Supersensitivity of coronary arteries in variant angina to spasm induced by intracoronary acetylcholine.

Acetylcholine (20 to 100 micrograms) was infused directly into coronary arteries in 10 patients with variant angina (group A), 13 subjects without coronary artery disease (group B) and 8 patients with significant organic coronary artery stenosis (greater than or equal to 50%) but without variant angina (group C) during coronary arteriography, to clarify the action of this agent on coronary arteries. Temporary pacing was performed at a demand heart rate of 40 beats/min while bradyarrhythmia developed. Coronary arteriography after administration of acetylcholine showed coronary vasoconstriction in all 10 patients (100%) of group A. Angina accompanied by electrocardiographic ischemic changes in 9 of 10 (90%, 7 ST-segment elevation and 2 depression) was provoked during this test. In the patients of group B, acetylcholine also induced vasoconstriction in 8 of 22 (36%) coronary arterial systems examined, chest pain in 3 (14%) and ST-segment deviation in none (0%). In the patients of group C, acetylcholine induced vasoconstriction in 3 of 9 (33%), chest pain in 2 (22%) and ST-segment depression in 1 (11%). No definite coronary artery dilation induced by acetylcholine was noted. Coronary vasoconstriction (p less than 0.05), electrocardiographic ischemic findings (p less than 0.01) and chest pain (p less than 0.01) were induced significantly more frequently in group A than in both groups B and group C. No significant difference was found between group B and group C. The coronary arteries in the patients with variant angina seem to be more susceptible to acetylcholine than those of patients without variant angina irrespective of the presence of significant atherosclerosis.