Coronary Artery Spasm and the Polymorphisms of the Endothelial Nitric Oxide Synthase Gene

Abstract

oronary spasm plays an important role in the pathogenesis of vasospastic angina. It may also contribute to the development of other acute coronary syndromes. [1][2][3][4] Acute myocardial infarction can occur at the site of atherosclerotic plaques that do not narrow the coronary artery lumen. 5 Plaque rupture followed by thrombosis, and vasoconstriction at the site of the plaque, are involved in coronary artery occlusion. 6,7 Coronary vasospasm has been suggested to occur as a result of reduced endotheliumdependent vasodilatation and hyperactivity of vascular smooth muscle cells. [8][9][10][11] Kugiyama et al demonstrated a deficiency in the vasodilatory activity of endothelial nitric oxide (NO) in spastic arteries. 12 NO is biosynthesized from L-arginine by a family of NO synthases (NOSs). [13][14][15] Endothelial NOS (ecNOS), or NOS3, is constitutively expressed in the endothelium and catalyzes the synthesis of NO that regulates vascular tone. Wang et al reported that a polymorphism of intron 4 of the ecNOS gene (27-bp tandem repeats: a allele (4 repeats, rare, NOS4a), b allele (5 repeats, common)) is associated with the smoking-dependent risk for coronary artery disease. 16 The same research group also reported that these genotypes account for over 25% of the basal plasma NO production. 17 Other polymorphisms, Circulation Journal Vol.70, April 2006G894T (Glu298Asp) in exon 7 and T-786C in the 5' flanking region of the ecNOS gene, have been reported to be a risk factor for coronary artery disease, including coronary spasm. [18][19][20][21][22][23] The aim of this study is to assess the relationship between the polymorphisms of ecNOS genes, especially NOS4a, and coronary vascular behavior at spasm provocation tests in detail, by using quantitative coronary angiography (QCA). Methods Study PatientsOf 1,094 Japanese patients who underwent coronary angiography at the Cardiovascular Institute Hospital, Tokyo, Japan, 165 patients were clinically suspected of having angina and did not have fixed stenoses in their coronary arteries. Spasm provocation by serial infusions of acetylcholine (Ach) was performed on these 165 patients according to the method of Yasue et al. 24 In brief, Ach chloride (Daiichi Seiyaku) dissolved in 5 ml of warmed 0.9% saline in incremental doses of 25, 50 and 100 g was injected into the left coronary artery and then 25 and 50 g into the right coronary artery. A coronary arteriogram was obtained when ST segment changes and/or chest pain appeared or 1 min after each injection. When spasm was documented, 0.1 mg nitroglycerin (NTG) was injected into the coronary artery if the attack did not disappear within 2 min. A venous blood sample was obtained from the 165 patients. Blood samples were also obtained from 400 healthy subjects at the time of the health examination at Mitsui Memorial Hospital to determine the population incidence of polymorphisms of the ecNOS gene among Background Coronary artery spasm plays an important role in the pathogenesis of vasospastic angina, and contributes to the devel...

Differential Effects of Calcium-Channel Blockers on Vascular Endothelial Function in Patients With Coronary Spastic Angina

“…In addition to an altered contractile response of coronary smooth muscle, impaired endothelial function, especially NO function, is associated with coronary vasospasm. 21,22 In the present study, we showed that endothelium-dependent FMD was decreased in vasospastic angina patients compared with control subjects, thus confirming the impaired vascular endothelial function in these patients and in agreement with previous reports. 11,12 Furthermore, of the 3 CCBs, only benidipine, a dihydropyridine, provided a significant improvement in endotheliumdependent FMD and plasma cGMP concentration in patients with coronary vasospasm.…”

Clinical and Angiographic Characteristics of Acute Myocardial Infarction Caused by Vasospastic Angina Without Organic Coronary Heart Disease

“…The precise mechanism of coronary spasm remains obscure, but endothelial dysfunction and smooth muscle hypercontraction have been reported as important factors. 12 Kaneda et al recently reported that polymorphisms of the endothelial nitric oxide synthase gene are associated with coronary artery spasm 13 and Mashiba et al reported that VA is influenced by polymorphism of the paraoxonase 1 gene A632G. 14 Racial differences in the angiographic patterns and prevalence of coronary spasm appear to exist between Asian and Caucasians, and the prevalence of VA appears to be higher in Asians than in Caucasians.…”

Eosinophils May Be Involved in Thrombus Growth in Acute Coronary Syndrome Histologic Examination of Aspiration Samples

“…Some clinical studies have shown that Japanese ACS patients experience a higher incidence of coronary spasms than do Caucasians. 24,25) Although this racial difference may relate to differences in endothelial nitric oxide synthesis or autonomic nervous system activity, 25,26) the reason for this is not clear. Recent report suggests that coronary spasticity is related to airway hyper-responsiveness.…”