Recent insights into the mechanisms of vasospastic angina

Abstract

Coronary artery spasm plays an important role in the pathogenesis of many types of ischemic heart disease, not only in vasospastic angina but also in myocardial infarction and sudden death, particularly in the asian population. Patients with vasospastic angina are known to have defective endothelial function due to reduced nitric oxide bioavailability. Moreover, markers of oxidative stress and plasma levels of C-reactive protein are elevated. Smoking, polymorphysms of endothelial nitric oxide synthetase (eNOS), and low-grade inflammation have been regarded as the most important risk factors for vasospastic angina. The recent body of evidence indicates that RhoA and its down stream effector, ROCK/Rho-kinase, are associated with hypercontraction of vascular smooth muscle of the coronary artery and regulation of eNOS activity. Thus, endothelial dysfunction through abnormalities of eNOS and enhanced contractility of vascular smooth muscle in coronary artery segments are considered major mechanisms in vasospastic angina. However, the precise mechanisms for coronary vasospasm are not well understood. This article will review current understanding of the mechanism of coronary artery spasm.

Keywords: Coronary vasospasm; Vascular endothelium; Vascular smooth muscle.

Fig. 1

Mechanisms and precipitating factors of vasospastic angina. A number of mechanisms and precipitating factors may play a role in pathogenesis of vasospastic angina. Endothelial nitric oxide activity is reduced and markers of low-grade inflammation and oxidative stress are elevated in patients with vasospastic angina. Magnesium deficiency may be related to coronary vasospasm in some patients, and smoking is regarded as an independent risk factor for development of vasospastic angina. Recently, hyper-contraction of smooth muscle of the coronary artery in the presence of increased Ca²⁺ sensitivity has been considered an important molecular mechanism of coronary vasospasm. Pathologic mechanisms of coronary artery vasospasm causing myocardial ischemia might be multiple, or might interact with each other.

Fig. 2

Endothelium-dependent relaxation of smooth muscle. Nitric oxide (NO) is synthesized in endothelial cells from L-arginine by endothelial NO synthase. Following uptake into vascular smooth muscle cells, NO stimulates soluble guanylyl cyclase to form cyclic guanosine monophosphate (cGMP). cGMP activates cGMP-dependent protein kinase, resulting in protein phosphorylation, myosin light chain dephosphorylation, and relaxation (Adapted and modified from reference 67). GTP: guanosine triphosphate.

Fig. 3

Molecular mechanisms of coronary artery spasm. Upon stimulation by various agonists, the Rho/Rho-kinase-mediated pathway is activated, resulting in inhibition of myosin phosphatase (via phosphorylation of its myosin binding subunit), with a resultant increase in myosin light-chain phosphorylation and vascular smooth muscle hypercontraction. By contrast, the contribution of intracellular Ca²⁺ release may be minimal. With regard to the Rho/Rho-kinase-mediated pathway, several alterations could be involved, including enhanced expression of Rho/Rho-kinase, increased Rho-kinase activity, and inhibition of myosin phosphatase activity, all of which could eventually enhance myosin light-chain phosphorylation. PLC: phospholipase C, DAG: diacylglycerol, PKC: protein kinase C, IP3: inositol-1,4,5-triphosphate, CaM: calmodulin, MLC: myosin light chain, MBS: myosin binding subunit, MLCK: myosin light-chain kinase (Adapted and modified from reference 68).