2014 Williams Harvey Lecture: importance of coronary vasomotion abnormalities-from bench to bedside.

Coronary vasomotion abnormalities play important roles in the pathogenesis of ischaemic heart disease, in which endothelial dysfunction and coronary artery spasm are substantially involved. Endothelial vasodilator functions are heterogeneous depending on the vessel size, with relatively greater role of nitric oxide (NO) in conduit arteries and predominant role of endothelium-derived hyperpolarizing factor (EDHF) in resistance arteries, where endothelium-derived hydrogen peroxide serves as an important EDHF. The functions of NO synthases in the endothelium are also heterogeneous with multiple mechanisms involved, accounting for the diverse functions of the endothelium in vasomotor as well as metabolic modulations. Cardiovascular abnormalities and metabolic phenotypes become evident when all three NO synthases are deleted, suggesting the importance of both NO and EDHF. Coronary artery spasm plays important roles in the pathogenesis of a wide range of ischaemic heart disease. The central mechanism of the spasm is hypercontraction of vascular smooth muscle cells (VSMCs), but not endothelial dysfunction, where activation of Rho-kinase, a molecular switch of VSMC contraction, plays a major role through inhibition of myosin light-chain phosphatase. The Rho-kinase pathway is also involved in the pathogenesis of a wide range of cardiovascular diseases and new Rho-kinase inhibitors are under development for various indications. The registry study by the Japanese Coronary Spasm Association has demonstrated many important aspects of vasospastic angina. The ongoing international registry study of vasospastic angina in six nations should elucidate the unknown aspects of the disorder. Coronary vasomotion abnormalities appear to be an important therapeutic target in cardiovascular medicine.