Hiroaki Shimokawa - Coronary Vasomotion Abnormalities

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Stable coronary artery disease (CAD) is mainly caused by the various combinations of the three mechanisms, including epicardial organic coronary stenosis, epicardial coronary artery spasm, and coronary microvascular dysfunction (CMD). The representative manifestations of those three mechanisms are effort angina, vasospastic angina (VSA), and microvascular angina (MVA), respectively. Among them, VSA and MVA represent typical manifestations of coronary functional abnormalities. To date, much attention has been paid to the first mechanism, epicardial organic coronary stenosis, leading to the successful developments of percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG). However, it is also widely known that approximately 40% of patients with obstructive CAD still suffer from persistent/recurrent angina even after complete revascularization with PCI and/or CABG. Also, the prevalence of angina with nonobstructive CAD has been rapidly increasing worldwide, approximately 70% in women and 50% in men. Furthermore, to the surprise of the world, recently, the ISCHEMIA Trial has convincingly demonstrated that revascularization strategy with PCI or CABG has no prognostic benefit in patients with stable CAD with proven moderate to severe myocardial ischemia (NEJM, 2020). These lines of evidence indicate the importance of coronary artery vasomotion abnormalities in the pathogenesis of stable CAD.

In 1983, I succeeded in developing the first animal model of coronary artery spasm in pigs (Science, 1983) and have been performing a series of experimental and clinical studies since then for almost 40 years. My research group has demonstrated that coronary spasm is caused mainly by vascular smooth muscle hypercontraction mediated by Rho-kinase activation, that chronic adventitial inflammation is a central pathophysiology of the spasm, and that Rho-kinase inhibitor, fasudil, is very effective for the spasm. We have also performed domestic and international collaboration registry studies on coronary artery spasm, demonstrating the ethnic differences in clinical characteristics, treatments, and long-term prognosis of VSA patients.

We have also performed a series of experimental and clinical studies on CMD, in which we demonstrated that Rho-kinase activation also plays an important role in the pathogenesis of CMD and that epicardial spasm and CMD frequently co-exist. As a member of the Coronary Vasomotion Disorders International Study Group (COVADIS), I have also been performing an international prospective registry study on MVA, which demonstrated the ethnic differences in clinical patient characteristics, treatments, and long-term prognosis of MVA patients.

After almost 40 years of research, I have retired from Tohoku University in March 2020 and planned to publish a book that summarizes research works mainly from my laboratory to memorize my research on coronary vasomotion abnormalities. In Part I, we will focus on epicardial coronary artery spasm, including epidemiology of VSA, and pathophysiology, molecular mechanisms, diagnosis, and treatment of coronary artery spasm. In Part II, we will focus on CMD, including its epidemiology, pathophysiology, diagnosis, and treatment.

I hope that this book will help readers better understand the progress and current knowledge on coronary vasomotion abnormalities.