Pathophysiology of Ischemic Heart Disease with Special Reference to Coronary Artery Spasm

  • M. Nakamura


Traditionally, ischemic heart disease has been considered the sequence of fixed atherosclerotic obstruction of the large epicardial coronary arteries. However, clinical hemodynamic, angiographic, scintigraphic and metabolic and animal studies have provided independent evidence for an increase in vasomotor tone, especially coronary spasm, as an important cause of various stages of ischemic heart disease. Factors that initiate or sustain the syndrome related to coronary spasm have not been completely defined, and a porcine model of coronary spasm was prepared in our laboratory.

The hypothesis of coronary spasm as a cause of angina pectoris was proposed during the 19th century. In the 1920’s, the close association between angina and atherosclerotic coronary narrowing was confirmed by pathological studies and coronary angiographic support was obtained in 1960s and 1970s, which neglected the presence of coronary spasm.

Beginning in the 1930s, there were reports of spontaneous angina not associated with increased myocardial oxygen demand. In 1959, Prinzmetal et al. summarized these cases, and reported a variant form of angina pectoris, ignoring the myocardial oxygen demand-supply imbalance theory. They proposed that increased coronary artery tonus was the cause of this variant angina. During the 1970s, Maseri and other investigators clearly demonstrated that coronary spasm is a major cause of variant angina.

Coronary spasm is now accepted as a major cause of variant angina, a significant proportion of rest angina and rest and effort angina, some cases of effort angina and postmyocardial infarctional angina, and possibly acute ischemia related death including acute myocardial infarction. However the link between coronary spasm, progression of organic stenosis, and thrombotic occlusion of coronary arteries is missing.

The pathophysiology of acute myocardial infraction is also uncertain. Recent clinical and pathophysiological studies have indicated that coronary-occlusive thrombi occur frequently in the early stage of transmural infarct, but infrequently with subendocardial infarct and sudden ischemic death. Mechanisms and factors which initiate coronary thrombosis are unknown. Falk deduced from pathological studies that rupture of the atheromatous plaque surface was always accompanied by hemorrhage into the plaque, but occlusive thorombosis was rare unless the rupture was associated with a stenosis greater than 75%. Thrombi in arteries are frequently located on the surface of atherosclerotic plaques, and not necessarily in the arteries related to myocardial infarction.

The antithesis to thrombosis as a cause of acute myocardial infarction is intramural hemorrhage in the atheroma as the primary event causing coronary occlusion. Clinical evidence supporting coronary spasm as the pathogenesis of acute myocardial infarct has been reported. The recent hypothesis that acute myocardial infarction occurs as a direct result of coronary spasm has not been fully proven. Thus, various studies on the development of suitable animal models of coronary spasm have been performed.

An animal model of coronary spasm should be helpful in clarifying mechanisms and roles of spasm in various stages of ischemic heart disease, including progression of organic stenosis and possibly acute coronary occlusion.

Gensini et al. were the first to demonstrate diffuse coronary spasm by giving pitressin to a normal dog, in 1962. In 1983, we developed a porcine model of coronary spasm in mildly atherosclerotic miniature swine, by injecting histamine and serotonin. We have recently improved the animal model of coronary spasm in moderate coronary atherosclerosis by giving serotonin, ergonovine, and hyperventilation, similar to what occurs in patients with variant angina.

In isolated coronary artery segments from atherosclerotic miniature swine, we found that a decrease in endothelium-dependent relaxing function and abnormal hypercontraction of the media of atherosclerotic coronary arteries. These events may result from an increased number of receptors for agonists, and/or augumentation of signal transduction, but not by increased calcium sensitivity of contractile proteins in the medial smooth muscle cells.

I will discuss about the following; a) the role of preexisting coronary atherosclerosis, b) neural factors, such as the adrenergic and parasympathetic nervous systems, c) autacoids, such as histamine and serotonin in the development of coronary spasm, and d) variations in in vitro, in vivo, and inter-species evidence.


Coronary Artery Acute Myocardial Infarction Ischemic Heart Disease Angina Pectoris Human Coronary Artery 
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Copyright information

© Springer-Verlag Tokyo 1991

Authors and Affiliations

  • M. Nakamura
    • 1
  1. 1.Research Institute of Angiocardiology and Cardiovascular Clinic, Faculty of MedicineKyushu UniversityHigashi-ku, Fukuoka, 812Japan

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