High susceptibility of atherosclerotic coronary arteries to the onset of vasospasm and angina pectoris-like symptoms due to coronary spasm in WHHLMI rabbits

Abstract

We examined the relationship between atherosclerosis and the provocation of coronary spasm as well as the influence of coronary spasm on the onset of acute ischemic myocardial disease. Coronary spasm was provoked in anesthetized normal Japanese white (JW) rabbits and myocardial infarction-prone Watanabe heritable hyperlipidemic (WHHLMI) rabbits, an animal model for coronary atherosclerosis and myocardial infarction, by injecting ergonovine during the infusion of norepinephrine through a marginal ear vein. A decrease in contrast flow in the left circumflex artery was observed on coronary angiograms. Ischemic changes were observed on the electrocardiograms of 29% (2/7) of JW and 79% (27/34, P=0.007) of WHHLMI rabbits. The frequency of coronary spasm was significantly high in rabbits with severe coronary plaques showing diffuse lesions. Left ventricle motility in vasospasm-positive rabbits, which was evaluated with echocardiograms, was decreased by 29% following the ergonovine injection (P<0.001), and every serum ischemic marker markedly increased 4 h after the provocation of vasospasm. These results demonstrate that atherosclerotic coronary arteries are positively related to the provocation of vasospasm, and vasospasm in severe atherosclerotic coronary segments evokes angina pectoris-like findings and/or non-fatal myocardial infarction. WHHLMI rabbits may be a novel animal model for angina pectoris and acute ischemic heart disease.

The History of the WHHL Rabbit, an Animal Model of Familial Hypercholesterolemia (I) - Contribution to the Elucidation of the Pathophysiology of Human Hypercholesterolemia and Coronary Heart Disease -

“…It has been clarified that the vasoconstrictor response was enhanced in the atherosclerotic coronary arteries 64) . This study suggests that the development of atherosclerotic lesions is likely to cause coronary artery spasm and has led to later studies on the provocation of acute coronary syndromes by spasm 22,65) . It is well known that coronary arteries expand in response to the progression of atherosclerotic lesions, and this coronary artery enlargement is called compensatory remodeling.…”

“…Therefore, it should be noted that the pathogenesis of ath- Table 3. Characteristics of coronary lesions elucidated in studies using WHHL rabbit family • Differences between coronary artery lesions rich in fibers and aortic lesions rich in lipids 15,61) • The relevance of factors other than conventional risk factors (such as serum total cholesterol levels, HDL levels, oxidative stress, hyperglycemia, hypertension, and others) in the development and progression of coronary lesions 75) • Involvement of genetic factors different from aortic lesions in the development of coronary artery lesions 75) , and involvement of the coronary curvature in the progression and composition of lesions 68) • The relevance of additional factor(s) in the rupture of unstable coronary lesions characterized by thin-capped fibroatheroma 4,22,65) • Involvement of coronary spasm in rupture of coronary lesions and the occurrence of acute coronary syndromes 22,65) • The relevance of several serum lipid molecules identified with lipidome analyses in the development and progression of coronary lesions 75) • Involvement of macrophages infiltrated into the deep area of intima through vasa vasorum 29) in coronary outward remodeling 67) • Suppression and destabilization of atherosclerotic lesions by lowering serum lipid levels 5) human coronary lesions 30) , various types of coronary lesions were observed in WHHLMI rabbits (Fig. 3), such as fatty streak, fibrous lesion, fibroatheroma, thin-capped fibroatheroma, and advanced complicated lesions with reduced cellular components, calcification, vasa vasorum, etc.…”

“…These observations suggest that the second stimulation, such as mechanical force, plays an important role in the rupture of vulnerable lesions. We provoked coronary spasm by an intravenous injection of ergonovine during an intravenous infusion of norepinephrine 22,65) . As a result, serum markers for myocardial injury (heart-type fatty acidbinding protein, cardiac troponin-I, and myoglobin) were markedly increased 4 h after spasm provocation, and fractional shortening of the left ventricle evaluated by echocardiogram was decreased at spasm provocation.…”

Coronary Plaque Characteristics and Cut-Off Stenosis for Developing Spasm in Patients with Vasospastic Angina

“…The concept that plaque can be a trigger for vasospasm or reversely, spasm itself can initiate or aggravate the atherosclerosis is already well known by experimental and clinical studies 7 . The spasm itself could cause atherosclerotic progression, plaque injury or rupture and could even lead to ST-elevation myocardial infarction from clinical or experimental evidences 1,[8][9][10][11] .…”