Vasospastic and Microvascular Coronary Artery Disease Attilio Maseri, MD University Vita-Salute San Raffaele – Milan, Italy 15th GWICC Beijing, October 2004

Coronary Vasoconstriction  Coronary perfusion can be transiently or persistently impaired by coronary vasoconstriction resulting in myocardial ischemia.  Vasoconstriction may occur in large coronary arteries and in the microcirculation.

Vasoconstriction of Epicardial Coronary Arteries  Coronary vasomotion modulates residual coronary flow reserve, resulting in a variable effort tolerance when stenosing plaques have a preserved muscular media which can vary the residual lumen

Coronary Artery Spasm  Coronary spasm can cause persistent coronary occlusion when associated with local thrombosis, resulting in acute infarction  Soon after acute MI, intracoronary acetilcoline cause coronary spasm in about 60% of Japanese patients, but only in 20% of Italians Pristipino et al, Circulation 2000; 101:

Vasoconstriction of Epicardial Coronary Arteries  Variant angina is typically characterized by angina at rest, particularly at night or in the morning, in the presence of a normal effect tolerance, but often causes infarction and fatal arrhythmias

Suspicion of Variant Angina  Predominantly spontaneous attacks with preserved effort tolerance, often in clusters of 2-3  Lasting 1-10 mins, relieved by GTN  Predominantly spontaneous attacks with preserved effort tolerance, often in clusters of 2-3  Lasting 1-10 mins, relieved by GTN  Often at night or early morning with waxing and waning over periods of weeks and months  Predominantly spontaneous attacks with preserved effort tolerance, often in clusters of 2-3  Lasting 1-10 mins, relieved by GTN  Often at night or early morning with waxing and waning over periods of weeks and months  Sometimes associated with syncope  Negative exercise test after GTN

Prevalence of Variant Angina  Pisa, London, Rome = 1.0% of admissions  Diagnosed only after weeks, months or years  Rome ( ): 64 cases aged years  60% had normal angiograms  40% major events  40% had stenosis  6% major events

Pathogenetics Mechanisms of Spasm  A local coronary hyper-response Hackett 1986 Hence: a smooth muscle post-receptorial alteration Maseri 1990  Provocation by stimuli acting on different receptors:  Ergonovine Higgins 1976  Metacholine Endo 1976  Dopamine Crea 1986  Hystamine Ginsburg Kaski 1986  Acetylcholine Yasue 1986  Serotonin Mc Fadden 1991

Treatment of Variant Angina  Reduce aspecifically smooth muscle constrictor response by nitrates and calcium-antagonists Sometimes very high doses required Frenneaux et al. Am J Cardiol 1988;62:832 Lefroy et al. Coronary artery disease 1992;3:745  Pace-maker, implantable defibrillator

Microvascular Constriction This syndrome includes 60-70% of women (about 60% post-menopausal and 40% pre-menopausal) but also 30-40% of men. It is characterized by angina pectoris and ‘normal’ coronary angiography. Its incidence may vary from 10% to 50% of patients submitted to coronary arteriography. The diagnosis of myocardial ischemia is difficult for a number of reasons.

 In spite of the absence of increased risk of infarction and cardiac death, these patients may be crippled by pain. Syndrome X: PROBLEM  The inconsistent response to nitrates and anti-anginal drugs and to non conventional anti-ischemic therapy, indicates the need for research on multiple, potential causes of coronary vascular dysfunction, in order to develop rational forms of therapy.

Suspicion of Microvascular Angina  Long-lasting (>10-30’), poorly responsive to GTN  Transient ECG changes or positive myocardial scintigraphy  Cardiac origin of pain  No evidence of left ventricular dysfunction  Worsening of exercise test following GTN Lanza et al, Circulation 1994

Mechanisms of Microvascular Angina No flow limiting stenosis Prearterioles 0.1 mm Conduit Distribution Epicardial 0.5 mm Endo Epi Arterioles < 0.1 mm Metabolic flow control Maseri A et al, JACC 1991; 17: Maseri A et al, AJC 1992; 70:

Myocardial Phosphorus-31 NMR Spectroscopy in women with angina and normal coronary arteries Buchthal SD et al, NEJM 2000; 342 Ischemia-reperfusion damage after pacing in patients with cardiac syndrome X Buffon A et al, Am J Physiol Heart Circ Physiol 2000; 279 Subendocardial perfusion reserve index in patients with syndrome X is reduced Panting JR et al, NEJM 2002 Evidence of Myocardial Ischemia

NPY  Clarke et al, Lancet 1977 Endothelin  Larkin et al, Am J Cardiol 1989 Altered adrenergic function  Lanza et al, Circulation 1997 Serotonin  Mc Fadden et al, NEJM 1991 Acetylcholine  Neumann et al, Am J Cardiol 1990 Na + /H + exchanger upregulation  Karen et al, Eur Heart J 1997 Potential Causes of Microvascular Dysfunction

Enhanced Pain Perception Generalized  Turiel et al. Am J Cardiol 1987; 60  Cannon et al. JACC 1990; 16 Cardiac  Shapiro et al. Br Med J 1988; 296  Pasceri et al. JACC 1998; 31

Coronary Microvascular Constriction in CAD  Maseri A, NEJM 91; 325:  Pupita G et al, NEJM 1990; 323:  Uren N et al, NEJM 1994; 331:222-7

Conclusions  Clinical history can provide clues of the causes of recurring angina in patients with angiographically normal coronary arteries:  Microvascular dysfunction  Vasospastic angina ( “A variant of the variant”, Cheng et al)  Microvascular and vasospastic angina can be rsponsible for angina also in the presence of coronary stenosis