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

2. 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.

3. 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

4. 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; 101:1102-1108

5. 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

6. 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

7. Prevalence of Variant Angina  Pisa, London, Rome = 1.0% of admissions  Diagnosed only after weeks, months or years  Rome (1991-96): 64 cases aged 19-75 years  60% had normal angiograms  40% major events  40% had stenosis  6% major events

8. 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 1981- Kaski 1986  Acetylcholine Yasue 1986  Serotonin Mc Fadden 1991

9. 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

10. 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.

11.  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.

12. 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

13. 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: 499-506 Maseri A et al, AJC 1992; 70: 1602-1605

14. 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

15. 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

16. 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

17. Coronary Microvascular Constriction in CAD  Maseri A, NEJM 91; 325: 1579-80  Pupita G et al, NEJM 1990; 323:514-20  Uren N et al, NEJM 1994; 331:222-7

18. 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