Vasospastic and Microvascular Vasospastic and Microvascular Coronary Artery DiseaseCoronary Artery Disease

Attilio Maseri, MDUniversity Vita-Salute San Raffaele – Milan, Italy

15th GWICC Beijing, October 2004

Coronary VasoconstrictionCoronary 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 Vasoconstriction of Epicardial Coronary ArteriesCoronary 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; 101:1102-1108

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

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 (1991-96): 64 cases aged 19-75 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 1981- 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;62:832Lefroy et al. Coronary artery disease 1992;3:745

Pace-maker, implantable defibrillator

Microvascular ConstrictionMicrovascular 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: 499-506

Maseri A et al, AJC 1992; 70: 1602-1605

Myocardial Phosphorus-31 NMR Spectroscopy in women with angina and normal coronary arteries Buchthal SD et al, NEJM 2000; 342

Ischemia-reperfusion damage after pacingin 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: 1579-80

Pupita G et al, NEJM 1990; 323:514-20

Uren N et al, NEJM 1994; 331:222-7

ConclusionsConclusionsClinical history can provide clues of the

causes of recurring angina in patients with angiographically normal coronary arteries:Microvascular dysfunctionVasospastic 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