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Prof. Gaetano A. Lanza
Prof. Filippo Crea,
Early diagnosis of variant angina is crucial to avoid major cardiac events (sudden death, myocardial infarction). Therapy with calcium-antagonists and nitrates, at the usual or maximally tolerated doses, is effective in the vast majority of patients. In the few refractory patients potential interventions include nicorandil, anti-adrenergic drugs, rho-kinase inhibitors and coronary stenting. An implantable defibrillator and a pacemaker should be considered in those with life-threatening tachy- or brady-arrhythmias, respectively.
Vasospastic angina indicates a form of angina caused by coronary artery spasm, which consists of a sudden occlusive vasoconstriction of a segment of an epicardial artery, resulting in a dramatic reduction of coronary blood flow1. This usually determines transmural myocardial ischemia, typically manifested by ST segment elevation on the electrocardiogram (ECG). In the most classical form, vasospastic angina occurs at rest (Prinzmetal’s variant angina), but, in some patients, spasm can also be triggered by efforts or stress conditions. Spasm may occur at the level of significant or non significant coronary stenoses as well as in angiographically normal epicardial arteries. In some cases it may involve more coronary segments (multifocal spasm).
Vasospastic angina represents about 2.0% of hospital admissions with a clinical pattern of unstable angina. It most frequently appears in the adult age (50 to 60 years) and shows a 5:1 ratio in male:female prevalence. Smoking is the only recognized risk factor; the use of some substances (e.g., alcohol, cocaine, 5-fluoro-uracile, sumatriptan), on the other hand, may favour vasospastic angina. In rare cases, variant angina is associated with systemic vasomotor disorders such as migraine and Raynaud's phenomenon, suggesting the presence of a general vascular disorder.
Coronary spasm results from the interaction of two components: 1) a local hyperreactivity to vasoconstrictor stimuli of a coronary segment, and 2) ongoing vasoconstrictor stimuli which trigger the spasm in the hyperreactive segment2. The vascular smooth muscle hyperreactivity is likely due to a post-receptorial cellular abnormality in the regulation of myofibril contraction, as suggested by the possibility of inducing the spasm by multiple stimuli acting on different cellular receptors3,4, and by the failure of specific receptor antagonists (e.g., a-blockers, serotonin antagonists, etc.) to significantly prevent angina attacks in these patients. Recent findings suggest that an increased activity of the intracellular enzyme rho-kinase5 and an impairment of the K+-ATP-dependent channels function may be among the cellular pathways potentially involved in coronary spasm. Also an increased activity of the membrane Na+-H+ exchanger, a major regulator of intracellular pH, has been described as a possible mechanism contributing to abnormal vasoreactivity6.
Vasospastic angina should be suspected in each patient presenting with angina attacks occurring exclusively or predominantly at rest. Although most patients with rest angina have the most usual form of unstable angina characterized by coronary thrombosis, the individuation of the subgroup of patients with variant angina among these patients is crucial, as the possibility to prevent coronary spasm by vasodilator drug administration (i.e., calcium-antagonists and nitrates) will avoid life-threatening complications of coronary spasm, including cardiac arrest and acute myocardial infarction. Angina attacks are usually short in duration (2-5 minutes, but sometimes only 30 sec) and may recur in clusters of more episodes within 20-30 minutes. Angina usually responds promptly to sublingual nitrates and may show a circadian pattern with a prevalence in the early morning or nocturnal hours. Effort tolerance is typically well preserved, but exercise may induce spasm in about one fourth of patients. Variant angina may present “hot phases”, with frequent recurrence of angina, alternated to “cold phases”, with remission of symptoms for weeks or months. The diagnosis can be confirmed by recording transient ST-segment elevation (>1 mm) on the ECG during angina. When it is difficult to obtain 12-lead ECG during pain, the diagnosis can often be achieved by ambulatory ECG recording of 24 or more hours, which frequently reveals the presence of silent ischemic episodes, representing 75-80% of all ischemic attacks. In a few cases provocative pharmacologic tests are needed to confirm the diagnosis of vasospastic (variant) angina. Intracoronary or intravenous administration of ergonovine or intracoronary infusion of acetylcholine can be used to induce and directly demonstrate coronary spasm during coronary angiography. Intravenous ergonovine test, on the other had, can be safely performed also non invasively, under careful clinical and 12-lead ECG monitoring, with coronary spasm confirmed by the induction of angina and ST segment elevation.
In a minority of patients severe ventricular tachyarrhythmias or bradyarrhythmias (sinus arrest, atrio-ventricular block) may develop during myocardial ischemia caused by coronary spasm, which may result in syncope or pre-syncope, or even cardiac arrest (mainly due to ischemia-induced ventricular fibrillation)7. Furthermore, in some cases spasm may be prolonged and/or complicated by local coronary thrombosis, which may cause acute myocardial infarction.
Vasospastic angina attacks can be effectively prevented by average or high doses of calcium antagonists (non dihydropiridine and dihydropiridine drugs, alone or also in association) in about 90% of patients. In some cases (e.g., persistence of episodes, side effects of calcium-antagonists) the addition of long-term nitrates is helpful for the controls of symptoms. In about 10% of cases, coronary artery spasm may be refractory to optimal vasodilator therapy and require very high doses of calcium-antagonists/nitrates. In case of persistence of vasospastic angina attacks, anti-alpha-adrenergic drugs, such as guanetidine or clonidine, may be helpful. Use of anti-oxidant vitamins (C and E) have been suggested to improve endothelial function and decrease vascular reactivity in vasospastic angina8 and might, therefore, improve the effects of vasodilator drugs, but data on this possible approach are lacking. Where available, the K+-channel opener nicorandil can be added. Recent data, on the other hand, suggest that coronary angioplasty with stenting might help to prevent coronary spasm in refractory variant angina9. The observation that the rho-kinase inhibitor fasudil can prevent acetylcholine induced vasospasm suggests that it could play a role in the treatment of variant angina in the future5. Complete cardiac denervation with plexectomy, with or without coronary artery bypass surgery, was previously proposed for the most resistent cases; however, procedural risks are high and results have been inconsistent10. Due to the possibility of long-term remission of symptoms, gradual withdrawal of drug therapy can be attempted in patients who become symptomless, with vasodilator promptly readministered in case of angina recurrence. Long-life vasodilator treatment, however, is recommended in those patients with features of angina attacks at risk of life-threatening tachy- or brady-arrhythmias. In these patients the need for an implant of an automated cardiac defibrillator or of a cardiac pacemaker, respectively, should be considered.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.
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7/ Miwa K, Miyagi Y, Igawa A, et al. Vitamin E deficiency in variant angina. Circulation 1996;94:14-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8964112&dopt=Abstract
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9/ Bertrand ME, Lablanche JM, Tilmant PY, et al. Treatment of a severe coronary artery spasm, refractory to complete denervation of the heart (autotransplantation). Arch Mal Coeur Vaiss 1982 ;75:717-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6810800&dopt=Abstract
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