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Prof. John F Beltrame
Despite the availability of effective therapies for coronary artery spasm, the diagnosis of variant angina is infrequently considered in patients with angina. Read here how to diagnose and evaluate.
In 1772, William Heberden, a British physician, aptly described the features of classical angina of effort, remarking on its occurrence with exertion and prompt resolution with rest. This was later attributed to fixed obstructive coronary atherosclerotic disease and associated with dynamic ST segment depression on the electrocardiogram (ECG) during pain. In 1959 Prinzmetal et al (1) described 32 cases of angina occurring at rest, reporting that the clinical characteristics of these patients differed to those with Heberden’s classical angina of effort since:
Considering these differences, Prinzmetal coined the term "variant angina" and speculated that the condition was due to an "increased coronary tonus" or vasospasm. Since then, there have been significant advances in our understanding of this condition with the principle pathophysiologic mechanism responsible for the syndrome being occlusive spasm of an epicardial coronary artery. Consequently, provocative spasm testing has been developed to aid in its diagnosis. Despite these advances, clinicians are often unclear in the diagnosis of variant angina and this communiqué will endeavour to clarify these issues.
Clinically, the hallmark features of variant angina include:
A high index of suspicion for this diagnosis must be considered in patients awakening with recurrent brief episodes of nocturnal angina, promptly relieved with sublingual nitrates. The diagnosis must also be considered in patients with recurrent rest angina associated with syncope or even cardiac arrest, since patients with variant angina may experience malignant arrhythmias during their ischaemic episodes.Except for cigarette smoking, the conventional atherosclerotic risk factors do not appear to predispose patients to variant angina. Also in contrast to atherosclerotic disease, the condition appears to be more prevalent amongst the Japanese as compared with Caucasians (2). Whereas exercise does not typically precipitate an episode of variant angina, hyperventilation and exposure to the cold can provoke episodes.The temporal pattern of the rest angina warrants close consideration in evaluating these patients, both in relation to its waxing and waning nature and its distinct circadian rhythm. Variant angina may remain quiescent for prolonged periods and then recur with multiple frequent episodes. During these "hot phases", stimuli that would not usually provoke an episode of variant angina, may induce an episode. The circadian nature of this disorder is also well recognised and illustrated by Yasue et al (3) who could provoke ST elevation in variant angina patients in the early morning (5-8am) but seldom when repeated in these patients in the afternoon (3-4pm).
The clinical history and ECG recording during a spontaneous attack are paramount in the clinical diagnosis of variant angina. However since spontaneous episodes are infrequently captured on ECG, additional investigations must be considered.
The differential diagnoses for patients with suspected variant angina (rest pain with ST elevation) include an evolving myocardial infarct, mixed pattern angina, tako-tsubo cardiomyopathy, and coronary microvascular disorders. Although variant angina may progress on to ST elevation myocardial infarction, the former is distinguished by a history of recurrent chest pain and prompt response to nitrates. Mixed pattern angina (both exertional and rest pain) was coined by Maseri (4) and acknowledges the spectrum of coronary disorders from exertional angina due to fixed obstructive coronary artery disease to dynamic spasm as occurs with variant angina. Tako-tsubo cardiomyopathy may manifest as rest angina associated with ST elevation. Although the classical apical ballooning may distinguish it from variant angina, some investigators speculate that this curious entity is due to multivessel spasm. Coronary microvascular disorders may cause rest angina in patients with normal angiography, which may be distinguished from variant angina by excluding coronary artery spasm with provocative spasm testing. In the absence of documented ischaemia, other non-cardiac causes of rest pain (eg oesophageal spasm) need to be considered.
Two approaches have evolved in the diagnosis of variant angina. The first is based upon Prinzmetal’s clinical criteria for diagnosing variant angina including 1) rest angina, with 2) transient ST elevation, and 3) improvement/resolution with sublingual nitrates. Many early studies utilised this clinical approach but with the advent of imaging the coronary arteries via selective angiography, the focus has moved towards the diagnosis based upon provocative spasm testing. With this later approach, the term "vasospastic angina" was coined with the following diagnostic criteria, 1) rest angina, 2) reversible ST changes (elevation or depression), and/or 3) spontaneous/provoked coronary spasm on angiography. Although these diagnostic approaches differ, there is significant agreement since validation studies have reported a 90% sensitivity and 99% specificity in the provoked spasm on angiography with the Prinzmetal clinical diagnostic criteria (7). Guidelines for the diagnosis and management of vasospastic angina have been produced by the Japanese Circulation Society (6) although these still need to be developed in other countries (8).
The management of Prinzmetal angina focuses on:
Variant angina may be associated with significant morbidity and mortality with infarct-free survival being 60-95% at 5 years (Figure-1). Independent determinants of infarct-free survival include the use of calcium channel blockers, extent and severity of coronary artery disease, and multivessel spasm (9). As shown in Figure-1, Caucasian variant angina patients have poorer outcomes than their Japanese counterparts, which in part may be due to the increased prevalence of coronary artery disease.
Variant angina can be readily diagnosed by clinical criteria and/or provocative spasm testing, yet it is often not considered. Given that it can have life-threatening sequelae that are preventable with readily available therapies, it is essential that clinicians are vigilant in considering this condition.Figure 1: Long-term infarct-free survival in Japanese (9-11) (filled shapes) and Caucasian (12-15) (open shapes) patients with variant angina. Adapted from Beltrame et al (2], J Am Coll Cardiol. 1999, 33:1445.
1.A variant form of angina pectoris; preliminary report.Prinzmetal M, Kennamer R, Merliss R, Wada T, Bor N: Angina pectoris. I. Am J Med 1959, 27:375-388.2.Racial heterogeneity in coronary artery vasomotor reactivity: differences between Japanese and Caucasian patients.Beltrame JF, Sasayama S, Maseri A: J Am Coll Cardiol 1999, 33:1442-1452.3.Circadian variation of exercise capacity in patients with Prinzmetal's variant angina: role of exercise-induced coronary arterial spasm.Yasue H, Omote S, Takizawa A, Nagao M, Miwa K, Tanaka S: Circulation 1979, 59:938-948.4.Maseri A: Variant Angina. In Ischemic Heart Disease A Rational Basis for Clinical Practise and Clinical Research. New York: Churchill Livingstone; 1995: 559-5885.Variant angina of Prinzmetal with normal coronary arteriograms.Cheng TO, Bashour T, Kelser GA, Jr., Weiss L, Bacos J: A variant of the variant. Circulation 1973, 47:476-485.6.JCS Joint Working Group: Guidelines for diagnosis and treatment of patients with vasospastic angina (coronary spastic angina) (JCS 2008): digest version. Circ J 2010, 74:1745-1762. 7.Sensitivity and specificity of intracoronary injection of acetylcholine for the induction of coronary artery spasm.Okumura K, Yasue H, Matsuyama K, Goto K, Miyagi H, Ogawa H, Matsuyama K: J Am Coll Cardiol 1988, 12:883-888.8.Sueda S, Sasaki Y, Sakaue T: Recommendation for establishment of guidelines for Prinzmetal’s variant angina and vasospastic angina in the USA and Europe. J Cardiol Cases 2012, 6:e161-162.9.Long-term prognosis for patients with variant angina and influential factors. Yasue H, Takizawa A, Nagao M, Nishida S, Horie M, Kubota J, Omote S, Takaoka K, Okumura K: Circulation 1988, 78:1-9.10.Clinical characteristics associated with myocardial infarction, arrhythmias, and sudden death in patients with vasospastic angina. Nakamura M, Takeshita A, Nose Y: Circulation 1987, 75:1110-1116.11.Clinical characteristics and long-term prognosis of patients with variant angina. A comparative study between western and Japanese populations.Shimokawa H, Nagasawa K, Irie T, Egashira S, Egashira K, Sagara T, Kikuchi Y, Nakamura M: Int J Cardiol 1988, 18:331-349.12.Factors influencing the long-term prognosis of treated patients with variant angina.Waters DD, Miller DD, Szlachcic J, Bouchard A, Methe M, Kreeft J, Theroux P: Circulation 1983, 68:258-265.13.Clinical characteristics and long-term survival of patients with variant angina.Mark DB, Califf RM, Morris KG, Harrell FEJ, Pryor DB, Hlatky MA, Lee KL, Rosati RA: Circulation 1984, 69:880-888.14.Long-term prognosis of "variant" angina with medical treatment.Severi S, Davies G, Maseri A, Marzullo P, L'Abbate A: Am J Cardiol 1980, 46:226-232.15.Long-term prognosis of patients with variant angina.Walling A, Waters DD, Miller DD, Roy D, Pelletier GB, Theroux P: Circulation 1987, 76:990-997.
John F Beltrame BSc, BMBS, FRACP, PhD, FESC, FACC, FAHA, FCSANZAddress for correspondence:Prof John F BeltrameThe Queen Elizabeth HospitalDiscipline of MedicineUniversity of Adelaide 28 Woodville RoadWoodville South SA, Australia 5011Ph: +61 8 8222 6740Fax: +61 8 8222 6042Email: firstname.lastname@example.orgAuthors disclosures: None declared.
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