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Variant angina.

In 1950, Prinzmetal described a new syndrome of chest pain of ischemic origin, which was to be called Prinzmetal or vasospastic angina, whose symptoms are not determined by any regular triggers: exercise, stress, etc. According to the initial description of this disease, anginal episodes occur on consecutive days, with their onset during the night or in the early morning, and are associated with ST-segment elevation (Ming-Jui Hung 2014; Prinzmetal 1959).

Prinzmetal angina's prevalence changes for geography, the frequency in Western population being much smaller than in the Eastern one, especially in Asia; also for sex, which is rather more common in men. Current treatments with calcium channel blockers or vasodilators such as nitroglycerin, changing the disease activity and avoiding the compounds that determine constriction at coronary level, make the diagnosis of vasospastic angina quite difficult (JCS Joint Working Group 2010).

There is a great variability of symptoms, according to the length of the coronary spasm, which, if high enough, may cause angina or myocardial infarction. Asymptomatic episodes may lead to silent myocardial ischemia, its incidence being twice as frequent and capable to determine arrhythmias or increase the risk for sudden death (Hung MJ 2014).

Prinzmetal angina has a daily circadian rhythm with onset at rest, from midnight until early morning (Prinzmetal 1959) but it may be induced by exercise shortly after awakening. The coronary arteriograms were seen quantitatively (Yasue et al 2008) by measuring the diameter of the major coronary arteries in patients with Prinzmetals angina. It was found that in the morning the tone was raised with a diameter much smaller than usual, and during the day it was a normal gauge, typically dilated. This could be the reason why most of the pacients with vasospastic angina experience a circadian change in exercise capacity (Yasue 2008).

The ECG is often modified, but it may well be normal during intercritical periods or in early crisis. Although initial studies were performed using surface ECGs on the assumption that the frequency of crisis is regular, the use of constant recording (Holter) allows the detection of asymptomatic crisis with deterioration of the ST segment (Figueras et al 2012).

The most common electrocardiographic changes are related to repolarization, consequent to the fast progression of ischemia during the coronary vasospasm. In 50% of the cases, the first change is a high and symmetrical T-wave which is accompanied by a slight increase of the QT interval, while a negative U-wave will sometimes be seen, followed by a gradual increase of the ST segment, its duration being a few minutes; it coincides with the anginal episode, associated as it is with very high R-waves and severely diminished or absent S-waves followed by the normalization of both the T-wave and the ST-segment. In some cases, a depression of the ST-segment can be seen allowing us to locate the spastic artery. After the acute episode, deep negative and transients T-waves may occur, dependent on its severity and duration and resolving in a few minutes to several hours. (Bay'es de Luna et al 2014; Stern 2009).

The most common arrhythmia in patients with Prinzmetal angina is ventricular tachycardia, which initially occurs in 2/3 of the patients during anginal episodes, and 1/3 in resolution periods. Sudden death after transformation from ventricular tachycardia to ventricular fibrillation in patients with severe ischemic heart disease, heart failure or thyrotoxicosis, have been reported. Such serious arrhythmias--as high-grade atrioventricular blocks and bradyarrhythmias followed by syncopal episodes--occasionally occur during an attack of Prinzmetal angina (Matsue et al 2012; Shah 2010).

Smoking, age and high sensitive C-reactive protein (hs-CRP) are major risk factors for vasospastic angina, often coexisting and interacting with each other. Although older people are more likely to develop Prinzmetal angina, smoking has a stronger effect in determining the occurrence of pathology in the young population. Although elevated hs-CRPs are correlated with an increased risk of developing vasospastic angina, it is supposed to differ for gender. Men with diabetes and low hs-CRP develop Prinzmetal angina, while in women it occurrs in a context of elevated hs-CRP. With a difference for the obstructive coronary disease, women have no reduced risk for coronary vasospasticity, which suggests a different pathogenesis (Hung MJ 2014).

Precipitating factors contributing to the onset of angina Prinzmetal are greatly varied even for the same patient: physical and mental stress, alcohol, hyperventilation, deficiency in magnesium, Valsalva maneuver and the administration of pharmacological agents being known to determine coronary spasm (Hung MY 2013; Hung MJ 2014).


The causes and mechanisms underlying the development of Prinzmetal angina are not fully understood; they are multifactorial, though:

The autonomic nervous system. The relationship between the autonomic nervous system and vasospastic angina is complex, and it seems that the increase in both the parasympathetic and sympathetic tonus represents triggers. Acetylcholine is known to determine coronary artery spasm, suggesting a role of vagal activity in triggering the disease. Spontaneous ischemic episodes are often preceded by a decrease of the vagal activity, followed by an increase of catecholamines in the coronary level, to suggest that Prinzmetal angina is not necessarily induced by any vagal activity (Hung MJ 2014).

Inflammation. Chronic inflammation is associated with vasospastic angina by increasing the number of white blood cells in the periphery, monocytes, hs-CRP, interleukin-6 and adhesion molecules (Itoh 2007; Yasue H et al 2006). The activity of rho-kinase in the peripheral leukocyte level is an independent predictor for disease severity, and is correlated with the plasma levels of interleukin-6 (Hung MJ et al 2012).

Endothelial dysfunction. Acetylcholine, ergonovine, serotonin and histamine cause vasodilation by inducing the release of nitric oxide (NO) from the endothelial level, but its dysfunction may induce episodes of vasospastic angina (Yasue 2008). Treatments with vitamin E or statin improve the endothelial function and pacients experience less frequent symptoms (Yasue et al 2008).

Smooth muscle cell hypercontractility. The relaxation and contraction of smooth muscle cells is controlled by the phosphorylation and dephosphorylation of the myosin light chain. The increase of rho-kinase activity at smooth muscle cell level directly promotes contraction by increasing the conversion of the myosin light chain in Ca 2+ and indirectly by augmenting the phosphorylation of the same chain, so that the use of a Rho-kinase inhibitor (hidroxifasudil) is able to prevent the occurrence of vasospastic angina (Hung MJ 2014).

Oxidative stress. Several reactive oxygen species have a negative effect on the walls of the blood vessels, thus leading to inflammation, endothelial injury and the constrictor response of the vascular smooth muscle cells. In vasospastic angina a pathogenic role for oxidative stress is suggested by the presence of the low plasma levels of vitamin E and the elevated levels of thioredoxin (Hung MJ 2014).

Genetics. The research to determine genetic mutations or polymorphisms in the pathogenesis of Prinzmetal angina is inconsistent. Mutations in the endothelial gene responsible for NO synthesis are possibly associated with the occurrence of the disease, but they occur in only one third of the patients (Yasue 2008). Polymorphisms of several genes encoding other proteins described in vasospastic angina include adrenergic and serotonergic receptors, angiotensin-converting enzymes and inflammatory cytokines (Park et al 2006).


The diagnosis of Prinzmetal angina is complex and cannot be determined only by symptoms, electrocardiogram or stress testing. In case of a cycloergometer test, the emergence of an elevation or a depression of > 0.1 mV of the ST-segment in at least two adjacent derivatives, and the incidence of a negative U-wave, otherwise absent during the rest period, raises suspicions about a vasospastic angina (JCS Joint Working Group 2010; Hung MJ 2014).

Coronary angiography with provocative testing is the only reliable method for the diagnosis of Prinzmetal angina. In patients with ST-segment elevation during anginal episodes, but with a normal coronary angiography, it is not necessary to use provocative testing for a positive diagnosis. Provoked coronary spasm is defined as a reduction of >50% in the luminal diameter accompanied by symptoms and/or ischemic ST-segment changes from the evaluation after the administration of nitroglycerin (Kusama et al 2011).

Ergonovine and acetylcholine are the most commonly used agents for provocative testing. In early studies, ergonovine was administered intravenously, the patients receiving very high doses which led to severe angina and death; then this method was abandoned and replaced by intracoronary administration, a much safer method for the induction of the coronary spasm (Yasue et al 2008).

With a view to ensuring the efficiency of provocative testing, the treatment with such vasodilators as calcium antagonists and nitrates should be stopped 48 hours before the procedure, being allowed only if administration of nitroglycerin sublingually is necessary (JCS Joint Working Group 2010). Atropine and nitroglycerin must be prepared prior to the test, so that they can be administered as soon as the coronary spasm begins. A positive diagnosis can be attributed to the spontaneous improvement of the obstruction following the administration of intracoronary nitroglycerin, thus highlighting the importance of its administration before attempting to perform the coronary angiography exam. Although other methods have been proposed, histamine, adrenalin, dopamine, dobutamine, atrial stimulation and exercise, the administration of intracoronary methylergonovine is the most sensitive and specific diagnostic method to be performed safely for the patient (Yasue 2008).

Another diagnostic method is the hyperventilation test, but it is useful only in patients with multiple episodes of angina every day, and presents the risk of simultaneously inducing multi-vessel coronary artery spasm (Hung MJ 2014).

Complications in the provocative testing include angina, arrhythmias, hypotension, dyspnea, nausea and vomiting, but cases of myocardial infarction or death have not been reported. As ventricular fibrillation is a possible complication following the administration of intracoronary methylergonovine, tests outside the cardiac catheterization rooms are not recommended. Absolute contraindications to methylergonovine include pregnancy, severe hypertension, severe left ventricular dysfunction, severe aortic stenosis and moderate-severe mitral stenosis (Kusama et al 2011).

Treatment and prognosis

The early initiation of treatment in Prinzmetal angina is important in preventing complications such as myocardial infarction, arrhythmias or sudden death. Sublingual or intravenous nitroglycerin or isosorbide dinitrate are effective in the improvement of anginal episodes (Yasue 2008).

Calcium channel blockers are highly effective in preventing ischemic attacks, the success rates of nifedipine, diltiazem, verapamil and diltiazem associated with nifedipine being 94%, 90.8%, 85.7% and 100% in a study made in Japan. Both binedipine and amlodipine turned out to have very good results in the treatment of Prinzmetal angina (Kusama et al 2011).

Long-acting nitrates are effective in preventing ischemic attacks, but the intermittent usage due to the development of tolerance is recommended. Nicorandil, an association between a triphosphate-sensitive potasium channel opener and a nitrate, and Fasudil, an inhibitor of Rho-kinase, are useful for preventing anginal attacks. The intravenous administration of Fasudil in patients previously treated with intracoronary nitroglycerin has further action in dilating the coronary arteries in patients with vasospastic angina (Hung MJ 2014).

Combinations of various classes of drugs like calcium channel blockers, nitrates and/or Nicorandil are necessary in patients with Prinzmetal angina resistant to initial pharmacological treatments. In addition to these drug combinations, magnesium, antioxidants and statins contribute to suppressing the coronary spasm (Kusama et al 2011).

Due to the circadian variation of Prinzmetal angina, the therapy should be administered in order to cover the sensitive period specific to each patient. Suppression of both symptomatic and asymptomatic episodes is important (especially the asymptomatic ones, because of their much higher frequency), the ambulatory electrocardiographic monitoring being essential if we mean to assess the effectiveness of pharmacological treatment (Hung MJ 2014).

Prinzmetal angina prognosis is favorable if complications are prevented early. Events such as coronary bypass surgery, myocardial infarction or sudden death occur in the first stages of disease development; in 76% of the patients who experience such episodes, they occurr during the first month of the onset of vasospastic angina. The survival rate of patients without complications is very good, 5 to 10 years for 98% and 94% respectively (Yasue 2008).

While in most patients with Prinzmetal angina the attacks can be suppressed through antianginal drugs, drug combinations sometimes have no effect. With a view to the role of the coronary spasm in ischemic heart disease, the untreatable vasospastic angina was defined as the angina which cannot be controlled by two different types of coronary dilators. Given such data, it was found that vasospastic angina was present in 921 of 2,251 patients (40.9%) with angina pectoris and 126 of them (13.7%) had untreatable angina, the treatment of such patients involving the use of two different classes of calcium channel blockers, with nitrate and/or Nicorandil (Takagi et al 2013).

Prinzmetal angina with multivessel diseases has frequent episodes of life-threatening arrhythmias. With the help of external defibrillators, the survival rate for ventricular tachycardias or ventricular fibrillations was significantly increased, but their implantation remains a controversial treatment method. (Hung MY 2013)

As a conclusion, Prinzmetal angina is a multifactorial disorder with triggers that can cause episodes of angina in the same patient, but under different conditions. Identification of the pathology is important in daily clinical practice because of the differences in the treatment strategies between obstructive coronary disease and the vasospastic. The administration of intracoronary nitroglycerin previous to coronary angiography helps to distinguish Prinzmteal angina from the atherosclerotic coronary disease, thus minimizing the damage to the vessels and preventing unnecessary procedures. Quitting smoking and the optimal use of the calcium channel blocker remains the cornerstone of Prinzmetal angina therapy. The increased frequency of angina episodes in the general population requires additional studies to better define the molecular pathways responsible for the development of more effective treatments.


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Figueras J, Domingo E, Ferreira I et al (2012) Persistent angina pectoris, cardiac mortality, and myocardial infarction during a 12-years follow-up in 273 variant angina patients without significant fixed coronary stenosis. American Journal of Cardiology 9: 1249-1255.

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Yasue H, Mizuno Y, Harada E et al (2008) Effects of a 3-hydroxy-3-methylglutaryl coenzyme A reductaseinhibitor, fluvastatin, on coronary spasm after withdrawal of calcium-channel blockers. Journal of the American College of Cardiology 51: 1742-1748.

Yasue H, Nakagawa H, Itoh T, Harada E, Mizuno Y (2008) Coronary artery spasm: clinical features, diagnosis, pathogenesis, and treatment. Journal of Cardiology 51: 2-17.

Teodor Flaviu Vasilcu, Clinical Assistant Professor of Medical Semiology, Grigore T. Popa University of Medicine, Georgescu Institute of Cardiovascular Diseases; Iasi, Romania;

Radu Andy Sascau, MD, PhD; Clinical Associate Professor of Cardiology, Grigore T. Popa University of Medicine, Georgescu Institute of Cardiovascular Diseases; Iasi, Romania;

Cristian Statescu, MD, PhD; Clinical Associate Professor of Cardiology, Grigore T. Popa University of Medicine, Georgescu Institute of Cardiovascular Diseases; Iasi, Romania;
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Author:Vasilcu, Teodor Flaviu; Sascau, Radu Andy; Statescu, Cristian
Publication:Romanian Journal of Artistic Creativity
Article Type:Disease/Disorder overview
Date:Dec 22, 2017
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