Variant angina

Apr 18, 2000

Variant angina (also called Prinzmetal's angina) is a form of angina in which angina pectoris spontaneously occurs in association with ST segment elevation on the EKG [1]. Although it was thought to have been first described by Prinzmetal, this form of angina had actually been recognized in the 1930s by other investigators [2,3].

Prinzmetal proposed that episodic "temporary increased tonus" in a high-grade obstruction of a major coronary artery was responsible for the syndrome of variant angina [1,4]. It is now accepted that this hypothesis is correct.

Coronary vasospasm is a transient, abrupt, marked reduction in the luminal diameter of an epicardial coronary artery that results in myocardial ischemia; this process can usually be reversed by nitroglycerin or a calcium channel blocker. Spasm occurs in the absence of any preceding increase in myocardial oxygen demand and in either normal or diseased vessels. The reduction in diameter is focal and usually at a single site, although spasm in more than one site and diffuse spasm have recently been reported [5]. Spasm typically occurs within 1 cm of an atherosclerotic plaque in a diseased vessel.

CLINICAL CHARACTERISTICS — The clinical presentation and profile of the patient with variant angina are generally different from that of the patient with unstable or chronic stable angina [6]:

  •  Patients with variant angina are younger that those with typical angina and do not exhibit classic cardiovascular risk factors (except for cigarette smoking) [7].

  •  Variant angina may be associated with other vasospastic disorders, such as migraine headaches and Raynaud's phenomenon [6].

  •  Substance abuse (such as cocaine) is an important risk factor. This may be the putative cause of myocardial infarction in the absence of angiographically documented coronary disease in cocaine users [8].

  •  Exercise and hyperventilation can precipitate attacks of vasospastic angina. The majority of patients, however, have normal exercise tolerance [6,9,10].

  •  There is a circadian variation with an increased prevalence of angina attacks in the early morning hours [11].

  •  Coronary vasospasm has been reported after blunt thoracic trauma [12].

Arrhythmias are common and may be life-threatening during a episode of coronary spasm. The type of arrhythmia is determined in part by the vessel involved: heart block with spasm of the right coronary artery; and ventricular tachycardia with spasm of the left anterior descending artery.

The susceptibility to ventricular arrhythmias may be related to inhomogeneity of repolarization that is present even in the absence of ischemia. One study found that baseline QT dispersion, a noninvasive marker of heterogeneity, was greater among 50 patients with variant angina compared to 50 patients with atypical chest pain [13]. Among the patients with variant angina, those with arrhythmia had a greater degree of baseline QT dispersion.

PATHOGENESIS — Although the pathogenesis of coronary vasospastic angina is not well understood, several contributing factors (other than cocaine abuse) have been identified. These include the autonomic nervous system (particularly alpha-adrenergic receptors), endothelial dysfunction, and adhesion molecules.

Autonomic nervous system — The precipitation of spasm by acetylcholine and methacholine and its prevention by atropine and alpha receptor blockers (phenoxybenzamine, phentolamine, prazosin and clonidine) suggest a role for the parasympathetic nervous system and for the activation of alpha-adrenergic vascular receptors [14,15,16,17,18,19]. Further support for this mechanism comes from the observations that episodes of vasospasm are common in the early morning hours between 4 and 6 AM and that surgical sympathetic denervation (plexectomy) may be an effective therapy for medically refractory patients [19,20]. Vasospastic episodes in the early morning hours may be secondary to higher vasomotor tone, which could lower the threshold for vasoconstrictor stimuli in susceptible coronary artery lesions [21,22,23].

In an effort to further evaluate the role of the autonomic nervous system in variant angina, one study performed imaging with iodine-123 metaiodobenzylguanidine (MIBG) in 104 patients with suspected vasospastic angina [24]. A low regional washout rate, representing strong suppression of norepinephrine release by enhanced parasympathetic activity, had a a sensitivity of 70 to 80 percent for the detection of vasospastic angina. Another study reported that regional uptake of MIBG is abnormally low in patients with vasospasm and that this abnormality persists for up to 6 months, despite pharmacologic suppression of anginal episodes [25].

Another study analyzed changes in heart variability when ST segment elevations were detected on ambulatory monitoring [23]. During the two minutes preceding ST segment elevation, 40 percent of episodes showed a decrease in the high frequency component, a marker for reduced vagal activity, which returned to basal levels at peak ST segment elevation. There was also a significant increase in heart rate and the low frequency component, indicative of enhanced sympathetic activity, which occurred at peak ST segment elevation. In contrast, these patients showed no change in heart rate variability when ST segment elevation was induced by balloon inflation during PTCA. This observations supports the hypothesis that changes in autonomic tone can trigger or predispose to coronary artery spasm in selected patients.

Endothelial dysfunction — Since coronary spasm is due to contraction of vascular smooth muscle in the coronary circulation, one or more abnormalities in endothelial function could be responsible, including:

  •  Eicosanoid imbalance (eg, less prostacyclin)
  •  Impairment of flow-dependent coronary dilation due to decreased production and release of the vasodilator nitric oxide [21,26], which in some patients may be the result of a mutation in the endothelial nitric oxide synthase gene [27].
  •  Increased release and activity of the vasoconstrictor endothelin [22,28]
  •  Oxidative stress, which may be improved by vitamin E [29] (see "Antioxidants in coronary heart disease: Vitamin E and beta carotene")

Coronary vasospasm also may produce local vascular injury of the vessel wall, resulting in the development and progression of an organic lesion. In one study of 22 patients with variant angina, 100 with chronic stable angina, and 80 with restenosis after an intervention, plaque histology of those with variant angina was similar to that of patients with restenosis and included neointimal hyperplasia, thrombus formation, and intimal hemorrhage [30].

Intracellular mechanisms — Phosphorylation of the myosin light chain is one of the most important steps for vascular smooth muscle contraction. In an animal model, coronary artery spasm was associated with enhanced monophosphorylation of myosin light chain, regardless of the presence or absence of the endothelium [31]. This supports the concept that coronary spasm is caused primarily by hypercontraction of vascular smooth muscle rather than reduced vasodilating function of the endothelium.

Adhesion molecules — Soluble glycoprotein P-selectin, a leukocyte adhesion molecule, is released into coronary circulation after coronary artery spasm [32]. As a result, coronary spasm may promote an inflammatory reaction which induces leukocyte adhesion in the coronary vasculature, possibly resulting in myocardial injury.

DIAGNOSIS — The key to the diagnosis of variant angina lies in the detection of ST segment elevation during chest discomfort with return of the ST segment to baseline upon resolution of symptoms. It has been proposed that the ST elevation in this setting reflects reversible transmural ischemia. In contrast, typical angina due to coronary disease presents with ST segment depression during symptoms with return of the ST segment to baseline upon the resolution of discomfort. Depending upon the severity and duration of such noninfarction ischemia with variant angina, the ST elevations may either resolve completely within minutes or be followed by T wave inversions that persist for hours or even days.

Exercise testing — Exercise treadmill testing is of limited value in variant angina since exercise tolerance is usually well preserved. However, exercise-induced spasm can occur [33]. In these patients, thallium-201 scintigraphy combined with exercise testing seems to be more sensitive than treadmill testing alone in detecting myocardial ischemia [34].

Coronary angiography — Coronary angiography may demonstrate an apparently normal vessel, or proximal fixed obstruction of varying severity in one or more of the coronary arteries. In general, those patients with variant angina in whom angiography suggests normal coronary arteries present with nonexertional angina and ECG changes in the inferior wall distribution. The latter finding is consistent with the observation that coronary vasospasm most commonly occurs in the right coronary artery; however, other vessels may be involved [6]. The ACC/AHA Committee on Coronary Angiography has published recommendations for the use of coronary angiography in these patients (show table 1) [35].

Dobutamine echocardiography — Dobutamine echocardiography is highly sensitive, specific, and accurate for the detection of coronary heart disease that is due to a fixed organic stenosis. However, it may provoke vasospasm in some patients with variant angina. This was seen in one study of 51 patients with documented vasospastic angina, 14 percent of whom had a positive dobutamine echocardiogram associated with chest discomfort and ST segment elevation [36]. (See "Stress echocardiography in the diagnosis of coronary heart disease").

Provocational tests — Two provocational tests, performed in the catheterization laboratory, are useful in making the diagnosis of suspected variant angina. In 1999 an ACC/AHA task force published recommendations for the use of pharmacologic agents in the assessment of vasospasm (show table 2). The most sensitive and specific test for provoking coronary spasm angina is the infusion of ergonovine. Ergonovine, ranging from 0.05 to 0.40 mg given intravenously, can elicit focal coronary vasospasm in a patient with variant angina; in comparison, the luminal reduction is mild and diffuse in patients with normal coronary arteries. The effect by ergonovine is quickly reversible by nitroglycerin. Acetylcholine has also been used by a number of investigators [15,18]; it is associated with a low frequency of serious complications, reported to be 0.6 percent [37].

Although a positive response to ergonovine is based upon the presence of coronary artery vasospasm associated with ECG changes, one study evaluated the response in 20 patients and 27 normal subjects based upon changes in coronary flow velocity as measured with a Doppler guidewire [38]. In the normal subjects, diastolic flow velocity either did not change or increased slightly in response to ergonovine; patients with variant angina had either an initial increase in flow followed by an abrupt decrease or a gradual reduction (show figure 1). These abnormal flow velocities occurred before ischemic ST segment changes were noted. When a 50 percent reduction in flow was considered abnormal, the sensitivity of flow measured 3 minutes after ergonovine was 85 percent.

Hyperventilation performed for 6 minutes in the early morning is another test for vasospasm. One study of 206 patients with angiographically documented spasm and 183 patients without spasm found that the provocation of ST segment elevation or depression with hyperventilation had a sensitivity and specificity of 62 and 100 percent, respectively [39]. Compared to patients with a negative test, those with a positive hyperventilation test had a higher frequency of anginal attacks (

5 per week), multivessel spasm, and high degree AV block or ventricular tachycardia during an attack.

These tests are performed only when the diagnosis of variant angina is suspected, but not firmly established. As a result, when the ECG shows ST segment elevation during angina which is reversed upon resolution of this symptom, the diagnosis of variant angina is established and provocative tests are not necessary or recommended.

TREATMENT — Medical management of the patient with variant angina includes the use of calcium channel blockers (nifedipine, diltiazem, and verapamil) or nitrates, and the modification of risk factors. Both classes of drugs are effective in preventing vasoconstriction and promoting vasodilation in the coronary vasculature [40]. However, there are no "set rules" for the treatment of the patient with variant angina and therapy must be tailored to the individual. As a result, the judicious use of calcium channel blockers and nitrates is recommended depending upon individual response.

At our institution, we begin with a calcium channel blocker (eg, diltiazem at a dose of 240 to 360 mg per day). We subsequently add nitrates depending upon the response to calcium channel blockers. Treatment with alpha-receptor blockers has been reported to be of some benefit, especially for patients with an incomplete response to calcium channel blockers and nitrates [16,19]. However, nonselective beta-blockers, such as propranolol can exacerbate vasospasm and should be avoided [41]. In addition, aspirin should be used with caution and is best avoided, since it is an inhibitor of prostacyclin production [42].

Risk factor modification such as cessation of smoking and lowering of serum lipids should also be strongly encouraged. Rarely, a patient with variant angina in the absence of coronary disease is refractory to pharmacologic therapy. In this setting, surgical denervation and plexectomy have been effective [20,21].

Coronary revascularization is contraindicated in patients with focal spasm and minimal obstructive disease. However, revascularization may be helpful if obstructive coronary disease is present. The results are less predictable in this setting and depend in part upon the severity of the fixed obstruction [6,43].

Coronary artery stenting may be an effective therapy for selected patients with medically refractory vasospasm that is associated with mild to moderate coronary disease and in whom the vasospastic segment can be clearly identified [44].

PROGNOSIS — Patients with variant angina have an excellent prognosis, with an 89 to 97 percent overall survival at five years [45]. A recent study documented a relatively low incidence of sudden death (3.6 percent) and myocardial infarction (6.5 percent) after a median follow-up of seven years [46]. The prognosis is also good for those patients who have a cardiac arrest due to spasm. For example, one study of seven patients with ventricular tachycardia or fibrillation due to ergonovine-documented spasm found that six patients remained free of symptoms on calcium channel blockers after an average follow-up of 58 months [47]. One patient, who continued to smoke, had a recurrent episode.

Prognosis, however, may vary based upon the severity of the underlying disease. As an example, one study found that patients with one-vessel disease and a stenoses of 70 percent or less in any major coronary artery had 1 and 5 year survival rates of 99 and 95 percent, respectively [48]. By comparison, patients with multivessel disease had 1 and 5 year survival rates of 87 and 77 percent.

Patients with obstructive coronary artery disease and variant angina have a worse prognosis, although there is some evidence that regression of stenosis or atherosclerosis results in cessation of vasospastic activity, perhaps due to stabilization of endothelial function [49]. Arrhythmic complications are also associated with a poorer prognosis.

Possible role of lipoprotein(a) in myocardial infarction — The mechanism for a myocardial infarction in coronary vasospasm may be the triggering of thrombus formation and its slow removal due to impaired fibrinolysis. Lipoprotein(a) interferes with fibrinolysis by competing with plasminogen binding to molecules and cells. This causes impairments in plasminogen activation, plasmin generation, and fibrinolysis. (See "Lp(a) metabolism and approach to the patient with high Lp(a) levels"). A possible role of Lp(a) in the occurrence of an infarction in these patients was evaluated in one report of 77 patients with coronary spasm, including 16 with a prior infarction [50]. The Lp(a) concentration in these patients was higher than in 81 normal controls, but lower than in 177 patients with coronary artery disease. The incidence of high concentrations of Lp(a), defined as >25 mg/dL, was higher in the patients with coronary spasm who had a myocardial infarction (56 versus 21 percent in those without an infarction); patients with higher Lp(a) levels had a higher incidence of prior infarction compared to those without high Lp(a) levels (41 versus 13 percent).