Coronary Vasospasm-Induced Ventricular Tachyarrhythmias

David J. D’Agate, DO, Richard Schwartz, DO, Jason M. Lazar, MD
David J. D’Agate, DO, Richard Schwartz, DO, Jason M. Lazar, MD
In 1959, Prinzmetal et al. first described a syndrome of “variant” angina occurring at rest with ST-segment elevations, often associated with arrhythmias. He also noted that the syndrome often coexisted with typical angina and was associated with atherosclerosis.1–3 The exact prevalence of variant angina is unknown; however, it is considered to be far less common than either typical, exertional angina or unstable angina. We present a patient with coronary vasospasm-induced arrhythmia and review the prevalence, mechanism, prognosis and management of this problem. Case Report. A 75-year-old woman with a history of hypertension and diverticulitis presented to the hospital with 24 hours of intermittent retrosternal pressure, radiating to her neck and associated with nausea. The patient denied any other concomitant symptoms. There was no history of diabetes, smoking, hypercholesterolemia, previous coronary intervention or family history of coronary artery disease. On physical exam, blood pressure was 130/80 mmHg, pulse was 75 beats/minute, the patient had a regular respiratory rate of 16 breaths/minute and was afebrile. The cardiac exam was normal, without a murmur, gallop, rub or elevated jugular venous pressure. Lungs were clear. Electrocardiogram (ECG) showed normal sinus rhythm at 67, with biphasic T-waves in leads V1–V4. There were no new conduction delays or pathological Q-waves. Chest x-ray was unremarkable. The complete blood count and chemistry profiles were normal. The patient was treated with aspirin, intravenous heparin, intravenous nitroglycerin and beta-blocker. Cardiac enzymes were normal. She underwent diagnostic catheterization, which showed an 80% stenosis of the mid-left anterior descending (LAD) coronary artery and spasm of the proximal LAD. A stent was placed with no residual stenosis and intracoronary nitroglycerin 100 µg was administered with good results. The patient was medically managed with oral metoprolol 50 mg bid, oral enteric-coated aspirin 325 mg qd, oral clopidogrel 300 mg qd, subcutaneous enoxaparin 60 mg bid and oral enalapril 5 mg bid. The day after coronary stent placement, the patient complained of chest discomfort similar to the initial presentation. A repeat electrocardiogram showed ST-elevation in leads V2–V4. Immediately after treatment with 325 mg of oral aspirin, the patient lost consciousness and was pulseless. A 12-lead ECG showed monomorphic ventricular tachycardia. Cardiopulmonary resuscitation was performed, and the patient was electrically cardioverted 3 times up to 360 J with return of normal sinus rhythm and stable blood pressure. The patient was given a lidocaine bolus of 100 mg and started on a 2 mg/hour drip. She was then transferred to the catheterization laboratory. Repeat catheterization showed a patent coronary stent with transient vasospasm of the proximal LAD. Subsequently, intracoronary nitroglycerin 100 µg was administered with resolution of spasm. Oral verapamil SR 240 mg qd and oral isosorbide mononitrate 60 mg qd were added to the previous medical regimen. The remainder of the hospital stay was unremarkable and the patient was discharged home 2 days later. Discussion. Variant angina is characterized by a pressure-like, squeezing retrosternal chest discomfort of several minutes duration associated with transient ST-segment elevation. Both chest pain and ST-segment elevation resolve spontaneously or with administration of nitroglycerin. Episodes tend to occur at night and early morning hours. Patients with variant angina tend to be female and younger in age.4 Coronary artery spasm has been shown to play an important role in the pathogenesis of not only variant angina but also ischemic heart disease in general, including other forms of angina pectoris, acute myocardial infarction (MI) and sudden death.5,6 Coronary vasospasm may occur in both severely diseased and “normal” appearing coronary arteries. Approximately two-thirds of coronary artery spasm events occur at the site of an atherosclerotic lesion.7 However, upon closer examination, even the “normal” appearing coronary arteries often have evidence of minimal atherosclerosis.8 Hong et al. used intravascular ultrasound to show that sites of coronary artery spasm that appear to be angiographically normal often have features consistent with mild atherosclerosis.9 In both instances, the coronary vasospasm occurs in a segment with endothelium dysfunction, which may allow the smooth muscle of the arterial media to be exposed to abnormally high concentrations of a variety of vasoconstrictors.10 Persistent vasospastic activity has been associated with atherosclerosis progression.11 It has also been suggested that an imbalance between certain endothelium-derived relaxing factors (i.e., prostacyclin, nitric oxide) and contracting factors may lead to overall coronary artery spasm.12 One study showed that patients with variant angina appeared to have a diffuse abnormality of vasomotor tone, with an exaggerated response to vasoconstricting and vasodilating substances.13 Coronary vasospasm has not been reduced by alpha-adrenergic blockade,14 inhibition of thromboxane A2 production,15 serotonin receptor blockade,16 quinapril17 or administration of prostacyclin.18 Coronary vasospasm caused by parasympathetic nervous system over-reactivity19 and reduced sympathetic activity20 has been suggested; however, transplanted denervated hearts have been demonstrated to experience coronary vasospasm,21 arguing against a central neural etiology. Recently, oxidized low-density lipoprotein was observed to enhance coronary vasoconstriction.22 The exact mechanism of coronary vasospasm remains unknown; however, many studies have suggested that alteration in nitric oxide metabolism plays a large role. Decreased nitric oxide end-products increase basal coronary artery tone in patients with vasospastic angina.23 In a study by Nakayama et al., thirty percent of Japanese patients with coronary spasm were found to have mutations in the eNOS (endothelial nitric oxide synthase) gene, which regulates the production of nitric oxide.24 This gene mutation was found to be the best predictor of coronary spasm. The second most predictive risk factor was cigarette smoking.24 Other associations with coronary vasospasm have included hyperinsulinemia,25 magnesium deficiency,26 carcinoid crisis,27 pseudoephedrine,28 anaphylaxis,29 5-fluorouracil,30 anticholinesterase medications31 and vitamin E deficiency.32 Kawano et al. observed a cyclic variation in endothelial function and frequency of myocardial ischemia that was associated with a variation in estrogen levels in premenopausal women with variant angina, thus supporting the observation that estrogen directly relaxes vascular smooth muscle by antagonizing calcium channels.33 There may be racial differences in the susceptibility to coronary vasospasm. White patients appear to have a more focal abnormality, whereas Asian patients with coronary vasospasm tend to have a more generalized coronary artery hyperactivity.34 Recently, Japanese patients were observed to have a significantly higher incidence of multivessel spasm, lower incidence of vasodilation and higher incidence of stenosis in segments unresponsive to acetylcholine.35 These observations were made in both infarct and non-infarct related arteries within 14 days of myocardial infarction. Prevalence of arrhythmias. Previous studies have demonstrated that a variety of ventricular tachyarrhythmias may be associated with episodes of transient ischemia in patients with Printzmetal’s angina.36–38 However, the prevalence of arrhythmias in patients with coronary vasospasm varies depending on the patient population studied and the presence of coronary atherosclerosis. Approximately 25–50% of hospitalized patients with variant angina have been reported to have ventricular ectopy during spontaneous coronary arterial spasm.39,40 In a study of 56 patients with variant angina, ambulatory ECG monitoring identified a variety of arrhythmias during ST-elevation, including premature ventricular contractions (PVC), ventricular tachycardia, high-grade atrioventricular block and sinus arrest. These arrhythmias occurred in 53% of patients and in 9% of total episodes of ST-segment elevation, with 76% of ST-segment elevation episodes silent.41 Arrhythmias were more common during symptomatic episodes than silent episodes. In another study of 254 patients with transmural ischemia related to coronary spasm, a total of 15% experienced serious arrhythmias such as ventricular tachycardia, ventricular fibrillation or high-grade atrioventricular block. In yet another study of 356 survivors of out-of-hospital cardiac arrest, thirteen patients had unexplained events; among these, five were found to have coronary spasm associated with various arrhythmias.42 Two out of 5 occurred during reperfusion rather than ischemia. Another study of 8 patients noted that asystole was present in 5 patients, polymorphic ventricular tachycardia was present in 1, ventricular fibrillation was present in 1, and idioventricular rhythm was present in the remaining patient.43 Therefore, it would appear that prevalence of coronary arrhythmias during coronary spasm depends on the population studied and the specific arrhythmia considered. Mechanism of arrhythmia. The exact mechanism of arrhythmia in the setting of coronary vasospasm remains unknown. In the absence of myocardial abnormalities, electrophysiologic testing is usually normal in patients with coronary spasm-related arrhythmias.42 One study established a relationship between silent ischemia due to coronary artery spasm and potentially fatal ventricular arrhythmias in patients without confounding structural heart disease.42 Ventricular ectopy has been observed to occur within the first 2–3 minutes of ST deviation but not during the resolution of ST alterations,41 suggesting that ventricular ectopy in patients with variant angina occurs during spasm-induced myocardial ischemia. Ventricular ectopy is associated with the magnitude but not duration of ST elevations with variant angina.41,44 This finding, in conjunction with the observation that symptoms are more likely to occur during symptomatic versus silent episodes of ST-segment elevation, suggests that it is the degree rather than duration of ischemia that is important.44 Another study observed that prolonged spasm may promote an intracoronary thrombosis, which may persist to cause ischemia and myocardial infarction.45 Nishizaki et al. observed that patients with vasospastic angina had increased ventricular vulnerability with programmed stimulation, even during the symptom-free period without ischemic events. This may predispose to the development of ventricular tachyarrhythmias.46 Patients with vasospastic angina have been shown to exhibit an increased baseline QTc dispersion compared to patients with atypical chest pain. This suggests that inhomogeneity of repolarization and susceptibility to ventricular arrhythmias increase in patients with vasospastic angina, even when asymptomatic.47 Recently, it was observed that vasospastic attacks that preceded the development of polymorphic ventricular tachycardia, even if asymptomatic, were possibly associated with repolarization abnormality and increased risk of sudden death.48 Prognosis. Water et al.45 reported that the survival rates of patients with variant angina were 95%, 90% and 87% at 1, 2 and 3 years, respectively. For the same time periods, myocardial infarction-free survival was 80%, 78% and 75%, respectively. Interestingly, 20 of the 22 patients with MI and 8 of the 14 deaths occurred within the first 3 months. This initial high-risk period of variant angina is similar to that following acute myocardial infarction49 or coronary angioplasty.50 Mark et al.51 reported a higher probability of death and nonfatal myocardial infarction in patients with variant angina as compared to those with nonvariant coronary disease with all other prognostic factors held constant.52 Additional factors found to adversely affect long-term prognosis in variant angina include extent and severity of coronary artery disease, ST-segment elevation in both anterior and inferior leads without myocardial infarction and left ventricular dysfunction.52 Survival was also better in patients who did not smoke cigarettes or drink alcohol,53 both of which have been shown to provoke coronary spasm in patients with variant angina. Survival and nonfatal myocardial infarction rates have been shown to be nearly identical in patients with single-vessel disease and those without stenosis of >= 70%.54 Patients with arrhythmias during chest pain had a mortality rate twice as high as those without chest pain, (25% versus 12%),50 and ventricular arrhythmias during variant angina attacks were predictive of subsequent sudden death.55 The impact of epicardial coronary atherosclerosis on angina-linked cardiac arrest has been controversial. Intuition would suggest that increased severity of coronary artery obstruction would correlate directly with poor outcome, which has been observed in prior studies.55,56 However, it has been suggested that patients with a lesser degree of coronary obstruction are at greater risk for angina-linked cardiac arrest or sudden death.57 A possible explanation for this apparent paradox may be the degree of collateral circulation distal to the obstructed vessel, which has been observed in animal data.58 Several studies have shown the significance of collateral arteries in coronary spasm.58 Another explanation to support the above paradox is the possibility that vasospasm in the absence of significant coronary artery disease is a more aggressive disease because greater degrees of spasm would be required to result in myocardial ischemia.59 Preconditioning may be another factor that helps explain the above observations. It has been demonstrated in experimental studies that ischemic preconditioning reduces ventricular tachyarrhythmias appearing in the ischemic or reperfusion phase of ischemic events in patients with vasospastic angina.60 Treatment. Spontaneous remission is a common outcome,61 but myocardial infarction is also common, especially within 3 months of follow-up and in patients with multi-vessel disease.62 It has been demonstrated that silent ischemia from coronary vasospasm may be arrhythmogenic, which suggests a potential benefit of anti-ischemic therapy.42 Nitrates may relieve coronary spasm within minutes and should be considered in the acute phase. However, the use of long-acting nitrates is limited due to the development of nitrate tolerance. The drug family of choice to prevent cardiac death and acute myocardial infarction is calcium-channel antagonists, alone or in combination with long-acting nitrates.53,63,64 The incidence of sudden death, chest pain, sublingual nitroglycerin use and episodes of transient ST-segment deviation (as per ambulatory electrocardiographic monitoring) was lower in patients treated with a calcium-channel blocker than in those who were not treated with these drugs.53,63–65 The 3 major classes of calcium-channel blockers appear to have similar efficacy. Evidence from uncontrolled studies suggests that treatment with calcium-channel blocker reduces the risk of myocardial infarction.66 If the patient does not respond to one calcium-channel blocker, switching to a different agent has been recommended.67 If angina persists despite trying several calcium-channel blockers at maximally tolerated doses, then long-acting nitrates should be prescribed. If effective, calcium antagonists should not be discontinued, particularly in those patients with episode of angina-linked cardiac arrest, recurrent attacks or multivessel coronary spasm. However, if the patient does not have a recurrence after 12 months, the physician has the option to withdraw anti anginal medication, provided there was no history of cardiac arrest.68 Approximately 20% of coronary spasm patients will not respond to treatment with two calcium-channel blockers plus a long-acting nitrate. Alternative therapies for refractory cases that are not approved by the Food and Drug Administration include amiodarone,69 guanethidine70 and clonidine.70 Recently, both intracoronary glutathione71 and intravenous magnesium72 have been shown to suppress acetylcholine-induced coronary spasm in patients with vasospastic angina. These observations may provide potential strategies for future therapies. Beta-adrenergic blockers should be avoided in coronary vasospasm because of their propensity to increase the frequency and duration of attacks.73,74 The adverse effects of beta-blockers are thought to be due to unopposed a-adrenergic vasoconstriction and the blockade of b2-receptors in coronary vascular smooth muscle; stimulation of these receptors would cause coronary vascular smooth muscles to relax and thus reduce coronary vascular resistance.75 Treatment of ventricular arrhythmias that accompany attacks should be aimed at treating the coronary spasm.76 Patients with coronary spasm should be treated with low-dose aspirin to reduce the risk of myocardial infarction, although caution is needed because high-dose aspirin has been reported to aggravate coronary spasm.76 All patients with suspected coronary vasospasm should probably undergo coronary angiography unless an absolute contraindication exists. This will help distinguish patients with severe multivessel coronary artery disease from those with mild or normal coronary arteries. Nonmedical therapies for patients with refractory variant angina and atherosclerotic coronary artery disease, i.e., angioplasty and coronary artery bypass grafting (CABG), have been shown to be inferior to the results that are obtained in patients with exertional angina.49,77,78 Many patients have coronary lesions that are amenable to angioplasty; when the patient is pretreated with calcium-channel blockers and intracoronary nitroglycerin, the immediate success rate is high.79,80 The restenosis rate in coronary vasospasm patients is higher than usual.49,80 Angioplasty is not indicated for patients who have normal arteries on coronary angiography. Several reports suggest that stent placement may represent a valid alternative treatment in patients with refractory angina; however, this will require larger long-term studies.78,81 In one report, a coronary stent was placed at a site of focal vasospasm with good results extending to 3 years.82 Patients with coronary spasm and multivessel disease should be considered for CABG. Operative mortality and peri operative infarction rates are higher than for comparable patients without coronary spasm.51,83 However, long-term outcome of surgery is excellent, almost always eliminating future coronary spasm events.51 Bypass grafting is less successful for diffuse spasm, and is not indicated for coronary spasm in the absence of significant stenosis. Large-scale studies of implantable cardioverter defibrillator (ICD) for sudden cardiac death secondary to severe coronary vasospasm have not been conducted. However, individual case reports have suggested that ICD with medical therapy in patients who have coronary vasospasm resistant to medical therapy alone is efficacious.84
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