Author + information
- Julia H. Indik, MD, PhD∗ ()
- ↵∗Reprint requests and correspondence:
Dr. Julia H. Indik, Sarver Heart Center, University of Arizona, 1501 North Campbell Avenue, Tucson, Arizona 85724.
Coronary arterial spasm has long been recognized to cause chest pain and myocardial ischemia, with attacks occurring predominantly at rest and during the night. In 1959, Prinzmetal et al. (1) described a “variant form of angina pectoris” that occurred at rest with ST-segment elevation or depression. Angiographic evidence for coronary spasm with chest pain reversed by isosorbide was described soon after by Gensini et al. (2) and further demonstrated to have simultaneous ST-segment elevation by Oliva et al. (3) in 1973.
The prevalence of coronary spasm in the United States is uncertain, probably because provocative testing is not routinely performed in this country. However, coronary spasm is more commonly reported in Japan and Korea, where provocative testing is used more frequently; in a survey of institutions in Japan, angiographic evidence of coronary spasm was seen in 40.9% of patients with angina (4). Nonetheless, the incidence of coronary spasm has been declining over the years, perhaps in part due to the more widespread use of calcium channel blockers for hypertension and a decline in smoking. The mechanisms that trigger coronary spasm are unclear and are likely to be multifactorial. Signaling pathways that control myosin light chain kinase and its phosphorylation lead to increased sensitivity to intracellular calcium, and, in turn, to vasoconstriction. RhoA GTPase and ROCK/Rho kinase inhibit myosin light chain phosphatase, which promotes vasoconstriction, and this pathway is inhibited by statins (5) and endothelial nitric oxide activity (6). Chronic low-grade inflammation, which is seen in smokers (7), has also been suggested to promote coronary spasm (8,9).
Although many physicians view variant angina as a low-risk disorder, it is important to recognize that it is a cause for sudden cardiac death. Among 200 cardiac arrest survivors from the multicenter CASPER (Canadian Cardiac Arrest Survivors with Preserved Ejection Fraction Registry) study who were free of coronary disease, left ventricular dysfunction, or apparent repolarization syndrome, further testing eventually yielded a diagnosis in 81 patients, 7 of whom had coronary spasm (8%) (10). Furthermore, in a Japanese registry of 1,429 patients with variant angina, out-of-hospital cardiac arrest (OHCA) was seen in 35 patients and was the factor with the highest hazard ratio for future major adverse cardiac events (11,12). Therefore, it is important to recognize that patients with variant angina may die suddenly, and that this etiology must be considered when evaluating cardiac arrest survivors believed to have idiopathic ventricular fibrillation.
Are there clinical factors that may distinguish patients with variant angina who are at high risk for sudden death? Can vasodilator therapy protect against sudden death?
In this issue of the Journal, Ahn et al. (13) address these questions in the largest cohort of patients with variant angina reported to date. They studied a population of 2,032 patients from South Korea that included 188 (9.3%) patients who survived aborted sudden cardiac death (ASCD) and who were followed for a median of 7.5 years. These ASCD patients had all experienced OHCA due to ventricular fibrillation, rapid ventricular tachycardia, or pulseless electrical activity. They found that compared with patients without ASCD, patients with ASCD were far more likely to have had multivessel spasm (17.0% vs. 9.3%; p = 0.001), involvement of the left anterior descending artery (56.9% vs. 45.4%; p = 0.003), and ST-segment abnormalities (p < 0.001) of either ST-segment elevation (54.3% vs. 27.6%) or depression (18.6% vs. 12.9%). A family history of sudden death was uncommon, although this was more likely in ASCD patients (2.7% vs 0.9%; p = 0.021). Smoking prevalence was similar between patients with and without ASCD. Over time, patients with ASCD remained at high risk, with a hazard ratio (HR) for cardiac death (which was nearly entirely due to arrhythmic death) of 7.26 in a multivariate analysis and a HR of 9.81 in a propensity-matched cohort analysis. In a Kaplan-Meier analysis, the survival curves separated within the first few months, with a cumulative mortality estimate of 18.9% in the ASCD group compared with 8.5% in the group without ASCD. Cumulative Kaplan-Meier estimates of cardiac death were 16.7% in ASCD patients versus 2.5% in those without ASCD. Overall, the independent predictors of future cardiac death were an initial presentation of ASCD (HR: 5.92; p < 0.001), and use of nitrates (HR: 2.60; p = 0.043) and aspirin (HR: 1.82; p = 0.029), whereas the use of statins was protective (HR: 0.32; p < 0.001) as was a history of hypertension (HR: 0.43; p = 0.008).
At least 94% of patients were prescribed calcium channel blockers and three-quarters were prescribed long-acting nitrates. The investigators (13) stressed that in South Korea every attempt is made to ensure all patients are appropriately treated with vasodilator medications. Assuming compliance was not a confounding factor, this data demonstrated that vasodilator medications were not protective against death in patients with variant angina who previously survived an OHCA.
Is an implantable cardioverter-defibrillator (ICD) the answer for these high-risk patients? This cohort from South Korea, similar to the cohort from Japan, was underpowered to answer this question because few patients received ICDs [24 in the South Korean cohort (13) and 14 in the Japanese cohort (11)]. Nonetheless, Ahn et al. (13) reported appropriate ICD therapies during follow-up in 6 of these 24 patients, and 1 individual died of recurrent intractable ventricular fibrillation. ASCD patients who received an ICD had mortality of 4.3% in follow-up compared with 19.3% of those that did not receive an ICD. It is unknown what factors might have biased physicians to implant an ICD; therefore, it remains unproven whether an ICD can lower the risk of death in patients with variant angina resuscitated from OHCA. Nonetheless, the observation of apparent improved survival in ICD patients is compelling and warrants further prospective research.
Although this large cohort from South Korea and the cohort from Japan have taught us much about the clinical characteristics of patients with variant angina, how should we proceed to best protect patients who have not experienced sudden death to avoid a future risk of death? In the South Korean (13) cohort, there was a Kaplan-Meier estimate of cardiac death of 2.5% and overall mortality of 8.5% in patients who had not initially presented with sudden cardiac death. The finding that statins had a protective effect for cardiac death and mortality is intriguing, and future prospective studies could shed light on whether such therapy may further improve survival.
There are important lessons to be learned. Coronary arterial spasm may be lethal in its first presentation, and those that survive remain at high risk despite vasodilator therapies. An ICD appears to be protective. Patients who have not experienced sudden death have improved survival but are also at risk of death.
True or false: prognosis is excellent for sudden cardiac death survivors due to variant angina. Answer: False.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Indik has reported that she has no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation
- Gensini G.G.,
- Di Giorgi S.,
- Murad-Netto S.,
- Black A.
- Rikitake Y.,
- Liao J.K.
- Sauzeau V.,
- Rolli-Derkinderen M.,
- Marionneau C.,
- Loirand G.,
- Pacaud P.
- Herman A.R.,
- Cheung C.,
- Gerull B.,
- et al.
- Takagi Y.,
- Yasuda S.,
- Tsunoda R.,
- et al.
- Takagi Y.,
- Takahashi J.,
- Yasuda S.,
- et al.
- Ahn J.-M.,
- Lee K.H.,
- Yoo S.-Y.,
- et al.