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A Short History of Vasospastic Angina

Raffaele Bugiardini and Edina Cenko

Introduction

The syndrome of chest pain and/or myocardial ischemia with normal or nonobstructive coronary arteries at angiography is common and is of practical importance to the general medical audience. Many studies have tried to address this topic over the last 4 decades. Only 1 thing is clear: for patients with ongoing signs and symptoms of ischemia in acute coronary syndromes, the prognosis is not so favorable, as believed earlier in the 1990s. Yet, physicians remain confused by other patients who refer a history of effort angina or angina-like chest pain whose coronary angiograms show no evidence of obstructive coronary artery disease (CAD) and who have no structural heart disease. In these cases, diagnosis, risk stratification and management remain controversial and a matter of debate. Indeed, many patients do not experience cardiac chest pain, but the uncertainty is often difficult to allay, for their medical attendants as well as for the patients themselves, making for perpetuation of symptoms and for difficulties in management. Among these patients are an unknown number who can be shown to be experiencing cardiac chest pain presumed to be ischemic. In all of these patients, a diagnosis of “vasospastic angina” or coronary artery spasm may be considered.

Vasospastic Angina

The idea that some forms of ischemic heart disease may be caused by increased contractile tone of coronary arteries is not new, having been proposed by William Osler >100 years ago as the cause of angina pectoris. However, until Prinzmetal’s 1959 work in patients with what he first termed “variant angina,” attention has been paid more to the demand side of the myocardial oxygenation equation than the supply side. As coronary angiography became widely practiced, it was apparent that not all patients with clinical suspicion of myocardial ischemia had fixed atherosclerotic obstructions in the epicardial coronary arteries. In 1978, Maseri et al. described the angiographic features of a number of patients with Prinzmetal angina and concluded that coronary artery spasm was the underlying pathogenetic factor of variant angina. The authors of this article defined coronary artery spasm as a “local segmental coronary hyperreactivity of the smooth muscle to a variety of stimuli that produce only mild constriction in nonspastic segments of the coronary arteries.” In 1981, using quantitative angiography and a model of adrenergic stimulation, coronary spasm was shown to be localized only to the region of a pre-existing coronary atheroma. Twenty-four years ago, our group considered whether diffused severe epicardial coronary constriction ≥50% of lumen diameter could limit blood flow supply to the myocardium, producing myocardial ischemia and angina in patients with normal smooth coronary arteries at angiography and published our initial findings in the Journal. We proposed “vasotonic angina” as a suitable descriptor for this syndrome, commenting that as a group:

[T]hese patients show epicardial vasoconstriction which is usually severe and confined to the distal segments of the coronary arteries. Patients may present with symptoms of both stable and unstable angina. Despite diffuse coronary epicardial vasoconstriction the microcirculation is still the major culprit as assessed by coronary blood flow measurements in the coronary sinus. In some cases, the functional abnormalities may be exclusive to large or small arteries; in others, components of the entire coronary tree may be involved.

We concluded that “endothelial dysfunction could indeed underlie a nonspecific enhancement of the response to all vasoconstrictor stimuli”. More contemporary evidence indicates that endothelial dysfunction is significantly associated with diffuse epicardial vasoconstrictor response to acetylcholine and more adverse cardiovascular events over a 2-, 4-, and 7-year follow-up. Assessment of endothelial function may also detect early changes in endothelial vasoactive function important in the development of atherosclerosis rather than identifying atherosclerosis per se. The term “vasospastic angina” was officially coined by the Japanese Circulation Society in 2010. As the authors point out in their recommendations, it was perhaps time to revise the paradigm existing since 1959 of only 1 form of angina caused by coronary artery spasm and producing transient ST-segment elevation, namely, variant angina. A coronary artery may be partially occluded or diffusely narrowed by spasm causing anginal attacks even with ST-segment depression. The guidelines established that “these pathological conditions should be collectively termed vasospastic angina. Variant angina, characterized by ST-segment elevation during angina attacks, is a type of vasospastic angina.”

New Research

In this issue of the Journal, Aziz et al. report on their retrospective analysis of 1,379 patients who underwent acetylcholine provocation test during coronary angiography at their institution between 2007 and 2014 and document that nearly 25% of patients undergoing diagnostic angiography for assessment of chest pain had nonobstructive coronary artery disease accompanied by either focal or diffuse spasm. In this study, patients with epicardial vasomotor dysfunction were labeled as having epicardial vasospasm or coronary microvascular dysfunction, depending on the degree of lumen diameter reduction during acetylcholine infusion. Patients were regarded as positive for epicardial vasospasm, regardless of the type of response—focal or diffuse—when meeting 3 criteria: 1) induction of patient’s usual symptoms (i.e., chest pain or dyspnea); 2) ischemic electrocardiographic changes; and 3) >75% vessel diameter constriction. Patients having ≤75% lumen diameter reduction during acetylcholine, but feeling symptoms and showing ischemic electrocardiographic changes, were categorized as having microvascular spasm (by default, based on normal or near normal coronary angiograms). The authors also found that women had vasomotor dysfunction at lower doses of acetylcholine compared with men. The study’s findings are in line with previous observations from the same researchers published for the first 921 consecutive patients examined at their institution between 2007 and 2014. Some features of the current study deserve comment.

Focal Versus Diffuse Spasm

In the study by Aziz et al. in this issue of the Journal, both diffuse and focal vasoconstrictions of >75% were lumped together and defined as epicardial vasospasm. The authors acknowledged that this definition is not consistent with standard accepted diagnostic criteria where acetylcholine- or ergonovine-induced coronary spasm is defined as transient, total, or subtotal occlusion (>90% stenosis) of a coronary artery. The lack of information on the boundaries and severity of vessel contraction is critically important. Indeed, coronary spasm can be divided into 2 major categories that are distinct entities and likely should be managed differently. Focal coronary artery spasm can be treated effectively by calcium-channel blockers and nitrates. Renin-angiotensin system inhibitors may work as well on its long-term clinical outcomes. Spontaneous remission may occur in many patients with variant angina, and some may be able to wean or reduce their therapy after symptom-free periods ranging from 3 to 4 months. In contrast, there have been no reports on the therapeutic management of diffuse coronary spasm. Diffuse spasm is a manifestation of endothelia dysfunction and, as so, strategies aimed at reducing cardiovascular risk factors, angiotensin-converting enzyme inhibitor therapy, supplementation with folic acid, and physical exercise may translate into an improvement in endothelial health and revert abnormal vasoconstriction.

Nonobstructive Plaques or Normal Smooth Angiography?

There is no information in the study by Aziz et al. on the relationship between abnormal acetylcholine response and presence of CAD or about the relationship between vasoconstrictor response and the risk for adverse cardiac outcomes. The perception of nonobstructive CAD may be incorrect. Angiography does not miss life-threatening CAD, even when it is represented by nonobstructive plaques. In stable symptomatic patients, 1-year mortality rates are associated with increasing CAD extent. Patients with stenoses between 20% and 70% have a nearly 3-fold increased risk of death compared with those without apparent CAD at angiography. The presence of nonobstructive atherosclerotic plaques in the coronary arteries is not normal. Such lesions would not be expected to obstruct blood flow or result in anginal symptoms. Nevertheless, CAD progresses in a nonlinear fashion, due to multiple plaque ruptures and ST-segment elevation myocardial infarction typically occurs in patients with mild and moderate plaques. This is of particular importance when considering that atherosclerosis may progress more quickly in those patients who have been demonstrated to have abnormal coronary endothelial function. Consistent with this notion, nonobstructive and obstructive CAD are associated with similar risks of myocardial infarction and death if nonobstructive lesions affect a larger number of coronary arterial segments. Thus, strong evidence supports addressing the extent and “activity” of the atherosclerotic burden. A positive acetylcholine response may provide a link between the “activity” of the atherosclerotic plaques and increased risk of future cardiac events without the need of further investigations. Patients who do have severe endothelial dysfunction may benefit from more aggressive preventive treatment and follow-up. Risk characteristics and the need for assessment conceivably differ in patients without apparent CAD at angiography. Further testing using intravascular ultrasound imaging, cardiac computed tomography, flow, and other abnormalities in the coronary circulation may identify the cause for chest pain and guide treatment strategies.

Focus on Coronary Microvascular Dysfunction

Findings consistent with a microvascular etiology for ischemia and symptoms have been reported by several groups. Aziz et al. suggested that epicardial coronary artery constriction of ≤75%, reproduction of symptoms, and ischemic electrocardiographic changes during acetylcholine testing are criteria for the diagnosis of microvascular dysfunction due to microvascular spasm. However, these findings must be interpreted cautiously in light of a recent report. The combination of endothelial dysfunction (defined as a decrease in luminal diameter of >20% after intracoronary acetylcholine) and microvascular dysfunction (defined as an index of microcirculatory resistance of ≥25) was present only in 10% of the overall population of patients with nonobstructive CAD. The majority of these patients were found to have myocardial bridging (55%), and a substantial number of patients (23%) had no coronary hemodynamic explanation for their angina. All patients had at least some evidence of atherosclerosis based on intravascular ultrasound examination. It follows that endothelial dysfunction and atherosclerosis, although causally related in many patients, are distinct problems and may exist separately. As well, other patients may show endothelial dysfunction and normal microvascular function.

Remarks

In Table 1, we summarize key issues that deserve attention in the diagnosis and care of patients with anginal pain and nonobstructive CAD. The study by Aziz et al. has provided a worthy new piece to the jigsaw puzzle surrounding the pathogenetic pathway of angina pain with no flow-limiting stenoses. These investigators remind us that changes in vasomotor tone are a possible explanation of variations in the limit of coronary flow reserve and may potentially induce ischemia. We need to provide best care for the right patient. Focal coronary spasm (variant angina) is a distinct entity and should be managed accordingly. The cause of chest discomfort and ST-segment depression in patients with normal or near normal coronary angiography is not well understood. A number of variables may be contributory. The most frequently proposed cause is impaired endothelium-dependent arterial vasodilation with diffuse coronary vasoconstriction (vasotonic angina) in response to intracoronary acetylcholine. Testing that separates those patients whose symptoms are due to myocardial ischemia from those whose pain is nonischemic should be validated by multiple groups. This point is critical. People who believe that their illness may have been caused by a cardiac disease are likely to increase or prolong their perceived symptoms. Symptom-relieving drugs have been found to be effective in reducing the number of episodes of chest discomfort only in patients with documented myocardial ischemia. Even minimal atherosclerotic disease on angiography (or intravascular ultrasound imaging) warrants risk-factor modification and prevention therapies.