Asking the right questions
According to Professor Filippo Crea (Università Cattolica del Sacro Cuore, Rome), the problem is not because it can be difficult to achieve a diagnosis, however. Rather, he believes it is down to a lack of awareness of the peculiar features of variant angina caused by coronary spasm, such as the onset of chest pain at rest, often during the early hours of the morning, and the need to pursue appropriate investigations.

“It is important to ask the right questions and my feeling is that the right questions frequently are not asked, based on the observation that in our population of patients with variant angina, the diagnosis in 50% of patients is made more than 6 months after the onset of symptoms,” explained Professor Crea to CardioDebate.

He noted that clinicians tend to assume that the coronary circulation is normal in patients with chest pain when effort tolerance is preserved, particularly if there is no evidence of significant coronary artery obstruction on angiography.

According to Crea, the diagnostic process is actually relatively straightforward, provided careful questioning is carried out in the first instance to establish the history. The next step is electrocardiography – usually Holter monitoring being required to capture alterations during episodes of pain – followed, if necessary, by angiography and provocative vasoconstrictive testing, involving the intracoronary injection of ergonovine or acetylcholine. In line with this, Professor Crea insisted that the risks of provocative testing are minimal and greatly outweighed by the benefits. “The risk of intracoronary ergonovine testing is really very, very low – it’s really the risk of the catheterisation more than the risk of injection of ergonovine. But if we miss the diagnosis, especially if not properly treated, the patient runs the risk of severe myocardial infarction or sudden cardiac death.”

A provocative issue
Professor John Beltrame (University of Adelaide, South Australia) is also concerned that coronary spasm is under-recognised. This is evidenced, he told CardioDebate, by case reports of the inadvertent administration of intra-coronary nitrates, with consequent resolution of the narrowed coronary lesion without the need for percutaneous coronary intervention (PCI).

He added: “ST-[segment]-elevation is the hallmark of variant angina, yet how often are intravenous nitrates administered before thrombolysis/PCI in acute ST-elevation myocardial infarction?”

Furthermore, other than in Japan, where the reported incidence of coronary spasm is much higher than among other populations, “patients without obstructive coronary artery disease do not routinely undergo provocative spasm testing to exclude vasospastic angina as a cause of their chest pain,” Beltrame noted.

This may be partly because provocative testing has itself been labelled controversial, owing to reports of serious, life-threatening arrhythmic complications associated with the procedure, and doubts as to whether it has any effect on treatment decisions. However, a recent study from Japan demonstrated a relatively low rate of arrhythmic complications related to spasm provocation (around 7%; very similar to that observed during spontaneous angina attacks), which did not impact on the prognosis of patients with vasospastic angina.

On the other hand, the same study found the presence of mixed, multivessel spasm on provocative testing was associated with a poor prognosis, with these patients at a nearly threefold increased risk of major adverse cardiac events.[1] Similarly, an earlier study demonstrated that acetycholine-provoked coronary spasm was a significant predictor of major adverse cardiac events in Japanese patients with acute myocardial infarction.[2]

Professor Beltrame similarly indicated that “more judicious” use of provocative spasm testing, in patients with suspicious chest pain but no obstructive coronary artery stenoses, is needed. He also advocated use of intracoronary nitrates in patients with obstructive coronary artery disease on angiography, before undertaking revascularisation, “to ascertain if there is a significant dynamic component to the lesion”.

Raising awareness
Even with better detection, however, a significant minority of patients diagnosed with coronary spasm will not benefit from conventional treatment – currently around 10% of patients with coronary artery spasm do not respond to usual doses of nitrates or calcium antagonists. Some can be managed by increasing the doses, or with use of an alpha-adrenergic-antagonist, but a minority will still have a residual risk of sudden death or myocardial infarction, and as with cases complicated by brady- or tachyarrhythmias, may need to be fitted with a pacemaker or implantable cardioverter defibrillator. Little information is available regarding the beneficial effects of ICD implantation in these patients and therefore further research is required in this area.

In some severe cases, patients have been treated by– and have allegedly benefited from – stenting of the spastic coronary segment, or sympathectomy, but these represent anecdotal cases.

Such cases remain challenging, and further research is needed to identify prognostic factors and methods for risk stratification to better guide treatment. In addition, the molecular mechanisms underlying coronary spasm remain poorly understood. The most promising potential therapeutic target to date is the enzyme Rho kinase, which is important in calcium-dependent vascular smooth muscle cell contraction; the Rho kinase inhibitor fasudil has shown some promise in boosting the vasodilatory response in vasospasm patients treated with calcium antagonists or nitrates. However, fasudil is currently only available in Japan and a few other countries.

Nevertheless, a major advance in improving the management of coronary spasm would simply be to raise awareness and understanding that this is not a rare phenomenon – and that patients must be investigated so that treatment can be initiated if it is needed.

To this end, Beltrame explained that experts are currently planning discussions regarding a position statement on diagnosis and management of coronary artery spasm. “In spite of what is already written in guidelines, this syndrome is not as well known as it should be. So a position paper on this issue would be highly desirable,” he said.

References

1. Takagi Y, Yasuda S, Takahashi J et al. Clinical implications of provocation tests for coronary artery spasm: safety, arrhythmic complications, and prognostic impact: Multicentre Registry Study of the Japanese Coronary Spasm Association. Eur Heart J 2012; Advance online publication.

2. Wakabayashi K, Suzuki H, Honda Y et al. Provoked coronary spasm predicts adverse outcome in patients with acute myocardial infarction. J Am Coll Cardiol 2008; 52: 518–522