Coronary Reactivity Testing Shows Promise in Patients with Unobstructed Arteries

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Intracoronary acetylcholine provocation testing is a safe method of assessing coronary vasomotor function. An evaluation of the test in Caucasian patients, published online February 26, 2014, ahead of print in Circulation, found that both epicardial and microvascular spasms frequently occur, and the former is most often diffuse and located in the distal coronary segments.

Coronary spasm is typically more prevalent among Asians than Caucasians and appears to be on the decline in Western countries.

Researchers led by Peter Ong, MD, of Robert-Bosch-Krankenhaus (Stuttgart, Germany), enrolled 921 consecutive patients (39.3% male; aged 62 ± 12 years) who underwent diagnostic angiography for suspected myocardial ischemia between September 2007 and June 2010 and were found to have unobstructed coronary arteries. Acetylcholine testing was performed immediately after angiography.

Predictors of Response Identified

Among the 847 patients (92%) in whom the test was successfully performed, 33.4% reported epicardial spasm (> 75% diameter reduction with angina and ischemic ECG shifts) and 24.2% reported microvascular spasm (angina and ischemic ECG shifts without epicardial spasm). The test was negative in 13.8% of patients and inconclusive in another 28.6%.

Overall, patients with positive acetylcholine tests were older, tended to be female, more often presented with exertional chest pain, and were less often smokers compared with patients who had negative tests. In addition, they were more likely to have a family history of cardiovascular disease and showed a pathologic response to noninvasive stress testing. Compared with patients with microvascular spasm, those with epicardial spasm were more often male, smokers, and more likely to have a history of obstructive CAD. Also, they more often presented with resting chest pain and ACS.

Multivariable analysis showed that female sex, history of CAD, and presentation with exertional or mixed angina were independent predictors of a pathologic acetylcholine response (table 1).

Table 1. Independent Predictors: Pathologic vs Normal Acetylcholine Test

 
Moreover, male sex, older age, smoking, history of CAD, resting angina, lower LVEF, and presentation with ACS were identified as independent predictors of epicardial vs microvascular spasm.

Epicardial coronary spasm was observed in 378 vessels (n = 282 patients) and was most frequently distal and diffuse (40%; P < 0.01). Only 3.2% of patients had proximal and focal epicardial spasm.

There were no fatal or serious nonfatal complications, but 9 patients (1%) suffered minor complications including non-sustained ventricular tachycardia, fast paroxysmal A-fib, symptomatic bradycardia, and catheter-induced spasm.

Safe Option for Investigating Symptoms of Unknown Origin

The acetylcholine test “is a safe method for the assessment of coronary vasomotor function when performed with an appropriate protocol,” Dr. Ong and colleagues write. “Due to its invasive nature, there has been a lot of skepticism regarding intracoronary provocation testing for coronary spasm because of the potential complications associated with the test. Interestingly, it is not the fact that coronary angiography is required for performing the test which raises concern but the fear of irreversible spasm leading to arrhythmia and death due to the provocative testing itself.”

The complication rates observed are comparable to those in other studies, the authors write. “Thus, there is compelling evidence that the [acetylcholine testing] using a stepwise approach with increasing doses, as reported in our study, is a safe procedure that can routinely be performed in the catheterization laboratory,” they say. “One has to view these complication rates in context with current complication rates for diagnostic coronary angiography, which are similar to those reported for acetylcholine testing.”

Acetylcholine testing “not only leads to reassurance of the patient that a cause for the symptoms is found but also enables the physician to initiate appropriate medical therapy (ie, calcium channel blockers and nitrates) aiming at reducing morbidity and mortality,” they write. Most healthcare-related costs in patients with unobstructed coronary arteries are due to recurrent or ongoing angina, the authors explain.

“This report should also encourage interventionalists to add the [acetylcholine test] to their portfolio in search of functional causes for angina in patients with unobstructed coronary arteries,” Dr. Ong and colleagues suggest. “In patients presenting with symptoms other than angina pectoris (eg, syncope or heart failure), [acetylcholine testing] may also be useful as these conditions can also be caused by coronary spasm.”

Value Only for Small Patient Population

In an editorial accompanying the study, Scott Kinlay, MBBS, PhD, of the VA Boston Healthcare System (West Roxbury, MA), explains that given the complex history of provocative testing, “it is not surprising that they should find focal and diffuse patterns of vasoconstriction to acetylcholine.” The study protocol’s high concentrations of acetylcholine, lesser degree of constriction required to define spasm, and a patient population that included advanced or acute coronary disease led to the high prevalence of spasm, he says.

“The presence of modest coronary stenoses was not reported,” Dr. Kinlay explains, “but in their prior report nearly half of the patients had a 20-49% stenosis.”

Even so, the study “does remind us of the importance of vasomotor dysfunction as a contributor to myocardial ischemia,” he observes. Although the risks of the procedure are small, they are potentially higher in patients with left main disease, multivessel disease, severe left ventricular dysfunction, or incipient heart failure. In these patients, acetylcholine delivered into the left main could prove catastrophic if it precipitated severe multivessel vasoconstriction.”

Going forward, “the need for routine provocative testing is uncertain as it is unlikely to change clinical practice in most patients with coronary artery disease,” the editorial states. Acetylcholine testing will likely be valuable for a small group of patients with “non-obstructive disease and recalcitrant symptoms or unexplained sudden cardiac death. . . . Testing for vasomotor function should be used cautiously in patients at higher risk of adverse events, and operators should have interventional equipment and skills to treat severe vasospasm with intracoronary vasodilators and obstructive disease with percutaneous coronary intervention.”

Study Details

Incremental doses of 2 μg, 20 μg, 100 μg, and 200 μg of acetylcholine were manually infused over a period of 3 minutes into the LCA via the angiographic catheter. In patients who remained asymptomatic and showed no diagnostic ST-segment changes during LCA infusion, an additional 80 μg of acetylcholine were injected into the RCA.

 

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Sources:
1. Ong P, Athanasiadis A, Borgulya G, et al. Clinical usefulness, angiographic characteristics and safety evaluation of intracoronary acetylcholine provocation testing among 921 consecutive Caucasian patients with unobstructed coronary arteries. Circulation. 2014;Epub ahead of print.

2. Kinlay S. Coronary artery spasm as a cause of angina [editorial]. Circulation. 2014;Epub ahead of print.

 

 

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