• Study: Acetylcholine Rechallenge May Help Detect Microvascular Spasms

    Acetylcholine (Ach) rechallenge is superior to the current standard in the detection of co-existing microvascular spasm patients with epicardial spasm, according to new research – suggesting a second challenge should be added to routine ACh testing to help identify co-existing endotypes and to evaluate individual treatment response.

    The study, published online Monday and in the Jan. 10 issue of JACC: Cardiovascular Interventions, noted that coronary artery spasm of the epicardial and microvascular vessels is frequently encountered in patients with angina and non-obstructed coronary artery disease (ANOCA).

    However, the frequency of co-existence of both endotypes – epicardial spasm and microvascular spasm – is unknown, said the authors of the new study, led by Andreas Seitz, MD, from the Department of Cardiology and Angiology at Robert-Bosch-Krankenhaus, Stuttgart, Germany.

    Seitz and colleagues, therefore, assessed the feasibility and clinical value of ACh rechallenge for the detection of co-existing epicardial and microvascular spasm, and to determine the efficacy of nitroglycerin in these spasm endotypes.

    “ACh testing followed by nitroglycerin administration and immediate ACh rechallenge is a feasible and safe novel diagnostic tool that allows the assessment of co-existing coronary spasm endotypes as well as their responsiveness to anti-vasospastic drugs in a single catheter laboratory session,” said the authors, noting that ACh rechallenge may be added to routine testing.

    Furthermore, they noted that since ACh rechallenge helps to unmask combined spasm disorders, it “may pave the way toward a more tailored treatment of patients with vasospastic angina.”

    Study details

    The multi-center study enrolled 95 patients with coronary spasm to undergo ACh rechallenge, which consisted of repeated ACh provocation 3 minutes after intracoronary nitroglycerin administration using the same dose that previously induced spasm.

    Of the 95 patients, 55 (58%) had micro-vascular spasm, and 40 (42%) had epicardial spasm during initial ACh provocation, reported Seitz and colleagues.

    “We observed a high frequency of coexisting microvascular spasm masked by apparent epicardial spasm during routine ACh testing,” they said, noting that in 48% of patients with epicardial spasm, ACh rechallenge revealed co-existing nitroglycerin-persistent microvascular spasm.

    “Thus, clinicians should keep in mind that the patient group currently labeled as “epicardial spasm” still represents a heterogeneous group of patients with a high rate of additional microvascular spasm.”

    This observation may explain the large differences in treatment response among patients with epicardial spasm (vasospastic angina), the authors said – noting that ACh rechallenge may allow improved detection and differentiation of multiple functional coronary disorders present in patients with ANOCA.

    Nitrate therapy question

    Seitz and colleagues also noted that treatment in patients with coronary spasm can often be difficult, with the efficacy of nitrate-based therapies in patients with microvascular spasm questioned, despite equal first-line guideline recommendations.

    “This study demonstrates a high frequency of epicardial spasm with co-existing nitroglycerin-persistent microvascular spasm,” they said, adding that nitroglycerin was found to be effective in preventing epicardial spasm, but that the therapy was much less effective in microvascular spasm – a finding that challenges current guideline recommendations.

    “Intracoronary nitroglycerin was very effective in preventing reinducibility of epicardial spasm, whereas it prevented microvascular spasm in only 20% of patients,” they said.

    Indeed, the study found that nitroglycerin administration before ACh rechallenge prevented reinducibility of epicardial spasm in all patients with focal spasm and in 80% of patients with diffuse spasm. However, nitroglycerin administration prevented microvascular spasm in only 20% of patients.

    The team concluded that clinical trials are now needed to investigate whether tailored treatment according to the result of the ACh rechallenge will help to improve patient care in daily clinical practice.

    Promising concept

    Writing in an accompanying editorial, Thomas J. Ford, MBCHB, PhD, and Philopatir Mikhail, MBBS, from Gosford Hospital and the University of Newcastle, Australia, noted that the study is the first to evaluate the safety and feasibility of ACh rechallenge during the index provocation procedure.

    “The concept of ACh rechallenge is novel, and the paper is very well illustrated,” they said, adding that the problem of microvascular spasm is “underrecognized and clinically relevant.”

    “ACh rechallenge is a promising concept that could be a useful clinical and research tool to consider patients’ responses to vasoactive medications, including nitrates, calcium-channel blockers, and even beta-blockers,” the editorialists noted.

    “This study highlights a simple but elegant way of considering how individual patients with angina with coronary spasm may receive treatment tailored on the basis of provocation testing response during coronary angiography.”

    Ford and Mikhail warned, however, that the trial design would have benefited from a control arm evaluating ACh test and retest with placebo such as normal saline. Furthermore, they noted that the test-retest reliability of ACh provocation testing has not been studied in a single laboratory session.


    Seitz A, Feenstra R, Konst RE, et al. Acetylcholine Rechallenge: A First Step Toward Tailored Treatment in Patients With Coronary Artery Spasm. JACC Cardiovasc Interv 2022;15:65-75.

    Ford TJ, Mikhail P. Acetylcholine (Re)challenge: From Diagnosis to Targeted Therapy. JACC Cardiovasc Interv 2022;15:76-79.

    Image Credit: 7activestudio – stock.adobe.com

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