Acetylcholine Rechallenge Helps Sort Types of Coronary Spasm Acetylcholine Rechallenge Helps Sort Types of Coronary Spasm

Acetylcholine (ACh) rechallenge may be a novel method to improve detection of coexisting coronary spasm endotypes, and at the same time, assess the treatment response to nitrate-based therapies, a new study suggests.

“ACh rechallenge could pave the way from trial and error to tailored therapies in patients with coronary spasm,” the study team concludes.

The study was published online January 3 in JACC: Cardiovascular Interventions.

Refining the ACh Challenge

A total of 95 patients with coronary spasm underwent ACh rechallenge, which consisted of repeated ACh provocation 3 minutes after intracoronary nitroglycerin administration using the same dose that previously induced spasm.

During initial ACh provocation, 55 patients (58%) had isolated microvascular spasm and 40 patients (42%) had isolated epicardial spasm (78% diffuse, 22% focal). 

ACh rechallenge, however, revealed coexisting microvascular spasm in 48% of patients with epicardial spasm (19 of 40).

Nitroglycerin administration prevented provocation of epicardial spasm during ACh rechallenge in all patients with focal epicardial spasm during initial ACh testing and in 80% of patients with diffuse spasm.

In contrast, microvascular spasm was prevented in only 20% of patients by prior nitroglycerin administration but was attenuated in another 49% of patients, the researchers report. 

“Nitroglycerin was overall much more effective in preventing epicardial spasm compared to microvascular spasm,” first author Andreas Seitz, MD, Department of Cardiology and Angiology, Robert-Bosch-Hospital, Stuttgart, Germany, told theheart.org | Medscape Cardiology.

“However, a certain subset of patients with microvascular spasm may benefit from nitrate-based treatments, and the novel ACh rechallenge may help to identify them,” said Seitz.

“A substantial number of patients with coronary spasm are known to have a high residual symptom burden despite medical treatment. This may be due to the coexistence of different coronary spasm endotypes (ie, epicardial and microvascular spasm) as well as a lack of targeted treatment recommendations,” Seitz explained.

This study shows points to ACh rechallenge as a “step toward a more targeted treatment of patients with coronary spasm,” he added. 

Technically, ACh rechallenge is feasible, safe, and ready to use, Seitz said.  

“However, this was a mechanistic registry study and there is currently no clinical follow-up data available regarding the benefit of a treatment stratified by ACh rechallenge, yet,” he added. “Thus, future trials are now needed to investigate the clinical benefit of a personalized treatment approach based on the ACh rechallenge.”

Promising Concept

In a linked editorial, Thomas J. Ford, MBChB, and Philopatir Mikhail, MBBS, with Department of Cardiology, Gosford Hospital, Central Coast, Australia, say the problem of microvascular spasm is “under recognized and clinically relevant.” 

While more study is needed, they say 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.”

“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 add.

Offering perspective on the study, Matthew Tomey, MD, cardiologist at Mount Sinai Morningside in New York City, noted that coronary vasospasm as a cause of chest pain is “relatively uncommon, but it is incompletely understood and likely underdiagnosed. Vasospasm can occur in the larger epicardial coronary arteries, in the coronary microvasculature, or both.”

“An experimental design involving rechallenge with acetylcholine helped in this study to dissociate epicardial and microvascular spasm in the laboratory environment,” Tomey told theheart.org | Medscape Cardiology.

He said this study “first serves to remind us that mechanisms other than obstruction of arteries by plaque or clot can account for true chest pain. Many, and likely most, patients with clinically relevant vasospasm do not undergo invasive provocative studies for diagnosis.”

“In the absence of invasive testing as demonstrated here, clinical cardiologists might take away from this study the message that not all patients with coronary vasospasm will respond equally to nitrates,” Tomey said.

“Selected patients with vasospasm, perhaps particularly those with a predominance of microvascular spasm, may be nonresponsive. Accordingly, we should not exclude the possibility of coronary vasospasm in patients with a compelling history merely based on response to nitrates,” he noted.

The study was supported by the Robert Bosch Foundation, Stuttgart, Germany, and the Berthold Leibinger Foundation, Ditzingen, Germany. Seitz and Tomey have disclosed no relevant financial relationships. Ford is a consultant and speaker for and has received honoraria from Abbott Vascular, Boston Scientific, Boehringer Ingelheim, Biotronik, Bio-Excel, and Novartis. Mikhail has no relevant disclosures.  

JACC Cardiol Interv. Published online January 3, 2022. Abstract, Editorial

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