Coronary artery disease (CAD) encompasses a spectrum of distinct phenotypes that ranges from obstructive epicardial atherosclerosis to diffuse non-obstructive disease and coronary vasomotor dysfunction (CVDys).^1,2 The majority of patients with angina have non-obstructive CAD (ANOCA), and among these, CVDys is highly prevalent (60-90%).³ Myocardial ischemia and associated angina in CVDys originate from epicardial vasospasm, microvascular spasm, and/or coronary microvascular dysfunction.^2,3 These endotypes might be present in isolation or in combination, and often overlap with obstructive and/or diffuse non-obstructive epicardial atherosclerosis. Thus, the management of patients with CVDys is often challenging with high morbidity, reduced quality of life, and worse cardiovascular outcomes.^2,3

Although microvascular dysfunction may be identified through the non-invasive quantification of myocardial blood flow (MBF) and coronary flow reserve (CFR) on functional testing, current imaging protocols do not evaluate vasospastic endotypes. Hence, an invasive coronary function testing (CFT) is required during the work up for CVDys to assess for all endotypes.^3,4 The identification and discrimination of endotypes might be of utility to tailor therapies as endotypes may respond or even deteriorate with different therapies.² Calcium channel blocker (CCB) are regarded as first-line for the management of vasospastic angina and an alternative to beta-blockers in microvascular angina,^1,2 yet there is paucity of randomized control trials evaluating their efficacy in CVDys and its endotypes.³

The EDIT-CMD trial⁵ sought to determine the efficacy of diltiazem in CVDys. A total of 85 adults with ANOCA refractory to medical therapy and CVDys by standard CFT criteria³ were randomized 1:1 to diltiazem (up to 360 mg a day) or placebo. Up to 50% of patients had epicardial spasm, 25% had microvascular spasm and 63% had microvascular dysfunction. After 6 weeks, diltiazem compared to placebo did not improve CVDys, nor reduced angina or improved quality of life. However, diltiazem seems to reduce the prevalence of only epicardial spasm compared to placebo (47% vs. 6% p=0.006). Unfortunately, this was an overall negative study for this much in need. morbid population. This highlights the heterogeneity and complexity of patients with CVDys. Future studies are needed to validate the promising impact of diltiazem on the epicardial vasospasm endotype, assess the differential impact of dihydropyridine and non-dihydropyridine CCB, and more importantly, determine whether CCB therapy in this group results in improvements in angina, quality of life, and outcomes.

References

1. Montalescot G, Sechtem U, Achenbach S, et al. 2013 ESC guidelines on the management of stable coronary artery disease:  the task force on the management of stable coronary artery disease of the European Society of Cardiology.  Eur Heart J 2013;34:2949–3003.
2. Padro T, Manfrini O, Bugiardini R, et al. ESC working group on coronary pathophysiology and microcirculation position paper on coronary microvascular dysfunction in cardiovascular disease. Cardiovasc Res 2020;116:741-55.
3. Kunadian V,Chieffo A, Camici PG, et al. An EAPCI expert consensus document on ischaemia with non-obstructive coronary arteries in collaboration with European Society of Cardiology working group on coronary pathophysiology and microcirculation endorsed by Coronary Vasomotor Disorders International study group. Eur Heart J 2020;41:3504–20.
4. Mathew RC, Bourque JM, Salerno M, Kramer CM. Cardiovasc imaging techniques to assess microvascular dysfunction. JACC Cardiovasc Imaging 2020;13:1577-90.
5. Jansen TPJ, Konst RE, de Vos A, et al. Efficacy of diltiazem to improve coronary vasomotor dysfunction in ANOCA: the EDIT-CMD randomized clinical trial. JACC Cardiovasc Imaging 2022;Apr 2:[Epub ahead of print].

Clinical Topics: Stable Ischemic Heart Disease, Atherosclerotic Disease (CAD/PAD), Chronic Angina, Noninvasive Imaging

Keywords: ACC22, ACC Annual Scientific Session, Microvascular Angina, Coronary Vasospasm, Coronary Artery Disease, Calcium Channel Blockers, Diltiazem, Quality of Life, Prevalence, Dihydropyridines, Atherosclerosis, Phenotype, Spasm, Randomized Controlled Trials as Topic

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