Clinical characteristics and prognosis of patients with microvascular angina: an international and prospective cohort study by the Coronary Vasomotor Disorders International Study (COVADIS) Group

Hiroaki Shimokawa, Akira Suda, Jun Takahashi, Colin Berry, Paolo G Camici, Filippo Crea, Javier Escaned, Tom Ford, Eric Yii, Juan Carlos Kaski, Takahiko Kiyooka, Puja K Mehta, Peter Ong, Yukio Ozaki, Carl Pepine, Ornella Rimoldi, Basmah Safdar, Udo Sechtem, Kenichi Tsujita, Satoshi Yasuda, John F Beltrame, C Noel Bairey Merz, on behalf of the Coronary Vasomotor Disorders International Study (COVADIS) Group, Clinical characteristics and prognosis of patients with microvascular angina: an international and prospective cohort study by the Coronary Vasomotor Disorders International Study (COVADIS) Group, European Heart Journal, 2021;, ehab282,



To provide multi-national, multi-ethnic data on the clinical characteristics and prognosis of patients with microvascular angina (MVA).

Methods and results

The Coronary Vasomotor Disorders International Study Group proposed the diagnostic criteria for MVA. We prospectively evaluated the clinical characteristics of patients according to these criteria and their prognosis. The primary endpoint was the composite of major cardiovascular events (MACE), verified by institutional investigators, which included cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization due to heart failure or unstable angina. During the period from 1 July 2015 to 31 December 2018, 686 patients with MVA were registered from 14 institutes in 7 countries from 4 continents. Among them, 64% were female and the main ethnic groups were Caucasians (61%) and Asians (29%). During follow-up of a median of 398 days (IQR 365–744), 78 MACE occurred (6.4% in men vs. 8.6% in women, P = 0.19). Multivariable Cox proportional hazard analysis disclosed that hypertension and previous history of coronary artery disease (CAD), including acute coronary syndrome and stable angina pectoris, were independent predictors of MACE. There was no sex or ethnic difference in prognosis, although women had lower Seattle Angina Questionnaire scores than men (P < 0.05).


This first international study provides novel evidence that MVA is an important health problem regardless of sex or ethnicity that a diagnosis of MVA portends a substantial risk for MACE associated with hypertension and previous history of CAD, and that women have a lower quality of life than men despite the comparable prognosis.

Graphical Abstract


Angina pectoris has been considered to be mainly caused by atherosclerotic obstructive coronary artery disease (CAD). However, up to 50% of patients undergoing diagnostic coronary angiography for typical chest pain have angiographically normal coronary arteries or non-obstructive CAD. In such cases, coronary functional abnormalities are implicated, including epicardial coronary artery spasm and coronary microvascular dysfunction (CMD). The latter is typically defined as increased susceptibility to vasoconstrictor stimuli resulting in microvascular spasm and/or impaired dilatation of coronary microvessels, with resultant inadequate increase in blood flow in response to stress. Thus, CMD may be the underlying mechanism in a large proportion of angina patients.

The term microvascular angina (MVA), originally proposed by Cannon and Epstein in 1988, is used for angina/myocardial ischaemia attributable to CMD. Recently, several studies with either invasive or non-invasive techniques for assessment of coronary physiology have provided extensive data, improving what is known about CMD and microvascular ischaemia. In addition, as the COronary VAsomotor Disorders International Study (COVADIS) Group, we have proposed the diagnostic criteria of MVA. Briefly, the diagnosis of MVA is established based upon symptoms suggestive of myocardial ischaemia in the absence of obstructive CAD (<50% diameter reduction and/or fractional flow reserve >0.80) associated with objective evidence of myocardial ischaemia and impaired coronary microvascular function defined by the following four findings: reduced coronary flow reserve (CFR), microvascular spasm, increased microvascular resistance, and/or coronary ‘slow flow phenomenon’.

To date, clinical studies have mainly been the single centre. Given the lack of evidence from international multi-centre studies, the clinical characteristics, and prognosis of patients with MVA remain to be fully elucidated. Our first objective was to study the clinical characteristics and health outcomes of patients with MVA in a large, prospective, international registry. Our second objective was to assess for associations by sex and ethnicity. Thus, in the present study, we undertook a multinational, multi-centre, multi-ethnic, prospective, observational, and longitudinal cohort study.


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Authors: Shimokawa, Hiroaki; Suda, Akira

Publication: European Heart Journal

Publisher: Oxford University Press

Date published: May 26th, 2021


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