Coronary Microvascular Dysfunction in Cardiovascular Research: Time to Turn on the Spotlight!

Colin Berry; Dirk Duncker; Tomasz Guzik


Eur Heart J. 2020;41(5):612-613. 

Coronary microvascular dysfunction (CMD) is an area of previously under-appreciated clinical importance.[1,2] Recent work has highlighted that CMD is an underlying pathology in ischaemic heart disease (IHD) and is the cause of one-third of angina pectoris in patients with stable symptoms.[3,4] There is a high prevalence of CMD in individuals with heart failure with preserved ejection fraction (HFpEF), where it is associated with systemic endothelial dysfunction and heart failure severity.[5] Dysfunction of the coronary microvasculature is also a central consequence of myocardial infarction, with strong implications for patient prognosis.[6] Additionally, microvascular disease can be considered as a multi-system entity with links between CMD and small vessel disease in other organs such as the kidney, retina, and brain.[7] Beyond cardiovascular pathology, CMD is present in other clinical conditions related to cardiovascular disease.[8]

It is therefore not surprising that the field has generated a huge amount of scientific interest from both clinical and basic researchers in recent years. Thus, the upcoming Spotlight Issue on the topic to be published in Cardiovascular Research on the 15 March 2020 aims to be a reference point for key topics from an international group of world-leading authors in the field.

A Position Paper, 'Coronary Microvascular Dysfunction in Coronary Microvascular Disease', from the European Society of Cardiology (ESC) Working Group on Coronary Pathophysiology and Microcirculation opens the Spotlight Issue. This is fitting as it was clinical guidelines issued by ESC in 2013 that were first to address the diagnosis and management of stable coronary artery disease, where CMD plays a significant role.[9] The Position Paper in this issue by Badimon et al. highlights the fact that CMD is often detectable, even when the main coronary arteries appear normal or 'near normal' in angiography. The manuscript goes on to give an excellent overview of the untapped potential of assessing CMD as a tool for personalized medicine, providing earlier diagnosis of disease and clinically meaningful risk stratification.

A central objective when curating this issue was to capture the ground-breaking translational work carried out in this field by collaboration between physicians and basic scientists. Ong et al. cover the diagnosis of CMD in an article that discusses the invasive and non-invasive methods for the assessment of CMD in humans and, additionally, where and when it is appropriate to use such techniques. The latter part of the manuscript focusses on the 'interventional diagnostic procedure', the current gold standard for assessing coronary vasomotor responses. A review from Bairey Merz et al. complements this article, where the authors discuss the next stage in patient care—to treat. The authors focus mainly on pharmacotherapies with efficacy in alleviating CMD. The article touches on seminal clinical trials in CMD, such as CorMicA and WARRIOR. In addition, there is an extended discussion on novel therapeutics, including gene and cell-based therapies. An article led by Duncker et al. discusses the benefits and pitfalls of existing small and large animal models of CMD, with a unique slant on metabolic disturbances and co-morbidities. Such models will be invaluable for investigating clinical observations on a molecular level and act as a pre-clinical test bed for novel therapeutics.

A collection of articles reviews the literature on CMD in different cardiovascular disease settings. An article by Sechtem et al. extensively covers CMD in stable IHD. van Royen et al. examines the coronary microvascular perturbations in individuals who have had a ST-elevation myocardial infarction (STEMI). The authors state that the current standard of care, primary percutaneous coronary intervention, is successful in the vast majority of cases for restoring blood flow to the main epicardial arteries but perfusion to the coronary microvasculature is less successful—a phenomenon termed 'no-reflow'—resulting in increased morbidity and mortality. The manuscript discusses pathophysiology, diagnosis, and treatment in the specific setting of STEMI, as well as the contribution from pre-clinical models. Finally, a paper by Camici et al. discusses the mechanisms by which CMD can be a contributing factor to the transition from left ventricular hypertrophy lo left ventricular dysfunction, and ultimately heart failure, in patients with no evidence of main coronary artery disease.

An ambitious article by Maas et al. explores the multi-faceted nature of CMD in a two-fold approach (i) CMD in co-morbidities such as diabetes, obesity, and rheumatic disease and (ii) CMD as a multi-system disease. Secondary CMD occurs because of structural and functional alterations caused by primary disease processes, such as oxidative stress and chronic inflammation. These disease processes are common among the co-morbidities discussed. However, certain co-morbidities are more strongly related to different cardiovascular outcomes. A further disease modifier of CMD pathology is sex. Women who are under investigation for myocardial ischaemia are more likely to have non-obstructive coronary artery disease on coronary angiography; thus, CMD may play a prominent role. Meta et al. explores the unique factors such as inflammation, mental stress, autonomic, and neuro-endocrine dysfunction that may cause women to be more likely to develop CMD relative to men. Sex differences have implications for both diagnosis and treatment of cardiovascular disease.

The Guest Editors are grateful to the authors who have contributed their time and expertise and to the COVADIS and ESC Working Group on Coronary Pathophysiology and Microcirculation for their collaboration.

Figure 1 shows an overall schematic of how the concepts covered in the Spotlight Issue fit together in the context of disease. It is clear from the diagram that the underlying causes of CMD are heterogeneous; as well as the disease processes in which CMD plays a role. Thus, diagnosis and eventual treatment are not straightforward. It is the editors' hope that by bringing this collection of articles together, it will draw attention to this exciting field of research and act as a springboard for discovery of novel mechanisms underlying pathological processes in the coronary microvasculature with the eventual aim of providing better outcomes for patients.

Figure 1.

Coronary microvascular dysfunction schematic.