Assessment and Pathophysiology of Microvascular Disease

Recent Progress and Clinical Implications

Stefano Masi; Damiano Rizzoni; Stefano Taddei; Robert Jay Widmer; Augusto C. Montezano; Thomas F. Lüscher; Ernesto L. Schiffrin; Rhian M. Touyz; Francesco Paneni; Amir Lerman; Gaetano A. Lanza; Agostino Virdis


Eur Heart J. 2021;42(26):2590-2604. 

In This Article

Abstract and Introduction


The development of novel, non-invasive techniques and standardization of protocols to assess microvascular dysfunction have elucidated the key role of microvascular changes in the evolution of cardiovascular (CV) damage, and their capacity to predict an increased risk of adverse events. These technical advances parallel with the development of novel biological assays that enabled the ex vivo identification of pathways promoting microvascular dysfunction, providing novel potential treatment targets for preventing cerebral-CV disease. In this article, we provide an update of diagnostic testing strategies to detect and characterize microvascular dysfunction and suggestions on how to standardize and maximize the information obtained from each microvascular assay. We examine emerging data highlighting the significance of microvascular dysfunction in the development CV disease manifestations. Finally, we summarize the pathophysiology of microvascular dysfunction emphasizing the role of oxidative stress and its regulation by epigenetic mechanisms, which might represent potential targets for novel interventions beyond conventional approaches, representing a new frontier in CV disease reduction.

Graphical Abstract


The microcirculation, constituted by pre-arterioles (lumen diameter 100–500 μm), arterioles (lumen diameter <100 μm), capillaries, and venules, is responsible for most part of the resistance to flow that modulates blood pressure (BP) and tissue perfusion. As such, the microvascular structures have key roles in regulating systemic haemodynamics, tissue oxygenation and nutrition, transport of mediators, exchanges of gases and metabolites to and from tissues.[1] Over the years, microvascular dysfunction has been recognized as an early marker of cardiovascular (CV) disease and a key feature of several clinical manifestations (see the paragraph 'Historical Perspectives' in the Supplementary material online, Addendum).

This has led to the development of novel methods and refinement of old techniques for the assessment of microcirculation. Reference values to identify microvascular dysfunction are now being generated and have the potential to promote harmonization in the interpretation of the results between different laboratories worldwide. In parallel, advances have been made in the understanding of the biological processes regulating microvascular function, including cross-talk between inflammation, oxidative stress, and cellular ageing pathways.

In this article, we discuss how coronary and peripheral microcirculation can be investigated, the strengths and limitations of each method, and the reference values that could be used for a correct interpretation of the results. We also provide recent advances on the molecular mechanisms underpinning microvascular dysfunction, with particular emphasis on the role of epigenetic alterations regulating inflammation, oxidative stress, and cellular ageing pathways. We conclude that a more integrated approach to microvascular research should be adopted in the future, whereby central and peripheral assessment methods should be more frequently combined given their capacity to provide important complementary information. Such an integrated approach has the potential to overcome current limitations in the development of microvascular active drugs (Take home figure).

Take Home Figure.

The importance of an integrated approach to microvascular research. The potential contribution of microvascular dysfunction to a specific diseased condition or clinical presentation is suspected and confirmed through central microvascular assessment methods (for example, by estimating the coronary flow reserve by left anterior descending transthoracic echocardiography). Subsequently, non-invasive, reproducible peripheral microvascular assessment techniques might help the identification of potential risk factors associated with microvascular dysfunction in the specific diseased condition. Mechanistic studies can be used to confirm the impact of the putative risk factor and the specific pathways through which it induces microvascular dysfunction. Finally, in situ studies performed on isolated arteries can be used to identify novel potential therapeutic targets. The use of drugs directed against such targets requires clinical validation, closing the circle of the microvascular research framework.