ESC Working Group on Coronary Pathophysiology and Microcirculation position paper on 'coronary microvascular dysfunction in cardiovascular disease'

Abstract

Although myocardial ischaemia usually manifests as a consequence of atherosclerosis-dependent obstructive epicardial coronary artery disease, a significant percentage of patients suffer ischaemic events in the absence of epicardial coronary artery obstruction. Experimental and clinical evidence highlight the abnormalities of the coronary microcirculation as a main cause of myocardial ischaemia in patients with 'normal or near normal' coronary arteries on angiography. Coronary microvascular disturbances have been associated with early stages of atherosclerosis even prior to any angiographic evidence of epicardial coronary stenosis, as well as to other cardiac pathologies such as myocardial hypertrophy and heart failure. The main objectives of the manuscript are (i) to provide updated evidence in our current understanding of the pathophysiological consequences of microvascular dysfunction in the heart; (ii) to report on the current knowledge on the relevance of cardiovascular risk factors and comorbid conditions for microcirculatory dysfunction; and (iii) to evidence the relevance of the clinical consequences of microvascular dysfunction. Highlighting the clinical importance of coronary microvascular dysfunction will open the field for research and the development of novel strategies for intervention will encourage early detection of subclinical disease and will help in the stratification of cardiovascular risk in agreement with the new concept of precision medicine.

Keywords: Coronary microcirculation; Ischaemic heart disease; Microvessels; Molecular and cellular targets; Risk factors.

Figure 1

Coronary microvascular dysfunction in non-obstructive and obstructive coronary artery disease. COX, cyclooxygenase; EC, endothelial cell; ET-1, endothelin-1; ETA, endothelin receptor A; ETB, endothelin receptor B; NO, nitric oxide; RAAS, renin–angiotensin–aldosterone system; ROS, reactive oxygen species; VSMC, vascular smooth muscle cell.

Figure 2

Microvascular dysfunction as underlying pathophysiological mechanism for acute coronary syndromes.

Figure 3

Pathophysiological mechanisms of microvascular dysfunction associated to the non-reflow phenomenon.

Figure 4

Microvascular response to risk factors. NO, nitric oxide; ROS, reactive oxygen species.

Figure 5

Invasive assessment of coronary physiology and intravascular imaging for patients with non-obstructive CAD. Ach, acetylcholine; ACS, acute coronary syndromes; CAD, coronary artery disease; CFR, coronary flow reserve; ER, ergonovine; HMR, hyperaemic microvascular resistance index; IMR, index of microcirculatory resistance; IVUS, intravascular ultrasounds; MI, myocardial infarction; MINOCA, myocardial infarction with non-obstructed coronary arteries; OCT, optical coherence tomography; OMT, optimal medical therapy; SCAD, spontaneous coronary artery dissection. **Contraindications to provocative coronary testing include emergent coronary angiography in patients with ACS/MI, pregnancy, severe hypertension, severe left ventricular dysfunction, heart failure (New York Heart Association Class III or IV), moderate/severe aortic stenosis, left main coronary stenosis >50%, multivessel CAD, spontaneous spasm during angiography; uncontrolled ventricular arrhythmia, renal insufficiency, severe bronchial asthma; use of isosorbide dinitrate (shortly before).

Figure 6

Secondary prevention strategies in patients with microvascular dysfunction or MINOCA. (i) Contraindications to beta-blockers include decompensated heart failure, symptomatic bradycardia and atrioventricular blocks, hypotension, and asthma acute bronchospasm. In case of AMI all the aforementioned with the inclusion of Killip Classes III (acute pulmonary oedema) and IV (cardiogenic shock). (ii) Contraindications to ACE inhibitors or ARBs include acute and worsening renal failure, advanced chronic kidney disease, bilateral renal artery stenosis, hyperkaliaemia, hypotension, history of angio-oedema and hereditary or idiopathic angio-oedema, and pregnancy due to teratogenicity. AMI, acute myocardial infarction; LVEF, left ventricular ejection fraction; MINOCA, myocardial infarction with non-obstructive coronary arteries; OMT, optimal medical therapy. ^aCalcium-channel blockers are the first line treatment in patients with varian angina. ^bClinical studies investigating the protective role of ticagrelor on the microconduction are ongoing.