The coronary arterial system consists of a continuous network of functionally distinct
vessels of decreasing size.
1
The epicardial arteries (>500 μm) have primarily a conductance function and, therefore,
physiologically offer minimal resistance to flow. The microcirculation, including
pre-arterioles (100 to 500 μm) and arterioles (<100 μm), on the other hand, is the
main active determinant of resistance within the coronary tree, responsible for the
metabolic regulation of regional blood flow to the myocardium.
1,2
Structural and/or functional abnormalities in coronary microcirculation (i.e., coronary
microvascular dysfunction, CMD), occurring in a wide spectrum of cardiovascular diseases,
are classifiable into four groups
1
(Figure 1):
10.7717/gcsp.202030/fig-1
Figure 1.
Classification of coronary microvascular dysfunction.
CMD: coronary microvascular dysfunction. CAD: coronary artery disease. CMP: cardiomyopathies.
HCM: hypertrophic cardiomyopathy. DCM: dilated cardiomyopathy. Group 1: Metabolic
dysregulation due to dyslipidemia, obesity, smoking, diabetes and metabolic syndrome
may impair microvascular structure and endothelium dependent and independent vascular
function.
18
Group 2: CMD has been reported in both primary cardiomyopathies (hypertrophic cardiomyopathy,
dilated cardiomyopathy, Anderson-Fabry disease and amyloidosis) and secondary hypertrophy
settings (aortic stenosis and hypertension).
19–21
Group 3: Chronic coronary obstruction can trigger CMD that may persist even after
successful revascularization.
22,23
In revascularized acute coronary syndromes CMD may be responsible for suboptimal reperfusion
(i.e., “no reflow” phenomenon
24
), caused by endothelial injury and/or distal embolization and is associated with
adverse cardiovascular events in STEMI patients.
25
Group 4: After percutaneous coronary intervention, vasoconstriction due to epicardial
and arteriolar alfa adrenergic receptors activation
26
and embolization of plaque deriving material in the microcirculation may cause microinfarcts
affecting long term clinical outcome.
27
(1)
Coronary microvascular dysfunction in the absence of obstructive coronary artery disease
(CAD) and myocardial diseases,
(2)
Coronary microvascular dysfunction in the presence of myocardial diseases,
(3)
Coronary microvascular dysfunction in the presence of obstructive CAD,
(4)
Iatrogenic coronary microvascular dysfunction.
CMD is an intricate and often key component of heart pathophysiology. It arises from
changes in both microvascular function and structure and is strongly associated with
endothelial dysfunction. CMD is highly prevalent and determines the fate of numerous
chronic heart diseases, but may be pivotal also in acute conditions such as acute
myocardial infarction and various types of shock. Hence, the growing necessity of
a deeper understanding of microcirculatory pathophysiology and developing effective
therapeutic interventions.
Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response
to infection
3
, and a leading cause of intensive care unit morbidity and mortality.
4
Cardiac involvement in septic patients is associated with severe outcome
5,6
and coronary microcirculation is of paramount importance in this setting. CMD due
to inflammatory dysregulation is part of the wider spectrum of CMD and, although not
included in the original classification, appears classifiable as a type 1 dysfunction.
In septic patients, endothelial proinflammatory activation increases endothelial permeability
leading to myocardial oedema, which has been reported in both experimental and clinical
sepsis.
7,8
Acute myocardial oedema has severe pathophysiological consequences including systolic
9
and diastolic dysfunction, in both active (cross bridge detachment) and passive (myocardial
stiffness) components.
10,11
Such impairment continues even after the resolution of the oedema.
12
Furthermore, inflammatory stimuli upregulate cell adhesion molecules and enhance leucocyte
adhesion and activity exposing the myocardium to contractile depressant factors (e.g.,
TNF alfa and IL-1) and reactive oxygen species.
13
In a recent issue of the journal, McBride et. al
14
provide important insights into sepsis-related microvascular dysfunction, by reviewing
its peculiar pathogenesis and features as compared to dengue fever-associated shock.
As reviewed by the Authors, septic shock and dengue share common pathophysiological
features including reduced endothelial (nitric oxide) dependent vasodilation, endothelial
and immune system cell activation, glycocalyx shedding and plasma leakage through
slack endothelial junctions. The latter phenomenon, however, is exaggerated in dengue
shock, while microvascular tone impairment appears less marked compared to septic
shock. The reasons behind the peculiar behaviour and specific pattern of dengue shock
remain unresolved and may involve the degradation of glycocalyx components mediated
by viral glycoprotein non-structural 1 (NS1) and the excessive host inflammatory response
to dengue infection.
While largely unexplained, this pathophysiological difference has important management
implications, implying a greater need for fluid-based rather than vasopressor-mediated
approach in dengue shock, as opposed to classic septic shock.
Research into novel treatment for microvascular dysfunction remains an unmet clinical
need both in the acute (sepsis, STEMI) and chronic (hypertensive heart disease, microvascular
angina, cardiomyopathies) setting. Data on the use of platelet inhibitors are insufficiently
established to provide clinical recommendations. Yet, clinical studies investigating
the adenosine-mediated vasodilator effect of ticagrelor are ongoing.
15
Furthermore ACE inhibitors and statins may counteract oxidative stress and may be
benefit in patients with CMD, particularly when associated with the classic cardiovascular
risk factors.
16
In other contexts such as cardiomyopathies, however, promising preclinical studies
have failed to translate into successful clinical results.
17
Further research is urgently warranted on this anatomically micro, clinically macro,
problem.