Classification of CMD according to the involvement of pathogenic mechanisms and the clinical setting.
The heart is one of the most demanding organs of the human body. The high nutrient and oxygen demands need to be met through an adequate vascularization of the myocardium. In fact, the myocardium vascular supply is achieved through an extensive vascular network that includes larger arteries, also known as coronary arteries, smaller arteries (arterioles) and capillaries. This set of arterioles and capillaries is known as microcirculation. Coronary artery disease is usually associated with larger epicardial coronary arteries. However, several studies have shown an important role of coronary microvascular dysfunction. This review aimed to explore the (a) morphology, with particular interest on the anatomical and histological aspects; (b) physiology, providing an insight on the several endothelium-dependent and endothelium-independent regulatory mechanisms; and (c) pathophysiology of the cardiac microcirculation, with a special focus on the changes in the regulatory mechanisms, on the atherogenesis and on the correlation to the systemic cardiovascular disease.
- coronary microcirculation
- coronary microvascular morphology
- coronary microvascular physiology
- microcirculation regulatory mechanisms
- coronary microvascular dysfunction
- coronary microvascular pathology
The heart is one of the most demanding organs of the human body as it presents high demands for nutrients and oxygen. These demands are physiologically met through an extensive and unique vascular network, which is usually known as
Historically, the large epicardial arteries were considered the coronary circulation. Nowadays, the scientific reports suggest the coronary circulation is characterized by an extreme complexity in terms of morphology but also physiology. Moreover, the theory that the coronary circulation involves the larger epicardial arteries is no longer acceptable given the extensive vascular network present in the myocardium.
Coronary artery disease (CAD) is usually associated with larger epicardial coronary arteries. However, previous studies have shown an important link between microcirculatory dysfunction and cardiovascular disease. In fact, pathological changes in smaller vessels have been detected prior to clinical manifestations of cardiovascular disease . Moreover, microcirculatory dysfunction may even be a risk indicator for metabolic syndrome and associated cardiovascular disease [1, 2].
This review aimed to explore the (a) morphology, with particular interest on the anatomical and histological aspects; (b) physiology, providing an insight on the several endothelium-dependent and endothelium-independent regulatory mechanisms; and (c) pathophysiology of the cardiac microcirculation, with a special focus on the changes in the regulatory mechanisms, on the atherogenesis and on the correlation to the systemic cardiovascular disease.
2. Morphology and basic function
Based on the morphology and function, the coronary circulation involves several types of vessels as follows (from the larger arteries to the largest veins): epicardial arteries or coronary arteries, small arteries or intramural arteries, arterioles, capillaries, venules and epicardial veins. These vessels may be grouped according to their size into (a)
The anatomy of these vessels varies along their length: the proximal and middle portions tend to present similar characteristics to the larger arteries, although with a thick tunica media [several layers of vascular smooth muscle cells (VSMCs)], while the distal portions, also termed terminal or precapillary arterioles, may present a thinner tunica media (one to two layers of VSMCs) or not even present any VSMC layer, which is replaced by small unique cells that will be explored in the following subsection, the
The connection between the arterial and the venous systems is fundamentally achieved by a capillary network placed amid the arterioles and the venules (Figure 1).
These vessels present structural differences to other vessels as the wall is essentially composed of two layers: an inner layer, the
According to their morphology, capillaries may be classified into three main categories: (a) continuous capillaries, (b) fenestrated capillaries and (c) discontinuous capillaries . In the coronary microcirculation, the
Pericytes may vary morphologically and physiologically depending on the vascular bed and on the position in the vascular bed itself . Nevertheless, they generally extend processes along and around capillaries [12, 13]. In the central nervous system and kidneys, pericytes play an important role in angiogenesis, regulation of the endothelium, among other functions [12, 13]. These cells seem to be particularly relevant in the central nervous system where the regional blood flow regulation is of crucial importance . These pericytes may also present contractile properties [12, 13]. Several proteins have been suggested to confer contractility to pericytes, such as α-smooth muscle actin and tropomyosin . However, previous studies suggest that the contractile mechanisms differ from the VSMCs .
Although the role of pericytes in coronary physiology is not yet fully understood, the high number of these cells in cardiac capillaries and the similar characteristics to the central nervous system pericytes indicates these cells may play an important role in the regulation of the vessel diameter as well as permeability .
In the capillary network, other structures may be found such as
After the exchange of nutrients and oxygen at the capillary level, the deoxygenated blood, containing metabolic products, proceeds to the
The venules usually present a diameter ranging from 10 to 50 μm and similar anatomical characteristics to the arterioles . The proximal venules, that is postcapillary venules, usually exhibit only two layers: an inner layer, the
The distal venules are morphologically different relatively to the postcapillary venules, as they may present a thin tunica media (one to two layers of VSMCs) and a thin tunica adventitia on the outer side of the vessel . The absence of pericytes is a key characteristic of these distal venules . These venules initially course parallel to the muscle fibres, accompanying the arterioles and capillaries, then changing their position and configuration to meet the larger coronary veins .
2.4. Special circulatory considerations
2.4.1. Arteriovenous shunts
In healthy conditions, the myocardial blood supply is fundamentally provided through the normal coronary circulation. However, in the presence of cardiac disease, such as chronic cardiac disease or regional ischemic injuries, the myocardial perfusion may be compromised [4, 5]. Compensatory circulatory communications named
2.4.2. Heart chamber-coronary circulation direct communication
The direct communication between the heart chamber and the coronary circulation is generally referred to
3. Microcirculatory physiology
3.1. General considerations
The physiologic behaviour of the coronary circulation is inherently linked to a balance between the blood supply and the metabolic demand of the heart . Furthermore, the physiological responses in the microcirculation seem to depend on the vessel size and type and appear to vary within the microcirculation itself and from those in the macrocirculation [19–21]. Physiologically, the coronary microcirculation is able to respond to a wide range of stimuli, such as growth and physical exercise, through adaptive processes, essential to the maintenance of its physiology . In fact, vessels present a high adaptation ability and may undergo both acute and chronic adjustments. The acute adjustments involve changes in the vascular smooth muscle tone, while the chronic adjustments involve wall structure changes .
3.2. Myogenic tone
3.3. Metabolic regulation
The coronary blood flow is intrinsically linked with metabolic demands of the myocardium, namely of oxygen. At rest, the myocardial oxygen extraction averages 60–70%, which leads to the coronary venous pO2 of about 20 mmHg . During physical exercise, several mechanisms of adaptation are triggered in the myocardium, pO2 seems to be kept constant, which highlights the role of several pathways, namely the myocardial aerobic metabolism . This energy production is generally dependent on mitochondrial oxidative phosphorylation pathways . Among several metabolites produced in these intracellular pathways, carbon dioxide (CO2) and reactive oxygen species (ROS) seem to play an important role in physiological conditions [19, 28].
As previously mentioned,
After the conversion of oxaloacetate into citrate, the citric acid cycle involves several reactions in chain. Some of them also involve the production of CO2, such as the production of α-ketoglutarate (reaction 2) and succinyl-CoA (reaction 3).
The increased production of CO2 may also induce a decrease in pH due to the increase in proton concentration, as presented in the following reaction:
As can be seen in Figure 2, the metabolic production of
The vasodilator properties of H2O2 have long been studied, but the precise underlying mechanisms are not yet fully established . Previous studies suggested H2O2 behaves as an endothelium-derived hyperpolarizing factor (EDHF) [34, 35], as described in the following subsection. However, other previous studies suggested the mechanism may involve the stimulation of the nitric oxide (NO) production or be mediated by the guanylyl cyclase in human coronary arterioles . These pathways will be further discussed in the following subsections.
Other studies have suggested additional mechanisms involved in the metabolic regulation exerted by H2O2 on the coronary blood flow. The involvement of oxidation of thiol groups as a pathway of coronary metabolic dilation in isolated coronary arterioles has been previously proposed . The thiol groups are involved in many pathophysiological mechanisms and play a key role in the biological protection against oxidative injuries [38, 39]. This oxidation process promotes modifications in the protein conformation and includes the conversion of protein-bound thiols (-SH) into sulfenic (SO−, reaction 5), sulphinic (SOO−) and sulphonic (SOOO−) acids as well as disulphide bridges (S-S, reaction 6) [37, 39].
Furthermore, these modifications in the redox state of the cell may also affect the hyperpolarization mediated by thiol-dependent voltage-dependent K+ (KV) channels, which will be further explored in the following subsection .
Other metabolic vasodilators may also be involved, such as adenosine (which concentration is dependent on the metabolism) and potassium ions, which will be explored further below.
3.4. Endothelial function
Although NO is considered the major pathway of endothelium-mediated vasodilation in the systemic circulation, multiple pathways may be involved in this physiological response, such as the prostaglandins-induced vasodilation (Figure 4). The
Several vasoactive substances have been included in the
The hyperpolarization of the VSMC may involve several ionic channels, such as the voltage-activated Ca2+ (CaV) channels, which regulate the intracellular Ca2+ concentration, the KV channels and the Ca2+-activated K+ (KCa) channels [35, 40]. The KCa channels may be subdivided into small (SKCa or KCa 2.3 isoform), intermediate (IKCa or KCa 3.1 isoform) and large (BKCa) conductance Ca2+-activated K+ channels, which are located in specific cellular and subcellular sites . The hyperpolarization of the VSMCs may be triggered directly, through receptors on the VSMC membrane, or indirectly, through the hyperpolarization of the endothelial cells .
As can be seen in Figure 5, the
Moreover, the VSMCs may be
Besides the hyperpolarization of the VSMCs, the EDHFs, particularly H2O2, may also promote vasodilation through other mechanisms, namely by stimulating the production of prostaglandin E2 in the endothelial cell, thus promoting the endothelium-dependent vasodilation .
The relative importance of each pathway is still unestablished, but it has been proposed to depend for example on the activation state of the VSMCs, the density of MEJs and the expression of KIR and Na+/K+-ATPase .
3.4.1. Shear stress
As previously mentioned, in addition to the stimulation of receptors on the endothelial cell membrane, other factors may modulate the endothelial function, namely the forces exerted by the blood flow on the vessel wall. There are two major forces: (a) one perpendicular to the wall and (b) another parallel to the wall, known as
Previous studies showed the sensitivity to these pathways of vasodilation increases with decreasing vessel diameter thus assuming a particularly important role in the coronary microcirculation . Previous studies have also suggested the relative weight of these pathways changes from childhood to adulthood and between healthy and pathological conditions. In a preliminary study with human-isolated arterioles, Zinkevich et al.  proposed the flow-mediated dilation (FMD) in infants was exclusively COX-dependent, that is mediated by prostaglandins, while in adulthood the main pathway involved the NO. However, in the presence of coronary artery disease (CAD), both these mechanisms seem to remain as secondary pathways as the EDHF-mediated vasodilation (especially by H2O2) gains importance, serving as backup mechanisms in disease . In fact, low response to shear forces and high mechanical stress seem to predispose to vascular dysfunction and disease .
3.4.2. Endothelium-cardiomyocyte interaction
The heart is a highly organized organ where several cells may be found, namely endothelial cells and cardiomyocytes. Therefore, the physiological mechanisms depend on the communication between the several types of cells. Until today, many endothelial-derived cardio-active factors have been identified and characterized (Figure 7). The cardiac modulator effects of some of these factors, such as NO, PGI2, ET-1 and neuregulin-1 (NRG-1), have been previously acknowledged. Other factors, namely Dickkopf-3 (DKK3), periostin, thrombospondin-1 (TSP-1), follistatin (FST), apelin and connective tissue growth factor (CTGF), also appear to modulate the cardiomyocyte function, though with little evidence so far. These cardio-active factors seem to be interdependent (additive, synergistic or inhibitory) as their modulator effects may be exerted on the same target cell .
3.5. Autonomic innervation and circulating factors
The previously explored pathways are nowadays considered the major pathways of regulation of the vessel tone. However, other mechanisms may also come into play, such as the autonomic nervous system and circulating factors.
The innervation of the coronary circulation by the sympathetic and the parasympathetic divisions of the
4. Microcirculation pathophysiology
As previously discussed, the coronary microcirculation plays a key role in the myocardial perfusion. Therefore, the presence of functional and/or structural abnormalities of this circulatory pathway may impair the myocardial perfusion and be involved alone as the main mechanism of myocardial ischaemia. These abnormalities are normally designated as
|CMD type||Clinical setting||Pathogenic mechanisms|
|In the absence of myocardial disease or obstructive CAD||Cardiovascular risk factors (e.g. ageing, arterial hypertension, smoking, diabetes)|
Vascular wall remodeling
|In the presence of myocardial disease||Cardiomyopathies (e.g. HCM, DCM)|
|Vascular wall remodeling|
|In the presence of obstructive CAD||Acute coronary syndrome|
|Iatrogenic microembolization||Coronary reperfusion procedures (e.g. PCI)|
Revascularization (i.e. CABG)
CMD may present several pathogenic underlying mechanisms, depending on the source of the abnormality, namely structural and functional (Table 1), which will be discussed in this section. According to the underlying clinical setting, the CMD may also be classified into four types: type 1, in the absence of cardiomyopathies or obstructive CAD; type 2, in the presence of cardiomyopathies; type 3, in the presence of CAD; and type 4, iatrogenic [3, 20, 73, 74].
4.1. Functional abnormalities
The most common functional abnormalities are the
4.1.1. Endothelial and/or VSMC dysfunction
As presented in Table 1, the traditional cardiovascular risk factors (i.e. ageing, gender, obesity, smoking, hypertension, dyslipidaemia and diabetes) may impair the endothelial function by several mechanisms, namely increased production of EDCFs and/or decreased production of EDRFs [3, 73]. Furthermore, this impairment may also contribute to the dysfunction of the VSMCs, which may also result from structural changes, derived from cardiomyopathies or arterial hypertension, described further below.
Similarly to smoking,
The vascular effects of
The impairment of the vasodilator response of the coronary microcirculation may also be present in patients with angina-like chest pain but without evidence of obstructive CAD or myocardial disease. This situation is usually known as
4.1.2. Autonomic nervous system dysfunction
The autonomic nervous system dysfunction, following acute myocardial infarction (AMI) and/or coronary reperfusion procedures, may also contribute to the CMD. In fact, increased coronary vasoconstriction has been previously shown, after AMI and successful percutaneous coronary angioplasty, both at the site of stenosis and distal to it, suggesting abnormal coronary vasodilator response [73, 100].
After AMI, the CMD may result from autonomic dysfunction and luminal obstruction, discussed further below. The autonomic dysfunction in the AMI-associated CMD involves increased sympathetic activation with increased vasoconstriction. These findings were confirmed by Gregorini et al. , who showed this impaired autonomic function might be reverted with α-blockers, such as phentolamine (nonselective α-blocker) and urapidil (α1-selective blocker), which may improve the recovery of myocardial perfusion after coronary stenting in patients with AMI [101–103]. Autonomic dysfunction secondary to percutaneous coronary angioplasty was also showed by Gregorini et al.  who linked the left ventricular macro- and microcirculatory dysfunction in patients with transient ischaemia. In this study, phentolamine and urapidil were similarly used to block the α-adrenergic neurotransmission and propranolol (nonselective β-blocker) and the β-adrenergic neurotransmission, and the results showed that the increased coronary vasoconstriction, secondary to percutaneous coronary angioplasty, may be prevented with α-adrenergic receptor antagonists as no effect was demonstrated for the β-adrenergic blockade. Moreover, this study suggested that CFR may still be decreased for 7 days to 3 months after the procedure . In a similar study, Kozàkovà et al.  confirmed the potential usefulness of urapidil to improve the left ventricular function in the angioplasty follow-up. Moreover, persistent yet reversible CMD after coronary revascularization was also previously showed .
4.2. Structural abnormalities
In addition to functional abnormalities, structural abnormalities, namely vascular remodelling, vascular rarefaction, perivascular fibrosis, luminal obstruction and infiltration of the myocardium and vascular wall, may also contribute to CMD [3, 73].
4.2.1. Vascular wall remodelling
The remodelling of the vessel wall involves persistent modifications which may result from several
In addition to the functional changes,
Other situations may also contribute to the vascular remodelling, especially arterial hypertension and cardiomyopathies. Previous studies have suggested that
4.2.2. Vascular rarefaction and perivascular fibrosis
The coronary microvascular function may also be influenced by modifications in the vascular density, particularly by vascular rarefaction, that is the reduction in the number of microcirculatory vessels, which may also be recognized as hypotrophic remodelling . The presence of arterial hypertension and the extravascular compression, observed in aortic stenosis and cardiomyopathies, induces vascular rarefaction leading to the reduction in the CFR. In addition to the vascular rarefaction, both situations may also induce perivascular fibrosis promoting structural modifications of the vessel wall [73, 114].
4.2.3. Luminal obstruction
CMD may also be characterized by luminal obstruction originated from (a) obstructive CAD or (b) iatrogenic microembolization .
According to the mechanisms underlying the associated CMD as well as the clinical findings, the
In patients with
Similarly to stable CAD,
Luminal obstruction is a key characteristic of the
As previously mentioned, CMD may also be originated from
4.2.4. Vascular wall infiltration
In addition to the previous explored structural changes, the infiltration of the vessel wall with metabolic deposits may also be found. This infiltration is commonly found in infiltrative diseases, such as Anderson-Fabry disease and other metabolic disorders. The Anderson-Fabry disease involves a genetically linked (X chromosome) deficiency of lysosomal α-galactosidase A, which leads to damages in several organs, namely the heart, through the deposition of glycosphingolipid in cardiomyocytes and in the vascular wall . In turn, this infiltration promotes the hypertrophy and fibrosis of cardiomyocytes as well as CMD and perivascular fibrosis . In fact, Elliott et al.  demonstrated these patients present a marked decrease in CFR, confirming the presence of CMD in the pathogenesis of the cardiomyopathy induced by this disease.
This review provides an insight on the morphology, physiology and pathophysiology of the cardiac microcirculation. As discussed, the heart is one of the most nutrient and oxygen demanding organs as this demand needs to be satisfied with an adequate vascularization of the myocardium through an extensive macro- and microvascular network. Although most of the cardiac diseases, such as the acute coronary syndrome, are commonly associated with the coronary macrocirculation (i.e. epicardial coronary arteries), the coronary microcirculation also seems to play a key role in the coronary pathophysiology. This role involves both molecular and clinical aspects that should not be overlooked and that constitute potential diagnostic and therapeutic targets, particularly important in the early pathogenesis of these diseases.
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