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Coronary Microvascular Dysfunction
Introduction
Atherosclerotic disease of the epicardial coronary arteries has been recognized as the cause of angina pectoris for more than 2 centuries, and sudden thrombotic occlusion of an epicardial coronary artery has been well established as the cause of acute myocardial infarction (AMI) for more than 100 years. The introduction of coronary arteriography in the late 1950s has made it possible to visualize the contour of the epicardial coronary arterial tree in vivo. This was followed in the 1970s by the development of coronary artery bypass grafting and of percutaneous coronary intervention (PCI). These three techniques have been refined progressively over the years and successfully applied to millions of patients worldwide.
However, the epicardial arteries are only one segment of the arterial coronary circulation. They give rise to smaller arteries and arterioles that in turn feed the capillaries and constitute the coronary microcirculation, which is the main site of regulation of myocardial blood flow. During the past 2 decades several studies have demonstrated that abnormalities in the function and structure of the coronary microcirculation occur in different clinical conditions. In some instances, these abnormalities represent epiphenomena, whereas in others they represent important markers of risk or may even contribute to the pathogenesis of myocardial ischemia, thus becoming therapeutic targets.
Functional Anatomy of the Coronary Circulation
The coronary arterial system is composed of three compartments with different functions, although the borders of each compartment cannot be clearly defined anatomically ( Fig. 5.1 ). The proximal compartment is represented by the large epicardial coronary arteries, known also as conductance vessels . They are surrounded largely by adipose tissue, have a thick wall with three, well-represented layers (adventitia, media, and intima), possess vasa vasorum, and have diameters ranging from approximately 500 μm up to 2–5 mm. These arteries have a capacitance function and offer little resistance to coronary blood flow (CBF) ( Fig. 5.1A ). Their distribution has been divided into three patterns. The type I branching pattern is characterized by numerous branches reducing their diameter as they approach the endocardium. The type II pattern is characterized by fewer proximal branches that channel transmurally toward the subendocardium of the trabeculae and papillary muscles, an arrangement that favors blood flow to the subendocardium. The type III pattern is characterized by epicardial vessels with small proximal branches that vascularize the subepicardial layer. During systole, the epicardial arteries accumulate elastic energy as they increase their blood content up to approximately 25%. This elastic energy is converted into blood kinetic energy at the beginning of diastole and contributes to the prompt reopening of intramyocardial vessels that are squeezed closed by systole. The latter function is of particular relevance if one considers that 90% of CBF occurs in diastole. The more distal branches of the coronary arteries have an intramyocardial path (intramural arteries) and thinner walls than the epicardial branches, and they do not possess vasa vasorum (see Fig. 5.1A ).
The intermediate compartment is represented by the prearteriolar vessels ( Fig. 5.1B ). These small arteries have diameters ranging from approximately 100 to 500 μm, are characterized by a measurable pressure drop along their length, and are not under direct vasomotor control by diffusible myocardial metabolites. Their specific function is to maintain pressure at the origin of arterioles within a narrow range when coronary perfusion pressure or flow changes. The more proximal (500 to 150 μm) are predominantly responsive to changes in flow, whereas the more distal (150 to 100 μm) are more responsive to changes in pressure. The distal compartment is represented by the arterioles, which have diameters of less than 100 μm and are characterized by a considerable drop in pressure along their path. Arterioles are the site of metabolic regulation of blood flow, as their tone is influenced by substances produced by surrounding cardiac myocytes during their metabolic activity.
Regulation of Myocardial Blood Flow
Myocardial blood flow (MBF) is used to indicate tissue perfusion, ie, the volume of blood per unit of time per unit of cardiac mass (mL/min per g). MBF should be kept distinct from CBF, which is used to indicate the volume of blood that flows along a vascular bed over a time unit (mL/min).
The cardiac pump is an aerobic organ that requires continuous perfusion with oxygenated blood to generate the adenosine triphosphate (ATP) that is necessary for contraction. The role of the coronary circulation is to provide an adequate matching between myocardial oxygen demand and supply. Under resting conditions, the tone of the coronary microvasculature is high. This intrinsically high resting tone allows the coronary circulation to increase flow when myocardial oxygen consumption increases (as oxygen extraction from arterial blood is already close to 60–70% under baseline conditions) through rapid changes in arteriolar diameter, a mechanism known as functional hyperemia . The fall in arteriolar resistance drives a number of subsequent vascular adaptations that involve all upstream coronary vessels. The initial arteriolar response is driven by the strict cross-talk that exists between these vessels and contracting cardiomyocytes, which is the basis of metabolic vasodilatation.
The integrated coronary response to changes in myocardial oxygen consumption involves (1) metabolic vasodilation, (2) prearteriolar autoregulation, (3) flow-mediated (endothelium-dependent) vasodilation, (4) extravascular tissue pressure, and (5) neurohumoral control.
Metabolic Vasodilatation
During Normoxic Conditions
Metabolites that control blood flow in a feed-forward manner are produced at a rate directly proportional to oxidative metabolism ( Fig. 5.2 ). Examples of such metabolites are carbon dioxide (CO 2 ), which is generated in decarboxylation reactions of the citric acid cycle, and reactive oxygen species (ROS), which are formed in the respiratory chain in proportion to oxygen consumption. CO 2 is produced in proportion to oxygen consumption and results from the pyruvate dehydrogenase reaction and further decarboxylation reactions in the citric acid cycle. Increased concentrations of CO 2 result in an increase of proton (H + ) concentration, which likely constitutes the direct stimulus for coronary vasodilatation. Similar to the production of CO 2 , the production of hydrogen peroxide (H 2 O 2 ) is a feed-forward response, in that the production of this ROS is directly linked to myocardial oxygen consumption. H 2 O 2 is generated by two-electron reduction of oxygen. This can occur in one enzymatic step, or more typically it involves generation of the intermediate ROS, superoxide anion ( • O 2 – ). With regard to the origin of H 2 O 2 associated with metabolic vasodilatation, there is evidence supporting its endothelial mitochondrial generation. The vasodilator properties of H 2 O 2 have been recognized for a number of years. H 2 O 2 -induced dilatation is principally mediated by 4-aminopyridine sensitive ion channels, presumably Kv channels. The coronary dilator effect of H 2 O 2 might also be mediated by the large conductance Maxi-K channel or by prostanoids.
During Hypoxic Conditions
Hypoxia is the most powerful physiologic stimulus for coronary vasodilatation, and adenosine has been proposed as a regulator of CBF in response to hypoxia. Adenosine is formed by degradation of adenine nucleotides under conditions in which ATP utilization exceeds the capacity of myocardial cells to resynthesize high-energy compounds. This results in the formation of adenosine monophosphate, which in turn is converted to adenosine by the enzyme 5′-nucleotidase. Adenosine then diffuses from the myocytes into the interstitial fluid, where it exerts powerful arteriolar dilator effects through the direct stimulation of A 2 adenosine receptors on vascular smooth muscle cells. Several findings support the critical role of adenosine in the metabolic regulation of blood flow. Indeed, its production increases in cases of imbalance in the supply/demand ratio of myocardial oxygen, with the rise in interstitial concentration of adenosine paralleling the increase in CBF.
Vasodilatation ensues when Ca 2+ concentration in the cytosol of the vascular smooth muscle decreases or sensitivity to Ca 2+ of contractile elements is impaired. Ca 2+ entry is prevented by vascular smooth muscle membrane hyperpolarization in response to K ATP channels activation (see Fig. 5.2 ).
Autoregulation, the Prearteriolar Adaptations to Metabolic Vasodilatation
Arteriolar dilatation decreases both resistance in overall network and pressure in distal prearteriolar vessels, which in turn induce the dilatation of these vessels. It is worth noting that the coronary circulation exhibits an intrinsic tendency to maintain blood flow at a constant rate despite changes in perfusion pressure, a mechanism known as autoregulation . The mechanism responsible for autoregulation is a myogenic response to transmural distending pressure eliciting wall tension, which involves primarily distal prearteriolar vessels: they dilate in response to a reduction of perfusion pressure and constrict in response to an increase of perfusion pressure. In vitro, active smooth muscle tone increases almost linearly with transmural pressure, leading to a substantial diameter reduction. A key mechanism of this myogenic response is membrane depolarization of vascular smooth muscle in response to stretch detected by a sensor (extracellular matrix-integrin interactions) that then initiates signaling mechanisms that lead to the opening of nonspecific cation channels promoting an inward Na + and/or Ca 2+ current, although other mechanisms also contribute to this phenomenon ( Fig. 5.3 ). Myogenic contraction is ultimately caused by activation of smooth muscle contractile proteins by myosin light chain kinase.
Flow-Mediated Vasodilatation
Shear stress, the tractive force that acts on the vascular wall, is proportional to blood shear rate, or velocity, and to viscosity. When flow changes, epicardial coronary arteries and proximal prearterioles have an intrinsic tendency to maintain a given level of shear stress by endothelial-dependent dilatation, ie, the production of endothelial-derived factors such as nitric oxide (NO) and prostacyclin (PGI 2 ), and endothelial-derived hyperpolarizing factors (EDHFs) stimulated by the activation of specific receptors (muscarinic, bradykinin, histamine) or mechanical deformation sensed by cytoskeletal elements and glycocalix (see Fig. 5.3 ). In fact, both very high and very low shear stress may jeopardize the interaction between blood elements and the vascular endothelium. In the absence of changes in perfusion pressure, variations of flow in epicardial coronary arteries can be achieved by intracoronary injection of arteriolar vasodilators such as adenosine. Human angiographic studies have shown that epicardial coronary arteries dilate in response to an increase in blood flow, and that the increase in coronary diameter is proportional to the increase in flow, thus maintaining shear stress constant. Vasodilators released by endothelial cells in response to an increase in shear stress, NO, EDHFs, and PGI 2 operate through different mechanisms on the underlying smooth muscle (see Fig. 5.3 ). NO is generated by the conversion of l -arginine to l -citrulline by the endothelial NO synthase (eNOS) in the presence of cofactors such as tetrahydrobiopterin (BH4). NO induces hyperpolarization primarily by activating cyclic guanosine monophosphate (cGMP) signaling and K Ca channels. In the human heart more than one EDHF is produced during shear stress, and it appears that the common pathway is the opening of K + channels causing hyperpolarization and relaxation of smooth muscle cells. PGI 2 causes relaxation by activating adenylyl cyclase/cyclic adenosine monophosphate (cAMP)-dependent hyperpolarization; the latter are released into the coronary circulation mainly during episodes of hypoxia/ischemia (see Fig. 5.3 ).
Endothelial-derived vasoconstrictors under normal conditions exert a relatively weak effect on the coronary microcirculation (see Fig. 5.3 ). There is some evidence supporting a more significant role of endothelin-1 in atherosclerotic disease or for angiotensin-II in obesity, hypertension, or coronary artery disease.
Extravascular Resistance
In addition to vascular resistance there is an extravascular component of resistance due to the compressive forces produced during cardiac contraction that impinge upon the walls of intramyocardial vessels. These extravascular systolic compressive forces have two components: the first is related to the pressure developed within the left ventricular (LV) cavity, which is directly transmitted to the subendocardium, but falls off to almost zero at the epicardial surface. The second is vascular narrowing caused by compression and bending of vessels coursing through the ventricular wall (see Fig. 5.1A ). Because of this cyclic extravascular pressure, both vascular resistance and flow vary considerably during the cardiac cycle. Extravascular pressure can exceed coronary perfusion pressure during systole, particularly in the inner subendocardial layers. As a consequence, during systole, subendocardial microvessels become more narrowed, or even occluded, in comparison to those in the subepicardium, and, at the onset of diastole, they present a higher resistance to flow, needing a longer time to resume their full diastolic caliber. This is the reason why most of the blood flow to the left ventricle occurs during diastole when perfusion pressure exceeds the value of extravascular pressure. At peak systole there is even backflow in the coronary arteries, particularly in the intramural and small epicardial vessels.
Neural and Biohumoral Regulation of the Microcirculation
Small arteries and arterioles are richly innervated by both sympathetic and parasympathetic nerve terminals that play an important role in the regulation of CBF. Under normal circumstances, in addition to its well-known β 1 adrenoceptor-mediated chronotropic, inotropic, and dromotropic effects, the net effect of sympathetic activation is to increase CBF through β 2 adrenoceptor-mediated vasodilatation of small coronary arterioles, thus contributing to the feed-forward control that does not require an error signal such as decreased oxygen tension. In isolated subepicardial arterioles of swine, β 2 adrenoceptor mRNA is expressed nearly 3-fold more than in subendocardial arterioles, indicating transmural heterogeneity. Coronary vessels are also rich in α adrenoceptors, with α 1 being more predominant in larger vessels and α 2 in the microcirculation. Activation of vascular α-adrenoceptors results in vasoconstriction that competes with metabolic vasodilatation. Sympathetic α adrenoceptor-mediated coronary vasoconstriction has been demonstrated during adrenergic activation, such as during exercise or during a cold pressor reflex in humans.
Based on experimental evidence, Feigl hypothesized that there was a beneficial effect of this paradoxic vasoconstrictor influence in that it helps preserve flow to the vulnerable inner layer of the left ventricle, but only when heart rate, contractility, and coronary flow are high. However, this hypothesis was not confirmed by subsequent studies that failed to demonstrate a favorable effect of α-adrenergic coronary vasoconstriction on the transmural blood flow distribution under physiologic conditions. On the other hand, α-adrenergic coronary vasoconstriction is operative in ischemic myocardium, and several studies have demonstrated improved subendocardial blood flow following administration of α-adrenergic blockers.
Parasympathetic control of CBF has been extensively studied in dogs. Vagal stimulation produces uniform vasodilation across the LV wall independent of changes in myocardial metabolism. The vagal response, which is activated during carotid baroreceptor and/or chemoreceptor stimulation, depends on the species and the integrity of the endothelium. Parasympathetic vasodilatation is attributed to the release of acetylcholine at the adventitial-medial border mediated via muscarinic receptors M1 and M2 and subsequent activation of endothelial NO mediated dilation.
Reactive Hyperemia and Coronary Flow Reserve
When a major epicardial coronary artery is occluded for a short period of time, occlusion release is followed by a significant increase in CBF, a phenomenon known as reactive hyperemia . The maximum increase in blood flow occurs within a few seconds after the release of the occlusion, and the peak flow, which has been shown to reach 4 or 5 times the value of preischemic flow, is dependent on the duration of the ischemic period for occlusion times up to 15 to 20 s. Although occlusions of longer duration do not further modify the peak of the hyperemic response, they do affect the duration of the entire hyperemic process, which increases with the length of the occlusion. It is generally accepted that myocardial ischemia, even of brief duration, is the most effective stimulus for vasodilatation of coronary resistive vessels and that, under normal circumstances, reactive hyperemic peak flow represents the maximum flow available at a given coronary perfusion pressure. Values of CBF comparable to the peak flow of reactive hyperemia can be achieved using coronary vasodilators such as adenosine or dipyridamole, which induce a “near maximal” vasodilatation of the coronary microcirculation.
The coronary flow reserve (CFR) is an indirect parameter to evaluate the global function of the coronary circulation. CFR is the ratio of CBF or MBF during near maximal coronary vasodilatation to resting flow and is an integrated measure of flow through both the large epicardial coronary arteries and the microcirculation ( Fig. 5.4 ). Resting blood flow is the denominator in the formula used to compute CFR; thus an increase in resting blood flow, such as that often seen in patients with arterial hypertension, will lead to a net decrease in the available CFR even if maximum flow is normal. The driving perfusion pressure that determines flow at any given level of vascular resistance is the pressure at the origin of arteriolar vessels, which, under normal circumstances, corresponds closely to aortic pressure. During maximal coronary dilatation, the slope of the pressure/flow curve becomes very steep with a sizeable linear increase of CBF with increasing pressure (see Fig. 5.4 ).
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