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 ).
Mechanisms of Coronary Microvascular Dysfunction
Coronary microvascular dysfunction (CMD) ( Boxes 5.1 and 5.2 ) can be sustained by several pathogenetic mechanisms, as summarized in Table 5.1 . The importance of these mechanisms appears to vary in different clinical settings, but several of them may coexist in the same condition.
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Intramyocardial arterioles below 500 μm in diameter that are the main site of myocardial perfusion regulation make up the coronary microcirculation.
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Coronary microvascular dysfunction is an additional mechanism of myocardial ischemia.
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Dysfunction of the coronary microcirculation is caused by functional and/or structural alterations of the intramyocardial arterioles as well as by increased extravascular compression.
- •
No technique allows direct visualization of the anatomy of the coronary microcirculation in vivo in humans.
- •
Microvascular function is assessed indirectly, by measuring coronary (CBF) or myocardial blood flow (MBF) and coronary flow reserve (CFR) or by calculating the index of microvascular resistance (IMR).
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CBF is the volume of blood that flows along a vascular bed over a time unit (mL/min).
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MBF is the volume of blood per unit of time per unit of cardiac mass (mL/min per g).
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CFR is the ratio of CBF or MBF during near maximal vasodilation achieved by means of drugs such as adenosine or dipyridamole to baseline CBF or MBF.
- •
IMR is calculated as the product of distal coronary pressure and mean transit time using a combined pressure/temperature wire.
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Invasive and noninvasive techniques can be used to assess CBF/MBF and CFR including intracoronary Doppler flow wires, transthoracic Doppler, positron emission tomography, and cardiac magnetic resonance imaging.
| Clinical Setting | Main PAthogenetic Mechanisms | |
|---|---|---|
| Type 1: In the absence of myocardial diseases and obstructive CAD | Risk factors | Endothelial dysfunction |
| Microvascular angina | SMC dysfunction | |
| Vascular remodelling | ||
| Type 2: In myocardial diseases | Hypertrophic cardiomyopathy | Vascular remodelling |
| Dilated cardiomyopathy | SMC dysfunction | |
| Anderson-Fabry disease | Extramural compression | |
| Amyloidosis | Luminal obstruction | |
| Myocarditis | ||
| Aortic stenosis | ||
| Type 3: In obstructive CAD | Stable angina | Endothelial dysfunction |
| Acute coronary syndrome | SMC dysfunction | |
| Luminal obstruction | ||
| Type 4: Iatrogenic | PCI | Luminal obstruction |
| Coronary artery grafting | Autonomic dysfunction |
Structural Alterations
Structural abnormalities responsible for CMD have been demonstrated in patients with hypertrophic cardiomyopathy (HCM) and in those with arterial hypertension. In both these conditions morphologic changes are characterized by an adverse remodeling of intramural coronary arterioles responsible for vessel wall thickening, mainly due to hypertrophy of smooth muscle cells and increased collagen deposition in the tunica media, with variable degrees of intimal thickening. The remodeled, hypertrophied vascular wall leads to an increase in medial wall area, with a relative reduction of the vessel lumen. Although qualitatively similar in the two conditions, these anatomic changes are usually more severe in patients with HCM. An important feature, common to patients with arterial hypertension and those with HCM, is the diffuse nature of the microvascular remodeling, which is extended to the entire left ventricle independently of the distribution of ventricular hypertrophy (ie, symmetric vs asymmetric) and may also involve portions of the right ventricle. The functional counterpart of these structural changes of the vessel wall is the demonstration that, in most of these patients, maximum MBF and CFR are blunted in the whole left ventricle. Structural abnormalities of coronary microcirculation have also been described in other clinical conditions characterized by CMD, including primary microvascular angina (MVA). This condition is defined as the occurrence of anginal symptoms in the absence of significant coronary artery disease (CAD) or cardiomyopathies. Analysis of endomyocardial biopsies obtained from these patients, however, has given discordant results, showing no alterations in some and heterogeneous findings in others, including medial hyperplasia and hypertrophy, intimal proliferation and degeneration, proliferation of endothelial cells, and capillary rarefaction. Finally, structural alterations of intramural coronary arterioles have been demonstrated in other myocardial diseases including amyloidosis and Fabry disease.
Functional Alterations
Functional CMD may be caused by a variable combination of mechanisms leading to impaired coronary microvascular dilatation and mechanisms resulting in increased coronary microvascular constriction (see Fig. 5.3 ).
Alterations of Endothelium-Dependent Vasodilatation
Alterations in endothelial function may impair CBF both at rest, favoring susceptibility to constrictor stimuli, and during increased myocardial workload, as typically occurs during exercise. NO production and release are the primary mechanisms of endothelium-mediated vasodilatation, and also the most vulnerable in the case of endothelial dysfunction. Unfortunately, NO is a volatile molecule, with a very short half-life (56 s); thus its direct measurement in vivo is difficult.
The detection of abnormalities in endothelium-dependent coronary microvascular dilatation in the clinical setting is mainly based on the blunting or even decrease of CBF in response to stimuli known to exert their vasodilator effect by inducing release of NO from endothelial cells. Stimulation of muscarinic receptors by intracoronary acetylcholine, in association with intracoronary Doppler flow recording, has been the most widespread stimulus used in clinical research, although it is limited to invasive procedures. A valid alternative to assess endothelium-dependent CMD is represented by cold pressure testing (CPT), which can be applied noninvasively in association with imaging techniques (eg, positron emission tomography [PET]) to measure MBF. If the endothelium is dysfunctional, the vasodilator response to these stimuli is blunted and can even turn into vasoconstriction in case of severe impairment of endothelial function, due to the complex vasoconstrictor effects elicited by CPT.
Impaired NO generation as a cause of endothelial dysfunction has been shown in several experimental studies. The most common cause is reduced activity of endothelial eNOS, the enzyme that catalyzes NO synthesis from the amino acid l -arginine, which can be caused by noxious stimuli activating acetylcholine/muscarinic, bradykinin, histamine receptors, or increasing frictional forces (ie, shear stress). In some cases, the administration of the NO synthase cofactor BH4 can improve and even normalize endothelial dysfunction, thus suggesting that a reduction of this cofactor can be involved in the impairment of endothelium-mediated dilatation, at least in some cases. Impairment of endothelium-dependent vasodilatation can be caused not only by impaired NO generation, but also by increased degradation. NO can be inactivated by several factors, with superoxide anion • O 2 – playing a major role. Excess generation of ROS reduces NO bioavailability by reacting directly with NO to form peroxynitrite ( • ONOO − ) and altering eNOS coupling. When uncoupled, instead of releasing NO, eNOS produces ROS, and ROS-mediated oxidation of the eNOS cofactor BH4 is the main mechanism responsible for eNOS uncoupling. This chain of events has been demonstrated in several conditions that are associated with impaired endothelium-dependent coronary microvascular dilatation, including diabetes, obesity, smoking, and other cardiovascular risk factors. Accordingly, antioxidant administration, which prevents superoxide anion formation including glutathione and antioxidant vitamins, has been shown to improve or even normalize endothelium-dependent coronary microvascular dilatation in both experimental and clinical conditions.
NO exerts its vasodilator effects by diffusing into smooth muscle cell cytoplasm and activating the guanylyl cyclase (GC) pathway by binding to the heme groups of the enzyme. Under certain circumstances, NO-dependent vasodilatation can be impaired despite normal levels of NO production. This might be due to oxidation of the heme groups of GC that renders the enzyme unresponsive to NO.
Endothelial dysfunction is also likely to reduce the activity of the EDHF and prostacyclin PGI 2 . Peroxynitrite can inhibit prostacyclin synthase, thus reducing PGI 2 release. This induces a shift in the PGI 2 precursor PGH 2 toward the synthesis of thromboxane A 2 (TXA 2 ), a powerful vasoconstrictor. How much and in which cases perturbation of these factors significantly contributes to CMD in the clinical setting remains substantially unknown, largely due to the lack of specific tests to assess these pathways in vivo.
Alterations of Endothelium-Independent Vasodilatation
An impaired endothelium-independent dilatation as a cause of CMD has been demonstrated in several experimental and clinical conditions, in which CBF increases and/or microvascular resistance decreases in response to direct arteriolar/prearteriolar vasodilators (eg, adenosine, dipyridamole, papaverine) were clearly abnormal.
Despite the large amount of data documenting the role of endothelium-independent dilatation of the coronary microcirculation, the cellular mechanisms involved remain incompletely understood. There are two main known intracellular pathways leading to smooth muscle cell relaxation. One pathway is based on activation of the enzyme adenylyl cyclase that results in the production of cAMP, which acts by opening K ATP channels and inhibiting calcium influx into smooth muscle cells (see Fig. 5.3 ). This pathway is mainly activated by stimulation of purinergic A 2 receptors and β 2 adrenoceptors. The second intracellular pathway, mentioned previously, relies on the activation of GC, which results in the production of cGMP. This latter pathway is mainly activated by NO released by the endothelium, as discussed previously,
Thus the mechanisms responsible for an impaired smooth muscle cell response to vasodilator stimuli are likely to be different in different clinical settings, as they may be related to abnormalities in specific receptors or in one or both of the main intracellular signaling pathways regulating smooth muscle cell relaxation. A reduced response to the vasodilator effect of prolonged nitrate administration (nitrate resistance), for instance, has been shown to occur because of a reduced production of cGMP, which might also be involved in a reduced response to NO (as shown previously).
Abnormalities in endothelium-independent coronary microvascular dilatation can also involve impaired opening of K ATP channels. Indeed, activation of intracellular cAMP and cGMP leads to the opening of K ATP channels, eventually resulting in cell hyperpolarization and closure of voltage-dependent calcium channels (see Fig. 5.3 ). Finally, alterations in other K + channels, such as K Ca and K v channels, may also be responsible for impairment of endothelium-independent coronary microvascular dilatation.
In summary, alterations in endothelium-independent smooth muscle cell relaxation in the coronary microcirculation may result in impaired vasodilator response to factors that mediate the metabolic regulation of CBF, autoregulation, and reactive hyperemia, as well as flow-mediated dilatation.
Vasoconstriction
Enhanced vasoconstriction of coronary microcirculation can result from either an increased release of vasoconstrictor agonists (systemically or locally) (see Fig. 5.3 ) and/or an increased susceptibility of smooth muscle cells to vasoconstrictor stimuli.
The notion that coronary microvascular constriction may cause myocardial ischemia has been demonstrated in both experimental models and humans. Some vasoconstrictors cause intense, selective microvascular constriction with minimal effects on the epicardial coronary arteries.
Experimental studies in dogs have provided evidence that administration of endothelin-1 in the left anterior descending coronary artery can cause a dose-dependent reduction of CBF leading to myocardial ischemia in the absence of any significant effect on epicardial arteries. Similar effects were observed with intracoronary injection of angiotensin II or phenylephrine, and, in rabbits, with the intracoronary injection of the tripeptide N -formyl- l -methionin- l -leucil- l -phenylamine, which acts through release of leukotrienes from activated neutrophils. These substances act on both subendocardial and subepicardial small coronary arteries and induce transmural myocardial ischemia.
In humans, evidence of myocardial ischemia due to coronary microvascular constriction comes from studies showing that intracoronary injections of neuropeptide Y or high doses of acetylcholine can cause chest pain and objective evidence of myocardial ischemia in patients with normal coronary angiograms, in the absence of significant changes in epicardial coronary arteries. In patients with flow-limiting stenoses, the intracoronary infusion of serotonin has been shown to cause myocardial ischemia with evidence of diffuse constriction of distal branches and reduced filling of collateral vessels, but with only minimal changes in stenosis severity. This response to serotonin is known to be due to stimulation of both endothelial and vascular smooth muscle 5HT receptors.
Abnormal microvascular constriction has been demonstrated in patients with chest pain and normal coronary arteries and in those with chronic stable angina. Intense coronary microvascular constriction is an important pathogenetic component of microvascular obstruction (MVO) observed in a substantial proportion of patients with ST elevation myocardial infarction (STEMI) after primary PCI.
Intravascular Plugging
Intravascular plugging caused by atherosclerotic debris and thrombus material typically occurs during PCI and is related to intracoronary manipulation of friable plaques, in particular in degenerated saphenous vein grafts. In these cases, microvascular plugging often causes “infarctlets,” characterized by a modest raise of biomarkers of myocardial injury, and it is associated with a worse prognosis compared with procedures that are not followed by any raise in these biomarkers. Intravascular plugging caused by microemboli and leukocyte-platelet aggregates is an additional mechanism of MVO in STEMI patients.
MVO is compounded by a complex interplay of ischemia/reperfusion-related events, including endothelial dysfunction with loss of vasodilator mechanisms, enhancement of vasoconstriction mediated by platelet activation, release of TXA 2 and 5HT, and inflammatory reaction.
Extravascular Mechanisms
Extramural Compression
During the cardiac cycle the pulsatile pattern of CBF follows typical physiologic variations, which are influenced by the variations in intramyocardial and intracavitary pressures occurring during systole and diastole (see Fig. 5.1 ). Approximately 90% of CBF occurs in diastole, and therefore diastolic abnormalities have a more significant impact on myocardial perfusion. Nevertheless, an increase in systolic intramyocardial and intracavitary pressures, for example in conditions of increased pressure overload, may negatively impact on myocardial perfusion. An increased microvascular compression during systole hinders subendocardial vessels’ tone restoration in diastole, thus impairing diastolic microvascular CBF in the subendocardial layers.
Diastolic CBF is impaired whenever intracavitary diastolic pressure is increased. This is the case in the presence of either primary or secondary LV hypertrophy (LVH) and also in the presence of diastolic dysfunction consequent to increased interstitial and perivascular fibrosis. Diastolic impairment of CBF is enhanced when arteriolar driving pressure during diastole is significantly lower than intracavitary pressure, as in patients with severe aortic stenosis, critical coronary stenoses, prearteriolar constriction, or merely hypotension.
Tissue Edema
Abnormalities of capillary permeability, which favor migration of intravascular fluid into the interstitium, cause myocardial edema and CMD. Experimental studies suggest that edema per se does not reduce CFR. Nevertheless, edema can worsen the impairment of CBF in the setting of MVO in STEMI. Edema results from a combination of several mechanisms, including (1) increased osmolality, caused by ischemic myocardial catabolites diffusing to the interstitial space during the ischemic phase, which recalls fluid from the intravascular compartment during reperfusion; (2) increased vascular permeability to water and protein, as well as abnormal ionic transport, consequent to endothelial damage occurring during ischemia/reperfusion; and (3) inflammation associated with reperfusion. Coronary microvascular compression is another component that favors intravascular cell plugging by neutrophil-platelet aggregates. Finally, myocardial edema can occur during open heart surgery. Increased venous pressure, mainly in the right chambers, may contribute to interstitial edema due to increased hydrostatic capillary pressure. Clinically, noninvasive assessment of myocardial edema and MVO is now possible using T2-based and inversion recovery cardiac magnetic resonance imaging.
Diastolic Time
Because CBF occurs predominantly during diastole, the duration of diastole plays a central role in preserving myocardial perfusion. In the normal heart both subendocardial and subepicardial perfusion is maintained at very short diastolic time, as during intense physical exercise. In contrast, a reduction of diastolic time can contribute to determine a critical reduction of myocardial perfusion at a time when coronary-driving pressure is significantly lower than intracavitary pressure, as in patients with aortic stenosis.
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