Coronary artery endothelial dysfunction: Basic concepts

INTRODUCTION — The coronary arterial circulation, which consists of conductance and resistance vessels, plays a major role in the delivery of blood to the myocardium. The endothelium is the layer of cells that lines these blood vessels. This layer maintains blood vessel (vascular) tone, regulates hemostasis, acts as barrier to potentially toxic materials, and regulates inflammation. Notably, the metabolic regulation of coronary blood flow that takes place at the site of resistance vessels allows a perfect matching between oxygen supply and demand. The increase of blood flow in the presence of an increase of oxygen demand is mainly mediated by the release of tiny amounts of free oxygen radicals.

Endothelial dysfunction is the inability of the endothelium to optimally perform one or more of these functions. Dysfunction of the endothelium is the principal determinant of chronic microvascular dysfunction but also may occur in the larger conduit arteries, especially when atherosclerosis is present. The principal clinical consequence of coronary microvascular dysfunction is myocardial ischemia but can also include vascular thrombosis, increased vascular permeability, and diastolic changes in the myocardium as observed in heart failure with preserved ejection fraction [1]. Endothelial dysfunction plays a key role in determining myocardial ischemia in all clinical manifestations of ischemic heart disease. Furthermore, the decrement in the noninvasive measurement of peripheral endothelial function has been shown in a large systematic review and meta-analysis encompassing over 17,000 patients to double the cardiovascular risk in moderate-risk individuals [2]. Coronary microvascular endothelial dysfunction is associated with more advanced coronary plaque characteristics in patients with chest pain and early nonobstructive coronary artery disease [3].

This topic will focus on basic concepts of normal endothelial function and dysfunction. More clinical aspects are discussed separately. (See "Coronary endothelial dysfunction: Clinical aspects".)

NORMAL ENDOTHELIAL FUNCTION — The endothelium is one of the largest organs in the body and it interacts with nearly every other organ or organ system [4,5]. It is a single (mono) layer of cells serving multiple purposes:

●Maintenance of hemostasis, the balance between thrombosis and clotting

●Maintenance of optimal vascular permeability

●Regulation of inflammation

●Control of vasculogenesis and angiogenesis

●Maintenance of optimal vascular tone, by controlling vasoconstriction and vasodilation; adequate end organ blood perfusion is maintained in this way.

With regard to this last function, the endothelium functions to maintain the vessel in a relatively neutral state, favoring dilatation over constriction under basal conditions. It has the capacity to respond to various stimuli, including shear stress, temperature, and transmural pressure, as well as external stimuli such as temperature, mental stress, neurohumoral responses, and medications among others. The control of local vascular tone is mediated principally by nitric oxide (NO), although prostacyclin and endothelium-dependent hyperpolarization factor play an important role in atherosclerotic arteries.

Nitric oxide generation — The endothelial-dependent response of vasodilation is principally regulated by release of NO from endothelial cells. It is synthesized from the amino acid L-arginine by endothelial nitric oxide synthase (NOS), which leads to the production of intracellular cyclic guanosine monophosphate (GMP) [6].

NO, a molecular gas, is enzymatically formed from L-arginine by three isoforms of NOS: neuronal-type (nNOS, NOS1), cytokine-inducible or macrophage NOS (iNOS, NOS2), and the endothelial-type (eNOS, NOS3) [7,8]. All three enzymes, which are cytochrome P450-like proteins, facilitate the addition of the guanidine nitrogen of the amino acid arginine to molecular oxygen, producing NO and water. These enzymes differ markedly in their localization and function. Many cell types, most notably endothelial cells, constitutively express eNOS, generating relatively low levels of NO that are under tight control by regulatory factors. In contrast, iNOS is normally not expressed, but when induced by inflammatory cytokines, can generate large amounts of NO far in excess of those made by eNOS.

Nitric oxide function — NO is a paracrine mediator that works differently from endocrine mediators, such as angiotensin II and antidiuretic hormone. NO, which is produced and released by individual cells, readily penetrates the biological membranes of neighboring cells, modulating a number of signaling cascades. Since it has an extremely short half-life, it exerts its effects locally and transiently.

The most recognized cellular target of NO is heme-containing soluble guanylate cyclase. The stimulation of this compound enhances the synthesis of cyclic GMP (cGMP) from guanosine triphosphate, increasing the cytosolic levels of cGMP. The effects of NO can be enhanced by inhibiting the breakdown of cGMP, a process catalyzed by a family of phosphodiesterases.

Other cellular targets for NO also exist:

●NO interacts with thiol groups on proteins and small molecules, resulting in the formation of S-nitrosothiols. The addition and removal of S-nitrosothiols is a highly regulated process.

●NO can target Fe/S groups at the catalytic centers of proteins, including hemoglobin [9]

●The formation of peroxynitrite from NO and superoxide radical, which occurs when large amounts of NO are generated, typically by iNOS, has been implicated in cellular toxicity via the propensity of peroxynitrite to induce post-translational changes in the tyrosine residues of proteins [10].

Biologic effects — The biologic effects of NO depend upon the concentration of NO produced as well as features specific to the local environment, particularly the presence and production of thiols and superoxide.

Vasodilation — NO exerts its vasodilatory effects through stimulation of the soluble guanylate cyclase. (See 'Nitric oxide function' above.)

Angiogenesis — NO and NO-related factors may play a role in the growth of vascular cells and blood vessels. NO is a physiologic inhibitor of smooth muscle growth. The effect of NO on vascular smooth muscle growth is mediated by cGMP [9-11]. In addition to inhibiting smooth muscle growth, NO may also promote apoptosis [12].

Endothelial cell proliferation — While NO and other cyclic GMP-activating agents inhibit the growth of vascular smooth muscle, they do not alter the rate of growth of endothelial cells [13]. On the other hand, proliferating cells (eg, following endothelial denudation) express about sixfold as much eNOS mRNA as confluent cells [13]. The net effect is that proliferating endothelial cells that grow back to recover exposed intima produce large amounts of NO; the NO will tend to minimize platelet adhesion and vascular smooth muscle proliferation in the area but will not interfere with the endothelial cell proliferation.

New vessel growth involves several distinct steps [14].

●Increased vascular permeability and dissolution of the bond between the endothelium and basement membrane

●Migration and reattachment of endothelial cells

●Proliferation and migration of endothelial cells and the formation of a tubule, which is the rudimentary vascular structure.

Almost universally, pathologic conditions that can lead to angiogenesis, such as tissue hypoxia and inflammation, are associated with the production and release of growth factors, suggesting that these substances are critical to the formation of new blood vessels. In addition, the respective growth factor receptors must be upregulated and inhibitory factors must be inhibited if the growth factors are to play a role in the initiation and later steps of vessel development [14-16]. (See "Coronary collateral circulation".)

There is also a strong relation between the release of NO and the regulation of blood vessel growth and development. Substance P and growth factors such as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF), all of which stimulate the release of NO [15,17,18], induce new vessel formation in vivo and increase the permeability, migration, and proliferation of post-capillary endothelial cells in tissue culture [18,19]. On the other hand, inhibitors of NO synthase suppress angiogenesis, and the proliferative effect of VEGF.

There are, however, contradictory observations concerning the role of NO in angiogenesis. In different models, NO synthase was involved in angiogenesis induced by VEGF but not that induced by FGF-2 [20] and, paradoxically, angiogenesis was inhibited by the NO donor sodium nitroprusside and the NO synthase substrate L-arginine, and increased by inhibitors of NO synthase [21,22]. It is possible that the effects of NO differ between species and between vascular beds within species.

In contrast to the robust angiogenic response seen in many animal models of chronic myocardial ischemia, the angiogenic effects of exogenously delivered growth factors, such as FGF-2 and VEGF, have been relatively modest or negative in human trials, especially when given intravascularly [23]. This difference could be related to a diminished response to angiogenic growth factors in the setting of atherosclerosis, hypercholesterolemia, diabetes, and other causes of endothelial dysfunction [24,25]. In addition, the expression of pro-angiogenic factors, such as VEGF, may be diminished and the expression of anti-angiogenic factors, such as endostatin and angiostatin, may be increased in conditions such as hypercholesterolemia and diabetes [26,27]. This may negatively affect both microvascular and macrovascular collateral growth in response to chronic coronary artery occlusion, and thus may affect overall myocardial perfusion.

The diminished potential of angiogenic growth factors to induce collateral development may have adverse implications for the use of gene-, protein- and, cell-based therapies to increase perfusion to ischemic myocardium [28-32]. It is possible that adjunctive therapies such as statins and NOS substrate (L-arginine) may improve the angiogenic potential of these growth factors as a therapeutic modality [24]. However, the role of statins in collateral growth is biphasic, and some studies have suggested that statins may not necessarily improve collateral development and may actually diminish perfusion [33]. (See "Therapeutic angiogenesis for management of refractory angina" and "Investigational therapies for management of heart failure", section on 'Stem cell therapy' and "Overview of the nonacute management of ST-elevation myocardial infarction".)

Other factors — Hydrogen peroxide produces vasodilation by oxidation of thiols and activation of p38 MAP kinase. Thus, coronary metabolic dilation appears to be mediated by redox-dependent signals [34]. Other factors also play a role, including abnormal autonomic regulation of vascular tone, changes in vascular smooth muscle reactivity, altered voltage-gated K+ channel function, and impaired vasodilatory response to hypoxia, which may have significant implications for the metabolic regulation of blood flow [35-37].

ENDOTHELIAL DYSFUNCTION — The principal cause of endothelial dysfunction is an imbalance in nitric oxide (NO) production and consumption, favoring consumption and reduced production. The major consequence is inability of the vessel to properly dilate. The principal clinical manifestation of endothelial dysfunction in the coronary circulation is myocardial ischemia. When NO-mediated vasodilation is compromised, the vasodilatory response is thought to be facilitated by cytochrome-derived factors, natriuretic peptide, prostacyclin, and other products of cyclooxygenase isoforms.

In addition, endothelial dysfunction creates conditions favorable for platelet plus leukocyte activation and adhesion, as well as the activation of cytokines that increase the permeability of the vessel wall to oxidized lipoproteins and inflammation mediators, finally resulting in structural damage of the arterial wall with smooth muscle cell proliferation and atherosclerotic plaque formation.

Abnormal nitric oxide metabolism — Biochemical causes of abnormal NO metabolism, which contribute to endothelial dysfunction through decreased production and/or increased consumption of NO, include:

●High oxidative stress and inflammation lead to abnormal NO metabolism (bioavailability, use/response, production, release, and degradation), which can be exacerbated with other conditions (cold, mental stress, anger) that are known to produce a global vasoconstriction. Increased oxidative stress is characterized by a measurable increase in reactive oxygen species (ROS), which can result from impaired NO synthase, decreased L-arginine uptake, increased oxidized low density lipoprotein cholesterol (Ox-LDL) [38], or reduced superoxide dismutase, an enzyme pivotal in the clearing of ROS [39]. Hyperlipidemia is known to increase ROS, which will reduce the bioavailability of NO; it can be ameliorated with correction of hyperlipidemia [40].

●A decrease in tetrahydrobiopterin (THB), which is a co-factor for endothelial nitric oxide synthase (eNOS) [41,42]. Replenishing THB stores appears to improve endothelial dysfunction, even in hyperlipidemic patients [43].

●Deficiencies in L-arginine, the substrate for eNOS, and the co-factor tetrahydrobiopterin lead to a reduction in the synthesis and release of NO.

●Abnormalities of G-protein signaling, resulting in reduced activation of eNOS in response to endothelial cell receptor activation. In addition, the enzyme arginase may be increased in activity after ischemia-reperfusion, decreasing the available L-arginine [44].

●Elevated asymmetric dimethylarginine (ADMA), which is an endogenous competitive inhibitor of NO [45,46]. ADMA has been linked to reduced endothelial function as well as erectile dysfunction in patients at moderate risk for cardiovascular disease [47]. Furthermore, Ox LDL can increase ADMA, further compounding known risk factors in patients with coronary artery disease [46,48], even leading to increased events in those found to have elevated levels of ADMA [49].

Role of endothelin — Increased vasomotor tone in atherosclerotic coronary arteries is partly due to endothelial dysfunction; however, endothelin-1 also contributes to the exaggerated vasoconstrictor response. Administration of an endothelin receptor antagonist produces significant dilation in atherosclerotic arteries, especially at stenoses (16.3 and 21.6 versus 7.3 percent in normal arteries), suggesting that endothelin significantly contributes to the resting tone in atherosclerotic arteries (74 versus 39 percent in normal arteries) [50].

Circulating endothelial progenitor cells (EPCs) as a marker of endothelial dysfunction — A measure of EPCs has evolved as a novel method of assessing endothelial dysfunction. Rarely found in the peripheral blood of healthy individuals, EPCs are restorative/regenerative cells, thought to possibly replace or renew damaged areas of the vessel intima [51]. Furthermore, EPCs possess the characteristic of being capable of augmenting revascularization and endothelial regeneration [52]. EPCs may also be involved in the regeneration of ischemic myocardium by modulation of angiogenesis and myogenesis, cardiomyocyte apoptosis, and remodeling in the ischemic cardiac tissue. EPCs have additionally been reported to participate in cerebral neovascularization after ischemic stroke. The significance of the role of EPCs in early vascular injury and repair was underscored by a report demonstrating a significant correlation between the number and the function of EPCs and peripheral endothelial function [53]. The assessment of the number and the function of EPCs may serve as an important additional marker of endothelial function and accordingly can serve as a marker for therapy. Thus, it is not simply the number of circulating EPCs found, but also the type and location of these EPCs that might have an impact on disease and potential therapies [54].

EPC release, induced by inflammatory cytokines such as NFkB and IL-8, has been documented at the site of endothelial injury in animal models. Flow cytometry studies in humans have noted an epidemiological trend toward increased EPCs in patients at high risk for cardiovascular events [55,56]. The characterization of osteogenic EPCs found at higher numbers and retained in greater quantity within the coronary circulation in patients with endothelial dysfunction provides some mechanistic framework for explaining the epidemiological phenomenon in humans at risk for coronary events [57].

Extracellular microparticles — Extracellular microvesicles, also referred to as microparticles, are dynamic, mobile, biological effectors likely having a role in mediating endothelial vascular communication and function. The release of extracellular microvesicles may induce autocrine and paracrine effects on target cells through cellular interactions and possibly the delivery of intra-vesicular material [58].

CONDITIONS ASSOCIATED WITH ENDOTHELIAL DYSFUNCTION

Atherosclerosis — Atherosclerosis is the most common clinical entity associated with endothelial dysfunction. (See "Pathogenesis of atherosclerosis".)

One of the first examples of an alteration in the coronary microcirculation in atherosclerosis was made in monkeys fed a high cholesterol diet for 18 months [59]. These animals developed impaired vasodilation, and in some cases paradoxical constrictions, in larger vessels in response to acetylcholine, bradykinin, and thrombin. Impaired vasodilation was also seen in the coronary microvasculature, where overt atherosclerosis does not develop. Similar findings have been made in other animal models of diet-induced atherosclerosis.

In atherosclerosis, the serotonin 1B receptor is upregulated and serotonin produces augmented vasoconstriction, a result of calcium mobilization [60]. Other studies using in vivo techniques showed that vasoconstriction caused by serotonin and ergonovine, which is normally modulated by the endothelium, was markedly enhanced in the coronary microcirculation of hypercholesterolemic monkeys [61]. These findings are striking because the coronary microcirculation is spared from overt atherosclerosis. Thus, vessels that have been exposed to a high cholesterol milieu, even in the absence of atherosclerosis, develop abnormal vasomotion.

Endothelial dysfunction results from the presence of risk factors (ie, smoking, diabetes, hypertension, or hyperlipidemia) and is further potentiated by atherosclerosis in a vicious circle.

Hyperlipidemia — Diminished flow responses to acetylcholine have been demonstrated in humans with hypercholesterolemia [62,63], an abnormality that can be corrected by reducing the serum cholesterol [63]. (See "Mechanisms of benefit of lipid-lowering drugs in patients with coronary heart disease", section on 'Reversal of endothelial dysfunction'.)

Hypertension — Impaired endothelium-mediated relaxation has also been demonstrated in humans with or experimental models of hypertension [64].

Diabetes mellitus — Diabetes is associated with vascular dysfunction. Increased oxidative stress, which is typically associated with diabetes, may inhibit NO, thus contributing to endothelial dysfunction.

Smoking — The potential impact of smoking on the coronary microcirculation is discussed separately. (See "Cardiovascular risk of smoking and benefits of smoking cessation", section on 'Pathogenesis'.)

Myocardial hypertrophy — Patients with cardiac hypertrophy due to a variety of causes have chest pain suggestive of myocardial ischemia. Ischemia due to microvascular disease is an important risk factor for cardiac events in patients with hypertrophic cardiomyopathy. (See "Hypertrophic cardiomyopathy: Natural history and prognosis", section on 'Mortality' and "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation".)

Cardiac hypertrophy is associated with a reduction in the maximal capacity of the coronary circulation to dilate in response to either reactive hyperemia or pharmacologic stimuli [65-67].

Two hypotheses have been proposed to explain this defect in vasodilator function:

●As the myocardium hypertrophies, the coronary resistance circulation does not increase to keep pace with the larger myocardial mass. Thus, peak flow normalized to myocardial mass is reduced because of the relative paucity of coronary arterioles.

●There is a structural alteration of the microcirculation, due to actual loss of coronary resistance vessels (seen in hypertension or diabetes) or due to medial hypertrophy of these vessels (seen in hypertrophic cardiomyopathy) (picture 1). These structural changes can alter autoregulation and the perfusion pressure in the subendocardium. However, while there is a significant association between diastolic dysfunction and measures of microvascular function in clinical diseases such as diabetes, the actual relationship between endothelial dysfunction, connective tissue content, and cardiac diastolic failure is not strong. Other factors probably have a more important role in the early pathogenesis of subclinical diastolic dysfunction in diabetes and other illnesses [68].

It has been assumed that the loss of maximal vasodilator reserve reflects a structural alteration of the coronary microcirculation. Consistent with this hypothesis is that the defect is observed during maximal vasodilator stimulation; in this setting, the resultant flow must reflect the driving pressure for perfusion and the cross-sectional area of the coronary resistance circulation. It is unlikely that the loss of maximal vasodilator reserve is due primarily to endothelial factors since some of the vasodilators administered in pharmacologic studies (adenosine and papaverine) largely act independent of the endothelium.

The defects in microvascular function tend to normalize when the underlying abnormality responsible for hypertrophy is corrected, as with aortic valve replacement for severe aortic stenosis. However, the normalization of microvascular function is not closely correlated with regression of hypertrophy in this setting. Possible mechanisms of improved myocardial blood flow after aortic valve replacement include reduced extravascular compression and increased diastolic perfusion [69].

Other disease associations — Other factors leading to impairment of NO function include:

●Low-flow vascular states such as reduced cardiac output, which reduces endothelial shear stress in conditions such as heart failure, possibly from reduced L-arginine [70]. In addition, vascular injury or occlusion can contribute to an alteration in bioavailable NO and varying endothelial function [71].

●Localized infection, particularly in the oral cavity, leading to increased systemic inflammation and impaired endothelial function, has been postulated to be a contributor to cardiovascular disease. Chlamydia pneumonia infections [72] and immediate systemic inflammatory states that would mirror sepsis [73] have been shown to increase global inflammatory markers and endothelial dysfunction. Furthermore, H. pylori-positive patients have reduced endothelial function ameliorated by treatment [74]. However, global treatments with antibiotics in high-risk patients show no benefit on cardiovascular disease outcomes [75,76].

●External beam radiation [77] and chemotherapy (particularly doxorubicin and daunorubicin) [78] have been shown to reduce endothelial function in patients independent of other risk factors, presumably through endothelial cell death and reduced NO availability.

●Microvascular angina, formerly called "cardiac syndrome X," applies to patients with myocardial ischemia and normal epicardial coronary arteries [79]. Multiple causes have been suggested, including impaired endothelium-mediated vasomotion in the cardiac microvasculature [80,81]. The pathogenesis is discussed separately. (See "Microvascular angina: Angina pectoris with normal coronary arteries", section on 'Pathogenesis'.)

●Inhalation anesthetic agents that are delivered during surgical operations may have significant influence on the coronary microcirculation. For example, isoflurane and halothane have been found to decrease endothelium-dependent responses in the coronary microcirculation [82]. Isoflurane attenuates flow-induced dilation, whereas halothane enhances it [83]. Sevoflurane maintains myogenic and endothelial determinants of myocardial blood flow distribution, but desflurane attenuates endothelium-dependent flow-induced dilation while mildly enhancing myogenic constriction [84]. Despite these effects, myocardial blood flow is probably adequate and little changed during anesthesia when the circulation is normal. However, most anesthetics may have important microvascular influences under conditions of tissue ischemia such as myocardial infarction, coronary artery disease, or during cardiac surgery.

●Ischemia followed by reperfusion injury in both the territory of the occluded artery [85,86] and the nonculprit arterial territory [87].

●Endothelial function of the coronary microcirculation is altered following cardioplegic arrest and extracorporeal circulation during coronary artery bypass graft surgery (CABG) [88,89]. This abnormality persists for some time after cardiopulmonary bypass and normalizes thereafter. A number of factors may be involved, including increased release of products of COX-2 [89,90].

Such a deficit in endothelial function may have important clinical implications because of the frequency with which cardioplegia is used in cardiovascular surgery. It is not uncommon for patients undergoing CABG with complete coronary revascularization to exhibit signs of myocardial ischemia during the hours following surgery; it is possible that the mechanism, in part, is alteration of endothelial function. (See "Early noncardiac complications of coronary artery bypass graft surgery".) In addition, it is likely that the arteriopathy often observed after cardiac transplantation is in part related to endothelial injury resulting from inadequate vascular preservation. (See "Heart transplantation in adults: Cardiac allograft vasculopathy pathogenesis and risk factors".)

●Chronic heart failure, due to either an ischemic or nonischemic cardiomyopathy, is associated with endothelial dysfunction and impaired endothelium-mediated, flow-dependent dilation of coronary and peripheral arteries due to a reduction in the synthesis, release, and response to NO [91-93]. (See "Coronary endothelial dysfunction: Clinical aspects" and "Pathophysiology of heart failure: Neurohumoral adaptations", section on 'Nitric oxide'.)

There is evidence for increased free radical formation in heart failure, and it is possible that these species inactivate NO. Support for this hypothesis comes from one study in which vitamin C improved endothelial function in patients with heart failure in association with an increased availability of NO [94].

●Heart transplantation can normalize peripheral endothelial function in patients with nonischemic cardiomyopathy, but has no effect in those with prior ischemic cardiomyopathy [95]. Endothelial dysfunction in patients with a nonischemic cardiomyopathy is probably a consequence of hemodynamic alterations that are reversible after transplantation, while endothelial dysfunction is also due to the presence of systemic atherosclerosis in patients with ischemic cardiomyopathy. Persistent endothelial dysfunction also may result from vascular inflammation associated with viral myocarditis [96].

The presence of endothelial dysfunction after heart transplantation is associated with the development of transplant vasculopathy. In one study, for example, 58 percent of transplant patients with such endothelial dysfunction developed angiographic evidence of arteriosclerosis at one year compared with only 13 percent of those with normal function [97]. The development of microvasculopathy in heart transplant patients is associated with reduced long-term survival [98]. (See "Heart transplantation in adults: Cardiac allograft vasculopathy pathogenesis and risk factors".)

●Patients with cyanotic congenital heart disease manifest a significant increase in basal coronary blood flow. However, coronary artery flow reserve remains normal. In necropsy specimens studied from hearts of patients with various congenital anomalies (including Eisenmenger's syndrome, structurally abnormal hearts with ventricular hypertrophy, structurally normal hearts with ventricular hypertrophy, and normal hearts) remodeling of the coronary microcirculation was noted to be the key mechanism for preservation of flow reserve in cyanotic congenital heart disease. The increase in vascular diameter compensated for lower arteriolar length density and was the principal anatomic basis for maintenance of normal flow reserve [99].

●The development of collateral vessels significantly alters coronary vascular reactivity. (See "Coronary collateral circulation".) When a coronary artery is gradually occluded, flow to the subtended myocardium persists via perfusion through collateral vessels. When these vessels fully develop, they are capable of providing normal resting perfusion to the region previously served by the occluded vessel, although at a lower perfusion pressure.

Since collateral vessels represent "new" vessels, there has been interest in factors that might modulate their reactivity. For the most part, these vessels have normal endothelium-dependent vascular relaxation and normal responses to most agents studied in vivo. Endothelial release of NO may be responsible for the vasodilation of coronary collaterals [100]. The factors responsible for the impaired microvascular endothelium-dependent relaxation in the collateral-dependent region have not been determined. This abnormality may be related to increased local levels of NO resulting from enhanced expression of inducible NOS, as occurs during ischemia [101]; such a change could lead to reduced activity of endothelial NO synthase [102]. Other possible contributing factors to impaired collateral flow include changes in shear stress or pulsatile flow in the collateral-dependent microvasculature [103] and increased expression of heparan sulfate matrix proteins, such as syndecan-4, that can affect vascular reactivity [104,105].

●Collateral growth and coronary microvessel function can be altered by the direct perivascular application or infusion of angiogenic growth factors such as fibroblast growth factors or vascular endothelial growth factor. These therapeutic interventions improve myocardial function and perfusion in chronic ischemic models and can normalize endothelium-dependent relaxation in the collateral-dependent vasculature [106-108]. However, there is little evidence that growth factor therapy or gene therapy improves myocardial perfusion in any clinical significant manner in clinical trials [31,32]. (See "Therapeutic angiogenesis for management of refractory angina".)

●Stress-induced cardiomyopathy (Takotsubo cardiomyopathy) is thought to result from microvessel myocardial constriction with resulting ischemia. There are noted reductions in endothelial function to mental stress in patients who have experienced stress-induced cardiomyopathy [109]; however, there are no prospective data indicating peripheral endothelial dysfunction can predict those who will develop this entity.

●Hypothyroidism has been shown to be associated with coronary endothelial function [110]. Historical observational data on nearly 1400 patients with nonobstructive coronary artery disease demonstrate that women with hypothyroidism have significantly worse coronary flow responses to acetylcholine compared with those who are normal or euthyroid. While mechanistic reasoning was not offered, these hypothesis-generating data should be further explored.

●Patients with heart failure who undergo left ventricular assist device (LVAD) implantation have been shown to have changes in endothelial function, which are associated with an increased event rate [111]. Interestingly, the lack of pulsatile flow through the arteries likely has an impact on the endothelial function and assessment thereof. Nevertheless, this small study does provide over six months of follow-up, and provides some mechanistic ideas regarding endothelial dysfunction in patients who undergo LVAD implantation and some of the catastrophic consequences of vascular events in this exceedingly tenuous patient population. Interestingly, a preliminary study in cows comparing assist device pulsatile and non-pulsatile perfusion did not demonstrate a significant difference in vascular permeability between groups [112].

●Osteoporosis has also been linked with poor endothelial function, with endothelial dysfunction being a predictive tool indicating which women might develop clinical and symptomatic osteoporosis [113].

SUMMARY

●The arterial coronary microcirculation, which consists of pre-arterioles and arterioles, plays a major role in the delivery of blood to the myocardium. The endothelium, which lines these vessels, maintains blood vessel (vascular) tone, regulates hemostasis, acts as barrier to potentially toxic materials, and regulates inflammation. (See 'Normal endothelial function' above.)

●Endothelial-mediated vasodilation is abnormal in a variety of pathologic conditions, including atherosclerosis, hypercholesterolemia, diabetes, hypertension, cigarette smoking, ischemia reperfusion, and aging. (See 'Endothelial dysfunction' above.)

●Patients with microvascular angina or with cardiac hypertrophy due to a variety of causes have chest pain suggestive of myocardial ischemia. Ischemia due to microvascular disease is an important risk factor for cardiac events. (See 'Myocardial hypertrophy' above and "Microvascular angina: Angina pectoris with normal coronary arteries", section on 'History'.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges the late Emile R. Mohler, III, MD, who contributed to an earlier version of this topic review.