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Official reprint from UpToDate®

www.uptodate.com © 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Coronary artery endothelial dysfunction: Basic concepts

Authors: Frank W Sellke, MD, Amir Lerman, MD, R Jay Widmer, MD, PhD, Filippo Crea, MD
Section Editor: Juan Carlos Kaski, DSc, MD, DM (Hons), FRCP, FESC, FACC, FAHA
Deputy Editor: Nisha Parikh, MD, MPH

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Feb 2023. | This topic last updated: Aug 15, 2022.

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].

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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
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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

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[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

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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

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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
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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".)

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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".)
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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].
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● 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

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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

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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

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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.)

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● 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.

Use of UpToDate is subject to the Terms of Use.

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Topic 1538 Version 25.0

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GRAPHICS

Small vessel disease in hypertrophic

cardiomyopathy

Patients with hypertrophic cardiomyopathy often have small vessel

disease which may be associated with symptoms of ischemia. The
small intramural vessels often demonstrate apparent lumenal
narrowing, caused by hypertrophy of the tunica media.

Courtesy of Professor Michael Davies, St. George's Hospital, London.

Graphic 73467 Version 1.0

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Contributor Disclosures
Frank W Sellke, MD Equity Ownership/Stock Options: MX Therapeutics[Extracellular matrix-based
myocardial regeneration]. Grant/Research/Clinical Trial Support: NIH[Anticoagulation for postoperative
atrial fibrillation, hydrid coronary revascularization, external support for coronary artery bypass grafts,
cardiovascular surgery training, coronary microcirculation after cardioplegia and cardiopulmonary bypass,
changes induced in coronary collateral development in response to diabetic medication].
Consultant/Advisory Boards: Allergen [Atrial fibrillation];NIH [Cardiothoracic surgical
network];Octapharma [Bleeding prevention];Stryker[Sternal closure devices post cardiac surgery]. Other
Financial Interest: Cytosorbent[Steering committee – Bleeding prevention trials]. All of the relevant
financial relationships listed have been mitigated. Amir Lerman, MD Consultant/Advisory Boards: Itamar
Medical [Endothelial function]; Phillis/Volcano [Interventional cardiology]. All of the relevant financial
relationships listed have been mitigated. R Jay Widmer, MD, PhD Consultant/Advisory Boards: Abbott
Vascular [Microvascular disease];Philips/Volcano [Innovation in interventional cardiology]. All of the
relevant financial relationships listed have been mitigated. Filippo Crea, MD Speaker's Bureau: Abbott
[Ischemic heart disease]; Amgen [Ischemic heart disease]; AstraZeneca [Ischemic heart disease]; Chiesi
[Ischemic heart disease]; Daiichy Sankyo [Ischemic heart disease]; Menarini [Ischemic heart disease]. All of
the relevant financial relationships listed have been mitigated. Juan Carlos Kaski, DSc, MD, DM (Hons),
FRCP, FESC, FACC, FAHA Consultant/Advisory Boards: Glycardial Diagnostic [Biomarkers]. Speaker's
Bureau: Menarini [Angina pectoris]; Servier [Angina pectoris]. All of the relevant financial relationships
listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible
companies to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
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