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Coronary endothelial dysfunction: Clinical aspects

Authors: R Jay Widmer, MD, PhD, Amir Lerman, MD, Frank W Sellke, MD, Filippo Crea, MD
Section Editor: Juan Carlos Kaski, DSc, MD, DM (Hons), FRCP, FESC, FACC, FAHA
Deputy Editor: Gordon M Saperia, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature rev iew current through: Apr 2020. | This topic last updated: Sep 10, 2019.
INTRODUCTION
The coronary arterial circulation, which consists of conductance and resistance vessels, plays a
key role in matching the delivery of blood to the metabolic demands of the myocardium. The
endothelium is the layer of cells that lines these blood vessels. This layer helps to maintain
blood vessel (vascular) tone, regulate hemostasis, acts as barrier to potentially toxic materials,
and regulates inflammation. Endothelial dysfunction is the inability of the endothelium to
optimally perform one or more of these. Dysfunction of the coronary arterial endothelium is a
principal determinant of coronary microvascular dysfunction and subsequent myocardial
ischemia. Coronary endothelial dysfunction is the inability of the endothelium to optimally
perform one or more of these.
Dysfunction of the coronary arterial endothelium is a principal determinant of microvascular

dysfunction. Coronary endothelial dysfunction is the inability of the endothelium to optimally
perform one or more of these.
This topic will focus on clinical aspects of endothelial dysfunction, which is present in a few
cardiac diseases, including large vessel (epicardial) coronary artery disease, small vessel
disease (microvascular angina), and transplant vasculopathy. The discussion of the basic
aspects of normal and abnormal endothelial function is found elsewhere. (See "Coronary artery
endothelial dysfunction: Basic concepts".)
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DEFINITION OF TERMS
The following terms are defined as follows:
● Coronary microvascular dysfunction – Microvascular dysfunction refers to the impairment

of the delivery of blood to the myocardium due to one or more pathologic conditions
occurring at the level of the pre-arterioles, arterioles, or capillaries. Patients may or may not
be symptomatic. There are four broad categories [1]:
• Endothelial dysfunction, which can be seen at the epicardial or microvascular level.
• Intraluminal obstruction (eg, embolization of clot as seen after percutaneous coronary

intervention in acute ST-elevation myocardial infarction [STEMI]).
• External compression (eg, left ventricular hypertrophy, elevated left ventricular end
diastolic pressure, and myocardial bridging).
• Smooth muscle cell dysfunction as seen in patients with hypertrophic cardiomyopathy

or vasospastic angina. (See "Hypertrophic cardiomyopathy: Clinical manifestations,
diagnosis, and evaluation", section on 'Chest pain' and "Vasospastic angina".)
● Endothelial dysfunction – Among patients with asymptomatic ischemic heart disease and
risk factors, endothelial dysfunction is a common condition. Endothelial dysfunction is a
disease of the endothelial monolayer that leads to an inability of the small arterioles to
vasodilate when needed to increase blood flow to the myocardium. This is a crucial step in
matching metabolic demands, as the only means to increase blood flow to the myocardium
is by increasing coronary blood flow. (See "Coronary artery endothelial dysfunction: Basic
concepts".)
Endothelial dysfunction appears to result from reduced levels of nitric oxide bioavailability
[2], and is largely related to baseline risk factors, thus making it an attractive alternative
metric to monitor for cardiovascular prevention [3].
● Microvascular angina – Microvascular angina, previously known as cardiac syndrome X,

refers to patients who have angina and evidence of myocardial ischemia on testing but do
not have large vessel obstructive disease or vasospastic angina. This term (syndrome X)
has been replaced by "nonobstructive coronary artery disease" and "ischemia and no
obstructive coronary artery disease." The pathophysiology of microvascular angina includes
endothelial and smooth muscle cell dysfunction, arteriolar remodeling, and sympathetic
activation [1]. This issue is discussed in detail elsewhere. (See "Microvascular angina:
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Angina pectoris with normal coronary arteries", section on 'Pathogenesis'.)
● Microvascular obstruction in STEMI – Coronary microvascular obstruction occurs in up to

half of patients submitted to apparently successful primary percutaneous coronary
intervention (PCI) and is associated with a much worse outcome. It is caused by a variable
combination of pre-existing microvascular dysfunction, ischemic damage, reperfusion
damage, and distal thromboembolization. The diagnosis can be made invasively at the time
of PCI or noninvasively after the procedure by assessing ST segment elevation resolution
or, more accurately, by cardiac magnetic resonance [4].
PREVALENCE
It is estimated that three to four million individuals with signs and symptoms of myocardial
ischemia are without obstructive coronary artery disease [5] (see "Myocardial infarction with no
obstructive coronary atherosclerosis", section on 'Prevalence'). The prevalence, specifically, of
coronary endothelial dysfunction is not fully known; however, observations demonstrate that 40
to 60 percent of community-dwelling participants who undergo coronary angiography are found
to have nonobstructive coronary artery disease, and of these nearly one-half have microvascular
disease (approximately 25 percent of the patients who undergo angiography in the United States
yearly) [6]. Similarly, the WISE study found that roughly 50 percent of those undergoing clinically
indicated coronary angiography, but without obstructive disease, were found to have coronary
endothelial dysfunction [7]. The prevalence of nonobstructive coronary artery disease could be
three to four million people in the United States [8]. Peripheral endothelial dysfunction,
depending on the defined cutoff value defining such, can be found in up to 80 percent in those
presenting with acute coronary syndrome and undergoing percutaneous coronary intervention
for such.
RISK FACTORS
Coronary endothelial dysfunction is seen in patients with a family history of early cardiovascular
disease and no other risk factors [9]; hypertriglyceridemia [10]; elevated low density lipoprotein
and reduced high density lipoprotein cholesterol [11]; nicotine use [12]; obese patients with
minimal coronary artery disease [13]; patients with insulin-resistant diabetes [14,15]; patients
with first degree relatives with type 2 diabetes mellitus [16]; microvascular angina; elderly
patients [17,18] irrespective of other comorbidities [19]; in women a history of polycystic ovaries
[20,21], toxemia of pregnancy [22], obstructive sleep apnea, atrial fibrillation, or autoimmune or
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inflammatory diseases such as Raynaud's disease [23]; and in patients subjected to prolonged
mental stress [24,25] (thought to be mediated through endothelin [26]).
Laboratory abnormalities that can be abnormal with endothelial dysfunction include thyroid
function [27], uric acid levels [18], markers of inflammation such as lipoprotein-associated
phospholipase A2 [19] and c-reactive protein [10], white blood cell count [20], and N-terminal
brain natriuretic peptide [21].
The progression of endothelial dysfunction is related to the intensity and duration of proven risk
factors, and to the total risk of the individual subjects [28,29]. The pathogenesis of endothelial
dysfunction is discussed separately. (See "Coronary artery endothelial dysfunction: Basic
concepts", section on 'Endothelial dysfunction'.)
CLINICAL ASSOCIATIONS
The following are clinical situations in which endothelial dysfunction may play a prominent role:
● Epicardial coronary artery disease – In patients with atherosclerotic epicardial (large vessel)
coronary artery disease, endothelial dysfunction in the microvascular circulation is often
present if tested for. Endothelial dysfunction in the epicardial and microvascular coronary
vessels is thought to be the initiating step in atherosclerosis leading to obstructive coronary
disease. (See "Pathogenesis of atherosclerosis", section on 'Endothelial dysfunction'.)
● Microvascular angina – Microvascular angina refers to patients who have angina and
evidence of myocardial ischemia on testing but do not have large vessel obstructive
disease or vasospastic angina [1]. (See "Microvascular angina: Angina pectoris with normal
coronary arteries", section on 'Pathogenesis'.)
● Transplant vasculopathy – Endothelial dysfunction is associated with the development of

transplant vasculopathy. In a study of 73 patients who underwent heart transplantation, the
presence of endothelial dysfunction predicted the development of clinical end points,
including angiographic vasculopathy or cardiac death (graft failure or sudden death) [4,30].
● Peripheral endothelial dysfunction in patients following percutaneous coronary intervention

is a known predictor of restenosis [31]. Surgical revascularization is also associated with
endothelial dysfunction and can be assessed properly by reactive hyperemia or laser
Doppler [32]. Patients who recently underwent revascularization via either stent implantation
or surgical coronary bypass surgery have reduced endothelial function largely related to
poor nitric oxide bioavailability and poor glycemic control [33].
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● Endothelial dysfunction is seen in patients with cardiac amyloidosis [34], and can serve as
a prognostic indicator in children with familial cardiomyopathies [35].
● Myocardial bridging is closely associated with coronary endothelial dysfunction, which can
be detected by intravascular ultrasound and fractional flow reserve [36]. (See "Myocardial
bridging of the coronary arteries".)
EVALUATION OF ENDOTHELIAL FUNCTION
Endothelial function can be tested directly or indirectly. Direct invasive testing, which is
performed for diagnostic and therapeutic purposes, involves an evaluation of the endothelial-
dependent and endothelial-independent components of the coronary circulation [37]. The
CorMica trial randomly assigned 391 patients without obstructive coronary disease to invasive
assessment of coronary physiology versus usual care. Despite no difference in major adverse
cardiac events between the two groups, there were significant improvements in anginal scores
and quality of life in the invasive arm [38]. Noninvasive testing, although carrying not as strong of
a guideline recommendation, can reclassify cardiac outcome prediction in nearly 25 percent of
patients, and involves an evaluation of the coronary or peripheral arterial circulations [39-41]. The
following discussion is about indirect testing.
The quantification of endothelial health is divided into peripheral endothelial function (a systemic
measure of endothelial function) versus coronary endothelial function, which must be assessed
with invasive angiography and further physiologic testing. Testing involves pharmacological
and/or physiological stimulation of the endothelial release of nitric oxide (NO) and other
vasoactive substances. All the techniques have in common that they measure the response of
the vessels to endothelial-dependent stimuli, mainly reactive hyperemia (shear stress) or
vasoactive substances. Indeed, both macrovascular endothelial dysfunction, as measured by
flow-mediated dilation [42,43], and microvascular endothelial dysfunction [44,45] have been
found to be independent predictors of future cardiovascular events in large cohort studies in
healthy individuals over and above traditional risk factor assessment. Endothelial function
testing modalities have also been found to correlate with other novel cardiovascular testing
modalities such as coronary calcium scoring [46,47].
Invasive testing — Quantitative coronary angiography can be used to directly and invasively
examine the change in diameter in response to intracoronary infusions of endothelium-
dependent vasodilators such as acetylcholine, and these methods have been extensively
detailed [37]. The assessment of the coronary circulation can be divided into endothelial-
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dependent and endothelium-independent mechanisms [37], and the correct delineation of the
coronary vascular pathophysiology will not only aid in diagnosis but also treatment.
Endothelium-independent function is assessed with intracoronary adenosine infusions to
assess coronary flow reserve. Endothelial-dependent function of the coronary vasculature can
be assessed with intracoronary Doppler techniques to measure coronary blood flow in
response to acetylcholine. The normal response is coronary microvascular relaxation, resulting
in an increase of coronary blood flow. In contrast, patients with endothelial dysfunction exhibit
reduced dilation or even coronary microvascular constriction when exposed to intracoronary
acetylcholine associated with angina and ischemia, as typically observed in microvascular
angina.
These invasive assessments in the cardiac catheterization lab can be performed with very high
fidelity and safety [48,49]. Aside from the usual risks of invasive coronary angiography [50,51],
there have only been rare reports of coronary artery dissection and even rarer reports of
pathologic vasospasm [23,48,52]. With careful attention to safety, these rare complications can
be avoided or quickly reversed to avert serious patient harm.
A similar method, based on slightly different physical properties, to test coronary microcirculatory
function utilizes thermodilution and index of microcirculatory resistance. This technique is
similar to pharmacological- and pressure-based techniques, but instead uses intracoronary
temperature measurements to approximate flow [53]. This has been shown to be independent
of epicardial vascular function, reproducible, and has even been evaluated in ST elevation
myocardial infarction patients, providing important prognostic information regarding ventricular
function at three months [54].
Noninvasive testing
● Brachial artery ultrasound – Brachial artery ultrasound is a commonly used and widely
accepted measure of peripheral macrovascular endothelial function [55]. In this test,
inflating a blood pressure cuff at suprasystolic pressures for five minutes occludes the
upper arm proximal to the ultrasound measurement. Upon the release of the occlusion, an
increase in shear stress results in an endothelial-dependent, nitric oxide NO-driven, flow-
mediated dilation (FMD) of the brachial artery. Both diameter and blood velocity are
assessed before and after occlusion with results being reported as a percent change from
baseline. These measurements should be made at the end of diastole. The reported
vascular response to increased flow has been shown to be a surrogate for measuring
coronary endothelial function [56]. Aside from reactive hyperemia, stimuli for measuring
endothelial reactivity can include exercise, mental stress, or sympathetic nervous activation
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through the cold pressor test. As with all vascular reactivity tests, brachial artery ultrasound
measurements can be potentially confounded by conditions such as the amount, type, and
time after food consumption; medications; exercise; ambient temperature; menstrual cycle
stage; type of machinery and equipment; and variations in the protocol between subjects or
experiments (supine, dark room, thermo-neutral settings). Furthermore, occlusions made
too proximal can exacerbate the FMD response, creating a potential for false negative
results [57].
Observational data from the MESA study demonstrate that peripheral endothelial
dysfunction, as measured by FMD of the brachial artery, is associated with a higher rate of
incident adverse cardiovascular disease (CVD) events during a five-year follow-up period
[42]. FMD has been linked with increased CVD risk in those patients with known CVD risk
factors [58]. Furthermore, data from a meta-analysis provide evidence that FMD could be
used as an independent prognostic indicator of future CVD events and offers incremental
risk factor stratification in addition to traditional risk factors [59]. While some have argued
that there are only minimal data that FMD adds to risk stratification [60], a more
overwhelming body of evidence argues for the use of FMD measurements to provide
important additional CVD risk factor stratification or response to therapies [61,62].
● Impedance plethysmography – Impedance plethysmography is a method of assessing

endothelial function via strain-gauge venous impedance plethysmography that examines
the changes in forearm blood flow in response to direct intravascular administration of
vascular agonists [63]. Due to the invasive nature of this test, it is primarily used in research
settings and rarely utilized clinically.
● Traditional imaging-based modalities have been clinically utilized to assess microvascular

function. Myocardial positron emission tomography imaging has been tested using a cold
pressor test in patients with diabetes [64] and verified in a larger cohort of patients [65].
Cardiac magnetic resonance perfusion has been correlated with endothelial dysfunction in
patients without overt coronary artery disease [66], as well as those with typical angina but
relatively normal angiograms [67]. However, cost and limited availability of the resources
necessary for such prevent widespread adoption of these modalities.
● Low-flow-mediated constriction – Low-flow-mediated constriction (L-FMC) quantitates the

reaction in forearm conduit artery diameter occurring in response to a reduction in blood
flow, and resultantly, shear stress [68]. This method is similar to FMD measurements of the
brachial artery, and is often used in concert to gain additional information regarding arterial
reactivity [69], as L-FMC is a better measure of resting, basal arterial tone, and thought to
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only be partially NO-mediated [70]. Exact mechanisms of this reaction are still being
elucidated, and it is becoming increasingly important as the rate of radial interventional
approaches increases [71]. Nevertheless, the combination of these two measurements has
been shown to be closely correlated to the severity of CAD [72] and even provides additive
risk factor stratification to traditional risk factors [73,74].
● Peripheral arterial tonometry – Peripheral arterial tonometry (PAT) is a technique

commonly used to assess microvascular endothelial function via changes in finger pulse
wave amplitude in response to reactive hyperemia [75-77]. Testing for endothelial function
involves the inflation of a blood pressure cuff to supra-systolic pressures. During this
process, there are two PAT probes connected to the fingers in both arms. The probe that is
connected to the arm where the blood pressure cuff is inflated for five minutes is used to
assess the reactive hyperemic response, a surrogate and a marker for endothelial function.
These methodologies are noninvasive, are designed to eliminate environmental
interference, and are independent of the subject’s knowledge and conscious control of
signals generated [75,76]. The RH-PAT index is defined as the ratio of the average pulsatile
blood volume response, at timed intervals after deflation, to the baseline pulsatile blood
volume response; ie, the average amplitude of the RH-PAT signal over 60 seconds at one,
two, three, and four minutes after cuff deflation divided by the average amplitude of the RH-
PAT signal over 3.5 minutes prior to cuff inflation (during baseline equilibration).
Work has shown a correlation between endothelial function, as measured through PAT, and
the accepted standard of invasive assessment of endothelial dysfunction of the coronary
arteries [75]. Moreover, it has been demonstrated that there is a characteristic PAT signal
response to mental stress, with diminution of the signal amplitude during stress [76].
However, this test is only thought to be partially dependent on NO [78], while other factors
such as the sympathetic nervous system are thought to affect the microvascular response
to certain stimuli [79]. There are discordant reports as to the agreement between FMD and
PAT, as some reports highlight a discordance with PAT and FMD measurements [80,81],
while others find an association between the two tests [79]. There still appears to be a
strong contribution by NO to both physiologic responses, leaving mechanistic work to
resolve these discrepancies yet to be finished [78].
In addition to the endothelial function test being a predictive parameter for coronary disease
onset, it can also predict the effectiveness of a treatment given to patients with
cardiovascular disease. One study followed a group of hypertensive women without
significant heart disease and who followed a similar antihypertensive regimen. While all
women had similar reductions in blood pressure, the individuals whose endothelial
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function improved had half as many cardiovascular events compared to those women who
showed no improvement in endothelial function [82]. Similarly, a high-risk group of patients
with significant coronary diseases were treated with optimal medical therapy and given
standard medications prescribed for their disease. The patients underwent endothelial
function tests at baseline and six months with improvement seen in 50 percent of the
patients. Those with improved endothelial function had fewer cardiovascular events during
the follow-up period, whereas the group that did not have improved endothelial function had
an increased CVD event rate [83].
Additional observational data examining microvascular endothelial function with PAT

demonstrates people with relatively normal risk factors, but reduced endothelial function,
had a higher incidence of heart disease, hospitalization, and death after seven years of
follow-up, as compared to those without endothelial dysfunction [84]. Intuitively, those with a
high Framingham risk score and endothelial dysfunction were at the greatest risk, followed
by those with a normal Framingham score but with endothelial dysfunction, and then those
with a high Framingham score but with normal endothelial function [84]. Finally, for those
patients already with obstructive CAD, PAT can predict future adverse CVD outcomes [83].
This was demonstrated in a study of patients admitted to a chest pain unit to rule out acute
coronary syndrome [85]. One-year outcomes were significantly worse in those with poor
peripheral endothelial function.
PROGNOSIS
In patients without obstructive coronary artery disease but impaired coronary vasodilatory
capacity in the face of a vasodilator challenge, there is a marked increase in cardiovascular
disease events over the following two years [86]. This notion was furthered in a similar study
following patients for nearly eight years, showing a 20 to 40 percent reduction in survival over the
subsequent 7.7 years, depending on their coronary vascular reactivity to any certain number of
stimuli [87,88].
A study in patients with coronary artery disease showed that persistent impairment of
endothelial vasomotor function despite optimized therapy to reduce risk factors has an adverse
impact on clinical outcome [83]. This was reaffirmed in the 10-year data from the Women's
Ischemia Syndrome Evaluation (WISE) study, demonstrating a 12 percent increase in mortality,
11 percent increase in major adverse cardiac events, and 5 percent increase in anginal
hospitalizations in women with abnormal vascular responses to intracoronary acetylcholine [89].
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PREVENTION AND TREATMENT
Accepted interventions — In most cases, coronary artery endothelial dysfunction will be

documented in patients who have atherosclerotic cardiovascular disease. All such patients
should receive strategies proven to prevent cardiovascular events. This typically involves
managing the risk factors of hyperlipidemia, smoking, hypertension, diabetes, and inactivity [90].
(See 'Risk factors' above and "Overview of the prevention of cardiovascular disease events in
those with established disease (secondary prevention) or at high risk" and "Overview of primary
prevention of coronary heart disease and stroke".)
In addition to lowering the risk of cardiovascular events, there is some evidence that these
preventive strategies improve endothelial function. It is not known whether improvement in
endothelial function is the mechanism by which cardiovascular events are reduced. However,
tailoring the therapy based on the assessment of endothelial-dependent versus nonendothelial-
dependent vascular abnormalities might offer a more individualized and direct treatment plan
[37].
● Mediterranean diet – A low fat diet is usually the first step in treating hypercholesterolemia.
A Mediterranean diet reduces serum low density lipoprotein cholesterol and lowers the risk
of cardiovascular events in patients with a myocardial infarction. These benefits are
associated with an improvement in endothelial function [91,92]. These findings have been
confirmed in a larger randomized controlled trial showing improved endothelial function in
participants who adhered to the Mediterranean diet and exercise [93].
● Other diets – There has been a plethora of trial data showing that substances such as dark
chocolate [94], nuts [95], olive oil [96], plant-based foods [97], green tea [98], and alcohol
consumption [99] have all shown to be beneficial to improving peripheral endothelial
function.
● Aerobic exercise – Regular aerobic exercise is associated with a reduced risk of

cardiovascular events, especially in middle-aged and older adults; it also can modify many
of the traditional risk factors for coronary disease, including endothelial dysfunction.
Although there has been some debate over the initial endothelial response to exercise, the
overall data have been positive toward this lifestyle behavior and endothelial function. As an
example, one study of 68 healthy men, aged 22 to 35 and 50 to 76, who were either
sedentary or endurance-exercise trained, found that endurance-trained men did not have an
age-associated decline of endothelium-dependent vasodilation; in addition, regular aerobic
exercise restored the loss of endothelium-dependent vasodilation in previously sedentary
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middle-aged and older healthy men [100].
● Weight loss, particularly in obese individuals, has been shown to be beneficial to

endothelial function [101-105].
● Blockade of the renin-angiotensin system – ACE inhibitors may improve endothelial

dysfunction, but this benefit may not be seen in all drugs in this class. In one report,
quinapril, which has high tissue specificity for ACE, improved endothelial dysfunction in
patients with coronary disease [106]. The efficacy of quinapril was also evaluated in the
TREND trial of men with coronary disease but without heart failure, hypertension, or lipid
abnormalities improving endothelial dysfunction at six months [107]. These benefits were
thought to be secondary to an improved NO-bioavailability through reduced bradykinin
breakdown as well as improved reactive oxygen species (ROS) scavenging. As stated
earlier, ACE inhibitors do improve coronary endothelial resistance through NO-dependent
mechanisms [108]. Most studies have shown an improvement in endothelial dysfunction
following the administration of an angiotensin II receptor blocker (ARB) in patients with
atherosclerosis or diabetes [109-111]. Furthermore, ARBs have been shown to improve
coronary endothelial dysfunction [112], and there is increasing evidence that direct renin
inhibition improves endothelial function in at-risk patients [113].
● Lipid lowering medications – Some, but not all, studies have found that endothelial
dysfunction can be ameliorated or even eliminated with the use of a statin, and theoretically,
these medications will already be a mainstay in reducing CVD risk in most patients due to
their lipid-lowering and anti-inflammatory mechanisms [114]. The combination of
angiotensin converting enzyme (ACE) inhibition and statin therapy has also been shown to
improve endothelial-dependent relaxation of the coronary vasculature through NO-
dependent mechanisms [115].
● Fibrate therapy also improves fasting and post-prandial endothelial function in patients with
type 2 diabetes, as does omega-3 fatty acid supplementation [116]. The mechanism for this
may be an increase in high density lipoproteins (HDL) and an attenuation of post-prandial
lipemia and the associated oxidative stress [117]. HDL lowering or niacin therapy appears
to have no beneficial effect on endothelial health [118].
● Nitrates – Long-acting oral nitrates have little benefit unless there is epicardial, smooth-
muscle-dependent spasm present on cardiac catheterization. These agents have little
beneficial effect on the coronary microcirculation. A small study with nitrates, amlodipine,
and atenolol demonstrated no benefit in terms of symptoms with oral isosorbide
mononitrate [119]. Similarly, there is no improvement in exercise performance or coronary
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blood flow found after short-term administration of isosorbide dinitrate [120].
Investigational interventions — We believe that the benefit from the following drugs or
categories of drugs is less certain than those discussed above:
● Aspirin – Studies suggest that aspirin improves endothelial dysfunction in patients with
known atherosclerosis, likely through inhibition of cyclooxygenase-dependent
vasoconstrictors such as prostacyclin [121].
● L-arginine – The intravenous or intracoronary administration of L-arginine, the physiologic

precursor for NO, can acutely improve endothelium-dependent vasodilation in patients with
hypercholesterolemia or coronary atherosclerosis [122]. The stereoisomer D-arginine is
ineffective [123]. Additionally, a small randomized trial consisting of 30 patients appeared to
show no benefit on multiple measures of endothelial health such as NO bioavailability, cell
adhesion molecules, or brachial artery flow-mediated dilation with 9 g daily of L-arginine
supplementation [124]. These patients, however, were on optimal medical therapy for
cardiovascular disease (CVD) prevention. In contrast, a similarly sized trial showed that a
similar dose of L-arginine after six months had a significant improvement in patients
coronary endothelial function and resultantly improved anginal symptoms [125]. Additional
work has shown short-term L-arginine supplementation to be of clinical benefit in a
randomized study of 36 patients with stable class II and III angina. Compared to placebo,
two weeks of therapy with a medical food bar enriched with L-arginine improved flow-
mediated vasodilation, treadmill exercise time, and quality-of-life scores [126]. Data
regarding L-Arginine and endothelial function appear to show that when given at doses of 2
g three times daily for one month, there is reduced blood pressure and angina symptoms in
concert with improved endothelial function and quality of life in hypertensive patients without
obstructive coronary artery disease (CAD) [127]. Thus, although a narrow clinical niche, and
a less-than-convenient dosing regimen, L-arginine supplementation can be beneficial in
patients with non-obstructive CAD and debilitating angina by improving CVD risk factor
parameters and symptoms. The longer-term effects of oral L-arginine have also been
evaluated. Among patients with heart failure, oral L-arginine improved endothelial function,
arterial compliance, and functional status [128]. The potential benefits associated with
L-arginine therapies are presumably mediated by increased NO activity, particularly as it
applies to improving the bioavailability of NO in areas of reduced endothelial shear stress
[129]. In addition to improved endothelial function, L-arginine supplementation has also
been implicated in reducing plasma endothelin levels [125], reduced symptomatic burden
via apoptosis of proliferating vascular smooth muscle cells leading to atherosclerotic
plaque regression and other changes that have been described include lower plasma
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endothelin concentrations [130], and finally arresting atherosclerotic plaque development in

an animal model [131].
● Nifedipine – Nifedipine may have antioxidant effects and effects on endothelial NO synthase
expression and activity. In a study of 454 patients undergoing percutaneous coronary
intervention, endothelium-dependent vasodilatation was assessed with intracoronary
acetylcholine after six months of therapy with nifedipine, showing an improvement in
endothelial function but no plaque regression [132].
● Dry sauna – Dry sauna has been shown to improve endothelial function in patients with
cardiovascular risk factors [133].
● Nebivolol – There appears to be some increase in NO bioavailability with this beta blocker
[134].
● N-acetylcysteine – N-acetylcysteine, a thiol, is a pharmacologic precursor of L-cysteine. It

augments the bioavailability of NO and can improve scavenging of ROS. One study of 16
patients with atherosclerosis found that N-acetylcysteine supplements improved coronary
and peripheral endothelium-dependent vasodilation; the response to nitroglycerin was not
affected, while the response to nitroprusside was potentiated only in the coronary arteries
[135].
● Estrogen – Reports of estrogen therapy improving endothelial function in post-menopausal

women [136] appear to have biologic plausibility as endothelial cells have estrogen
receptors [137], as well as through improved NO bioavailability [138] or through a reduction
in coronary endothelin-1 levels [139]. Similarly, Tamoxifen and raloxifene are selective
estrogen receptor modulators, having estrogen-like activity, and are also found to have
positive effects on flow-mediated dilation [140].
● Endothelin receptor antagonists – Elevated levels of endothelin are thought to play a role in
endothelial dysfunction seen in heart failure and hypertension and the transient dysfunction
induced by mental stress. A randomized, double-blind, placebo-controlled trial in patients at
high risk for CVD showed a significant improvement in coronary microvascular endothelial
function with atrasentan, one such agent [141].
● Insulin sensitizers – As diabetes and endothelial dysfunction are typically concomitant pre-
atherosclerotic conditions, there is a body of literature detailing conflicting reports of the
benefit of insulin sensitizers on endothelial function. Metformin is generally thought to
improve peripheral endothelial function [63] and those with metabolic syndrome [142]. Both
metformin and rosiglitazone have been found to improve endothelial function in women
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afflicted with polycystic ovary syndrome; however, confounding effects of reductions in

testosterone and homeostatic model assessment results, as well as normalization of
menstrual cycles have left this debate unresolved [20]. Rosiglitazone has been found to
attenuate impaired vasodilation in diabetic patients subjected to fatty acid meal challenges
[143]. Conversely, these results were not validated as it was pioglitazone, not rosiglitazone,
that reduced pharmacologically-induced vasoconstriction in internal mammary artery grafts
from diabetic patients [144]. Ultimately, these agents likely improve endothelial function in
patients with diabetes; however, the multiple confounders present in these studies leave
room for further work and research regarding their effect on endothelial function and CVD
outcomes in larger randomized controlled trails (RCTs). (See "Thiazolidinediones in the
treatment of type 2 diabetes mellitus" and "Thiazolidinediones in the treatment of type 2
diabetes mellitus", section on 'Mechanism of action'.)
● Ranolazine – This sodium channel inhibitor used for patients with refractory angina has
been shown to alleviate symptoms of microvascular angina pain; however, there was no
significant change seen in microvascular function [145]. Furthermore, there has been
improvement in endothelial function in smaller RCTs examining diabetic patients [146], as
well as patients with chronic stable angina [147]. (See "New therapies for angina pectoris",
section on 'Ranolazine'.)
● Phosphodiesterase inhibitors such as sildenafil have also been shown to be beneficial in

improving peripheral endothelial function in a small cohort of diabetic men, as well as
enhance penile blood flow and erectile function [148-150]. Larger-scale data, however, do
not exist, and these agents have not been found to be of benefit in patients with heart failure
and preserved endothelial function [149]. (See "Treatment of male sexual dysfunction",
section on 'Phosphodiesterase-5 inhibitors'.)
● There are also emerging data that Rho-kinase levels and activity correlate with coronary
endothelial dysfunction [151].
SUMMARY AND RECOMMENDATIONS
● Dysfunction of the coronary arterial endothelium is a principal determinant of microvascular

dysfunction. The endothelium is the layer of cells that lines these blood vessels. This layer
helps to maintain blood vessel (vascular) tone, regulates hemostasis, acts as a barrier to
potentially toxic materials, and regulates inflammation. Endothelial dysfunction is the
inability of the endothelium to optimally perform one or more of these. (See 'Definition of
14 of 29 5/6/2020, 6:37 PM
terms' above.)
● Multiple risk factors for endothelial dysfunction have been identified. Many of these are the
traditional risk factors for cardiovascular disease. (See 'Risk factors' above.)
● Endothelial dysfunction plays an important role in the pathogenesis and clinical course of
atherosclerotic coronary artery disease, cardiac transplant vasculopathy, microvascular
obstruction in ST-elevation myocardial infarction (STEMI), and microvascular angina. (See
'Clinical associations' above.)
● Endothelial function testing, using direct or indirect methods, is not routinely used in clinical
practice. (See 'Evaluation of endothelial function' above.)
● In most cases, coronary artery endothelial dysfunction will be documented in patients who
have atherosclerotic cardiovascular disease. All such patients should receive strategies
proven to prevent cardiovascular events. This typically involves managing the risk factors of
hyperlipidemia, smoking, hypertension, diabetes, and inactivity. Specific interventions are
needed in microvascular angina to improve symptoms and in microvascular obstruction in
STEMI to improve the outcome. (See 'Prevention and treatment' above.)
ACKNOWLEDGMENT
The editorial staff at UpToDate would like to acknowledge the late Emile R. Mohler, III, MD, who
contributed to an earlier version of this topic review.
Use of UpToDate is subject to the Subscription and License Agreement.
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Topic 1532 Version 24.0
Contributor Disclosures
R Jay Widm er, MD, PhD Nothing to disclose Am ir Lerm an, MD Consultant/Advisory Boards: Itamar
Medical [Endothelial function (EndoPAT)]; Phillis/Volcano. Frank W Sellke, MD Consultant/Advisory Boards:
Allergen [Atrial fibrillation]; Octapharma [bleeding prevention]; Stryker [Eternal closure]. Filippo Crea,
MD Nothing to disclose Juan Carlos Kaski, DSc, MD, DM (Hons), FRCP, FESC, FACC, FAHA Speaker’s
Bureau: Menarini [Angina pectoris (Ranolazine)]; Servier [Angina pectoris (Ivabradine)]; TEVA
Pharmaceuticals [Angina pectoris (generic antianginals)]. Consultant/Advisory Boards: Sanofi UK [Ischemic
heart disease]; Bayer [Anticoagulation (Xarelto)]; Servier [Angina (Ivabradine)]. Gordon M Saperia,
MD Nothing to disclose
Contributor disclosures are review ed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.
Conflict of interest policy
29 of 29 5/6/2020, 6:37 PM

Coronary Endothelial Dysfunction - Clinical Aspects - UpToDate

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Coronary endothelial dysfunction: Clinical aspects

Dysfunction of the coronary arterial endothelium is a principal determinant of microvascular

The following terms are defined as follows:

● Coronary microvascular dysfunction – Microvascular dysfunction refers to the impairment

• Endothelial dysfunction, which can be seen at the epicardial or microvascular level.

• Intraluminal obstruction (eg, embolization of clot as seen after percutaneous coronary

• Smooth muscle cell dysfunction as seen in patients with hypertrophic cardiomyopathy

● Microvascular angina – Microvascular angina, previously known as cardiac syndrome X,

Angina pectoris with normal coronary arteries", section on 'Pathogenesis'.)

● Microvascular obstruction in STEMI – Coronary microvascular obstruction occurs in up to

● Transplant vasculopathy – Endothelial dysfunction is associated with the development of

● Peripheral endothelial dysfunction in patients following percutaneous coronary intervention

EVALUATION OF ENDOTHELIAL FUNCTION

● Impedance plethysmography – Impedance plethysmography is a method of assessing

● Traditional imaging-based modalities have been clinically utilized to assess microvascular

● Low-flow-mediated constriction – Low-flow-mediated constriction (L-FMC) quantitates the

● Peripheral arterial tonometry – Peripheral arterial tonometry (PAT) is a technique

Additional observational data examining microvascular endothelial function with PAT

PREVENTION AND TREATMENT

Accepted interventions — In most cases, coronary artery endothelial dysfunction will be

● Aerobic exercise – Regular aerobic exercise is associated with a reduced risk of

middle-aged and older healthy men [100].

● Weight loss, particularly in obese individuals, has been shown to be beneficial to

● Blockade of the renin-angiotensin system – ACE inhibitors may improve endothelial

blood flow found after short-term administration of isosorbide dinitrate [120].

● L-arginine – The intravenous or intracoronary administration of L-arginine, the physiologic

endothelin concentrations [130], and finally arresting atherosclerotic plaque development in

● N-acetylcysteine – N-acetylcysteine, a thiol, is a pharmacologic precursor of L-cysteine. It

● Estrogen – Reports of estrogen therapy improving endothelial function in post-menopausal

afflicted with polycystic ovary syndrome; however, confounding effects of reductions in

● Phosphodiesterase inhibitors such as sildenafil have also been shown to be beneficial in

SUMMARY AND RECOMMENDATIONS

● Dysfunction of the coronary arterial endothelium is a principal determinant of microvascular

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