Introduction
The endothelium, by area alone, is one of the largest organs in the body comprised
of up to trillion cells, weighing over 1 kg, and covering nearly 3 m2 in a 70 kg male.
1,2
Moreover, it interacts with nearly every system in the body, and has been implicated
in end organ diseases of systems such as neurologic, renal, hepatic, vascular, dermatologic,
immunologic, and of course cardiac. The endothelium is a single vessel layer standing
as the ultimate layer between blood and vascular supply to other tissues, and serving
multiple purposes. The first and foremost is a hemostatic balance between thrombosis
and anticoagulation via a careful series of checks and balances discussed below. Additionally,
the endothelium regulates vascular tone, carefully balancing vasoconstriction and
vasodilation to provide adequate perfusion pressure to target organs. Other functions
include regulation of angiogenesis, wound healing, smooth muscle cell proliferation,
fibrosis, and inflammation. Factors that adversely affect the endothelium include
common cardiovascular risk factors such as tobacco use, obesity, age, hypertension,
hyperlipidemia, physical inactivity, and poor dietary habits. Alternatively, factors
that positively impact the function of the endothelium are, essentially, beneficial
lifestyle habits opposite to those mentioned above such as increased physical activity,
dietary habits which include anti-inflammatory and anti-oxidant foods, and some pharmaceutical
agents such as L-Arginine.
Presently there is no guideline directive – either pro or con – to routinely include
endothelial function testing in cardiovascular disease (CVD) risk assessment.
3–5
Endothelial physiology
Under basal conditions, the endothelium functions to maintain the vessel in a relatively
neutral state favoring dilatation over constriction. However, the endothelium has
the capacity to respond to various intrinsic physical stimuli, such as shear stress,
temperature, transmural pressure, and external stimuli such as temperature, mental
stress, neurohumoral responses, and medications among others. The endothelial-dependent
response to vasodilate is principally regulated in response to shear stress by a release
of nitric oxide (NO) synthesized from the amino acid L-arginine by endothelial nitric
oxide synthase (eNOS) which leads to the production of intracellular cyclic GMP.
6
In such a state when NO-mediated vasodilation is compromised, the vasodilatory response
is thought to be facilitated by cytochrome-derived factors, naturetic peptide, and
prostacyclin.
Dysfunctional endothelium is seen when there is an imbalance in NO production and
consumption, favoring consumption and reduced production. Such a pathologic state
creates favorable conditions 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.
Endothelial dysfunction is usually ubiquitous throughout the body as patients with
known atherosclerosis also have endothelial dysfunction in peripheral vascular beds
that may not be affected by frank atherosclerosis. Endothelial dysfunction is also
seen in patients with a family history of early CVD and no other risk factors,
7
hypertriglyceridemia,
8
elevated LDL and reduced HDL cholesterol,
9
nicotine use,
10
obese patients with minimal coronary artery disease (CAD),
11
patients with insulin resistant,
12,13
patients with first degree relatives with DM2,
14
cardiac syndrome X,
19
elderly patients
15,16
irrespective of other comorbidities,
17
and mental stress
18,19
which is thought to be mediated through endothelin.
20
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.
21,22
The impact of endothelial dysfunction typically manifests in frank atherosclerosis
requiring either percutaneous or surgical revascularization. Data from our group has
demonstrated that in a multi-center study, peripheral endothelial dysfunction is seen
in nearly 75% of patients following PCI [Widmer, RJ, et al. 2014. In Review]. Endothelial
dysfunction appears to result from reduced levels of NO bioavailability,
23
and largely related to baseline risk factors, thus making it an attractive alternative
metric to monitor for secondary prevention.
24
Furthermore, peripheral endothelial dysfunction in patients following PCI is a known
predictor of restenosis.
25
Surgical revascularization is also associated with endothelial dysfunction and can
be assessed properly by reactive hyperemia or laser Doppler.
26
Patients who recently underwent CABG have reduced endothelial function largely related
to poor NO bioavailability and poor glycemic control.
27
Other cardiovascular entities can also cause reduced endothelial function as microvascular
disease is seen in patients with cardiac amyloidosis.
28
Moreover, endothelial dysfunction can serve as a prognostic indicator in children
with familial cardiomyopathies.
29
Finally, myocardial bridging is closely associated with coronary endothelial dysfunction
which can be detected by fractional flow reserve.
30
Abnormal endothelial function is attributed to high oxidative stress and inflammation
– both processes 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-arg uptake, increased oxidized
LDL cholesterol (Ox-LDL),
31
or reduced superoxide dismutase (SOD) an enzyme pivotal in the clearing of ROS.
32
Hyperlipidemia is known to increase ROS which will reduce the bioavailability of NO,
yet can be ameliorated with correction of hyperlipidemia.
33
Another potential contributor to impaired NO bioavailability is a decrease in tetrahydrobiopterin
(THB).
34,35
Furthermore, replenishing THB stores appears to improve endothelial dysfunction, even
in hyperlipidemic patients.
36
Another potential contributor to endothelial dysfunction is elevated asymmetric dimethylarginine
(ADMA) which is an endogenous competitive inhibitor of NO.
37,38
ADMA has been linked to reduced endothelial function as well as erectile dysfunction
in patients at moderate risk for CVD.
39
Furthermore, Ox LDL can increase ADMA further compounding known risk factors in patients
with CAD
4,30
even leading to increased events in those found to have elevated levels of ADMA.
40
Finally, 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,
41
or with other vascular injury or occlusion can contribute to an alteration in bioavailable
NO and varying endothelial function.
42
Localized infection, particularly in the oral cavity, leading to increased systemic
inflammation and impaired endothelial function has been postulated to be a contributor
to CVD. Chlamydia pneumonia infections
43
and immediate systemic inflammatory states which would mirror sepsis
44
have been shown to increase global inflammatory markers and endothelial dysfunction.
Furthermore, H. pylori positive patients have reduced endothelial function ameliorated
by treatment.
45
However, global treatments with antibiotics in high risk patients show no benefit
on CVD outcomes.
46,47
External beam radiation
48
and chemotherapy (particularly doxorubicin and daunorubicin
49
) have been shown to reduce endothelial function in patients independent of other
risk factors presumably through endothelial cell death and reduced NO availability.
Endothelial dysfunction is also 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).
50
•
The endothelium makes up one of the largest organ systems in the body by surface area.
•
Normal endothelial function allows for the symbiotic balance between vasoconstrictive
and vasodilatory (namely via NO) stimuli to allow adequate end organ blood perfusion.
•
A disruption in normal endothelial physiology through a number of various mechanisms
causes endothelial dysfunction – a progenitor toward atherosclerosis and a predictor
of future cardiovascular events.
Endothelial dysfunction prevalence
The true prevalence of peripheral endothelial function worldwide is not fully known
as we only have samples of larger studies which assess peripheral endothelial function
in different methods and without specific guidelines regarding cut-off values for
which a patient's endothelium is considered dysfunctional. Older observations demonstrate
that nearly 60% of community-dwelling participants who undergo coronary angiography
and are found to have non-obstructive CAD.
51
Similarly, the WISE study found that roughly 50% of those undergoing clinically indicated
coronary angiography, but without obstructive disease were found to have coronary
endothelial dysfunction.
52
Peripheral endothelial dysfunction, depending on the defined cutoff value defining
such, can be found in up to 75% in those presenting with acute coronary syndrome (ACS)
and undergoing percutaneous coronary intervention (PCI) for such [Widmer RJ, et al.
2014. In Review].
Other systemic disorders known to be characterized by endothelial dysfunction include
transplant vasculopathy,
50
autoinflammatory diseases,
53
gastrointestinal disorders such as celiac disease and irritable bowel syndromes,
54,55
hematologic/oncologic survivors,
56
cryptogenic stroke,
57
and neurocognitive disorders.
58
•
Currently there is a wide range of reported prevalence of both coronary and peripheral
endothelial dysfunction secondary to the heterogeneity of the studies examining the
phenomenon and arbitrary cutoff values.
•
Endothelial dysfunction is prevalent in CVD, however can also be found in patients
with neurologic, gastrointestinal, rheumatologic, hematologic, and renal diseases.
Types of endothelial function testing
The quantification of endothelial health has commonly been divided into peripheral
endothelial function – a systemic measure of endothelial function – versus coronary
endothelial function, which must be assessed with invasive angiography. Testing involves
pharmacological and/or physiological stimulation of the endothelial release of 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,
59,60
and microvascular endothelial dysfunction,
61,62
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.
63,64
Invasive endothelial function testing (coronary)
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.
65,66
In healthy coronary epicardial and microvascular vessels, acetylcholine generates
an NO-mediated vasodilatory response quantitatively assessed by angiography or intravascular
ultrasound (IVUS). In patients with endothelial dysfunction, this effect is blunted
or vasoconstriction is paradoxical. Endothelial function of the coronary microvasculature
can be assessed with intracoronary Doppler techniques to measure coronary blood flow
in response to pharmacological (usually intracoronary adenosine or nitroprusside)
or physiological stimuli.
Noninvasive tests for assessment of coronary endothelial function include Doppler
echocardiography, positron emission tomography, and phase-contrast magnetic resonance
imaging. 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 CVD events over the subsequent two years.
66
This notion was furthered in a similar experiment following patients for nearly 8
years showing a 20–40% reduction in survival over the subsequent 7.7 years depending
on their coronary vascular reactivity to any certain number of stimuli.
67
Invasive coronary vasoactive testing can also be important in patients with known
CAD as a sub-study of the COURAGE trial evaluated the fractional flow reserve (FFR)
to differentiate between coronary lesions causing ischemia, and blockages not causing
ischemia.
68
The study showed that patients with ischemic blockages who were treated with revascularization
had a long-term significant improvement in comparison with those who were only given
medical intervention. In another multicenter study, patients with multi-vessel coronary
artery diseases who underwent invasive interventions (PCI) with drug-eluting stents
that were guided by FFR results had a significant reduction in the rate of the composite
end-point of death, myocardial infarction, and target vessel revascularization at
one year post-intervention.
69
Another example of the efficacy of the FFR test can be seen in a study that showed
an almost 43% potential reduction in the need for bypass surgery in patients who underwent
FFR after having a coronary angiogram.
70
It is therefore very important to examine the individual contribution to the physiology
of an ischemic lesion, and not just its anatomy.
A similar method, but based on slightly different physical properties, by which to
test coronary microcirculatory function deals with thermodilition and index of microcirculatory
resistance (IMR). This technique is similar to pharmacological and pressure-based
techniques, but in this case using intracoronary temperature measurements to approximate
flow.
71
This has been shown to be independent of epicardial vascular function, reproducible,
and has even been evaluated in STEMI patients, providing important prognostic information
regarding ventricular function at three months.
72
Non-invasive endothelial function testing (arterial)
Brachial artery ultrasound is a commonly used and widely accepted measure of peripheral
macrovascular endothelial function.
73
In this test, inflating a blood pressure cuff at suprasystolic pressures for 5 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, 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.
74
Aside from reactive hyperemia, stimuli for measuring endothelial reactivity can include
exercise, mental stress, or sympathetic nervous activation through the cold pressor
test. As will all vascular reactivity tests, brachial artery ultrasound measurements
can be potentially confounded by such 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.
75
Observational data from the MESA study demonstrates that peripheral endothelial dysfunction
as measured by FMD of the brachial artery is associated with a higher rate of incident
adverse CVD events during a five-year follow-up period.
59
FMD has been linked with increased CVD risk in those patients with known CVD risk
factors.
76
Furthermore, data from a recent meta-analysis provides 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.
77
While some have recently argued that there is only minimal data that FMD adds to risk
stratification,
78
a more overwhelming body of evidence argues for the use of FMD measurements to provide
important additional CVD risk factor stratification and or response to therapies.
79,80
Impedance plethysmography is a method of assessing endothelial function via strain-gauge
venous impedance plethysmography which examines the changes in forearm blood flow
in response to direct intravascular administration of vascular agonists.
81
Due to the invasive nature of this test it is primarily used in research settings,
and rarely utilized clinically (Figures 1,2).
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.
82
This method is similar to FMD measurements of the brachial artery, and is often used
in concert to gain additional information regarding arterial reactivity
83
as L-FMC is a better measure of resting, basal arterial tone and thought to only be
partially NO-mediated.
84
Exact mechanisms of this reaction are still being elucidated, and it is becoming increasingly
important as the rate of radial interventional approaches increases.
42
Nevertheless, the combination of these two measurements has been shown to be closely
correlated to the severity of CAD,
85
and even provide additive risk factor stratification to traditional risk factors.
86,87
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.
88–91
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 5 minutes is used to assess the reactive hyperemic response,
a surrogate and a marker for endothelial function. These methodologies are non-invasive,
are designed to eliminate environmental interference, and are independent of the subject's
knowledge and conscious control of signals generated.
88,90
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;
i.e. the average amplitude of the RH-PAT signal over 60 seconds at 1, 2, 3 and 4 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). A diagram of the
PAT device is shown in 3.
Recent 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.
92
Moreover, Goor et al. has demonstrated that there is a characteristic PAT signal response
to mental stress, with diminution of the signal amplitude during stress.
90
However, this test is only thought to be partially dependent on NO,
93
with other factors such as the sympathetic nervous system thought to affect the microvascular
response to certain stimuli.
94
There are discordant reports as to the agreement between FMD and PAT as some reports
highlight a discordance with PAT and FMD measurements,
95,96
while others find an association between the two tests.
94
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.
97
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
function improved had half as many cardiovascular events compared to those women who
showed no improvement in endothelial function.
98
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% 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.
99
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.
100
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.
100
Finally, those patients already with obstructive CAD, PAT can predict future adverse
CVD outcomes.
99
Other non-invasive measures of endothelial function
Measures of venous endothelial function are used as the pathogenesis of arterial and
venous clots share the characteristic of endothelial dysfunction in conditions favorable
for generation and as 70% of the circulating blood is contained within the venous
system. However, this is seldom used clinically, as the techniques typically involve
difficult measures that lack reproducibility such as the dorsal vein technique and
radionuclide venous plethysmography. Thus, as patients who will have venous endothelial
dysfunction typically have arterial endothelial dysfunction, we suggest using methods
mentioned above (Figures 4–
6).
Traditional imaging-based modalities have been clinically utilized and verified to
assess microvascular function. Myocardial PET imaging has been tested using a cold
pressor test in patients with diabetes,
101
and verified in a larger cohort of patients.
102
Furthermore, cardiac magnetic resonance perfusion has been correlated with endothelial
dysfunction in patients without overt coronary artery disease
103
as well as those with typical angina but relatively normal angiograms.
104
However cost and limited availability of the resources necessary for such prevent
widespread adoption of these modalities. Other measures of endothelial function are
currently in various stages of use and design – mainly in the research realm. Measures
of endothelial progenitor cells (EPCs) and subtypes which assist in endothelial repair
and function have been associated with Framingham scores
45
and various measures of CVD.
46
Statins,
48
erythropoeitin,
49
and exercise
50
all increase EPCs numbers and function. However, the exact subpopulation of beneficial
EPC subtypes remains to be defined.
Genome wide array sequencing (GWAS), single nucleotide polymorphisms (SNPs), microRNAs
(miRs), and even some urinary biomarkers have all been linked with various stages
of endothelial dysfunction and early atherosclerosis, however these are not yet in
clinical use (Table 1).
Urine microalbuminuria
21
and others have also been studied as markers of endothelial function, however they
are also not in clinical use.
•
Endothelial function can be tested in a variety of ways measuring both macrovascular
endothelial function with brachial artery ultrasound as well as microvascular endothelial
function with peripheral arterial tonometry.
•
Macrovascular endothelial function is typically measured by flow-mediated dilation
using ultrasound of the brachial artery measuring vascular reactivity to such stimuli
as medications and reactive hyperemia.
•
Low-flow-mediated constriction is a newer method of testing macrovascular function
specifically focusing on the resting state of the endothelium in a non-NO-dependent
manner.
•
Microvascular endothelial function measures vascular reactivity to the same stimuli,
however typically utilizing peripheral tonometry or pulse wave amplitude to approximate
blood flow.
•
There are no guideline-based recommendations to use endothelial function testing clinically,
however, such tests can augment combined risk factor assessments in patients who may
fall between two risk factor categories.
Preoperative Risk Assessment – Assessment of endothelial function by brachial ultrasound
has been used for preoperative risk stratification in patients undergoing vascular
surgery.
41
An FMD measurement for the purpose of perioperative risk stratification was assessed
in a study of 187 patients undergoing high-risk (vascular) surgery. Low flow-mediated
dilation was an independent predictor of a cardiac event at 30 days (odds ratio 9)
41
and of late events at 1.2-year follow-up.
105
Endothelial dysfunction treatments/therapies
[1]
Life style modifications (diet, exercise, smoking, weight reduction…)
Mediterranean diet – A low fat diet is usually the first step in treating hypercholesterolemia.
A Mediterranean diet reduces serum LDL-cholesterol and lowers the risk of cardiovascular
events in patients with a myocardial infarction. These benefits are associated with
an improvement in endothelial function.
123,124
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.
125
Other Dietary Interventions – Recently, there has been a plethora of trail data showing
that substances such as dark chocolate,
126
nuts,
127
olive oil,
128
plant-based foods,
129
green tea,
130
and alcohol consumption
131
have all shown to be beneficial to improving peripheral endothelial function. Indeed,
proper dietary measures should serve as a cornerstone toward improving endothelial
function.
Aerobic exercise and weight loss – 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 has 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 middle-aged and older healthy men.
132
Weight loss alone has been shown to be beneficial to endothelial function.
133
Exercise has also been seen to improve endothelial function in such high risk patients
as those with peripheral vascular disease
134
and heart failure.
135
Similarly, obesity has been linked with endothelial dysfunction,
136
and conversely weight loss is associated with a significant reduction in cytokine
levels and an improvement in endothelial dysfunction.
137,138
[2]
NO pathway (L-arginine, PDE-I)
L-arginine – The intravenous or intracoronary administration of L-arginine, the physiologic
precursor for NO, can acutely improve endothelium-dependent, but not endothelium-independent,
vasodilation in patients with hypercholesterolemia or coronary atherosclerosis.
92
L-arginine has been tested in multiple smaller, randomized, clinic trials, and shown
to have benefits; however, the stereoisomer, D-arginine, is ineffective.
93
Additionally, and 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 FMD with 9 g daily of L-arginine supplementation.
94
These patients, however, were on optimal medical therapy for CVD prevention.
In contrast, a similarly-sized trial showed that a similar dose of L-arginine after
6 months had a significant improvement in patients coronary endothelial function and
resultantly improved anginal symptoms.
95
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.
96
The most recent data regarding L-arginine and endothelial function appears to show
that when given at doses of 2 g thrice 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 CAD.
97
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.
98
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.
99
In addition to improved endothelial function, L-arginine supplementation has also
been implicated in reducing plasma endothelin levels,
95
reduced symptomatic burden via apoptosis of proliferating vascular smooth muscle cells
leading to atherosclerotic plaque regression other changes that have been described
include lower plasma endothelin concentrations,
100
and finally arresting atherosclerotic plaque development in an animal model.
101
Phosphodiesterase inhibitors such as sildenafil have also been shown to be beneficial
to improving peripheral endothelial function in a small cohort of diabetic men,
106
as well as enhance penile blood flow and erectile function.
107
Larger-scale data, however, does not exist, and these agents have recently been found
to be of no CVD benefit in patients with heart failure and preserved endothelial function.
108
Nicorandil – This anti-anginal, unavailable in the US, has dual nitrate and potassium-ATP
channel agonist properties by increasing the formation of cyclic GMP. This agent is
effective in improving endothelial function in patients without prior coronary artery
disease after one year with concomitant reductions in inflammatory markers.
109
Despite its theoretical promise, there have only been limited data published, albeit
positive, regarding the efficacy of nicorandil in patients (n = 65) with chronic stable
angina as well as induced plaque regression in animal and human studies.
110
[3]
Channel pathways (Ca, K.)
Nifedipine may have antioxidant effects and effects on endothelial nitric oxide 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.
111
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.
112
Furthermore, there has been improvement in endothelial function in smaller RCTs examining
diabetic patients,
113
as well as patients with chronic stable angina.
114
Supplementation of taurine, a semi-essential amino acid has also been shown to be
marginally beneficial to endothelial function.
115
[4]
Receptor and enzyme pathways (beta-blockers, ET, ACE-I, ARB)
Lipid lowering – 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.
116
The combination of ACE-inhibition and statin therapy has also been shown to improve
endothelial-dependent relaxation of the coronary vasculature through NO-dependent
mechanisms.
117
Fibrate therapy also improves fasting and postprandial endothelial function in patients
with type 2 diabetes, as does omega-3 fatty acid supplementation.
118
The mechanism for this may be an increase in high density lipoproteins (HDL) and an
attenuation of postprandial lipemia and the associated oxidative stress.
119
HDL lowering or niacin therapy appears to have no beneficial effect on endothelial
health.
120
Blockade of the renin-angiotensin system – Angiotensin converting enzyme (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.
121
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.
122
These benefits were thought to be secondary to an improved NO-bioavailability through
reduced bradykinin breakdown as well as improved ROS scavenging. As stated earlier,
ACE-inhibitors do improve coronary endothelial resistance through NO-dependent mechanisms.
117
Most studies have shown an improvement in endothelial dysfunction following the administration
of an angiotensin II receptor blocker in patients with atherosclerosis or diabetes.
123–125
Furthermore, ARBs have been shown to improve coronary endothelial dysfunction,
126
and there is increasing evidence that direct renin inhibition improves endothelial
function in at risk patients.
127
Nebivolol, as there appears to be some increase in NO bioavailability with this beta-blocker.
128
Aspirin – Studies suggest that aspirin improves endothelial dysfunction in patients
with known atherosclerosis, likely through inhibition of cyclooxygenase-dependent
vasoconstriction.
129
This can result in vasodilation and reduction in thrombosis, providing a potential
mechanism for the beneficial effects of aspirin in atherosclerosis. However, most
patients with endothelial dysfunction will already be on such a therapy, so the additive
benefit is not likely to be substantial.
N-acetylcysteine (NAC), 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 NAC 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.
130
Estrogen and other selective estrogen receptor modulators – Reports of estrogen therapy
improving endothelial function in post-menopausal women
131
appear to have biologic plausibility as endothelial cells have estrogen receptors,
132
as well as through improved NO bioavailability
133
or through a reduction in coronary endothelin-1 levels.
134
Similarly Tamoxifen and raloxifene are selective estrogen receptor modulators, having
estrogen-like activity, and also found to have positive effects on FMD.
135
However, consideration for the use of any of these hormonal therapies should be carefully
evaluated in terms of global risks and benefits for the patient.
Testosterone may improve endothelial dysfunction, however the data is only in the
form of a case series showing increased coronary artery vasodilatation.
136
Again, however, the overall risk of testosterone supplementation appears to outweigh
the benefit of augmenting endothelial function with such, and we would recommend against
this therapeutic option.
Endothelin receptor blockers – Elevated levels of endothelin is thought to play a
role in endothelial dysfunction seen in heart failure and hypertension and the transient
dysfunction induced by mental stress. A recent randomized, double-blind, placebo-controlled
trial in patients at high risk for CVD showed a significant improvement in coronary
microvascular endothelial function.
137
This therapy is still being researched for widespread use in targeted populations.
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 thoughts to improve peripheral endothelial function as evidenced by smaller
RCTs in diabetic patients
81
and those with metabolic syndrome.
138
Extending these results, both metformin and rosiglitazone have been found to improve
endothelial function in women afflicted with PCOS, however confounding effects of
reductions in testosterone and HOMA results as well as normalization of meunstral
cycles have left this debate unresolved.
139
Rosiglitazone has been found to attenuate impaired vasodilation in diabetic patients
subjected to fatty acid meal challenges.
140
Conversely these results were not mechanistically validated as it was pioglitazone,
not rosiglitazone, which reduced pharmacologically induced vasoconstriction in internal
mammary artery grafts from diabetic patients.
141
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 RCTs.
Prognosis after therapy – 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.
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Summary and recommendations
•
Currently, there are no FDA-approved treatments for endothelial dysfunction, as the
treatment should encompass addressing the underlying comorbidity that lead to endothelial
dysfunction.
•
L-arginine, in large quantities (9–18 g daily), has been shown to have beneficial
effects on both vascular reactivity and relief of symptoms from coronary endothelial
function.
•
ASA, statins, ACEI have all shown benefit in reducing CVD risk with endothelial function
improvement likely to be a concomitant factor.
•
Diet and exercise have both been shown to improve vascular reactivity, and should
be encouraged as part of lifestyle behaviors beneficial toward overall CVD health.