Version May 2024
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.
This topic will focus on clinical aspects of endothelial dysfunction, which is present in 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".)
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 microvascular spasm. (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. 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: 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 or ischemia with no obstructive coronary atherosclerosis", section on 'Epidemiology of MINOCA'). 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 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 – This 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].
●Cardiac amyloidosis – Endothelial function is present in amyloidosis [34] and can serve as a prognostic indicator in children with familial cardiomyopathies [35]. (See "Microvascular angina: Angina pectoris with normal coronary arteries", section on 'Secondary microvascular'.)
●Myocardial bridging – This is closely associated with coronary endothelial dysfunction and 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, is performed for diagnostic and therapeutic purposes, and 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 (2.6 percent in each), there were significant improvements in anginal scores (mean improvement of 11.7 units in the Seattle Angina Questionnaire summary score at six months) and quality of life (mean quality-of-life score EQ-5D index 0.10 units) in the invasive compared with the usual care group [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]. 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-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].
Finally, recent randomly controlled trial (RCT) data from the CorMica trial have demonstrated sustained improvements in angina and quality of life of at least one year if patients are provided invasive coronary vasoreactive testing for the diagnosis of coronary microvascular disease [55].
Noninvasive testing
●Brachial artery ultrasound – Brachial artery ultrasound is a commonly used and widely accepted measure of peripheral macrovascular endothelial function [56]. 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 [57]. Aside from reactive hyperemia, stimuli for measuring endothelial reactivity can include exercise, mental stress, or sympathetic nervous activation 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 [58].
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 [59]. 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 [60]. While some have argued that there are only minimal data that FMD adds to risk stratification [61], 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 [62,63].
●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 [64]. 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 [65] and verified in a larger cohort of patients [66]. Cardiac magnetic resonance perfusion has been correlated with endothelial dysfunction in patients without overt coronary artery disease [67], as well as those with typical angina but relatively normal angiograms [68]. 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 [69]. This method is similar to FMD measurements of the brachial artery, and is often used in concert to gain additional information regarding arterial reactivity [70], as L-FMC is a better measure of resting, basal arterial tone, and thought to only be partially NO-mediated [71]. Exact mechanisms of this reaction are still being elucidated, and it is becoming increasingly important as the rate of radial interventional approaches increases [72]. Nevertheless, the combination of these two measurements has been shown to be closely correlated to the severity of CAD [73] and even provides additive risk factor stratification to traditional risk factors [74,75].
●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 [76-78]. 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 [76,77]. 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 [76]. Moreover, it has been demonstrated that there is a characteristic PAT signal response to mental stress, with diminution of the signal amplitude during stress [77]. However, this test is only thought to be partially dependent on NO [79], while other factors such as the sympathetic nervous system are thought to affect the microvascular response to certain stimuli [80]. There are discordant reports as to the agreement between FMD and PAT, as some reports highlight a discordance with PAT and FMD measurements [81,82], while others find an association between the two tests [80]. 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 [79].
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 [83]. 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 [84].
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 [85]. 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 [85]. Finally, for those patients already with obstructive CAD, PAT can predict future adverse CVD outcomes [84]. This was demonstrated in a study of patients admitted to a chest pain unit to rule out acute coronary syndrome [86]. 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 [87]. 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 [88,89].
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 [84]. 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 [90].
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 [91]. (See 'Risk factors' above and "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk" and "Overview of primary prevention of cardiovascular disease".)
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 [92,93]. 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 [94].
●Other diets – There has been a plethora of trial data showing that substances such as dark chocolate [95], nuts [96], olive oil [97], plant-based foods [98], green tea [99], and alcohol consumption [100] 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 middle-aged and older healthy men [101].
●Weight loss, particularly in obese individuals, has been shown to be beneficial to endothelial function [102-106].
●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 [107]. 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 [108]. 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 [109]. 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 [110-112]. Furthermore, ARBs have been shown to improve coronary endothelial dysfunction [113], and there is increasing evidence that direct renin inhibition improves endothelial function in at-risk patients [114].
●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 [115]. 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 [116].
●Fibrate therapy also improves fasting and post-prandial endothelial function in patients with type 2 diabetes, as does omega-3 fatty acid supplementation [117]. 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 [118]. HDL lowering or niacin therapy appears to have no beneficial effect on endothelial health [119].
●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 [120]. Similarly, there is no improvement in exercise performance or coronary blood flow found after short-term administration of isosorbide dinitrate [121].
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 [122].
●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 [123]. The stereoisomer D-arginine is ineffective [124]. 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 [125]. 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 [126]. 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 [127]. 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) [128]. 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 [129]. 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 [130]. In addition to improved endothelial function, L-arginine supplementation has also been implicated in reducing plasma endothelin levels [126], 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 endothelin concentrations [131], and finally arresting atherosclerotic plaque development in an animal model [132].
●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 [133].
●Dry sauna – Dry sauna has been shown to improve endothelial function in patients with cardiovascular risk factors [134].
●Nebivolol – There appears to be some increase in NO bioavailability with this beta blocker [135].
●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 [136].
●Estrogen – Reports of estrogen therapy improving endothelial function in post-menopausal women [137] appear to have biologic plausibility as endothelial cells have estrogen receptors [138], as well as through improved NO bioavailability [139] or through a reduction in coronary endothelin-1 levels [140]. 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 [141].
●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 [142].
●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 endothelial function [64,143]. Both metformin and rosiglitazone have been found to improve endothelial function in women 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 [144]. 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 [145]. 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 trials (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 [146]. Furthermore, there has been improvement in endothelial function in smaller RCTs examining diabetic patients [147], as well as patients with chronic stable angina [148]. (See "New therapies for angina pectoris", section on 'Ranolazine'.)
●Phosphodiesterase inhibitors – Medications 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 [149-151]. 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 [150]. (See "Treatment of male sexual dysfunction", section on 'Initial therapy: PDE5 inhibitors'.)
●CD34+ stem cells – Two small prospective observational studies suggested CD34+ stem cell infusions may improve microvascular angina, microvascular blood flow, and coronary flow reserve. Randomized trials of CD34+ cell infusions are planned for the future [152,153].
●Rho-kinase inhibitors – There are emerging data that Rho-kinase levels and activity correlate with coronary endothelial dysfunction [154].
SUMMARY AND RECOMMENDATIONS
●Background – 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 terms' above.)
●Risk factors – Multiple risk factors for endothelial dysfunction have been identified. Many of these are the traditional risk factors for cardiovascular disease. (See 'Risk factors' above.)
●Role in pathogenesis of atherosclerosis – 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 – Testing using either direct or indirect methods, is not routinely used in clinical practice. (See 'Evaluation of endothelial function' above.)
●Role of secondary prevention – In most cases, coronary artery endothelial dysfunction will be documented in patients who have atherosclerotic cardiovascular disease. These 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 UpToDate editorial staff acknowledges the late Emile R. Mohler, III, MD, who contributed to an earlier version of this topic review.
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