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Endothelial Dysfunction and Metabolic Syndrome
Endothelial Dysfunction and Metabolic Syndrome
1Suegene K Lee, 2Jay Khambhati, 3Ankit Bhargava, 4Marc C Engels, 5Pratik B Sandesara, 6Arshed A Quyyumi
1-6Faculty Members
1-6Division of Cardiology, Department of Medicine, Emory ClinicalCardiovascular Research Institute, Emory University School ofMedicine, Atlanta, Georgia, USA
Correspondence Author: Arshed A Quyyumi, Emory ClinicalCardiovascular Research Institute, 1462 Clifton Road, NESuite 507, Atlanta, Georgia 30322, USA,
Phone: +4047273655
e-mail: aquyyum@emory.edu
Atherosclerotic cardiovascular disease (ASCVD) continues tobe the leading cause of death worldwide. Metabolic syndromeis associated with an increased risk of ASCVD. With theprevalence of metabolic syndrome continuing to increase, itis important to understand the relationship between these riskfactors and development of ASCVD. Endothelial dysfunction(ED), an early, essential step in atherosclerotic plaque formation,is the key link. Here we review diagnostic methods of EDand the mechanisms of each metabolic syndrome componentcontributing to ED. Finally, the effects of current treatments ofmetabolic syndrome on ED will also be discussed.
Keywords: Atherosclerotic cardiovascular disease, Endothelialdysfunction, Metabolic syndrome.
How to cite this article: Lee SK, Khambhati J, Bhargava A,Engels MC, Sandesara PB, Quyyumi AA. Endothelial Dysfunctionand Metabolic Syndrome. Hypertens J 2017;3(2):72-80.
Source of support: Nil
Conflict of interest: None


Metabolic syndrome has been recognized as a combinationof interrelated metabolic risk factors that directlypromote atherosclerotic cardiovascular disease (ASCVD),with the key link between this syndrome and adversecardiovascular events being endothelial dysfunction(ED). The Adult Treatment Panel (ATP) III criterion is themost commonly used definition: Central obesity (waistcircumference ≥102 cm in men or ≥88 cm in women),hyperlipidemia (triglyceride level ≥150 mg/dL or highdensitylipoprotein [HDL]-cholesterol < 40 mg/dL in menor < 50 mg/dL in women), hypertension (blood pressure≥130/85 mm Hg), and impaired fasting glucose (fastingblood glucose >100 mg/dL). According to this criterion,approximately 24% of US adults were estimated to havethree or more of the above in 2002.1

The predominant factors contributing to the metabolicsyndrome are thought to be insulin resistance (IR)2 and central obesity.3,4 Indeed, several metabolic pathways havebeen implicated linking IR as a central driver for the othermetabolic risk factors.5,6 Moreover, central obesity has beenassociated with accumulation of lipid in muscle and livertissues, which on its own predisposes to hyperlipidemiaand IR.7 The adipose tissue shows increased productionof proinflammatory cytokines and other inflammatorymarkers, which lead to a state of low-grade inflammation,8,9 and those with the metabolic syndrome havebeen found to have elevated levels of proinflammatorycytokines [e.g., interleukin (IL)-6 and tumor necrosis factoralpha (TNF)-α and acute-phase proteins [e.g., C-reactiveprotein (CRP) and fibrinogen].10,11 In addition, the metabolicsyndrome predisposes to a prothrombotic state, dueto elevated levels of procoagulation factors, such as plasminogenactivator inhibitor-1, tissue factor, and fibrinogen.12These numerous, complex biochemical changes lead to EDand increased risk for subsequent ASCVD.13


The healthy endothelial cell layer serves an essential rolein maintaining normal vascular homeostasis. In normalphysiology, the endothelium produces several paracrinefactors that regulate vascular tone, limit expression ofproinflammatory molecules, inhibit platelet aggregation,promote fibrinolysis, and limit smooth muscleproliferation.14-16 Endothelial-derived nitric oxide (NO)is the principal driver of the vasodilatory process. It isgenerated by the conversion of L-arginine to L-citrullinethrough the action of endothelial NO synthase (eNOS)and its cofactor tetrahydrobiopterin (BH4).17 NO moleculesvasodilate the local vascular smooth muscles bystimulating guanylyl cyclase and increasing productionof cyclic guanosine monophosphate.17 In addition to itsvasodilatory effects, NO also acts as a potent inhibitorof platelet aggregation and adhesion, interferes withleukocyte adhesion, and inhibits proliferation of vascularsmooth muscles.17-19 Disruption of these processesleads to ED, an early, essential step in the developmentof atherosclerosis.


Invasive Assessment

Coronary reactivity testing involves intra-arterial infusionsof endothelium-dependent vasodilators, such as acetylcholine (ACh), bradykinin, or substance P. Acetylcholineactivates the endothelial muscarinic receptorsthat metabolize L-arginine, stimulate NO synthase,and thus generate NO.20 In response to these infusions,coronary epicardial vessels dilate in the setting of normalor preserved endothelial function. In ED, ACh's directsmooth muscle constrictor effects on epicardial vesselsovercome the dilator effects of endothelium-dependentNO release.21

Endothelial Dysfunction and Metabolic Syndrome

Noninvasive Assessment

Doppler echocardiography, positron emission tomography,and magnetic resonance imaging have been usedto noninvasively assess either peripheral or coronaryvasculature. Ultrasound-based measurement of brachialartery reactivity or flow-mediated vasodilation (FMD) isthe most widely used technique: After a brief period ofupper-arm occlusion using a blood pressure cuff, shearstress-mediated brachial arterial dilation is measuredusing a high-frequency ultrasound transducer.22 TheFMD refers to the vasodilator response due to the shearmediatedNO release of the brachial artery with the stimulusbeing the ischemia after cuff deflation. Thus, FMDis used as a surrogate measure of endothelial function.

Associated Biomarkers

Biomarkers have been a subject of research interestfor their potential for adding independent prognosticvalue, in addition to clinical risk factors. Markers ofoxidative stress have been studied as a means to assessendothelial injury and dysfunction because reductionin NO bioavailability is often due to increased prooxidantstress.

Glutathione maintains thiol groups of biomoleculesin their reduced state and prevents peroxidation of membranelipids.23 Similarly, high cysteine levels are indicativeof increased oxidative stress. Glutathione is also involvedin transportation of NO.24 Our studies have found associationsbetween increased oxidative stress, measured aslower glutathione and/or higher cysteine levels and FMD,microvascular vasodilator function, arterial stiffness, andarterial thickness.25-30

Asymmetric dimethylarginine (ADMA) is a byproductof L-arginine metabolism, i.e., elevated in patientswith hypertension, dyslipidemia, and atherosclerosis.31-34The ADMA acts as a competitive inhibitor to eNOS,leading to decreased NO production and bioavailability.31Plasma ADMA levels correlate with ED32 and subclinicalatherosclerosis.35

Following oxidative stress or apoptosis, microparticlesare shed from plasma membranes. Those originatingfrom endothelial cells have been thought to impair endothelium-dependent dilation and the NO pathway.Circulating endothelium-derived microparticles werefound to correspond to the severity of coronary arterydisease in patients presenting with acute coronary syndromes.32


Components of the metabolic syndrome-impairedglucose metabolism, obesity, dyslipidemia, and hypertension-are all associated with ED. Endothelial vasodilationis increasingly impaired with the number ofcomponents present from the metabolic syndrome.36 Themechanisms by which these risk factors affect endothelialfunction are often interrelated and broadly fall intocommon pathways of endothelial injury, inflammation,reactive oxygen species (ROS) production, and disruptionof NO function and bioavailability.

Abnormal Glucose Metabolism

Endothelial dysfunction is present even in the earlystages of diabetes including impaired glucose toleranceand impaired fasting glucose.37 Insulin resistance ismarked by hyperinsulinemia and hyperglycemia. Undernormal conditions, insulin enhances the vasodilatoryaction of NO and increases its production. Endothelialcells in the insulin-resistant population, however,display paradoxical vasoconstriction when exposed toinsulin. The reasons for this are likely multifactorial. Inpatients with insulin-dependent diabetes mellitus, theserum insulin concentration is inversely correlated withendothelium-dependent vasodilation (EDV).38 Furthermore,insulin administration itself impairs endothelialfunction.39 However, this impairment can be reversedwith the administration of antioxidant vitamin C. Thissuggests that hyperinsulinemia increases oxidativestress in the vasculature.39 Vascular oxidative stress andoverproduction of ROS have a deleterious effect on eNOSactivity and synthesis of NO. The ROS in insulin-resistantsubjects enhance the oxidation of BH4 to 7,8-dihydrobiopterin(BH2), limiting the amount of active cofactoravailable for eNOS function. The activity of dihydropteridinereductase, an enzyme that regulates the rateof regeneration of BH4 from BH2, is reduced in IR andcompounds on the problem with pteridine metabolism.40Finally, ROS directly inactivate NO, thereby decreasingits bioavailability.

Hyperglycemia produces ED by blunting EDV throughan assortment of intracellular pathways. Hyperglycemiacan lead to the depletion of nicotinamide adeninedinucleotide phosphate, which is essential to the regenerationof antioxidant molecules, such as glutathione, tocopherol, and ascorbate.41 Accumulation of advancedglycosylation products formed in chronic hyperglycemiaalso inactivates NO, creating another avenue for ED.42Hyperglycemia also increases the synthesis of diacylglycerol,a key component to the initiation of the proteinkinase C (PKC) pathway. Activation of the PKC pathwayinduces endothelial expression of endothelin-1, a potentvasoconstrictor, as well as decreases the level of eNOSproduction. The PKC additionally increases productionof various growth factors and prothrombotic factors thatalter the vascular remodeling process and predispose tothrombosis respectively.41 Endothelial cells exposed tohyperglycemic conditions also undergo apoptosis thatleads to the loss of intimal integrity and detachmentof endothelial cells. In certain cases, the endotheliumdoes not detach as an entire cell, forming endothelialmicroparticles (EMPs) that have procoagulant activity.43This process of endothelial denudation normally leads toreparatory mechanisms to restore vascular integrity, suchas through the mobilization of endothelial progenitorcells (EPCs). Diabetic patients display a decreased reserveof EPCs secondary to reduced mobilization from the bonemarrow, stunted proliferation, and shortened survival.43

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Interestingly, other studies have shown that therelationship between diabetes and ED may not be unidirectional,but in fact, ED might precede the developmentof diabetes. A large prospective study of 121,700 womenfound that the elevated biomarkers of ED, E-selectin, andintercellular adhesion molecule-1 (ICAM-1) predictedincident diabetes.44 These support the experimentalfindings in mice with knockout mutations in the eNOSgene that also develop IR.45 Impaired endothelial permeabilitylimits insulin delivery to the interstitium.46Furthermore, insulin delivery to metabolically activemuscle tissue is thought to be diminished secondaryto impaired endothelial vasodilation, limiting capillaryrecruitment and compromising microvascular distributionof skeletal muscle blood flow.47,48


Obesity has been linked to impaired endotheliumdependentperipheral and coronary vasodilation. TheFramingham Heart Study examined this issue in a largecommunity-based sample and found body mass index(BMI) to be inversely correlated with FMD.49 A similarassociation was found in the coronary circulation; obesepatients with normal or mildly diseased coronary arteriesdemonstrated significantly attenuated coronary bloodflow in comparison with normal-weight subjects withintracoronary ACh.50

Excess adipose tissue in obese patients createsa disease state characterized by chronic, low-grade systemic inflammation. Plasma inflammatory markers,such as CRP, IL-6, TNF-α, fibrinogen, angiotensinogen,and various cell adhesion molecules are uniformlyelevated in obese individuals.15,51,52 Adipocytes functionas a metabolically active organ, producing a number ofproatherogenic and proinflammatory adipokines. Certainadipokines, such as adiponectin serve a protective rolein endothelial function. Adiponectin stimulates NO productionand downregulates TNF-α-induced adhesionmolecule expression by inhibiting nuclear factor kappaB (NF-κB).15 Obese individuals have reduced levels ofadiponectin. Hypoadiponectinemia is predictably associatedwith impaired EDV.53 These stores can be restoredwith therapeutic lifestyle interventions and weight loss.54
Increased production of ROS has also been linked toobesity. Central obesity is tied to oxidative stress throughan expanded supply of cytosolic triglycerides in nonadiposetissues, such as muscle, liver, and pancreatic betacells. Cytosolic triglycerides are the source of the metabolicallyactive long-chain acyl-coenzyme A esters. Theseesters inhibit the translocation of adenine dinucleotideinto the mitochondria, and the resulting intramitochondrialdeficiency is a powerful stimulator of mitochondrialoxygen free radical production.55 Identical to mechanismsat play in IR, oxidative stress decreases NO bioavailabilityand neutralizes NO function. Endothelin-1 activity isincreased in obese patients, and may further exacerbateabnormal vasomotor regulation by disrupting the NOand endothelin-1 balance.56

Dyslipidemia-Low HDL-C and

High-density lipoprotein cholesterol works to reversecholesterol transport and has a protective effect againstthe development of atherosclerosis. In contrast, decreasedHDL-C has been associated with a number of mechanismsthat predispose to ED. Hyperlipidemic patientswith a low HDL-C have higher levels of vascular celladhesion molecule-1 (VCAM-1) and ICAM-1. Thesemolecules mediate the adhesion of leukocytes to theendothelium and therefore, contribute to a proinflammatorystate.57 Low HDL-C is also associated with increasedlow-density lipoprotein cholesterol (LDL-C) oxidationand impaired FMD.58 The HDL-C has the ability to act asan antioxidant and has been shown to inhibit lipoproteinoxidation.59 The HDL-C contains antioxidant enzymesand proteins, including platelet-activating factor, acetylhydrolase,and paraoxonase, which are able to counteractLDL-C oxidation.

Oxidized LDL-C induces the activation of NF-κBthat ultimately stimulates endothelial cells to expressmonocyte-specific chemoattractants and cell adhesion molecules.60 Oxidized LDL-C also directly decreasesNO synthesis through early transcriptional inhibitionand destabilization of posttranscriptional messengerribonucleic acid.61 The proinflammatory signals are thusintertwined with the oxidative state, demonstrating theimportance of HDL-C in protecting the endotheliumfrom these processes.

Endothelial Dysfunction and Metabolic Syndrome

The contribution of hypertriglyceridemia to EDremains controversial. In a study by Lundman et al,62young healthy men with mild-to-moderate hypertriglyceridemiawere found to have impaired FMD. Patients inthis study also had increased levels of ADMA, an endogenouseNOS inhibitor. Increased ADMA in hypertriglyceridemiaconsequently reduces the bioavailability ofNO, offering one mechanism through which triglyceridescan impair endothelial function.62 Elevated levels of thesoluble forms of VCAM-1 and ICAM-1 were also foundin subjects with hypertriglyceridemia who otherwise hadno history of diabetes, hypertension, or other significantcardiovascular risk factors.63 Lewis et al64 found thatendothelium-dependent relaxation mediated by ACh wasdiminished in patients with hypertriglyceridemia andnormal LDL-C levels. A study by Chowienczyk et al,65in contrast, showed no impairment of the endothelium inpatients with severe hypertriglyceridemia in the contextof lipoprotein lipase dysfunction and normal LDL-C.This discrepancy may be attributed to lipoprotein lipasedeficiency, which is associated with a selective increasein chylomicrons and large very low-density lipoproteins.By virtue of their size, these lipoproteins are unable toinvade the vessel wall and initiate the process of atherogenesis.63 Lewis et al64 hypothesized that in their study,the difference may have been due to the higher BMI ofthe test subjects compared with the controls, indicatingthat there may have been a confounding effect of IR thatwas not accounted for in their study.


Patients with essential hypertension have bluntedresponses to ACh-mediated endothelial vasodilation inboth the peripheral and coronary vascular beds.66,67 Whensimultaneously exposed to ACh and NG-monomethyl-Larginine(L-NMMA), an inhibitor of the endothelial synthesisof NO, hypertensive patients do not demonstratea significant reduction in vasodilation compared withcontrol patients.68 This phenomenon suggests impairmentin NO bioactivity in hypertension. In hypertension, thisimpairment is largely attributable to NO breakdown andinactivation by ROS, as opposed to decreased endothelialNO synthesis. Intra-arterial administration of high-doseantioxidant vitamin C to patients with hypertension andimpaired forearm blood flow can acutely reverse thisdefect, giving more credence to this theory.69 Vitamin C scavenges radical oxygen species allowing for NO activity,which then unmasks the effect of L-NMMA.69 In parallelto increased oxidative stress, dysfunctional endotheliumin hypertensive patients is associated with increasedendothelial-derived constricting factors (EDCFs).These factors include endothelin-1, angiotensin II,and cyclooxygenase-derived products, such as thromboxaneA2 and prostaglandin H2. The EDCFs causevasoconstriction, further contributing to ED.70

Metabolic Syndrome

Metabolic syndrome encompasses the aforementionedconditions of hypertension, IR, dyslipidemia, and obesity.Many of these conditions coexist with one another,leading to a complex array of inflammation, NO inactivationand depletion, oxidative stress, and prothromboticstates. The Prospective Investigation of the Vasculature inUppsala Seniors (PIVUS) study evaluated 1,016 subjectsaged 70 years and measured EDV after intra-arterial AChinfusion. This study found that patients with metabolicsyndrome (per National Cholesterol Education Program/ATP III criteria) had EDV that was progressively moreimpaired with the increasing number of criteria met formetabolic syndrome. When the criteria were analyzedseparately and in multiple regression analysis, abdominalobesity was most closely related to EDV.36 Of course,abdominal obesity is commonly a comorbid condition tothe other criteria, and so it is important to recognize thatmultiple mechanisms are working together additively, ifnot synergistically in metabolic syndrome to result in ED.


br>Lifestyle Modifications

Lifestyle modifications, comprising of diet, exercise, andtobacco cessation, are the first-line intervention for metabolicsyndrome. Weight reduction and maintenance of alower weight should be the first priority.71 The AmericanDiabetes Association recommends the Mediterraneandiet, promoting high consumption of whole-grain foods,fruits, and vegetables for their beneficial effects on glycemiccontrol and cardiovascular risk factors.72 In thePREDIMED trial, 3,541 patients without diabetes at highcardiovascular risk were assigned to one of two Mediterraneandiets, supplemented with either free virgin oliveoil or nuts. Those assigned to the Mediterranean dietshad lower risk of diabetes compared with the low-fatcontrol diet.73

A randomized trial studied the effects of a Mediterranean-style diet on ED in patients with metabolicsyndrome with a follow-up of 2 years.74 The ED wasmeasured by platelet aggregation response to adenosine after applying a blood pressure cuff and administeringL-arginine. Those assigned to the Mediterraneandiet had an improved endothelial function score, but itremained unchanged in the control group. Marin et al75also conducted a smaller trial in 20 elderly subjects andassessed the effects of dietary fat on the release of EMPsand EPCs. The Mediterranean diet led to a lower EMPand higher EPC levels. Furthermore, they also foundlower urinary isoprostane concentrations after consumptionof a Mediterranean diet, signifying improvement inoxidative stress.

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The American Heart Association (AHA) andAmerican College of Sports Medicine recommend atleast 30 minutes of moderate-intensity physical activityfor at least 5 days of the week, or 20 minutes of vigorousaerobic exercise 3 days a week, or a combination of thetwo,76 and for those with metabolic syndrome, regularexercise is crucial.71 In healthy males, regular aerobicexercise for 3 months resulted in a 30% increase inACh-mediated vasodilation.77 These beneficial effects ofphysical activity on endothelial function were also foundin those with chronic heart failure78 and in those withcardiovascular risk factors.79 Exercise has been shownto improve endothelial function, independently of itsreduction in cardiovascular risk factors79-althoughexercise training significantly improved FMD, plasmalipids, blood pressure, blood glucose, waist-to-hip ratio,or BMI were unchanged after 8 weeks in patients underlyingvascular dysfunction. Furthermore, aerobic intervaltraining was found to be more effective in improvingED, compared with continuous moderate exercise (9%vs 5%; p < 0.001) in 32 metabolic syndrome patients,suggesting that exercise intensity is an important factorfor improving cardiorespiratory fitness and reversingcardiovascular risk factors.80

Smoking is a well-known and most important modifiablerisk factor for ASCVD and has been associated withED in asymptomatic young adults without any other riskfactors.81 The proposed mechanisms are thought to besecondary to smoking increasing adherence of plateletsand macrophages to the vessel wall, developing a procoagulantand inflammatory environment.82 Smoking cessation,for only 2 weeks, has been found to reduce plateletaggregations, and thus, decrease oxidative stress.83 Astudy of 1,504 current smokers found that after 1 year ofcessation, FMD improved despite weight gain, while inthose who did not quit, FMD did not change.84

Insulin Sensitizers

Metformin is a biguanide that reduces IR without directlyaffecting insulin secretion and causes weight loss.85 Metforminreduces the incidence of metabolic syndrome by17% compared with placebo.86 Patients with metabolic syndrome who received metformin showed significantimprovement in EDV compared with placebo.87 Subjectswith type II diabetes managed with diet but withoutmetabolic syndrome had improvement in ACh-stimulatedvasodilation in addition to IR.88 Potential mechanisms formetformin's effect include the improvement in IR, antioxidanteffects, and its effects on lipids and free fatty acids.89
Troglitazone, an activator of peroxisome proliferatoractivator receptor a, improved IR and controlled diabetes.Patients treated with troglitazone for 12 weeks hadimproved FMD, which strongly correlated with improvedfasting insulin levels.90 Rosiglitazone also improved EDafter 12 weeks in patients with type II diabetes, an effectattributed to increase in NO.91


The recent 2013 American College of Cardiology (ACC)/AHA guidelines recommend statin therapy for primaryprevention in patients with diabetes between the ages of40 and 75 years, with calculated 10-year ASCVD risk of7.5% or higher, with LDL cholesterol levels of 190 mg/dLor higher, and those with cardiovascular disease.92 Theevidence for statins' widespread use for primary ASCVDprevention, and specifically its benefits on ED, datesback to the 1990s. Six months of lovastatin dose 40 mgtwice-daily therapy significantly improved endotheliummediatedresponses in 23 patients with atherosclerosis.93

The effects of statins on ED were then found to occurearlier than 6 months in subsequent studies. Six weeks of40 mg of daily pravastatin increased FMD in patients withacute coronary syndrome, when compared with placebo,in the Reduction of Cholesterol in Ischemia and Functionof the Endothelium (RECIFE) trial.94 Another study founda significant increase in FMD in hypercholesterolemic,postmenopausal women receiving atorvastatin as earlyas 2 weeks.95

Interestingly, the RECIFE trial did not find any correlationsbetween the changes in FMD and decreases in totaland LDL cholesterol,94 suggesting another mechanismof ED improvement other than lipid lowering. Indeed,statins have been shown to increase the bioavailability ofNO: Patients with both normal and high levels of cholesterolhad significant improvement in EDV after L-NMMAwas administered and blocked statin therapy.96,97 Statinsmay also reduce leukocyte adhesion and thus improveendothelial function by reducing circulating levels ofadhesion molecules P-selectin and ICAM-1.98


The vascular endothelium serves as a modulator ofvascular disease, and ED is a critical early step in thedevelopment of atherosclerosis. The components of metabolic syndrome render patients more susceptibleto ASCVD as their endothelial function is disrupted byinflammation, oxidative stress, and biomechanical stress.This is a promising study population to identify potentialbiomarkers or other modes of endothelial functionassessment to ultimately better risk-stratify patients whoare likely to develop ASCVD and sustain major cardiovascularevents. Prospective trials are needed to assessthe prognostic value of risk assessment in these patients.Furthermore, novel, primary preventive interventionscould be developed targeting this early stage of atherosclerosisto decrease the ASCVD burden that continuesits devastation worldwide.

Endothelial Dysfunction and Metabolic Syndrome

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