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Endothelial Dysfunction and Metabolic Syndrome
  JOHTN
ENDOTHELIAL FACTORS IN 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
 
ABSTRACT
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
 
 

INTRODUCTION

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

 
ENDOTHELIAL DYSFUNCTION

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.

ENDOTHELIAL DYSFUNCTION ASSESSMENT

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
 
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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

 
METABOLIC SYNDROME AND MECHANISMS
CONTRIBUTING TO ENDOTHELIAL DYSFUNCTION


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

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
Hypertriglyceridemia


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.
 
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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.

Hypertension

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.

TREATMENT OF METABOLIC SYNDROME AND
ITS EFFECTS ON ENDOTHELIAL DYSFUNCTION

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

Statins

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

CONCLUSION

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.
 
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REFERENCES
  1. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolicsyndrome among US adults: findings from the third NationalHealth and Nutrition Examination Survey. JAMA 2002 Jan;287(3):356-359.
  2. Ferrannini E, Haffner SM, Mitchell BD, Stern MP. Hyperinsulinaemia:the key feature of a cardiovascular and metabolicsyndrome. Diabetologia 1991 Jun;34(6):416-422.
  3. Lemieux I, Pascot A, Couillard C, Lamarche B, Tchernof A,Almeras N, Bergeron J, Gaudet D, Tremblay G, Prud'homme D,et al. Hypertriglyceridemic waist. Circulation 2000 Jul;102(2):179-184.
  4. Carr DB, Utzschneider KM, Hull RL, Kodama K, Retzlaff BM,Brunzell JD, Shofer JB, Fish BE, Knopp RH, Kahn SE.Intra-abdominal fat is a major determinant of the NationalCholesterol Education Program Adult Treatment Panel IIIcriteria for the metabolic syndrome. Diabetes 2004 Aug;53(8):2087-2094.
  5. Reaven G. The metabolic syndrome or the insulin resistancesyndrome?Different names, different concepts, and differentgoals. Endocrinol Metab Clin North Am 2004 Jun; 33(2):283-303.
  6. Stolzenberg-Solomon RZ, Graubard BI, Chari S, Limburg P,Taylor PR, Virtamo J, Albanes D. Insulin, glucose, insulinresistance, and pancreatic cancer in male smokers. JAMA2005 Dec;294(22):2872-2878.
  7. Petersen KF, Shulman GI. Pathogenesis of skeletal muscleinsulin resistance in type 2 diabetes mellitus. Am J Cardiol2002 Sep;90(5A):11G-18G.
  8. Hu FB, Meigs JB, Li TY, Rifai N, Manson JE. Inflammatorymarkers and risk of developing type 2 diabetes in women.Diabetes 2004 Mar; 53(3):693-700.
  9. Hanley AJ, Festa A, D'Agostino RB Jr, Wagenknecht LE,Savage PJ, Tracy RP, Saad MF, Haffner SM. Metabolic andinflammation variable clusters and prediction of type 2diabetes. Diabetes 2004 Jul;53(7):1773-1781.
  10. Sesso HD, Buring JE, Rifai N, Blake GJ, Gaziano JM, RidkerPM. C-reactive protein and the risk of developing hypertension.JAMA 2003 Dec;290(22):2945-2951.
  11. Ridker PM, Wilson PW, Grundy SM. Should C-reactiveprotein be added to metabolic syndrome and to assessmentof global cardiovascular risk? Circulation 2004 Jun;109(23):2818-2825.
  12. Samad FR, Ruf W. Inflammation, obesity, and thrombosis.Blood 2013 Nov;122(20):3415-3422.
  13. van Dielen FM, Buurman WA, Hadfoune M, Nijhuis J,Greve JW. Macrophage inhibitory factor, plasminogen activatorinhibitor-1, other acute phase proteins, and inflammatorymediators normalize as a result of weight loss in morbidlyobese subjects treated with gastric restrictive surgery. J ClinEndocrinol Metab 2004 Aug;89(8):4062-4068.

 
  1. Vane JR, Anggard EE, Botting RM. Regulatory functions ofthe vascular endothelium. N Engl J Med 1990 Jul;323(1):27-36.
  2. Meyers MR, Gokce N. Endothelial dysfunction in obesity:etiological role in atherosclerosis. Curr Opin EndocrinolDiabetes Obes 2007 Oct;14(5):365-369.
  3. Deanfield JE, Halcox JP, Rabelink TJ. Endothelial functionand dysfunction: testing and clinical relevance. Circulation2007 Mar;115(10):1285-1295.
  4. Forstermann U, Sessa WC. Nitric oxide synthases: regulationand function. Eur Heart J 2012 Apr;33(7):829-837, 837a-837d.
  5. Alheid U, Frolich JC, Forstermann U. Endothelium-derivedrelaxing factor from cultured human endothelial cellsinhibits aggregation of human platelets. Thromb Res 1987Sep;47(5):561-571.
  6. Busse R, Luckhoff A, Bassenge E. Endothelium-derived relaxantfactor inhibits platelet activation. Naunyn SchmiedebergsArch Pharmacol 1987 Nov;336(5):566-571.
  7. Flavahan NA. Atherosclerosis or lipoprotein-inducedendothelial dysfunction: potential mechanism underlyingreduction in ADRF/nitric oxide activity. Circulation 1992May;85(5):1927-1938.
  8. Ludmer PL, Selwyn AP, Shook TL, Wayne RR, Mudge GH,Alexander RW, Ganz P. Paradoxical vasoconstriction inducedby acetylcholine in atherosclerotic arteries. N Engl J Med 1986Oct;315(17):1046-1051.
  9. Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D,Charbonneau F, Creager MA, Deanfield J, Drexler H,Gerhard-Herman M, Herrington D, et al. Guidelines forthe ultrasound assessment of endothelial-dependent flowmediatedvasodilation of the brachial artery: a report of theInternational Brachial Artery Reactivity Task Force. J AmColl Cardiol 2002 Jan;39(2):257-265.
  10. Molyneux CA, Glyn MC, Ward BJ. Oxidative stress andcardiac microvascular structure in ischemia and reperfusion:the protective effect of antioxidant vitamins. Microvasc Res2002 Sep;64(2):265-277.
  11. Bohlen HG, Zhou X, Unthank JL, Miller SJ, Bills R. Transferof nitric oxide by blood from upstream to downstream resistancevessels causes microvascular dilation. Am J PhysiolHeart Circ Physiol 2009 Oct;297(4):H1337-H1346.
  12. Mkhwanazi BN, Serumula MR, Myburg RB, Van Heerden FR,Musabayane CT. Antioxidant effects of maslinic acid inlivers, hearts and kidneys of streptozotocin-induced diabeticrats: effects on kidney function. Ren Fail 2014 Apr;36(3):419-431.
  13. Dhawan SS, Eshtehardi P, McDaniel MC, Fike LV, Jones DP,Quyyumi AA, Samady H. The role of plasma aminothiolsin the prediction of coronary microvascular dysfunctionand plaque vulnerability. Atherosclerosis 2011 Nov;219(1):266-272.
  14. Ashfaq S, Abramson JL, Jones DP, Rhodes SD, Weintraub WS,Hooper WC, Vaccarino V, Harrison DG, Quyyumi AA. Therelationship between plasma levels of oxidized and reducedthiols and early atherosclerosis in healthy adults. J Am CollCardiol 2006 Mar;47(5):1005-1011.

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Suegene K Lee et al

  1. Ashfaq S, Abramson JL, Jones DP, Rhodes SD, Weintraub WS,Hooper WC, Alexander RW, Vaccarino V, Harrison DG,Quyyumi AA. Endothelial function and aminothiol biomarkersof oxidative stress in healthy adults. Hypertension 2008Jul;52(1):80-85.
  2. Abramson JL, Hooper WC, Jones DP, Ashfaq S, Rhodes SD,Weintraub WS, Harrison DG, Quyyumi AA, Vaccarino V.Association between novel oxidative stress markers andC-reactive protein among adults without clinical coronaryheart disease. Atherosclerosis 2005 Jan;178(1):115-121.
  3. Patel RS, Al Mheid I, Morris AA, Ahmed Y, Kavtaradze N,Ali S, Uphoff I, Sher S, Dabhadkar K, Aznaouridis K, et al.The oxidized aminothiol cystine is associated with impairedarterial elasticity indices in healthy human subjects. Atherosclerosis2011 Sept;218(1):90-95. .
  4. Ignarro LJ, Napoli C. Novel features on nitric oxide, endothelialnitric oxide synthase and atherosclerosis. Curr AtherosclerRep 2004 Jul;6(4):281-287.
  5. Lekakis J, Abraham P, Balbarini A, Blann A, Boulanger CM,Cockcroft J, Cosentino F, Deanfield J, Gallino A, Ikonomidis I,et al. Methods for evaluating endothelial function: a positionstatement from the European Society of Cardiology WorkingGroup on Peripheral Circulation. Eur J Cardiovasc PrevRehabil 2011 Dec;18(6):775-789.
  6. Wang H, Liu J. Plasma asymmetric dimethylarginine andL-arginine levels in Chinese patients with essential hypertensionwithout coronary artery disease. J Cardiovasc Dis Res2011 Jul-Sep;2(3):177-180.
  7. Sitia S, Tomasoni L, Atzeni F, Ambrosio G, Cordiano C,Catapano A, Tramontana S, Perticone F, Naccarato P,Camici P, et al. From endothelial dysfunction to atherosclerosis.Autoimmun Rev 2010 Oct;9(12):830-834.
  8. Sen N, Poyraz F, Tavil Y, Yazici HU, Turfan M, Hizal F,Topal S, Erdamar H, Cakir E, Yalcin R, et al. Carotid intimamediathickness in patients with cardiac syndrome X andits association with high circulating levels of asymmetricdimethylarginine. Atherosclerosis 2009 Jun;204(2):e82-e85.
  9. Lind L. Endothelium-dependent vasodilation, insulin resistanceand the metabolic syndrome in an elderly cohort: theProspective Investigation of the Vasculature in UppsalaSeniors (PIVUS) study. Atherosclerosis 2008 Feb;196(2):795-802.
  10. Su Y, Liu XM, Sun YM, Wang YY, Luan Y, Wu Y. Endothelialdysfunction in impaired fasting glycemia, impaired glucosetolerance, and type 2 diabetes mellitus. Am J Cardiol 2008Aug;102(4):497-498.
  11. Johnstone MT, Creager SJ, Scales KM, Cusco JA, Lee BK,Creager MA. Impaired endothelium-dependent vasodilationin patients with insulin-dependent diabetes mellitus. Circulation1993 Dec;88(6):2510-2516.
  12. Arcaro G, Cretti A, Balzano S, Lechi A, Muggeo M, Bonora E,Bonadonna RC. Insulin causes endothelial dysfunctionin humans: sites and mechanisms. Circulation 2002Feb;105(5):576-582.
  13. Shinozaki K, Hirayama A, Nishio Y, Yoshida Y, Ohtani T,Okamura T, Masada M, Kikkawa R, Kodama K, Kashiwagi A.Coronary endothelial dysfunction in the insulin-resistantstate is linked to abnormal pteridine metabolism and vascularoxidative stress. J Am Coll Cardiol 2001 Dec;38(7):1821-1828.
  14. Deedwania PC. Mechanisms of endothelial dysfunction inthe metabolic syndrome. Curr Diab Rep 2003 Jul;3(4):289-292.

 
  1. Bucala R, Tracey KJ, Cerami A. Advanced glycosylation productsquench nitric oxide and mediate defective endotheliumdependentvasodilatation in experimental diabetes. J ClinInvest 1991 Feb;87(2):432-438.
  2. Avogaro A, Albiero M, Menegazzo L, de Kreutzenberg S,Fadini GP. Endothelial dysfunction in diabetes: the role ofreparatory mechanisms. Diabetes Care 2011 May;34(Suppl 2):S285-S290.
  3. Meigs JB, Hu FB, Rifai N, Manson JE. Biomarkers of endothelialdysfunction and risk of type 2 diabetes mellitus. JAMA2004 Apr;291(16):1978-1986.
  4. Duplain H, Burcelin R, Sartori C, Cook S, Egli M, Lepori M,Vollenweider P, Pedrazzini T, Nicod P, Thorens B, et al.Insulin resistance, hyperlipidemia, and hypertension in micelacking endothelial nitric oxide synthase. Circulation 2001Jul;104(3):342-345.
  5. Miles PD, Levisetti M, Reichart D, Khoursheed M, Moossa A,Olefsky JM. Kinetics of insulin action in vivo: identificationof rate-limiting steps. Diabetes 1995 Aug;44(8):947-953.
  6. Bonadonna RC, Saccomani MP, Del Prato S, Bonora E,DeFronzo RA, Cobelli C. Role of tissue-specific bloodflow and tissue recruitment in insulin-mediated glucoseuptake of human skeletal muscle. Circulation 1998 Jul;98(3):234-241.
  7. Pinkney JH, Stehouwer CD, Coppack SW, Yudkin JS. Endothelialdysfunction: cause of the insulin resistance syndrome.Diabetes 1997 Sep;46(Suppl 2):S9-S13.
  8. Benjamin EJ, Larson MG, Keyes MJ, Mitchell GF, Vasan RS,Keaney JF Jr, Lehman BT, Fan S, Osypiuk E, Vita JA. Clinicalcorrelates and heritability of flow-mediated dilation in thecommunity: the Framingham Heart Study. Circulation 2004Jun;109(5):613-619.
  9. Al Suwaidi J, Higano ST, Holmes DR Jr, Lennon R, Lerman A.Obesity is independently associated with coronary endothelialdysfunction in patients with normal or mildly diseasedcoronary arteries. J Am Coll Cardiol 2001 May;37(6):1523-1528.
  10. Yudkin JS, Stehouwer CD, Emeis JJ, Coppack SW. C-reactiveprotein in healthy subjects: associations with obesity, insulinresistance, and endothelial dysfunction: a potential role forcytokines originating from adipose tissue? ArteriosclerThromb Vasc Biol 1999 Apr;19(4):972-978.
  11. Berg AH, Scherer PE. Adipose tissue, inflammation, andcardiovascular disease. Circ Res 2005 May;96(9):939-949.
  12. Ouchi N, Ohishi M, Kihara S, Funahashi T, Nakamura T,Nagaretani H, Kumada M, Ohashi K, Okamoto Y, Nishizawa H,et al. Association of hypoadiponectinemia with impairedvasoreactivity. Hypertension 2003 Sep;42(3):231-234.
  13. Han SH, Quon MJ, Kim JA, Koh KK. Adiponectin and cardiovasculardisease: response to therapeutic interventions.J Am Coll Cardiol 2007 Jan;49(5):531-538.
  14. Bakker SJ, IJzerman RG, Teerlink T, Westerhoff HV, GansRO, Heine RJ. Cytosolic triglycerides and oxidative stressin central obesity: the missing link between excessive atherosclerosis,endothelial dysfunction, and beta-cell failure?Atherosclerosis 2000 Jan;148(1):17-21.
  15. Tesauro M, Cardillo C. Obesity, blood vessels and metabolicsyndrome. Acta Physiol (Oxf) 2011 Sep;203(1):279-286.
  16. Lupattelli G, Marchesi S, Lombardini R, Siepi D, Bagaglia F,Pirro M, Ciuffetti G, Schillaci G, Mannarino E. Mechanismsof high-density lipoprotein cholesterol effects on the endothelialfunction in hyperlipemia. Metabolism 2003 Sep;52(9):1191-1195.

 
78

Endothelial Dysfunction and Metabolic Syndrome

  1. Toikka JO, Ahotupa M, Viikari JS, Niinikoski H, Taskinen M,Irjala K, Hartiala JJ, Raitakari OT. Constantly low HDLcholesterolconcentration relates to endothelial dysfunctionand increased in vivo LDL-oxidation in healthy young men.Atherosclerosis 1999 Nov;147(1):133-138.
  2. Mackness MI, Arrol S, Durrington PN. Paraoxonase preventsaccumulation of lipoperoxides in low-density lipoprotein.FEBS Letters 1991 Jul;286(1-2):152-154.
  3. Watson AD, Berliner JA, Hama SY, La Du BN, Faull KF,Fogelman AM, Navab M. Protective effect of high densitylipoprotein associated paraoxonase. Inhibition of the biologicalactivity of minimally oxidized low density lipoprotein.J Clin Invest 1995 Dec;96(6):2882-2891.
  4. Liao JK, Shin WS, Lee WY, Clark SL. Oxidized low-densitylipoprotein decreases the expression of endothelial nitricoxide synthase. J Biol Chem 1995 Jan;270(1):319-324.
  5. Lundman PE, Eriksson MJ, Stuhlinger M, Cooke JP, Hamsten A,Tornvall P. Mild-to-moderate hypertriglyceridemia in youngmen is associated with endothelial dysfunction and increasedplasma concentrations of asymmetric dimethylarginine.J Am Coll Cardiol 2001 Jul;38(1):111-116.
  6. Lupattelli G, Lombardini R, Schillaci G, Ciuffetti G, Marchesi S,Siepi D, Mannarino E. Flow-mediated vasoactivity andcirculating adhesion molecules in hypertriglyceridemia:association with small, dense LDL cholesterol particles. AmHeart J 2000 Sep;140(3):521-526.
  7. Lewis TV, Dart AM, Chin-Dusting JPF. Endotheliumdependentrelaxation by acetylcholine is impaired in hypertriglyceridemichumans with normal levels of plasma LDLcholesterol. J Am Coll Cardiol 1999 Mar;33(3):805-812.
  8. Chowienczyk PJ, Watts GF, Wierzbicki AS, Cockcroft JR,Brett SE, Ritter JM. Preserved endothelial function in patientswith severe hypertriglyceridemia and low functional lipoproteinlipase activity. J Am Coll Cardiol 1997 Apr;29(5):964-968.
  9. Treasure CB, Klein JL, Vita JA, Manoukian SV, Renwick GH,Selwyn AP, Ganz P, Alexander RW. Hypertension andleft ventricular hypertrophy are associated with impairedendothelium-mediated relaxation in human coronary resistancevessels. Circulation 1993 Jan;87(1):86-93.
  10. Panza JA, Quyyumi AA, Brush JE Jr, Epstein SE. Abnormalendothelium-dependent vascular relaxation in patients withessential hypertension. New Engl J Med 1990 Jul;323(1):22-27.
  11. Panza JA, Casino PR, Kilcoyne CM, Quyyumi AA. Role ofendothelium-derived nitric oxide in the abnormal endothelium-dependent vascular relaxation of patients with essentialhypertension. Circulation 1993 May;87(5):1468-1474.
  12. Taddei S, Virdis A, Ghiadoni L, Magagna A, Salvetti A.Vitamin C improves endothelium-dependent vasodilationby restoring nitric oxide activity in essential hypertension.Circulation 1998 Jun;97(22):2222-2229.
  13. Versari D, Daghini E, Virdis A, Ghiadoni L, Taddei S.Endothelium-dependent contractions and endothelialdysfunction in human hypertension. Br J Pharmacol 2009Jun;157(4):527-536.
  14. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH,Franklin BA, Gordon DJ, Krauss RM, Savage PJ, Smith SC Jr,et al. Diagnosis and management of the metabolic syndrome:an American Heart Association/National Heart, Lung,and Blood Institute Scientific Statement. Circulation 2005Oct;112(17):2735-2752.

 
  1. Care ADASoM. Foundations of care: education, nutrition,physical activity, smoking cessation, psychoscoial care, andimmunization. Diabetes Care 2015 Jan;38(Suppl 1):S20-S30.
  2. Salas-Salvado J, Bullo M, Estruch R, Ros E, Covas MI,Ibarrola-Jurado N, Corella D, Aros F, Gomez-Gracia E,Ruiz-Gutierrez V, et al. Prevention of diabetes with Mediterraneandiets: a subgroup analysis of a randomized trial. AnnIntern Med 2014 Jan;160(1):1-10.
  3. Esposito K, Marfella R, Ciotola M, Di Palo C, Giugliano F,Giugliano G, D'Armiento M, D'Andrea F, Giugliano D. Effectof a Mediterranean-style diet on endothelial dysfunctionand markers of vascular inflammation in the metabolic syndrome:a randomized trial. JAMA 2004 Sep;292(12):1440-1446.
  4. Marin C, Ramirez R, Delgado-Lista J, Yubero-Serrano EM,Perez-Martinez P, Carracedo J, Garcia-Rios A, Rodriguez F,Gutierrez-Mariscal FM, Gomez P, et al. Mediterranean dietreduces endothelial damage and improves the regenerativecapacity of endothelium. Am J Clin Nutr 2011 Feb;93(2):267-274.
  5. Haskell WL, Lee IM, Pate RR, Powell KE, Blair SN, Franklin BA,Macera C, Heath GW, Thompson PD, Bauman A. Physicalactivity and public health: updated recommendation foradults from the American College of Sports Medicine andthe American Heart Association. Med Sci Sports Exerc 2007Sep;39(8):1423-1434.
  6. DeSouza CA, Shapiro LF, Clevenger CM, Dinenno FA,Monahan KD, Tanaka H, Seals DR. Regular aerobic exerciseprevents and restores age-related declines in endotheliumdependentvasodilation in healthy men. Circulation 2000Sep;102(12):1351-1357.
  7. Hambrecht R, Fiehn E, Weigl C, Gielen S, Hamann C, Kaiser R,Yu J, Adams V, Niebauer J, Schuler G. Regular physical exercisecorrects endothelial dysfunction and improves exercisecapacity in patients with chronic heart failure. Circulation1998 Dec;98(24):2709-2715.
  8. Green DJ, Walsh JH, Maiorana A, Best MJ, Taylor RR,O'Driscoll JG. Exercise-induced improvement in endothelialdysfunction is not mediated by changes in CV risk factors:pooled analysis of diverse patient populations. Am J PhysiolHeart Circ Physiol 2003 Dec;285(6):H2679-H2687.
  9. Tjonna AE, Lee SJ, Rognmo 0, Stolen TO, Bye A, Haram PM,Loennechen JP, Al-Share QY, Skogvoll E, Slordahl SA, et al.Aerobic interval training versus continuous moderate exerciseas a treatment for the metabolic syndrome: a pilot study.Circulation 2008 Jul;118(4):346-354.
  10. Celermajer DS, Sorensen KE, Georgakopoulos D, Bull C,Thomas O, Robinson J, Deanfield JE. Cigarette smokingis associated with dose-related and potentially reversibleimpairment of endothelium-dependent dilation in healthyyoung adults. Circulation 1993 Nov;88(5 Pt 1):2149-2155.
  11. Messner B, Bernhard D. Smoking and cardiovascular disease:mechanisms of endothelial dysfunction and early atherogenesis.Arterioscler Thromb Vasc Biol 2014 Mar;34(3):509-515.
  12. Morita H, Ikeda H, Haramaki N, Eguchi H, Imaizumi T. Onlytwo-week smoking cessation improves platelet aggregabilityand intraplatelet redox imbalance of long-term smokers. J AmColl Cardiol 2005 Feb;45(4):589-594.
  13. Johnson HM, Gossett LK, Piper ME, Aeschlimann SE,Korcarz CE, Baker TB, Fiore MC, Stein JH. Effects of smokingand smoking cessation on endothelial function: 1-year outcomesfrom a randomized clinical trial. J Am Coll Cardiol2010 May;55(18):1988-1995.

Hypertension Journal, April-June, Vol 3, 2017 79

Suegene K Lee et al

  1. Stumvoll M, Nurjhan N, Perriello G, Dailey G, Gerich JE.Metabolic effects of metformin in non-insulin-dependentdiabetes mellitus. N Engl J Med 1995 Aug;333(9):550-554.
  2. Orchard TJ, Temprosa M, Goldberg R, Haffner S, Ratner R,Marcovina S, Fowler S, Diabetes Prevention ProgramResearch Group. The effect of metformin and intensive lifestyleintervention on the metabolic syndrome: the DiabetesPrevention Program randomized trial. Ann Intern Med 2005Apr;142(8):611-619.
  3. Vitale C, Mercuro G, Cornoldi A, Fini M, Volterrani M, RosanoGM. Metformin improves endothelial function in patientswith metabolic syndrome. J Intern Med 2005 Sep;258(3):250-256.
  4. Mather KJ, Verma S, Anderson TJ. Improved endothelialfunction with metformin in type 2 diabetes mellitus. J AmColl Cardiol 2001 Apr;37(5):1344-1350.
  5. Bailey CJ, Turner RC. Metformin. N Engl J Med 1996Feb;334(9):574-579.
  6. Caballero AE, Saouaf R, Lim SC, Hamdy O, Abou-EleninK, O'Connor C, Logerfo FW, Horton ES, Veves A. Theeffects of troglitazone, an insulin-sensitizing agent, on theendothelial function in early and late type 2 diabetes: aplacebo-controlled randomized clinical trial. Metabolism2003 Feb;52(2):173-180.
  7. Pistrosch F, Passauer J, Fischer S, Fuecker K, Hanefeld M,Gross P. In type 2 diabetes, rosiglitazone therapy for insulinresistance ameliorates endothelial dysfunction independentof glucose control. Diabetes Care 2004 Feb;27(2):484-490.
  8. Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN,Blum CB, Eckel RH, Goldberg AC, Gordon D, Levy D,Lloyd-Jones DM, et al. 2013 ACC/AHA guideline on the treatmentof blood cholesterol to reduce atherosclerotic cardiovascularrisk in adults: a report of the American College of Cardiology/American Heart Association Task Force onPractice Guidelines. J Am Coll Cardiol 2014 Jul;63(25 Pt B):2889-2934.

 
  1. Treasure CB, Klein J, Weintraub WS, Talley JD, Stillabower ME,Kosinski AS, Zhang J, Boccuzzi SJ, Cedarholm JC, Alexander RW.Beneficial effects of cholesterol-lowering therapy on the coronaryendothelium in patients with coronary artery disease.N Engl J Med 1995 Feb;332(8):481-487.
  2. Dupuis J, Tardif J, Cernacek P, Theroux P. Cholesterolreduction rapidly improves endothelial function after acutecoronary syndromes: the RECIFE (reduction of cholesterol inischemia and function of the endothelium) trial. Circulation1999 Jun;99(25):3227-3233.
  3. Marchesi S, Lupattelli G, Siepi D, Schillaci G, Vaudo G,Roscini AR, Sinzinger H, Mannarino E. Short-term atorvastatintreatment improves endothelial function in hypercholesterolemicwomen. J Cardiovasc Pharmacol 2000Nov;36(5):617-621.
  4. John S, Schlaich M, Langenfeld M, Weihprecht H, Schmitz G,Weidinger G, Schmieder RE. Increased bioavailability ofnitric oxide after lipid-lowering therapy in hypercholesterolemicpatients: a randomized, placebo-controlled, doubleblindstudy. Circulation 1998 Mar;98:211-216.
  5. Masumoto A, Hirooka Y, Hironaga K, Eshima K, Setoguchi S,Egashira K, Takeshita A. Effect of pravastatin on endothelialfunction in patients with coronary artery disease (cholesterol-independent effect of pravastatin). Am J Cardiol 2001Dec;88(11):1291-1294.
  6. Romano M, Mezzetti A, Marulli C, Ciabattoni G, Febo F, DiIenno S, Roccaforte S, Vigneri S, Nubile G, Milani M, et al.Fluvastatin reduces soluble P-selectin and ICAM-1 levels inhypercholesterolemic patients: role of nitric oxide. J InvestigMed 2000 May;48(3):183-189.

 
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