Endothelial dysfunction in African-Americans

International Journal of Cardiology 132 (2009) 157–172www.elsevier.com/locate/ijcard

Review

Endothelial dysfunction in African-Americans

Pawan D. Patel, Jose L. Velazquez, Rohit R. Arora⁎

Department of Medicine, The Chicago Medical School, Chicago, IL, United States

Received 27 January 2008; received in revised form 25 July 2008; accepted 12 October 2008Available online 11 November 2008

Abstract

The journey of atherosclerosis begins with endothelial dysfunction and culminates into its most fearful destination producing ischemia,myocardial infarction and death. The excess cardiovascular disease morbidity and mortality in African-Americans is one of the major publichealth problems. In this review, we discuss vascular endothelial dysfunction as a key element for excess cardiovascular disease burden in thistarget population. It can be logical window of future atherosclerotic outcomes, and further efforts should be made to detect it at the earliest inAfrican American individuals even if they are appearing healthy as the therapeutic interventions if instituted early, might prevent thesubsequent cardiac events.Published by Elsevier Ireland Ltd.

Keywords: African-Americans; Endothelial dysfunction; Cardiovascular dis
ease
1. Introduction

Virtually ubiquitous worldwide, atherosclerosis is thecommonest cause of Ischemic heart disease and regardless ofthe risk factors for atherosclerosis, Endothelial Dysfunction(ED) is an initiating event for atherosclerosis.

2. Burden of cardiovascular disease inAfrican-Americans

Excess cardiovascular disease burden among African-Americans is a major public health problem [1]. AfricanAmericans have higher rates of hypertension [2], diabetesmellitus [3,4], stroke [5] andmyocardial infarction at youngerage [6]. Young and middle-aged blacks have a substantially

⁎ Corresponding author. Department of Cardiology, Chicago MedicalSchool, North Chicago VA Medical Centre-133B, 3001 Green Bay Road,North Chicago, IL-60064, United States. Tel.: +1 224 610 4503; fax: +1 224610 3878.

E-mail address: [email protected] (R.R. Arora).

0167-5273/$ - see front matter. Published by Elsevier Ireland Ltd.doi:10.1016/j.ijcard.2008.10.007

higher risk of subarachnoid or intracerebral hemorrhage thanwhites of similar age [7].

3. Vascular endothelium

The endothelium is a large paracrine organ in thebody. The endothelium has long been viewed as an inertcellophane-like membrane that lines the circulatory systemwith its primary essential function being the maintenance ofvessel wall permeability [8]. In the later half of the 20thcentury, the focus on endothelium started shifting from aninert layer to an active layer. Currently, the endothelium isviewed as a dynamic, heterogeneous, disseminated organ thatpossesses vital secretary, synthetic, metabolic, and immu-nologic functions [9].

Furchgott and Zawadzki [10] experimentally proved thesynthesis of Endothelium derived relaxing factor (EDRF) inthe aortic ring of rabbit which was later on found to be NitricOxide (NO) . Endothelial cells secrete both the vasodilator[e.g. Nitric oxide (NO) and Prostacyclin (PGI2)] and vaso-constrictor [e.g. Endothelin-1 (ET-1), Thromboxane A2 andPlatelet activating factor (PAF)] molecules (Table 1). NO is a

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Table 1Vasodilator substances released by endothelium

Substance Principal effect Other effects Secretion

NO (nitric oxide) Vasodilation Decreases platelet aggregation and adhesion, limits vascularsmooth muscle proliferation, inhibits neointima formation,prevents monocyte chemotaxis, and inhibits leukocyte adhesion.

Paracrine/Constitutive and induced by thrombin,serotonin, acetylcholine, adenosine 5′-diphosphate,bradykinin and substance P.

PGI2 (prostacyclin) Vasodilation Retards platelet aggregation and deposition Paracrine/Induced at sites of vascular perturbationEndothelium-derivedHyperpolarizing

factor (EDHF)

Vasodilation Maintains vasodilation in disease state when NO productiondecreases.

Paracrine/Induced

PAF (plateletactivating factor)

Vasoconstriction Promotes leukocyte adhesion at cell surface Juxtacrine/Induced

ET-1 (endothelin-1) Vasoconstriction Mitogenic effect on vascular smooth muscle cells, cardiacmyocytes, coronary vascular smooth muscle cells and renalmesangial cells. Promotes renal vasoconstriction and tubularsodium and water loss. Stimulate Angiotensin convertingenzyme activity and tissue rennin–angiotensin system.

Paracrine/Induced by hypoxia, shear stress, andischemia

158 P.D. Patel et al. / International Journal of Cardiology 132 (2009) 157–172

potent vasodilator and possesses many antiatherogenic pro-perties [11]. NO decreases platelet aggregation and adhesion,limits vascular smooth proliferation, inhibits neointima for-mation, prevents monocyte chemotaxis, and inhibits leuko-cyte adhesion to the endothelium [12].

The surface of the endothelium is lined by glycocalyx, amucopolysaccharide, which repels the clotting factors andplatelets thereby preventing activation of clotting cascade.Thrombomodulin is a protein, which is bound to endothe-lium, and then binds with thrombin thereby slowing theprocess of clotting [13].

Endothelial cells (EC) elaborate NO, a heterodiatomic freeradical product generated through the oxidation of L-arginineto L-citrulline by NO synthases (NOS) [14]. Three isoforms ofNOS have been described: NOS1 (nNOS), NOS2 (iNOS),and NOS3 (eNOS). eNOS is Calcium (Ca2+) dependent iso-form and is firmly attached to inhibitor protein caveolin.eNOS is constitutively active but is stimulated further byreceptor-dependent agonists. Receptor-dependent agoniststhat stimulate eNOS include thrombin, serotonin, acetylcho-line, adenosine 5′-diphosphate, bradykinin and substance P.

In the presence of eNOS agonists, intracellular Ca2+ isreleased from the endoplasmic reticulum. Ca2+ causes aninitial activation of eNOS, its dissociation from caveolin, andits translocation to intracellular sites [15]. Miniatis and col-leagues have demonstrated that NO production in pulmonaryendothelial cells is mostly mediated by caveolae internaliza-tion and is independent of the increase of intracellular cal-cium [16]. In addition under the influence of the agonists,mitogen-activated protein kinase (MAP-kinase) and/or theprotein kinase B/Akt pathway gets activated which causesphosphorylation of cytosolic eNOS and its second trans-location back to the cell membrane where it undergoesmyristoylation and palmitoylation, thus completing the fullactivation of eNOS. This fully activated eNOS in the endo-thelial cells plays a crucial role in the formation of NO whichdiffuses through the endothelial cells and causes vascularsmooth muscle relaxation [15].

Asymmetric dimethylarginine (ADMA; an endogenouscompetitive inhibitor of NO synthase) has been shown toreduce NO bioavailability by competing with L-arginine as asubstrate for endothelial NO synthase [17].

4. Endothelin (ET)

The ETs are a family of 3 peptides, ET-1, ET-2, and ET-3produced by the endothelial cells. ET-A receptor expressedon vascular smooth muscle cells, which results in anincreased intracellular calcium concentration and, in turn,increases vascular smooth muscle cell tone. NO shortens theduration of these effects by accelerating the restoration ofintracellular calcium to basal levels. In states of endothelialdysfunction, in which concentrations of bioactive NO arereduced, the relatively unopposed actions of ET-1 promotevasoconstriction. ET-1 has a role in the pathogenesis ofhypertension and its complications. In systemic vascularbed, ET-1 causes vasoconstriction and has mitogenic effecton vascular smooth muscle cells. In heart, it has mitogeniceffect on cardiac myocytes and coronary vascular smoothmuscle cells. In kidneys, ET-1 causes renal vasoconstriction(ETA) and tubular sodium and water loss (ETB). In addition,it has mitogenic effect on renal mesangial cells.

ET-1 can stimulate Angiotensin converting enzyme (ACE)activity and stimulates the tissue renin–angiotensin system(RAS). In addition, ET-1 stimulates the release of aldoste-rone. There is positive feedback loop linking Angiotensin IIand ET-1 in disease states such as heart failure. Antagonismof the endothelin system may help in patients with persistentRAS activation, despite maximally-tolerated ACE inhibition(ACEI) or angiotensin receptor blockade (ARB) [18].

5. Endothelium-derived hyperpolarizing factor (EDHF)

The endothelium also produces EDHF that promotesvascular relaxation. NO inhibits the production of EDHF.Hence in disease when NO production decreases, EDHF is

159P.D. Patel et al. / International Journal of Cardiology 132 (2009) 157–172

released and maintain vasodilatation [19]. EDHF-mediatedresponses are triggered by an increase in the endothelialintracellular calcium (Ca++) concentration that is followedby the opening of two types of potassium (K+) channels,which results in the hyperpolarization of the endothelialcells. This response is transmitted to the smooth muscle cellsby direct electrical coupling through myoendothelial junc-tions and/or by the accumulation of potassium ions in theintercellular myoendothelial space [20].

EDHF contributes substantially to basal forearm vascularresistance, as well as to forearm vasodilatation evoked bysubstance P and bradykinin in humans [21]. In patients withheart failure, forearm vasodilatation evoked by acetylcholineis impaired whereas that by substance P is preserved [22].Therefore, EDHF might play an important compensatoryrole for the loss of NO-induced forearm vasodilatation inpatients with heart failure [21].

6. Endothelial function as a biomarker of atherosclerosis

Methods of assessment of endothelial function are des-cribed in Table 2.

6.1. Assessment of endothelium-dependent vasodilatorfunction in human

6.1.1. Coronary circulationEndothelial function in human coronary arteries can be

assessed by measuring the vasomotor responses of epicardialarteries by quantitative coronary angiography in response tograded concentrations of acetylcholine or other agonists[27]. This method has been considered the “gold standard”against which other tests of endothelial function have beencompared. In healthy vessels, acetylcholine evokes a NO-mediated vasodilatory response; however, in patients withendothelial dysfunction, this effect is blunted or paradoxicalvasoconstriction may occur [28]. This technique is limitedby its invasive nature, expense, and relative inaccessibility.

6.1.2. Peripheral circulation

6.1.2.1. Invasive method. Endothelial function can be as-sessed by measurement of forearm blood flow using strain-gauge plethysmography in conjunction with intra-arterialinfusion of endothelium-dependent agonists and selectivepharmacological probes [29].

Table 2Methods of assessment of endothelial function

1]. Endothelial dependent vasodilator function. (See text)2]. Elevated levels of circulating cellular adhesion molecules [23].3]. Elevated levels of C-reactive protein [24].4]. Urinary NO metabolites [25].5]. Decreased level of antioxidant enzyme systemic superoxide dismutase

[25].6]. Imaging by positron emission tomography and magnetic resonance

imaging [26].

6.1.2.2. Non-invasive methodAssessment of endothelium-dependent, flow-mediated

dilation (FMD) of the forearm brachial artery using high-resolution ultrasound has provided an entirely noninvasiveapproach to evaluate endothelial function [43]. The ultra-sound approach has permitted studies of endothelial functionin populations of asymptomatic subjects in whom cardiaccatheterization is not indicated.

6.1.2.3. Effect of shear stress. Endothelial cells are ex-posed continuously to fluid shear stresses. Shear stress sti-mulates endothelial nitric oxide synthase (eNOS) [30]. Aneffect of shear stress on vascular biology is suggested by theobservation, e.g., arterial segments that are predisposed tothe development of atherosclerosis show early evidence ofdefective endothelium-dependent vasodilation in both patientswith and some patients without angiographic evidence ofatherosclerosis [31].

In this method, the forearm blood flow is occluded for5 min using a blood pressure cuff maintained at a standardpressure. When the pressure is released, reactive hyperemiaoccurs. In arteries lined by healthy endothelium, increasedflow (shear stress) causes dilatation of the vessels [32], viarelease of NO. This mechanism fails in endothelial dys-function [33]. By contrast, glyceryltrinitrite (GTN) causesvasodilatation by direct action on the smooth muscle, itseffects is therefore independent of the endothelium.

Although the brachial artery is not a common site for thedevelopment of angiographically evident atherosclerosis, itis well documented that the loss of endothelium dependentdilatation occurs early in atherosclerosis even prior to itsdetection of angiography [34]. Loss of brachial artery vaso-dilatation in the absence of overt stenosis has been observedin subjects with cardiovascular risk factors like hypercho-lesterolemia, hypertension, increased Lipoprotein (a) [Lp(a),obesity and diabetes [35–39]. Also recent follow up studieshave demonstrated usefulness of endothelial dysfunction inpredicting cardiac events [40].

Assessment of endothelial dysfunction by brachial arteryultrasonography has a high sensitivity (91%) and an excellentnegative predictive value (95%) for coronary artery disease(CAD) and thus has the potential for use as a screening toolfor CAD [41]. It is noninvasive, reliable, convenient methodand also useful for assessing the responses to therapeuticinterventions over time. This method is accurate and re-producible for measurement of small changes in arterial dia-meter, with low interobserver error for measurement of FMD[42].

For arteries of diameter less than 6.0 mm, flow mediateddilatation is about 10% of the resting diameter in controlsubjects; however, for arteries of more than 6.0 mm indiameter, flow mediated dilatation is small even in healthysubjects. So this method may be best applied to the study ofsmaller arteries in adults (such as brachial or internal carotid)and larger arteries in children (such as superficial femoral)[43]. Emerging studies suggest that other noninvasivemethods


can also provide information about endothelium-dependentvasodilatation, including fingertip pulse arterial tonometer[44] and measures of arterial stiffness [45,46].

7. Role of endothelium in ethnicity

In contrast to Caucasians, African-Americans have im-paired endothelial function as evident by decreased flowmediated forearm artery vasodilatation [47–49], an increasedcarotid intima-media thickness [50,51] and an increasedlevel of endothelin-1, a potent vasoconstrictor released byendothelium [52].

Cardillo et al. [53] studied forearm blood flow at rest andafter mental stress in normotensive African-American andwhite subjects. They found that stress-induced rise in bloodflow (endothelial dependent response) was markedly low inAfrican-Americans as compared to whites but after infusionof NO synthesis inhibitor i.e. NG-monomethyl-L-arginine (L-NMMA), stress-induced rise in blood flow responsewas significantly lower in whites. Further, after infusion ofsodium nitroprusside (an exogenous NO donor), the vaso-dilator response was lower in African-Americans than inwhites.

Also, Lang et al. [54] have shown the blunted vasodila-tion in normotensive black subjects in response to infusion ofisoproterenol (ß-adrenergic agent which release endothelialNO and smooth muscle stimulator).Similarly, others haveshown blunted endothelium-dependent vasodilation in nor-motensive blacks as compared to whites [55,56].

Kahn et al. [57] studied forearm microvascular function inresponse to infusion of methacholine (which stimulate NOrelease), nitroprusside and verapamil in normotensive andhypertensive black and white subjects. The vasodilator res-ponse to methacholine was markedly lower in black vs.white subjects with hypertension, but not in normotensivesubjects. On the contrary, Stein et al. [58] demonstratedblunted rise in blood flow even in normotensive African-Americans as compared to whites in response to methacho-line. All normotensive African American subjects might nothave impaired vasodilator function and this could explain thedisparity observed in these two studies.

Further, the protective role of gender on endothelial func-tion is lost in African-American females, unlike that observedin whites [47,59]. Also, brachial artery flowmediated dilationis diminished in postmenopausal African-American womenas compared to Caucasian women [60].

African Americans have low bioavailability of endothe-lial NO than whites. It is due to excess superoxide producedby NAD (P) H-oxidase that finally yields enhanced for-mation of peroxynitrite after stimulation of eNOS. This, inturn, leads to the eNOS uncoupling, which produces moresuperoxide [61]. Superoxide has been known to mediateendothelial dysfunction [62]. In addition, an excess of totalinfectious burden seen in young African American subjectsmay mediate impaired endothelial function, mainly by aninflammatory mechanism [63].

7.1. Hypertension

In black subjects, essential hypertension has a higherprevalence, earlier onset, and is associated with more severeend-organ damage, including left ventricular hypertrophy,renal failure, and stroke [64]. In diabetic patients, conco-mitant hypertension increases mortality by as much as 7.2-fold and the presence of nephropathy increases mortality byas much as 37-fold [65].

7.1.1. Postulated mechanisms for hypertension in AfricanAmericans

Studies have shown differences in the gene polymorph-isms for several proteins that modulate vascular function as aputative mechanism of hypertension in African Americans[66–74]. In addition, Transforming growth factor (TGF)-beta 1 overexpression is more frequent in blacks comparedwith whites. It promotes fibrosis and is associated with leftventricular hypertrophy and end-stage renal disease [75].

Platelets in African Americans have increased intracel-lular calcium stores or increased cellular calcium turnover, orboth, possibly linking calcium regulation to smooth musclecells as a contributing factor for hypertension in AfricanAmericans [76].

Behavioral factors such as anger-coping style and JohnHenryism [77] and elevated sympathetic nervous systemactivity, in part secondary to increased levels of socio-economic stress, is also hypothesized as playing a role inhypertension among blacks [78].

Impairment of endothelial function may be involved inracial differences in hemodynamic reactivity to stress andpossibly in the development of essential hypertension [55–57]. Treiber et al. [79] investigated plasma ET-1 levels at restand in response to acute stress in white and black adolescentswith family histories of essential hypertension. Both videogame challenge and forehead cold stimulation resulted in ahigher increase in ET-1 concentrations in blacks than inwhites.

Black hypertensive individuals have higher plasma ET-1concentrations than white hypertensives and black normoten-sives [80]. The vasoactive, mitogenic, and renal effects of theET system might contribute to the development, maintenanceand/or complications of hypertension in African Americans[81].

The relative density of endothelin-receptor subtypes Aand B (ET (A) and ET (B), respectively) on endothelial andsmooth muscle cells is the major determinant of the contractileresponse to endothelin-1 (ET-1). For example, endothelialdysfunction with loss of NO activity would be expected toattenuate ET (B)-mediated vasodilatation and promote ET (A)-mediated vasoconstriction [18]. The presence of racialdifferences in the distribution of ET receptors on peripheralvasculature has been described previously [82].

7.1.2. Salt-sensitivity and role of potassiumThe international cooperative INTERSALT study showed

that blood pressure tends to be related to urinary potassium


excretion and to the ratio of urinary sodium excretion topotassium excretion [83]. Blacks accumulate more sodiumwith increasing sodium intake than whites [84].

Aviv et al. [85] proposed a model to explain sodium sen-sitivity in blacks. According to their model there is anincreased activity of Na–K–2Cl cotransport in the thick as-cending limb of Henle's loop which causes decrease urinarypotassium excretion, increase sodium and water conservationcapacity, and increase glomerular capillary hydraulic pressureleading to glomerular hyperfiltration. This will damage theglomeruli, a phenomenon that may contribute to hypertension.In addition, glomerular hyperfiltrationwould cause an increasein the colloid osmotic pressure in peritubular arterioles, pro-moting an increase in proximal tubular reabsorption.

Salt sensitivity may be defined as an increase in bloodpressure in response to relatively high sodium intake. Bothnormotensive and hypertensive black individuals are knownto be more salt sensitive than white Americans [86,87].Sodium restriction causes a greater fall of blood pressure inhypertensive blacks as compared with whites which may bedue to the decrease responsiveness of the renin–angiotensin–aldosterone system (with a small rise in plasma renin activity(PRA), plasma angiotensin II and plasma aldosterone) inblack African Americans [88]. However, in humans thereexists a functional vascular RAS which is independent frombut related to the circulating RAS. The functional changes ofthe vascular RAS are opposite to those of circulating PRA sothat when PRA is increased as with low sodium diet, vascularACE activity and vascular Angiotensin II generation arereduced, and the opposite occurred when PRA is depressed aswith high sodium intake. The existence of a vascular RASmay not result in a systemic blood pressure effect but may beimplicated in local processes such as vascular hypertrophyand remodeling, atherosclerosis, and restenosis [89].

Normotensive salt-sensitivity is a precursor of hypertension.Morris et al. [90] demonstrated that when dietary potassiumwasset at a marginally deficient intake similar to that habituallyingested by many blacks (30 mmol/d), dietary salt loadinginduced a mean increase in blood pressure only in blacks, andsalt sensitivity occurred in most normotensive blacks but not innormotensive whites (79% vs. 36% (Pb0.02). Further, it wasdose-dependently suppressed when dietary potassium is in-creased within its normal range. Thus, increased dietary potas-sium might prevent or delay the occurrence of hypertension,particularly in the many blacks, in whom dietary potassium isdeficient.

Also, in normotensive African-Americans, a marginallyreduced dietary intake of potassium reversibly enhancesadrenergically mediated vasopressor responsiveness to stress[91]. According to earlier study, dietary potassium supple-mentation (65 mmol/day) in 32 African American womenwith mild to moderate essential hypertension caused a smallfall in blood pressure, significant for both systolic anddiastolic pressure after 4 weeks [92].

Increased dietary potassium can lower blood pressure,particularly in “salt-sensitive” hypertension as potassium may

increase urinary loss of sodium. The response to potassiumsupplementation is slow to appear and takes approximately4 weeks. It may decrease the need for antihypertensive medi-cation and may even reduce organ system complications (e.g.,stroke) [20].

7.1.3. Relation of salt-sensitivity and potassium toendothelial function

Campese et al. [93] studied a group of 27 essential hyper-tensive and 7 normotensive African Americans during lowand high salt intake. They found that high salt intake de-creases plasma Nitrate plus nitrite (NOx) concentration inblack hypertensive patients. Also Fujiwara et al. [94] reportedthe role of NO in the pathogenesis of salt sensitivity in humanhypertension, presumably via the change in ADMA levels(an endogenous competitive inhibitor of NO synthase). Intheir study after salt loading, the plasma NOx level wasdecreased and reversed after salt restriction. In addition,plasma ADMA level was increased after salt loading anddecreased after salt restriction. Salt-sensitive hypertension isassociated with endothelial dysfunction characterized by adefective endothelium-dependent vasodilation. Impairmentof the L-arginine–nitric oxide pathway may be responsiblefor this abnormal endothelial response [95].

ADMA causes salt retention [96] and elevated plasmaADMA concentrations are associated with decreased brachialFMD responses in healthy adults with an increased risk ofcardiovascular disease [97]. ADMA levels are significantlyhigher in healthy black African males than in white Europeanmales. This may contribute to the lower NO bioavailabilityand higher incidence of cardiovascular disease seen in blackAfricans [98].

K+ could be an Endothelium-derived hyperpolarizingfactor (EDHF) or contribute to the mechanism of EDHF-mediated responses [20]. As mentioned previously, in thepresence of endothelial dysfunction where NO productiondecreases, EDHF maintains vasodilation. However, in potas-sium-depleted state this beneficial action of EDHF is lostamong African Americans.

Recently potassium supplementation have shown to blockthe effects of high-salt diet on plasma ADMA, NOx level,urinary NOx excretion, and BP in normotensive salt-sensitiveChinese population [99]. Potassium supplementation mayincrease the NO bioactivity by inhibiting the ADMA pro-duction and preventing the BP elevation resulting from highsalt loading. However, further studies are required to vali-date these findings in normotensive salt-sensitive African-Americans.

7.2. Left Ventricular remodeling/hypertrophy (LVH) andendothelial dysfunction

Left ventricular mass is known to be a powerful in-dependent predictor for cardiovascular disease events inadults. Studies have shown that black subjects have higherLV mass index and relative wall thickness compared to white


subjects both with hypertensive [100,101] and in younghealthy adults [102,103].

Also, there is higher resting systemic vascular resis-tance index and lower resting cardiac index in younghealthy black subjects. Hinderliter et al. [104] showed thatthese ethnic differences in ventricular structure and he-modynamics might be a reflection of vascular propertiesthat may result in a higher peripheral resistance in African-Americans.

Endothelial dysfunction may be the intermediate pheno-type of Left Ventricular remodeling (LVH) prevalent amongAfrican Americans. Lapu-Bula et al. [105] studied the largestpopulation-based sample of African-Americans (to date) withand without hypertension, with FMD indices of endothelialfunction. Brachial artery FMD was inversely correlated withsystolic blood pressure, diastolic blood pressure, and meanblood pressure. Further in the same sample population, theydescribed a negative association between FMD and LV massindex. FMD was lower in patients with hypertensive geo-metric patterns (eccentric or concentric). Also, the alteredNO-redox balance may contribute to cardiac hypertrophy-mediated myocardial ischemia [106].

There is also racial difference in endothelium-dependentcoronary vasoreactivity among patients with LVH which canbe one of the contributory elements in the observed adversecoronary heart disease prognosis among African Americans.Houghton et al. [107] compared coronary endothelial func-tion and vasoreactivity in African American and White sub-jects with hypertensive LVH and normal coronary arteries.When compared with whites with similar LVH, AfricanAmerican subjects demonstrated markedly depressed aug-mentation of coronary blood flow (CBF) during the infu-sions of endothelium-dependent agonist acetylcholine. Thisresponse was independent of the geometric pattern of hyper-trophy. Adenosine responses, a measure of endothelium-independent function, were similar in both the ethnic groupsafter partitioning by LVH.

7.3. Heart failure and endothelial dysfunction

Heart failure in the US population affects about 3% of theAfrican American group; whereas, in the general population,the incidence is about 2% [108–110]. Heart failure in Afri-can Americans is characterized by an early age of onset,lower incidence of documented epicardial coronary disease;and a striking disproportionate incidence of hypertension asa cause of heart failure [111–113].

The mortality rate is markedly increased: a 1.8-fold in-crease for affected African American men and a 2.4-foldincrease for women compared with all other patients [111,114]Also, African-American subjects have increased mortality dueto dilated cardiomyopathy [115]. Systolic heart failure is moreprevalent in blacks as compared to white patients [112] andblacks with mild-to-moderate left ventricular systolic dysfunc-tion appear to be at higher risk for progression of heart failureand death [111].

Hospitalizations for Congestive heart failure (CHF), as wellas readmissions after an initial hospitalization, are also morecommon in black patients [116,117]. However, Deswal et al.[118] have demonstrated a lower short-term and intermediate-term mortality in black patients with a first hospitalization forCHF as compared with white patients. The observation ofbetter survival in black patients after a hospitalization for CHFwas not influenced by differences in healthcare utilization asthe study was done in the VA healthcare system, a systemdesigned to provide financially “equal access” to care for allenrolled patients. One possible explanation may be that blackswith CHF are younger at presentation and are more likely tohave hypertension and left ventricular hypertrophy with alower frequency of coronary artery disease. In addition, agreater susceptibility to sodium retention in black patients maymake this group more susceptible to sudden symptomaticpulmonary congestion with resultant need for hospitalizationat earlier stages of disease progression, but with better survivalafter that hospitalization. In the outpatient patient setting,identifying and targeting potentially modifiable factors such asuncontrolled hypertension in black patients may narrow theracial gap in hospitalizations [119].

In relation to diagnosis of heart failure, African Americanpatients with CHF have more pronounced discrepancy be-tween the perceived severity of CHF by Emergency De-partment physicians and severity as determined by BNPlevels suggesting the role of ethnicity [120]. It is now clearthat Natriuretic peptide precursor B gene (NPPB) sequencevariants affect BNP physiology, possibly via transcriptionalregulation pointing towards the influence of BNP pathwaygenetic variation on BNP levels [121]. However, furtherstudies are needed to define whether these variants impact theclinical interpretation of BNP levels in African Americans.

7.3.1. Evidence for endothelial dysfunction in contributionto heart failure

In the setting of heart failure, there seems to be decreasedbioavailability of nitric oxide due to reduced expression ofendothelial nitric oxide synthase, increased generation ofreactive oxygen species and impaired antioxidant defensescausing NO inactivation [122]. Also, blunted endothelial-dependent FMD has been described in patients with class IIIHeart failure indicating endothelial dysfunction [123,124].

Studies have shown that increased oxygen stress is ne-gatively correlated with LV ejection fraction (LVEF) andpositively correlated with duration of Heart failure withproducts of lipid peroxidation [125,126]. Lastly, impairedantioxidant defenses in HF may also lead to greater oxidantstress and diminished endothelial function [127]. Thus, en-dothelial dysfunction may be a prominent vascular abnorm-ality in heart failure.

7.3.2. Rationale for NO-enhancing therapy in heart failureamong African Americans

The retrospective analysis of both Vasodilator-HeartFailure Trials (V-HeFT) I and II by Carson et al. [128] have


showed an ethnic differences in Heart failure therapy. AfricanAmericans in the V-HeFT I study showed diminishedcumulative mortality with isosorbide dinitrate-hydralazineanalysis versus placebo. In V-HeFT II, comparing treatmentwith enalapril to hydralazine/isosorbide dinitrate, a significantsurvival advantage of enalapril was observed only inwhites. InAfrican American patients, there was no survival advantage ofenalapril over hydralazine/isosorbide dinitrate.

Similarly, in an analysis of Studies of Left VentricularDysfunction (SOLVD) database demonstrated significantreductions in hospitalizations and in the combined end pointof death or hospitalization for CHF in white patients in theenalapril treatment arm but not in African American patients[129]. Studies examining the antihypertensive effects ofangiotensin-converting enzyme inhibitors (ACE-I) in blacksand whites have shown a lesser blood pressure loweringeffect in blacks [130].

Experience with Beta-Blockers showed varying results.The Beta-Blocker Evaluation of Survival Trial (BEST) usingBucindolol raised questions about the efficacy of these agentsin blacks [131], but later it was reported that Bucindolol haspartial intrinsic sympathomimetic activity and hence lesslikely to be effective in Heart failure. Whereas, studies oncarvedilol showed different response. Retrospective analysisof the effects of carvedilol comparing African Americans towhites found no differences in response between ethnicgroups [132]. It was further supported by an analysis of theAfrican American cohort in the Carvedilol Prospective Ran-domized Cumulative Survival (COPERNICUS) study [133]and in the community-based Coreg Heart Failure Registry(COHERE) study [134].

The African-American Heart Failure Trial (A-HeFT) [135]was the first prospective trial which demonstrated that, inaddition to blockade of the renin–angiotensin system andsympathetic nervous system with conventional moderntherapy, an NO-enhancing therapy has a significant positiveimpact in black patients with heart failure. A fixed-dose com-bination of isosorbide dinitrate-hydralazine was used. Iso-sorbide dinitrate is an organic nitrate that stimulates nitric oxidesignaling, and hydralazine is a vasodilator and antioxidant thatinhibits the enzymatic formation reactive oxygen species suchas superoxide by NADH and NADPH oxidases [136].

In that trial there was a 43% reduction in the relative1-year mortality among blacks with NO-enhancing therapy.It also showed decreased heart failure hospitalizations (in-cluding first hospitalization), days in hospital, and im-provement in quality of life. This mortality benefit may be,in part explained by regression of LV remodeling [137].

7.4. Metabolic Syndrome (MS)

African Americans, especially African-American women,have a high prevalence of the metabolic syndrome. This maybe due to disproportionate occurrence of elevated bloodpressure, obesity, and diabetes in African Americans. Theprevalence of metabolic syndrome is higher in a subgroup

of African Americans who are first-degree relatives ofpatients with type 2 diabetes. In these genetically predis-posed African American subjects waist circumference ratherthan metabolic parameters may be the single most importantparameter likely to meet the metabolic syndrome criteria inAfrican American relatives [138] and the upper tertile ofHbA1c (range, 5.7–6.4%) may be considered as a majorsurrogate of MS [139].

Obese children and African-American children have lowerinsulin sensitivity than Caucasian children [140]. AfricanAmerican children have both lower insulin clearance andhigher insulin secretion compared with their white peers. Theincreased insulin secretion in African American children is notmerely a compensatory response to lower insulin sensitivity.Dietary factors may have a role [141].

Another possible explanation for increased insulin secre-tion is endothelial dysfunction. Insulin causes release ofendothelial nitric oxide [142] producing vasodilation [143].Consequently in healthy African-American subjects with en-dothelial dysfunction have less vasodilation diminishingglucose delivery to the skeletal muscle with compensatoryincreased insulin secretion [144].

Insulin-signaling pathways in vascular endothelium lead-ing to the activation of eNOS and increased production ofNO involves the activation of phosphatidylinositol 3-kinase(PI 3-K) and Akt (protein kinase B) [145] whereas insulin-stimulated secretion of vasoconstrictor ET-1 from vascularendothelial cells is mediated by MAP-kinase-dependentpathways but not PI 3-kinase-dependent pathways [146].

A key feature of insulin resistance is that it is characterizedby specific impairment in PI 3-kinase-dependent signalingpathways, whereas other insulin-signaling branches, includ-ing MAP-kinase-dependent pathways, are unaffected [147].Basal endothelial nitric oxide production is reduced ininsulin-resistant individuals [148] and nitric oxide-depen-dent, but not-independent, vasorelaxation is impaired inobese insulin-resistant patients [149].

In the recent study, Lteif et al. [150] have shown anassociation of endothelial dysfunction with insulin resistanceand systolic blood pressure in metabolic syndrome. How-ever, the significant dominant correlate of ED in blacks wassystolic blood pressure while insulin resistance wasdominant correlate of ED in whites. Hence, the relativeimportance of ethnic difference among these components ofmetabolic syndrome highlights the need for different ethnictherapeutic approaches in metabolic syndrome.

An intriguing relationship exists between insulin resistanceand ADMA levels (an endogenous competitive inhibitor ofNO synthase). Plasma levels of ADMA are positively cor-related with insulin resistance in nondiabetic, normotensiveand hypertensive individuals. Further, as previously men-tioned elevated ADMA level is associated with an impairedbrachial [97], so it can be speculated that this phenomenonmay play a significant role in the endothelial dysfunctiondescribed in clinical syndromes characterized by insulinresistance [151,152].


At the same time, insulin-resistant patients have elevatedplasma ET-1 levels due to unopposed MAPK pathway, andhyperinsulinemia increases ET-1 secretion in humans [153].Elevated levels of ET-1 may also contribute to endothelialdysfunction and the regulation of vascular tone in humanobesity and type 2 diabetes [154].

7.5. Obesity

African American women have a higher prevalence ofobesity than white women [155]. Obese African Americanwomen suffer more from obesity-related comorbidities thanWhite women [156,157].

African American women have an increased capacity tosynthesize triglyceride in omental adipose tissue comparedwith Caucasian women, which may be due to an increase inthe transport of fatty acid, mediated by the over expression ofthe transport proteins [via higher expression of (Peroxisomeproliferator-activated receptor gamma) PPAR] in the omentaladipose tissue. This might contribute to the higher pre-valence of obesity in African American women [158].

African American women lose less weight and at a slowerrate than Caucasianwomen. Lipolytic rates are lower in obeseblack American women. It may be due to higher densities ofbeta-adrenergic receptors in visceral adipose tissue and theactivation of these receptors may increase the levels ofadenosine which in turn suppress lipolysis [159,160].

Body fat distribution appears to affect insulin sensitivityand adiponectin concentrations. Adiponectin is positively re-lated to peripheral fat and inversely related to central fat. Also,adiponectin level is lower in African-American compared toCaucasian children. Lower adiponectin among African-Ame-rican children may be explained by higher acute insulinresponse to glucose [161]. Alternatively, as androgens haveshown to decrease plasma adiponectin and as African Ame-ricans enter puberty at an early age, higher androgen levels inthese boys may affect the low adiponectin level [162].

Adiponectin may act as a link between adipose tissue andthe vasculature. Low plasma adiponectin level is associatedwith impaired endothelium-dependent vasodilation [163]and may contribute to the observed endothelial dysfunctionin African Americans.

7.6. Dyslipidemia

Although the effects of obesity and diabetes on athero-genic lipoprotein subpopulation have been shown to besimilar for African Americans and Caucasians, some racialdifferences, particularly with respect to High Density Lipo-protein (HDL), may exists suggesting that race-specificcriteria may be needed to screen patients for CVD [164].

7.6.1. Lipoprotein (a) [Lp (a)]Lipoprotein (a) [Lp (a)] consists of 2 components, an

LDL particle and an attached apolipoprotein (a) [apo (a)].High levels of Lp (a) have been shown to be a risk factor for

cardiovascular disease. The Lp (a) level is determined pri-marily by the apo (a) gene, which varies in size according tothe copies of kringle 4 (K4) domains. Apo(a) size variationmay confer atherogenic properties [165]. In Caucasians, Lp(a) levels correlate negatively with apo(a) size, and K4 ofb22 copies have been shown to be associated with coronaryartery disease [166].

Recently, Wu et al. [167] reported high levels of plas-ma Lp(a) in African Americans compared to Caucasiansand an inverse correlation of Lipoprotein(a) levels to FMD(endothelium-dependent dilation). Furthermore apart fromLp (a) levels, apo (a) sizes were also found to have a sig-nificant negative effect on endothelial function and thiseffect held true even when the corresponding Lp (a) levelswere low. Thus the approach of taking into account apo(a) size in risk stratification may be especially important inAfrican Americans in whom Lp (a) levels correlate lessclosely with apo (a) sizes [168].

7.7. Importance of ethnic specific nutrient factors

Obese Black Americans are at particularly high risk forvitamin D deficiency and secondary hyperparathyroidism[169]. Melanin (natural sunscreen) in the dark skin mayreduce vitamin D production in the skin [170]. Bioavail-ability of Vitamin D is decreased from cutaneous and dietarysources because of its deposition in body fat compartmentsleading to Hypovitaminosis D in overweight population[171]. In addition, under normal conditions at most latitudesin North America, even healthy blacks do not achieve opti-mal vitamin D concentrations at any time of year [172].A recent survey have shown that low intake of vitamin Dalso contributes to vitamin D insufficiency among blacks andit may be due to lactose intolerance and limited consump-tion of milk, milk products, and ready-to-eat fortifiedbreakfast cereals by black men and women compared towhites [173].

Vitamin D may protect against cardiovascular disease[174,175] and low levels of vitamin D may be associatedwith CHF severity [176]. Hypovitaminosis D in CHF ofhousebound African Americans is associated with secondaryhyperparathyroidism. In addition to it, aldosteronism of CHFand loop diuretic therapy can exacerbate calcium and mag-nesium losses causing ionized hypocalcaemia and hypo-magnesaemia [177,178].

Also, the observed endothelial dysfunction in AfricanAmericans can be linked to Vitamin D deficiency as thedeficient state of vitamin has been associated with endo-thelial dysfunction [179].

Antioxidant defenses are altered in CHF. African Ameri-cans with CHF have decrease levels of Selenium and Zinc intheir body as compared to whites [177]. Selenium is anessential trace element with an antioxidant property and mayplay a role in the clinical severity of CHF [180]. Seleniumdepleted states have glutathione peroxidase deficiency (anti-oxidant) and increased 15-hydroperoxyeicosatetraenoic acid


(15-HPETE) with consequent decreased endothelial prosta-cyclin synthase activity [181,182].

Zinc also has protective effect on endothelial function. Ithas antioxidant and membrane-stabilizing properties and canmodulates PPAR signaling in the endothelial cells [183–185]. Thus Selenium and Zinc deficiency are associated withendothelial dysfunction and may contribute to the adversecardiovascular outcomes in African Americans.

7.8. Environmental influences

Racial differences reflect sociocultural factors: selectivemigration, health and medical care practices, and socio-economic status [186,187]. Psychosocial factors includestress at school or the experience of stressful life events,ongoing problems with social injustice and communitydisruption [188–190].

The relatively favorable outcome of coronary heart di-sease in Caribbean-born men may be explained by lowamounts of fat and moderate alcohol consumption. Also,Caribbean blacks are less obese and have low levels of low-density lipoprotein cholesterol, and high levels of high-density lipoprotein cholesterol [191]. However, healthy UKAfro-Caribbean people have greater and Jamaican Afro-Caribbean people have less impairment of vascular reactivitydespite belonging to the same ethnic group. This suggests thesignificance of multiple environmental factors and geneenvironment interactions, specific to ethnic groups in dif-ferent environments, as an approach to eliminating the ex-cess of vascular disease in such people [192].

In addition, physical activity and alcohol use are someof the potentially modifiable environmental factors whichpredispose African Americans for high-risk cardiovascularprofile [193,194]. Other contributing factors may includepopulation density, household crowding, and correlates ofresidential segregation, such as residence in an area that ismedically or socially underserved, or a high crime rate. Thedemographic data from Harlem and Black Belt Alabamahighlights the importance of accounting for social factors.Black Belt Alabama has the lowest excess mortality of thepoor black groups, although it has the highest rate of poverty,whereas Harlem has the highest excess mortality but thelowest poverty rate [195].

8. Therapeutic consideration for EndothelialDysfunction in African-Americans

8.1. Hypertension

Antihypertensive therapy is associated with a 35%–40%reduction in stroke, a 20%–25% reduction in MI, and a morethan 50% reduction in HF [196]. Importance of lifestyleinterventions (increase physical activity, weight loss, smok-ing cessation, sodium restriction, increase dietary potassiumsupplement, etc.) must be emphasized in African Americans[197].

Monotherapy with diuretics and calcium channel blockersmay be relatively more effective in lowering blood pressurein African Americans than other antihypertensive agents[198]. This may be attributable to reduced natriuretic capa-city in this population and also, hydrochlorothiazide hasbeen shown to have a direct vasodilator effect in the humanforearm vessel. This action is probably mediated by acti-vation of vascular potassium channels and unrelated to thepresence of the sodium-chloride co transporter [199].

However recent guidelines recommend combinationtherapy as the standard of care for patients with significantblood pressure elevation, especially those with diabetesmellitus and renal disease. These co morbidities are morecommon in African Americans and indicate the potentialneed for initial therapy with more than one agent or a com-bination of agents in one pill [198].

Effective combinations may include beta-adrenoceptorantagonist/diuretic, ACE inhibitor/diuretic, ACE inhibitor/calcium channel antagonist, and angiotensin receptor blocker/diuretic. The recommendations do not differ from other racial/ethnic groups where specific or compelling indications forthe use of specific classes of antihypertensive agents exist[197].

In the Antihypertensive and Lipid-Lowering Treatment toPrevent Heart Attack Trial (ALLHAT), which included morethan 10,000 African Americans, ACE inhibitors were lesseffective than either a thiazide-type diuretic or a calciumchannel blocker (CCB). However, the interracial differencesin blood pressure-lowering observed with these drugs dis-appeared when they were combined with a diuretic [200].Despite evidence from ALLHAT showing the superior effi-cacy of diuretics and CCBs in the African-American patient,ACE inhibitors should be used as part of a multidrug anti-hypertensive strategy due to their renoprotective [201,202]and cardioprotective benefits [203]. Furthermore, as Reninangiotensin system (RAS) may be involved in the elevationof serum ADMA in essential hypertension, ACE inhibitorsor Angiotensin AT1 receptor antagonists have vasculopro-tective benefits. It can be explained at least in part by theamelioration of endothelial injury (dysfunction) through thedecreased serum ADMA concentration [204,205].

However, African-Americans subjects with type 2 dia-betes who present with persistent microalbuminuria (pre-dictive of CAD) despite angiotensin-converting enzymeinhibitor (ACEI) therapy have severe endothelial dysfunc-tion which warrants the need of alternative therapy for suchhigh-risk population [206].

Third generation selective ß1-blocker Nebivolol has beenshown to be safe and well-tolerated antihypertensive agentand is associated with an improvement in glucose and lipidparameters, even in diabetic patients [207]. In the preli-minary study, Nebivolol has been shown to cause renal arteryvasodilation by increase in the NO production and endo-thelial NO synthase (eNOS) protein expression, decrease inthe expression of Ca(2+) activated K(+) channels, and di-minishing the MAP-kinase activity. Thus it has potential to


offer additional vascular protection for treating diabetesassociated with hypertension [208].

In African Americans, Nebivolol has shown to decreasesuperoxide and peroxynitrite concentration in the endothelialcells by inhibition of NAD (P) H oxidase activity with theresultant increase in NO bioavailability. In addition, it hasdirect antioxidant action on endothelial cells. Thus it is usefulin African American population characterized by endothelialdysfunction, independent of its ß1-selective blockade [209].

Nebivolol may a reasonable choice for diabetic hyperten-sive African Americans with persistent microalbuminuriaand endothelial dysfunction. But larger trials are needed tovalidate this finding.

8.2. Heart failure

For CHF, concomitant use of beta blockers especiallyCarvedilol and renin–angiotensin–aldosterone modulators(ACEI, ARB and Spironolactone) may be as effective inAfrican Americans as in non-African Americans [210].These agents may have an additional beneficial role in im-proving endothelial dysfunction seen in African Americans[211–214].

Carvedilol is unique among other ß-blockers. In additionto ß-blockade, it causes inhibition of alpha 1-adrenergicreceptors. Alpha 1-adrenergic receptors mediate endothelialfunction and vasoconstriction in peripheral vessels, regulaterenal blood flow, and have been implicated in myocardialhypertrophy. The vasodilatory effects reduce afterload andthe resulting decrease in impedance to LVejection offsets thenegative inotropic effect. Stroke volume and cardiac output ismaintained or even increased in CHF. It does not cause excessbradycardia and has negative effect on cardiac remodelingdue to hypertrophy. In addition, it has an antioxidant propertythereby preventing apoptotic cardiac cell death. Carvedilolhas protective effect on endothelial cells from oxygen radical-mediated injury and lipid peroxidation [211].

Though there may be concern that addition of Beta-blocker with a Thiazide-type diuretic precipitate or increaseinsulin resistance, but Giugliano et al. [215] showed animproved glucose and lipid metabolism with Carvedilol indiabetic patients. They speculated that carvedilol-inducedvasodilation may facilitate glucose uptake by muscle cellsand by its antioxidant property on endothelial cells, it re-duces lipid peroxidation.

Also, in the Glycolic Effect in DiabetesMellitus: Carvedilol-MetoprololComparison inHypertensive (GEMINI) trial the useof carvedilol in the presence of RAS blockade did not affectglycemic control and improved some components of themetabolic syndrome relative to metoprolol in diabetic hyper-tensive patients. About 15% of the GEMINI subjects wereAfrican Americans [216]. Carvedilol may also improve insulin-sensitivity [217].

Blacks may have heightened sensitivity to cardiac beta2-adrenergic stimuli and peripheralalpha1-adrenergic stimulithan whites [218] even in a marginally reduced dietary intake

of potassium [219]. Carvediolol [beta-blocker with anadditional alpha 1-blocking action] is useful in the settingof CHF where concomitant diuretic can further aggravatepotassium depletion.

Black Americans have greater vasodilator response tonitroglycerin [220]. As evident by the recent A-HeFT, com-bination of agents that enhance NO bioavailability [isosorbidedinitrate] while reducing nitroxidative stress [hydralazine]appears to be efficacious in the treatment of symptomatic Heartfailure in African American patients [135]. The fixed-dosecombination has been recently approved byUSFood andDrugAdministration (FDA) for use as an adjunct to standard therapyin self-identified black patients to improve survival, to prolongtime to hospitalization for Heart failure, and to improvepatient-reported functional status [221].

Nesiritide, a recombinant form of human B-type natriu-retic peptide, is the drug specifically approved for acutedecompensated heart failure [222]. Theoretically, Nesiritidemay be linked to endothelial NO. Molecular mechanisms ofBNP have shown to induce iNOS activity [223], increaseintracellular cyclic GMP [224] and NO levels [225].

8.3. Metabolic syndrome

Management of the metabolic syndrome consists primar-ily of modification or reversal of the root causes (overweight/obesity and physical inactivity) and drug therapy to reduce orcontrol the individual risk factors [226]. In one study,pharmacotherapy with rosiglitazone has shown to increaseinsulin sensitivity and decrease ADMA levels in nondiabeticsubjects [151]. In addition, it may improve endothelial func-tion even without any reduction in ADMA levels [227].Rosiglitazone may be of value for African Americans withmetabolic syndrome and/or diabetes with endothelial dys-function; however the underlying mechanism is still poorlyunderstood.

8.4. ADMA targeted therapy and L-argininesupplementation

As previously mentioned ADMA is an endogenous com-petitive inhibitor of NO synthase, thereby therapy targetingADMA may increase NO levels with better endothelialfunction. ACE I and Rosiglitazone therapy may decreaseADMA as mentioned earlier [151,204].

Another way to improve endothelial function is by sup-plementing L-arginine (precursor of NO). It can amelioratemicrovascular endothelial dysfunction in African Americans[228].

8.5. Stress

To address the environmental factor, selected stress re-duction approach, the Transcendental Meditation program,may be useful as an adjunct in the treatment of hypertension[229] and Heart failure [230] in African Americans.


8.6. Nutriceutical therapy

As previously mentioned, there may the need for nutri-ceutical therapy (Vitamin D, Selenium and Zinc) in AfricanAmericans to improve endothelial function. Also, Atorvas-tatin may increase vitamin D levels in CAD patients inaddition to its beneficial effect on dyslipidemia and en-dothelial function [231].

To conclude, there is a need to detect endothelial dys-function in African Americans using the tools of modernmedicine.

9. Summary

The discovery of the molecule of the decade i.e. (NO)has shifted the gate-keeping role of endothelium towardsa logical “window” of future atherosclerotic outcomes.Studies have shown that African American subjects havesubstantial morbidity and mortality related to cardiovas-cular diseases.

So, if endothelial dysfunction is established as pheno-typic marker for atherosclerosis, then every effort should bemade to detect it, either directly or indirectly, at the earliestin African American individuals who are at risk even ifthey are appearing healthy, and furthermore attemptsshould be made to stabilize the endothelial function sothat the future catastrophic events of atherosclerosis mightbe prevented.

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Endothelial dysfunction in African-Americans

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