REVIEW PAPER doi: 10.1111/j.1559-4572.2008.00011.x

Obesity, Hypertension, and the Heart

As the availability of foodstuffs hasincreased throughout the world,

obesity has become a significant prob-lem globally. Recent economic impro-vements in the Pacific rim, especially inthe world’s two most populous coun-tries, China and India, have led to thisproblem in areas where famine hadpreviously been the major concern. InChina, the prevalence of overweightand obesity has risen 400% in the last20 years, and while still quite low inIndia (<5%), a large number of inhabit-ants are overweight or obese (1% of theIndian population, or 10 million per-sons).1 Obesity is the reason for a pre-dicted drop in the US life expectancy2

and should surpass smoking as thenumber one preventable cause of deathin the United States.3 The age-adjustedprevalence of obesity among US adultsin the National Health and NutritionExamination Survey (NHANES) was22.9% between 1988 and 1994 andincreased to 30.5% in 1999 to 2000,based on the NHANES databases.4

(For an excellent review of the epidemi-ology of overweight/obesity, as well asmethodological considerations, see thereport of the Asia Pacific Cohort StudiesCollaboration.1)

In this paper, we discuss someclinical and physiologic aspects ofobesity. We also discuss some of thephysiologic milieu and what we knowabout obesity-related hypertension, itspathophysiology, and its ultimateimpact on the cardiovascular morbid-ity and mortality. Hypertension inthe setting of obesity appears to haveunique causes, such as adipocyte-related hormonal considerations, ahyperadrenergic state, central axishormonal changes with subsequentsodium avidity, and volume expan-sion related to stimulation ofthe renin-angiotensin system (RAS).Obstructive sleep apnea and otherrespiratory sleep disorders are verycommon in obesity and are correlated

closely with hypertension.5 Coronaryartery disease will not be discussedhere.

Diagnosis of ObesityThere are many common measures ofobesity. The most widely used is thebody mass index (BMI). BMI has beenused in several large population-basedstudies and has been recommendedby groups including the World HealthOrganization and the National Insti-tutes of Health. BMI is useful from apractical standpoint, as only two veryeasy measurements (height and weight)are needed. If BMI is used, most organi-zations recommend using a BMI >30kg/m2 as a definition of obesity.

Unfortunately, BMI does not takeinto account total fat content; thus,muscular and lean individuals may bemisclassified. Total fat content maybe measured by electrical impedance(unreliable) as well as by underwater

weights (the gold standard), but this isunwieldy, expensive, and probablynot practical in daily use and officepractice.

Distribution of fat may be a moreimportant measure of cardiovascularrisk than total fat content. In particular,abdominal obesity may be a better pre-dictor of risk. Measurement of abdomi-nal fat content was originally reportedby using computed tomography. Waistcircumference (WC) correlates wellwith computed tomography measure-ments and may be the best simplemeasure of cardiovascular risk.6 A mul-tidisciplinary panel recently releasedrecommendations regarding WC stat-ing that men with a WC >40 in andwomen with a WC >35 in have a muchgreater risk of cardiovascular disease.(Specific recommendations on ana-tomic landmarks and measuring WCare found in the study by Klein andcolleagues.6)

Controversy exists regarding the amount of risk caused by obesity, but there is general

consensus that it is associated with many serious disorders, mostly cardiovascular and

neoplastic. Obesity is clearly associated with hypertension, ventricular remodeling with

subsequent congestive heart failure, sleep-disordered breathing, and sudden death.

The physiologic alterations associated with establishing and perpetuating the obese

state are complex but are becoming clear. In discussing the cardiovascular conse-

quences of obesity, the implications and mechanism of the associated hypertension

need to be understood. There is growing recognition that adipose tissue is a very active

in the neurohormonal axis and is not simply a passive storage depot. Among other

things, adipocyte-related hormonal activity and resistance to feedback mechanisms

are associated with increased plasma volume and increased sympathetic tone.

J Cardiometab Syndr. 2008;3:168–172. ª2008 Le Jacq

David Good, MD;1 Stephen A. Morse, DO;2 Hector O. Ventura, MD;1

Efrain Reisin, MD2

From the Department of Cardiology, Ochsner Clinic Foundation, New Orleans, LA1 and

the Section of Nephrology and Hypertension, Louisiana State University Health

Services Center, New Orleans, LA2

Address for correspondence:

Efrain Reisin, MD, 2020 Gravier, 7th Floor, Suite D, Box E7-20, New Orleans,

LA 70112

E-mail: ereisi@lsuhsc.edu

Manuscript received August 16, 2007; accepted March 26, 2008

obesity, hypertension, and the heart JCMS summer 2008168

Hemodynamic Profilein ObesityObesity is associated with high cardiacoutput and normal total peripheralresistance.7 An increase in stroke vol-ume appears to be the result of elevatedfilling pressures and, along with increasein sympathetic tone, accounts for theincrease in stroke volume.

The hemodynamic profile of leanpersons with (essential) hypertension ischaracterized by high total peripheralresistance and low circulating intravas-cular volume. Although cardiac outputis increased in earlier stages, it tends todecrease with time.8 Initially, in thepatient with essential hypertension, thisdecrease in cardiovascular output overtime is probably the result of decliningdiastolic function resulting in lowerstroke volume.

These hemodynamic differencesultimately result in different patterns ofpathologic adaptation and remodeling(see the Cardiac Remodeling section).Although not completely informative, itis conceptually useful to consider hyper-tension in obesity a combination ofvolume-overloaded and pressure-over-loaded states.

Sympathetic ActivityShort-term regulation of blood pressureand vascular tone is regulated by theautonomic nervous system. Cardiacoutput must be variable to meet highlyvariable metabolic demands. Cerebralperfusion is critical in utilizing anupright posture, and human beingshave evolved a very intricate mechanismto achieve this. Changes in posture andphysical activity trigger numerous sym-pathetic and parasympathetic responsesthat compensate for variations in pre-load and afterload and the need to altercardiac output. These responses resultin changes in cardiac output by chang-ing venous pressure (preload), arterialresistance, heart rate, and the inotropicstate of the heart. In the obese, thisbalance is somewhat disturbed with adominant sympathetic state.

The normal circadian variation inblood pressure also appears to be influ-enced by obesity. Thus, 70% of obese

hypertensive persons do not show adrop in systolic and diastolic pressuresduring sleep.9 The mechanism of thenormal fall in blood pressure duringslow-wave sleep is the result of adecrease in sympathetic tone, with tran-sient increases occurring only duringREM sleep. The lack of a normaldecrease in blood pressure implieselevated nocturnal sympathetic tone.10

Studies appropriately controlled forbody mass have shown disturbances inautonomic activity in the obese in manyclinical settings, including obstructivesleep apnea (OSA),11 congestive heartfailure,12 and exposure to particulatematter.13

Other measures of sympatheticactivity such as R-R variability, sympa-thetic nerve traffic, and a lack ofvariability in daytime and nocturnalblood pressure are abnormal in theobese. There are many possible causesand consequences of this sympatheticstimulation. Overfeeding itself is associ-ated with increased turnover of tritiatednorepinephrine (a common researchmeasure of total sympathetic activity)in laboratory animals.14 Hyperinsu-linemia, as well as insulin-mediatedglucose uptake, cause an increase insympathetic nervous system activity. Innonobese and normoglycemic offspringof type 2 diabetics, sympathetic activityis much increased by hyperinsulinemiain those with insulin resistance (highesttertile of insulin levels), although not inthose with less resistance (lowest tertileof insulin levels).15

Sympathetic activity also affects thekidneys, mainly by altering efferent andafferent arteriolar tone. This decreasesglomerular flow rate and contributes tosodium retention. Regional sympathec-tomy of the kidney attenuates the pres-sor effect of obesity in dogs.16

Obstructive Sleep ApneaOSA and other syndromes of sleep-disordered breathing are very commonin the obese population. Hypertensionis highly correlated with OSA and isprobably related to increased sympa-thetic tone. A excellent study byGrassi and coworkers,11 using muscle

sympathetic nerve activity as an endpoint, demonstrated that sympatheticactivity is increased in lean patients withOSA as well as in obese patients withoutOSA. They also demonstrated that thetwo conditions, when combined, leadto a more profound sympathetic stimu-lation. This finding gives credence tothe idea that factors other than OSA, inparticular, elevated levels of leptin (seethe Leptin section), probably contributeto the hyperadrenergic state in obesity.

First-line treatment of OSA is typi-cally continuous positive airway pres-sure (CPAP). Studies on the efficacy ofCPAP to improve blood pressure levelshave led to mixed results. One well-performed CPAP trial using subthera-peutic pressures, as a control in arandomized fashion, did show an over-all response of daytime blood pressureto therapy for OSA.17 This responsewas augmented in patients receiv-ing antihypertensive medications. Inpatients with OSA, CPAP decreasedsympathetic output and blood pressureduring sleep, restoring normal diurnalvariation in blood pressure. In this andother trials, as the severity of OSAincreased, so did the benefit achievedwith CPAP.

Cardiac RemodelingCardiac hypertrophy and remodelingoccur in one of 3 stereotypical patterns.Concentric hypertrophy is the responseto pressure overload that leads to thick-ening of the ventricular wall withoutincreasing the cavity size. Concentrichypertrophy is the result of myocytethickening. Eccentric hypertrophy isthe result of volume overload and con-sists of wall thickening with concomi-tant cavity dilation as the result of fiberelongation. A third pattern occurs aftermyocardial infarction and is not rele-vant to our discussion.

Nonobese hypertensive patients tendto develop concentric cardiac hyper-trophy because of elevated total periph-eral resistance, increased ventricularafterload, and wall stress. In contrast,obese individuals develop eccentric car-diac hypertrophy as a result of increasedintravascular volume and end-diastolic

obesity, hypertension, and the heart JCMS summer 2008 169

volume. In patients with obesityand hypertension, a mixed eccentric/concentric cardiac hypertrophy is seen.Each of these factors lead to an increasein stroke work.

Ventricular enlargement is presentin healthy obese adults as well as inthose with OSA.1 Very early indicatorsof diastolic dysfunction are present inobese patients with and without OSA,although the implications of thesechanges are not clear.18 Left ventricularenlargement also occurs in obese adoles-cents, making early intervention in theyoung appear more urgent.19 Autopsydata from the Mayo Clinic have shownmarked increases in heart size with obes-ity. The average heart weight was 467 gin obese hypertensive individuals, ascompared with 367 g in obese individu-als and only 272 g in nonobese hyper-tensive individuals.20 The prognosticimplications of left ventricular hyper-trophy have been determined in a pro-spective fashion. Sudden death is morecommon in patients with an electro-cardiographic diagnosis of left ven-tricular hypertrophy, and the overallmortality rate of those with left ventri-cular hypertrophy is very high. This wasshown prospectively in the Framing-ham and other studies.21

Electrophysiologic ChangesObese persons also have a markeddecrease in R-R variation.22,23 Decrea-sed R-R variability has been found to bea marker of sudden death in many pop-ulations with known cardiac disease,such as post–myocardial infarction24

and in patients with congestive heartfailure25 as well as in population-basedstudies of diabetics3 and dialysispatients.26 Other markers of suddendeath occurring at a higher rate in theobese population are an increase ineither the QT interval or QT disper-sion.22,27 In one group of 85 severelyobese patients (BMI >45 kg/m2), anincreased corrected QT interval andQT dispersion were improved by suc-cessful obesity surgery.27

Natriuretic PeptidesNatriuretic peptides are a family ofrelated proteins that are widely found in

mammalian species. In the heart, atrialnatriuretic peptide (ANP) and brainnatriuretic peptide are synthesized inthe atria and ventricles, respectively.ANP is a posttranslational product of alarger constitutively produced protein.Both peptides are released by increasesin atrial pressure. Natriuretic peptideshave specific guanylyl cyclase-coupledreceptors that are widely distributed.There is also a receptor that binds natri-uretic peptides that is not associatedwith a signaling protein and appears tobe involved in clearance. The so-callednatriuretic peptide receptor type C(clearance) (NPr-C) is also diffuselydistributed.

As their name suggests, one of theactions of natriuretic peptides is natri-uresis. They are important rapid regula-tors of vascular volume and tone.Analogs of these peptides are used inclinical medicine in the treatment ofacute decompensated heart failure andat high doses lead to rapid reductions inpulmonary capillary wedge pressure,symptoms of congestive heart failure,diuresis, and decrease in blood pressureby a decrease in vascular resistance.28

The elevated blood volume in obes-ity does not appear to be associated withelevated levels of natriuretic peptides.The ability to secrete natriuretic pep-tides in response to saline volumeexpansion is blunted in obese persons.29

Weight loss is associated with a diuresis/natriuresis that is associated with anincrease in ANP levels.30

One explanation for natriuretic pep-tide resistance is the extensive presenceof natriuretic peptide receptors inadipose tissue, both active as well asNPr-C type. In adipose tissue, the ratioof active receptor to NPr-C is lower inthe obese.31 Natriuretic peptide recep-tors have a lipolytic effect on adiposetissue. Therefore, decreased levels ofcirculating brain natriuretic peptidecould perpetuate obesity regardless themechanism.

The overall importance of the roleplayed by natriuretic peptides in themaintenance of adiposity as well as themaintenance of the volume-expandedstate is unclear. Other phenomena(such as leptin and activation of the

RAS) are obviously important tohypertension, as discussed below. Atthe very least, the blunting of thenatriuretic response and the normalcirculating levels of natriuretic peptidesin the volume-overloaded state repre-sent the removal of an importantcompensatory mechanism.

LeptinLeptin is a hormone that is the productof the OB gene. The OB gene wasdiscovered by positional cloning froma strain of mice that are massivelyobese.32 Leptin administration in theseanimals reverses obesity due to a varietyof behavioral and metabolic effects.Levels of serum leptin are increased inmice in dietary-induced obesity,33 aswell as in obese humans. In mice,peripheral injection of leptin has verylittle effect in obesity, while directcentral nervous system administration isassociated with a major decrease incaloric intake as well as weight loss.33

Genetically leptin-deficient obese micehave lower blood pressure than theirlittermates with normal body weights.Yellow agouti mice, who are leptin-intact, have much higher blood pres-sures than their lean littermates.34

Leptin is constitutively produced bywhite adipose tissue and appears to bepart of a feedback loop that increaseslipolysis and inhibits caloric intake.35

Serum leptin levels are elevated in obes-ity. This has led to the hypothesis thatexcess adiposity is the result of a leptin-resistant state. In animal experiments,‘‘leptin resistance’’ means the inabilityof leptin to reduce food intake.36 Leptinresistance may also be caused bydifferent mechanisms, such as decreasedblood brain barrier transport, decreasedsensitivity to central effects, anddecreases in peripheral actions.35 Ciliaryneurotrophic growth factor is involvedin these signaling cascades, and itsadministration reverses some of theeffects of leptin resistance37 and leads toweight loss in humans.38 Theoretically,the sensitivity to leptin may be manipu-lated in several ways and is the subjectof much interest.37

Although leptin has some beneficialeffect on endothelial function and

obesity, hypertension, and the heart JCMS summer 2008170

vascular volume, the predominant effectof chronically elevated levels is anincrease in sympathetic output.39,40

This occurs whether leptin is injected inthe central nervous system41 or periph-erally42 or introduced transgenically.16

This effect is antagonized by a-block-ade. Elevated leptin levels may explainto a large degree the hyperadrenergicstate that is seen in obese individualswithout OSA.11 The overall effect ofleptin is to raise blood pressure.42

Leptin is probably directly responsi-ble for some of cardiac remodeling.Leptin activates mitogen-activatedprotein kinases (MAPKs) in neonatalrat myocytes.43 MAPKs have multiplesecondary signaling cascades, and theultimate effect depends on the relativeactivation of the various arms. Inthis way, MAPK activation may leadto either ventricular hypertrophy orapoptotic death.44 MAPKs may alsobe responsible for electrophysiologicabnormalities altering repolarization bychanging the expression K channelIto.44

The RASThe RAS is critical to the maintenanceof blood volume and blood pressurein mammals. This has been reviewed

extensively, and the interested readermay refer to the study by Schmiederand colleagues.45 Briefly, angiotensino-gen is synthesized by the liver. Thisprotein is cleaved by several catalyticenzymes, most importantly renin, toform angiotensin 1. Angiotensin 1 isfurther degraded to angiotensin 2(ang-2) by angiotensin-convertingenzyme 1 (ACE-1) circulating in theserum as well as in tissues. Otherenzymes are important contributors tothe generation of ang-2 in the heart,such as chymase. Ang-2 is the mostpotent of the pressor products of thiscascade. The receptors for thismolecule include the AT1 and the AT2subtypes.

Activation of this cascade alsoleads to the production of aldosteroneand the resultant expansion of plasmavolume. Antagonizing this system eitherby inhibiting the ACE-1 enzyme, byblocking the ang-2 receptor, or byantagonizing the action of aldosteroneis an effective means of lowering theblood pressure. The significant thera-peutic implications of these pathwaysare beyond the scope of this review.

The ang-2 receptors have a variety ofacute as well as chronic actions. Themost important to us are the direct

pressor effect on vascular smooth mus-cle and alterations in renal hemodynam-ics. These effects tend to raise pressureby increasing cardiac output as well asraising vascular resistance. In volumeexpansion, the RAS would typically besuppressed; however, in the obese thisdoes not occur.46 Indeed, plasma reninactivity is correlated with BMI. Ethnicdifferences may also exist, as standingaldosterone levels were correlated withBMI in French Canadians but not inblacks.47 Weight loss decreases this acti-vation of the RAS in the obese.48

ConclusionsObesity is associated with multiplestructural and functional cardiac chan-ges that are associated with morbidityand mortality. Increases in intravascularvolume cause the heart to operate atunnecessarily high filling pressures.Continued sympathetic activationalong with increased cardiac outputfrom elevated filling pressures lead tohypertension in the vast majority ofobese individuals. This is most likelydue to high circulating levels of leptin.Hypertrophy of the left ventricle, coro-nary artery disease, as well as derangedautonomic function occur, all of whichmay lead to sudden death.

REFERENCES

1 Asia Pacific Cohort Studies Collaboration.The burden of overweight and obesity in theAsia-Pacific region. Obes Rev. 2007;8(3):191–196.

2 Olshansky SJ, Passaro DJ, Hershow RC, et al.A potential decline in life expectancy in theUnited States in the 21st century. N Engl JMed. 2005;352:1138–1145.

3 Lavie CJ, Milani RV. Obesity and cardiovas-cular disease: the hippocrates paradox? J AmColl Cardiol. 2003;42(4):677–679.

4 Flegal KM, Carroll MD, Ogden CL, et al.Prevalence and trends in obesity among USadults, 1999–2000. JAMA. 2002;288:1723–1727.

5 Hoffmann M, Bybee K, Accurso V, et al.Sleep apnea and hypertension. Minerva Med.2004;95(4):281–290.

6 Klein S, Allison DB, Heymsfield SB, et al.Association for Weight Management andObesity Prevention. Waist circumference andcardiometabolic risk: a consensus statementfrom Shaping America’s Health: Associationfor Weight Management and Obesity Preven-tion; NAASO, The Obesity Society; theAmerican Society for Nutrition; and theAmerican Diabetes Association. Am J ClinNutr. 2007;85(5):1197–1202.

7 Messerli FH, Christie B, DeCarvalho JG,et al. Obesity and essential hypertension. He-modynamics, intravascular volume, sodiumexcretion, and plasma renin activity. ArchIntern Med. 1981;141:81–85.

8 Tarazi R. Hemodynamics of hypertension. In:Hypertension, Physiopathology and Treatment.2nd ed. Genest J, ed. New York, NY:McGraw-Hill; 1983:15.

9 Weir MR, Reisin E, Falkner B, et al. Noctur-nal reduction of blood pressure and theantihypertensive response to a diuretic orangiotensin converting enzyme inhibitor inobese hypertensive patients. TROPHY StudyGroup. Am J Hypertens. 1998;11:914–920.

10 Mancia G. Autonomic modulation of thecardiovascular system during sleep. N Engl JMed. 1993;328:347–349.

11 Grassi G, Facchini A, Trevano FQ, et al.Obstructive sleep apnea-dependent and -inde-pendent adrenergic activation in obesityhypertension. Hypertension. 2005;46:321–325.

12 Grassi G, Seravalle G, Quarti-Trevano F,et al. Excessive sympathetic activation in heartfailure with obesity and metabolic syndrome:characteristics and mechanisms. Hypertension.2007;49(3):535–541.

13 Chen JC, Cavallari JM, Stone PH, et al.Obesity is a modifier of autonomic car-diac responses to fine metal particulates.Environ Health Perspect. 2007;115:1002–1006.

14 Scheurink AJ, Balkan B, Strubbe JH, et al.Overfeeding, autonomic regulation and meta-bolic consequences. Cardiovasc Drugs Ther.1996;10:263–273.

15 Frontoni S, Pellegrinotti M, Bracaglia D,et al. Hyperinsulinaemia in offspring of type 2diabetic patients: impaired response ofcarbohydrate metabolism, but preserved car-diovascular response. Diabet Med. 2000;17(8):606–611.

16 Ogawa Y, Masuzaki H, Ebihara K, et al.Pathophysiogical role of leptin in lifestyle-related diseases. Studies with transgenicskinny mice. J Diabetes Complications. 2002;16(1):119–122.

17 Pepperell JCT, Ramdassingh-Dow S,Crosthwaite N, et al. Ambulatory bloodpressure after therapeutic and subtherapeuticnasal continuous positive airway pressurefor obstructive sleep apnoea: a rando-mised parallel trial. Lancet. 2002;359:204–210.

obesity, hypertension, and the heart JCMS summer 2008 171

18 Otto ME, Belohlavek M, Romero-CorralA, et al. Comparison of cardiac structuraland functional changes in obese otherwisehealthy adults with versus without obstructivesleep apnea. Am J Cardiol. 2007;99(9):1298–1302.

19 Ogden CL, Yanovski SZ, Carroll MD, et al.The epidemiology of obesity. Gastroenterology.2007;132(6):2087–2102.

20 Smith HL, Willius FA. Adiposity of theheart: a clinical pathologic study of 136obese patients. Arch Intern Med. 1933;52:910–939.

21 Kannel WB, Cobb J. Left ventricular hyper-trophy and mortality–results from the Fra-mingham Study. Cardiology. 1992;81(4–5):291–298.

22 Bezante GP, Scopinaro A, Papadia F, et al.Biliopancreatic diversion reduces QT intervaland dispersion in severely obese patients.Obesity (Silver Spring). 2007;15(6):1448–1454.

23 Peterson HR, Rothschild M, Weinberg CR,et al. Body fat and the activity of the auto-nomic nervous system. N Engl J Med.1988;318(17):1077–1083.

24 Anderson KP, Bigger JT Jr, Freedman RA.Electrocardiographic predictors in theESVEM trial: unsustained ventriculartachycardia, heart period variability, and thesignal-averaged electrocardiogram. ProgCardiovasc Dis. 1996;38(6):463–488.

25 Rashba EJ, Estes NA, Wang P, et al.Preserved heart rate variability identifies low-risk patients with nonischemic dilatedcardiomyopathy: results from the DEFI-NITE trial. Heart Rhythm. 2006;3(3):281–286.

26 Opie LH, Commerford PJ, Gersh BJ, et al.Controversies in ventricular remodelling.Lancet. 2006;367(9507):356–367.

27 Fraley MA, Birchem JA, Senkottaiyan N,et al. Obesity and the electrocardiogram. ObesRev. 2005;6(4):275–281.

28 Mills RM, LeJemtel TH, Horton DP, et al.Sustained hemodynamic effects of an infusionof nesiritide (human b-type natriureticpeptide) in heart failure: a randomized, dou-ble-blind, placebo-controlled clinical trial.Natrecor Study Group. J Am Coll Cardiol.1999;34(1):155–162.

29 Licata G, Volpe M, Scaglione R, et al. Salt-regulating hormones in young normotensiveobese subjects. Effects of saline load. Hyper-tension. 1994;23:I20–I24.

30 Maoz E, Shamiss A, Peleg E, et al. The role ofatrial natriuretic peptide in natriuresis of fast-ing. J Hypertens. 1992;10:1041–1044.

31 Dessi-Fulgheri P, Sarzani R, Tamburrini P,et al. Plasma atrial natriuretic peptide andnatriuretic peptide receptor gene expression inadipose tissue of normotensive and hyperten-sive obese patients. J Hypertens. 1997;15:1695–1699.

32 Zhang Y, Proenca R, Maffei M, et al. Posi-tional cloning of the mouse obese gene and itshuman homologue. Nature. 1994;372:425–432.

33 Van Heek M, Compton DS, France CF, et al.Diet-induced obese mice develop peripheral,but not central, resistance to leptin. J ClinInvest. 1997;99(3):385–390.

34 Mark AL, Shaffer RA, Correia ML, et al.Contrasting blood pressure effects of obesityin leptin-deficient ob/ob mice and agoutiyellow obese mice. J Hypertens. 1999;17:1949–1953.

35 Haynes WG, Morgan DA, Walsh SA, et al.Receptor-mediated regional sympatheticnerve activation by leptin. J Clin Invest.1997;100:270–278.

36 Considine RV, Sinha MK, Heiman ML, et al.Serum immunoreactive-leptin concentrationsin normal-weight and obese humans. N EnglJ Med. 1996;334:292–295.

37 Foster-Schubert KE, Cummings DE. Emerg-ing therapeutic strategies for obesity. EndocrRev. 2006;27(7):779–793.

38 Ettinger MP, Littlejohn TW, Schwartz SL,et al. Recombinant variant of ciliary neuro-trophic factor for weight loss in obese adults:a randomized, dose-ranging study. JAMA.2003;289(14):1763–1764.

39 Haynes WG, Sivitz WI, Morgan DA, et al.Sympathetic and cardiorenal actions of leptin.Hypertension. 1997;30:619–623.

40 Carlyle M, Jones OB, Kuo JJ, et al. Chroniccardiovascular and renal actions of leptin: roleof adrenergic activity. Hypertension. 2002;39:496–501.

41 Correia ML, Morgan DA, Sivitz WI, et al.Leptin acts in the central nervous system toproduce dose-dependent changes in arterialpressure. Hypertension. 2001;37:936–942.

42 Shek EW, Brands MW, Hall JE. Chronicleptin infusion increases arterial pressure.Hypertension. 1998;31:409–414.

43 Rajapurohitam V, Gan XT, KirshenbaumLA, et al. The obesity-associated peptideleptin induces hypertrophy in neonatal ratventricular myocytes. Circ Res. 2003;93:277–279.

44 Jia Y, Takimoto K. Mitogen-activated proteinkinases control cardiac KChIP2 gene expres-sion. Circ Res. 2006;98:386–393.

45 Schmieder RE, Hilgers KF, Schlaich MP,et al. Renin-angiotensin system and cardiovas-cular risk. Lancet. 2007;369(9568):1208–1219.

46 Engeli S, Sharma AM. The renin-angiotensinsystem and natriuretic peptides in obesity-associated hypertension. J Mol Med. 2001;79:21–29.

47 Grim CE, Cowley AW Jr, Hamet P,et al. Hyperaldosteronism and hypertension:ethnic differences. Hypertension. 2005;45:766–772.

48 Tuck ML, Sowers J, Dornfeld L, et al. Theeffect of weight reduction on blood pressure,plasma renin activity, and plasma aldosteronelevels in obese patients. N Engl J Med.1981;304:930–933.

obesity, hypertension, and the heart JCMS summer 2008172