HYPERTENSION AND OBESITY (E REISIN, SECTION EDITOR)

Treatment of Obesity-Related Hypertension in Childrenand Adolescents

Susan M. Halbach & Joseph Flynn

Published online: 9 March 2013# Springer Science+Business Media New York 2013

Abstract The obesity epidemic has become a commonconcern among pediatricians, with an estimated 32 % ofUS children and adolescents classified as overweight and18 % as obese. Along with the increase in obesity, a growingbody of evidence demonstrates that chronic diseases, suchas Type 2 diabetes, primary hypertension, and hyperlipid-emia, once thought to be confined solely to adulthood, arecommonly seen among the obese in childhood. Following abrief summary of the diagnosis and evaluation of hyperten-sion in obese children and adolescents, this review willhighlight recent research on the treatment of obesity-relatedhypertension. Pharmacologic and non-pharmacologictreatment will be discussed. Additionally, current andemerging therapies for the primary treatment of obesityin children and adolescents, which have been gaining inpopularity, will be reviewed.

Keywords Blood pressure . BP . Hypertension . Obesity .

Child . Adolescent . Body mass index . BMI . Target organdamage . Comorbidity . Treatment . Bariatric surgery .

Lifestyle changes

Introduction

The worldwide obesity epidemic is changing the face ofpediatric hypertension. A growing body of evidence showsan alarmingly high prevalence of overweight and obesityamong children and adolescents not only in the United

States, but in other developed countries and, to some extent,in the developing world as well. The most recent NationalHealth and Nutrition Examination Study (NHANES) datashow nearly 18 % of children and adolescents meet criteriafor obesity and 32 % meet criteria for overweight (currentlydefined as body mass index [BMI]≥95th and ≥85th percen-tiles for age and sex, respectively) [1•]. Although the USappears to be leading the way in rates of childhood obesity,similar findings have been reported from other countriesas well. Rates of childhood obesity range from 4 % inBelgium and Norway to 10–14 % in Greece, Spain andPortugal [2–4]. Studies of obesity trends among childrenin China, Brazil, India and other developing countries showobesity rates that are on the rise over the past 10–20 yearsand in some cases approaching that of the US [5, 6••, 7].

Although there is evidence that obesity rates are begin-ning to plateau in the US and in other developed countries,the absolute number of children affected by the epidemicremains sufficiently high such that the healthcare and eco-nomic burden will continue to be quite significant [1•, 8].Following several decades of trending downward, theprevalence of elevated blood pressure (BP) among US chil-dren and adolescents has been increasing since the late1980s [9]. The increase in childhood obesity, whichpreceded this upward trend by about 10 years, is likelythe major contributor to these changes. Using data frommultiple cross-sectional studies, including those that offerthe advantage of repeated measurements on up to threeseparate occasions, the overall prevalence of hyperten-sion among children and adolescents is estimated to bebetween 3-5 % [9–13].

An analysis of NHANES data from 1988 to 2006 byOstchega and colleagues showed obesity to be independent-ly associated with elevated BP and pre-elevated BP. In theirmultivariate analysis, obese girls ages 8–17 years had 2.33greater odds of elevated BP compared to their normalweight peers and the magnitude of the relationship was evenhigher in boys (ages 8–12 y: OR 6.06, ages 13–17 y: OR

S. M. Halbach : J. FlynnDivision of Nephrology, Seattle Children’s Hospital, University ofWashington School of Medicine, Seattle, WA, USA

S. M. Halbach (*)Seattle Children’s Hospital, 4800 Sand Point Way NE,M/S OC.9.820,Seattle, WA 98105, USAe-mail: susan.halbach@seattlechildrens.org

Curr Hypertens Rep (2013) 15:224–231DOI 10.1007/s11906-013-0334-7

9.64). Interestingly, the increases in elevated BP and pre-elevated BP seen over the study period were diminished ornot significant when adjusted for BMI, suggesting obesity isan important driver of the increase in hypertension preva-lence [14]. Other epidemiologic studies in a variety ofsettings (both Western and non-Western countries) confirmthe association between obesity and increased risk for eitherpre-hypertension or hypertension [11–13, 15•].

Evaluation of the Obese Child or Adolescentwith Elevated Blood Pressure

Obtaining accurate BP readings in an obese patient can bechallenging. Many obese children and adolescents have armcircumferences that require a large-adult or even thigh cufffor reliable measurements. As arm sizes in children increase,it becomes essential for primary care offices to have BPcuffs available in a range of sizes to ensure that reliablemeasurements are obtained [16].

The criteria for diagnosing hypertension in adults rely onabsolute blood pressure cut-points (prehypertension: systol-ic BP 120–139 and diastolic BP 80–89, hypertension: sys-tolic BP≥140 and diastolic BP≥90) and require repeatedmeasurements on at least two visits [17]. Current guidelinesdefine hypertension in children as a BP greater than the 95thpercentile for age, sex and height on three or more occasionsand prehypertension as a BP greater than the 90th percentilefor age, sex and height, or >120/80, but less than the 95thpercentile on three or more occasions [18]. Except in thecase of the adolescent patient, the primary care practitionermust generally consult a table or chart to determine whethera patient’s blood pressure reading is elevated. A study byHansen et al of nearly 15,000 children and adolescents seenin primary care practices in northeastern Ohio sought toevaluate the frequency with which hypertension was cor-rectly identified. Of the 507 patients whose BP readings metcriteria for hypertension, they found that only 26 % hada corresponding diagnosis code for hypertension or ele-vated BP documented in the chart. Certain patient char-acteristics, such as older age and obesity, increased theodds of diagnosis, but the authors hypothesized thatlack of familiarity with normal BP ranges in this pop-ulation was a barrier to diagnosis [19].

Once the diagnosis of hypertension has been confirmedby repeat measurements or 24-hour ambulatory BP moni-toring (ABPM), the practitioner must determine a plan foradditional evaluation. A detailed history and physical exam-ination may provide clues to a cause of secondary hyperten-sion as well as other sequelae of obesity. The evaluationshould include targeted testing for secondary causes ofhypertension, when indicated, as well as testing for targetorgan damage and other cardiovascular risk factors. Basic

recommended screening labs include: urinalysis, serum glu-cose, serum chemistries (electrolytes, BUN, creatinine) andlipid panel [18].

Historically, the majority of pediatric hypertension wasattributed to secondary causes, but more recent studies dem-onstrate that the balance is shifting, particularly in olderchildren and adolescents. Among 351 children enrolled intwo recent multicenter drug trials, only children <6 yearswere found to have predominantly secondary hypertension(83 %). Older children tended to have higher BMIs and themajority had primary hypertension (60–62 %) [20••]. A2009 study from the Midwest Pediatric Nephrology Con-sortium studied 166 otherwise healthy children ages 5 to18 years referred to tertiary care centers for elevated BP.Excluding patients in whom secondary hypertension wouldhave been expected prior to evaluation (kidney transplantrecipients, for example), the researchers found the propor-tion of referred patients with primary hypertension to be91 % [21•]. In addition to age, other factors commonly seenin children and adolescents with primary hypertension in-clude obesity and positive family history of hypertension,diabetes or obesity [22–25]. Consensus guidelines recom-mend an abbreviated evaluation for secondary hyperten-sion in older patients with stage 1 hypertension [19]. Atleast two recent studies, however, have found little correla-tion between primary or secondary hypertension and hyper-tension stage [21•, 25]. Until more data are available, theclinician should continue to use clinical judgment and cluesfrom the history and physical to determine extent of testing inobese patients with hypertension.

Screening for Target Organ Damage and Co-Morbidities

An important step in the evaluation of the child or adoles-cent with hypertension is screening for hypertensive targetorgan damage and co-morbidities commonly associatedwith obesity. All patients with confirmed hypertensionshould have an echocardiogram to screen for the presenceof left ventricular hypertrophy (LVH), the most commonlocation of target organ damage found in children [19, 26,27]. In addition to an association with hypertension, LVHhas also been found to be independently associated withobesity and it presumed to be another indicator of earlycardiovascular disease [27, 28•]. Hypertensive retinopathyhas been reported in children but appears to have a lowprevalence and is not well-studied [29].

As part of the initial evaluation, all obese children andadolescents should be screened for other co-morbidities ofobesity. Abnormal glucose metabolism is common, rangingfrom impaired glucose tolerance and hyperinsulinemia toovert type 2 diabetes. Other co-morbid conditions include:hyperlipidemia, polycystic ovarian syndrome, non-alcoholic

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fatty liver disease, gastroesophageal reflux disease, muscu-loskeletal problems (joint complaints, slipped capitol femo-ral epiphysis), depression and obstructive sleep apnea(OSA) [30]. The latter problem is especially important toidentify as it is independently associated with elevatedblood pressure [31–33]. Although the pathway leading toelevated BP among patients with OSA is not completelyunderstood, activation of the sympathetic nervous system(SNS) is believed to play an important role. Hypoxia, dis-turbed sleep patterns, and frequent arousals can all lead toSNS activation. In addition to elevated BP, studies inchildren and adolescents with OSA have also foundchanges in cardiac geometry, including LVH and dia-stolic dysfunction [34, 35]. There is evidence that thesefindings can improve or normalize when OSA is treated.Therefore, a thorough history with inquiry specificallyinto sleep quality and snoring should be part of thestandard evaluation of any child or adolescent withelevated BP.

Treatment: Non-Pharmacologic

Lifestyle changes should be the cornerstone of any treatmentplan for children and adolescents with hypertension (Table 1).This would include recommendations to lower the sodiumcontent in the diet, change eating patterns with the goal ofeither weight loss or slower weight gain, and increased phys-ical activity. Sodium intake for most individuals in the USabove the age of 6 years is in excess of both basic dailyrequirements and amounts recommended by the USDA(≤2300 mg/day in healthy individuals, ≤1500 mg/day inhigh risk groups) [36]. While the benefits of a lower-sodium diet on blood pressure are well-established fromclinical trials in adults and are suggested in pediatricstudies, adhering to a low-sodium diet can be quitechallenging [37–39]. Most of the daily sodium intakein the US population comes from the consumption of

processed and restaurant food, both of which have be-come mainstays of the American diet [40].

The Dietary Approaches to Stop Hypertension (DASH)diet, which emphasizes a higher intake of fresh fruits andvegetables, whole grains, lean meats and low-fat dairy prod-ucts, is frequently utilized for nutritional counseling in hy-pertensive patients. The original trial demonstrated BP-lowering effects of adhering to the diet independent ofsodium intake; additional benefits were seen after furtherlimiting sodium intake among adult subjects following thediet [38, 41]. At least one study in adolescents with elevatedBP found a greater reduction in BP using a DASH dietcompared to routine nutritional counseling, suggesting thisapproach is likely to be effective among pediatric patients[42]. Among obese children and adolescents, the benefits oflower sodium intake may be more pronounced, as demon-strated in an analysis of NHANES data by Yang and co-workers. They found the magnitude of the relationshipbetween sodium intake and risk for prehypertension/hypertension to be much greater among overweightand obese children compared to the study populationas a whole (OR 3.5 versus 2) [43••].

While weight loss is clearly beneficial, the most effectiveintervention to achieve and maintain weight loss remainsless understood. Recent years have seen an explosion ofstudies at the individual, family and community level aimedat weight management. Common themes that have emergedfrom these studies include the need for a multidisciplinaryapproach that focuses on diet, activity and eating behaviorsand family-inclusive interventions [44, 45]. The intensity oftreatment also seems to play a role, with more intense pro-grams (those offering frequent sessions with nutritionists,exercise physiologists and social workers) showing promis-ing, though modest, results [44, 46]. Expert guidelines bythe American Dietetic Association (ADA) and the Endo-crine Society currently recommend intensive lifestyle mod-ification at the level of the family for all children andadolescents classified as obese or overweight [30, 47].

Table 1 Treatment of hyperten-sion in obese children andadolescents

aUse with caution in patientswith diabetes or impaired glu-cose tolerance; generally re-served for second-line use inobese patients due to metabolicside-effects

Non-Pharmacologic Pharmacologic

Recommended for: All patients Diabetes (types 1 and 2)

Secondary hypertension

Target-organ damage

Failure of non-pharmacologic therapy alone

Therapies: Low-sodium diet (1500-2300mg/day) Medication classes:

Weight loss ACE inhibitor

Physical activity (60min/day) ARB

CCB

Diuretica

Beta-blockera

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Given the scope of the obesity problem in the US, thenumber of eligible patients for such programs would beenormous. Many of these programs are offered only atreferral centers and such services are frequently not coveredby insurance [48]. Additional work is needed to elucidateeffective interventions or approaches that can beimplemented at the primary care level.

Another recent area of interest involves changing eatingpatterns at the population level via public policy initiatives.The consumption of sugar-sweetened beverages (SSB) is animportant source of calories in children and adolescents andlinked with obesity [49]. Dietary sodium is an importantdriver of thirst, so it is not surprising that higher salt intakein children and adolescents is associated with higher SSBconsumption [50]. A reduction of both is likely to be ben-eficial. Two randomized trials conducted in children andadolescents aimed at reducing the intake of SSB showedconsumption of alternative, non-caloric beverages reducedweight gain for up to one year of intervention compared tocontrols [51, 52]. Soda taxation, regulations surroundingsnack foods and SSB in schools, food advertising, menu-calorie labeling, and decreasing the amount sodium added tofood during manufacturing are some approaches that havebeen attempted or proposed as a public policy response tothe obesity epidemic [53].

The third essential component of a lifestyle program toaddress obesity-associated hypertension in children and ado-lescents is increased physical activity. Current guidelines rec-ommend 60 minutes of aerobic exercise daily as part of acomprehensive weight management program [30]. In obesehypertensives, the benefits of exercise appear to extend be-yond weight loss. A Swiss exercise intervention trial in pre-pubertal obese children compared cardiovascular indicatorsamong those who completed a 3-month exercise program tothose in a control group. They found improvements in officesystolic BP, 24-hour ambulatory BP, and rate of hypertensionin the exercise arm that were independent of BMI changes [54].A follow up study 2 years later found continued improvementsin rates of hypertension andmeanBP among study participants,suggesting a sustained benefit from the intervention [55]. Theassociation between obesity and known precursors to athero-sclerosis, such as carotid intima medial thickness (cIMT) andarterial stiffness, has been well documented in children andadolescents [56–58]. The Swiss group also found stabilizationof cIMT and arterial stiffness after 6 months, supporting thebenefits of exercise in slowing the development of these earlymarkers of cardiovascular disease [54].

Treatment: Pharmacologic

While non-pharmacologic treatment is recommended for allchildren and adolescents with elevated BP, a subset will also

require treatment with antihypertensive medication. Indica-tions for prescribing antihypertensive medication include:diabetes, secondary hypertension, stage 2 hypertension, fail-ure of non-pharmacologic therapy or evidence of hyperten-sive target organ damage (Table 1). Treatment goals differbased on the existence of co-morbid conditions: <95th per-centile for patients with primary hypertension and <90thpercentile for those with secondary hypertension, diabetesor evidence of target organ damage [18].

Unfortunately, there are no evidence-based recommenda-tions to guide the choice of pharmacologic agent for hyper-tensive children and adolescents. In adult patients, evidencefrom comparative clinical trials using objective outcomessuch as stroke and mortality have helped guide specifictreatment recommendations, as outlined in the Seventh Re-port of the Joint National Committee on Prevention, Detec-tion, Evaluation and Treatment of High Blood Pressure(JNC 7) [17]. To date, no such trials have been conductedin children or adolescents nor is it realistic to design apediatric study with outcomes that are exceedingly rare inchildhood. Long-term studies looking at the benefits and/oradverse effects of antihypertensive use in childhood andadolescents would be helpful but are also currently lack-ing. Passage of the 1997 FDAMA and Best Pharmaceu-ticals for Children Act did, however, provide financialincentives for drug manufacturers to conduct pediatricstudies. As a result, more antihypertensive medicationshave been specifically labeled for pediatric use and havehelpful dosing information available [59].

Classes of agents commonly prescribed for pediatrichypertension include: angiotensin-converting enzyme(ACE) inhibitors, angiotensin receptor blockers (ARB),beta-blockers, diuretics, and calcium channel blockers(Table 1). All but diuretics have been studied in recentpediatric trials to demonstrate efficacy, with ACE inhibitorshaving perhaps the largest number of studies [60]. Exceptfor diuretics and beta-blockers, most agents are consideredsuitable choices for first-line therapy in obese patients. Wegenerally reserve diuretics and beta-blockers for use assecond-line agents due to their adverse metabolic effects.When choosing a medication, the practitioner should alsokeep co-morbid conditions in mind: patients with diabetesor chronic kidney disease, for example, are best served bytreatment with ACE inhibitors or ARBs, which have addi-tional renal protective effects aside from lowering BP.

What is known about the mechanisms of obesity-relatedhypertension has been described in detail elsewhere [61, 62].In brief, it is thought that chronic activation of the SNS inobese patients leads to vasoconstriction and activation of therenin-angiotensin-aldosterone system (RAAS), which leads tosubsequent salt and water retention. These phenomena all leadto elevated BP. For this reason, ACE inhibitors have becomethe drug of choice in treating obesity-related hypertension in

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adult patients [61]. It is not surprising, then, that ACE in-hibitors are also one of the most frequently prescribed class ofdrugs in adolescents with primary hypertension, as outlinedby Yoon and colleagues in a retrospective review of Medicaidclaims in the state of Michigan. In their study population ofnearly 4300 adolescents with primary hypertension, 23 %received prescriptions for antihypertensive medications. Ofthose who received prescriptions, 28 % were prescribed“combination therapy” (68 % of these prescribed as one-pillcombination drugs, 32 % as multiple pills). The most com-mon medications for those characterized as receiving“monotherapy” were ACE inhibitors (36.8 %), diuretics(27.8 %) and beta-blockers (23.5 %). Interestingly, they foundthat the majority of the patients received prescriptions fromadult primary care providers (63 %) and only 24 % hadprescriptions provided by specialty providers [63•]. Anotherstudy looking at prescribing practices for almost 3000 chil-dren and adolescents with primary and secondary hyperten-sion found the most common classes of antihypertensives tobe ACE inhibitors and calcium channel blockers [59]. Giventhe enormous need to address elevated BP and other co-morbidities of obesity in children and adolescents, more stud-ies intended to guide the choice of first-line pharmacologictherapy are needed.

Medical and Surgical Treatment for Obesity

Although the body of literature aimed at identifying themost successful approach to lifestyle interventions forweight reduction demonstrates positive responses, thereare no long term data with regard to maintenance of weightloss. Current clinical guidelines recommend considerationof pharmacologic treatment of obesity in children and ado-lescents only after a period of intensive treatment withlifestyle changes fails to yield a decrease in weight gain orimprove comorbidities. Severe, significant comorbidities ora strong family history of Type 2 diabetes mellitus (DM) orcardiovascular risk factors make the case for pharmacologictherapy more compelling. The guideline also recommendsthat use of antiobesity medications be limited to practi-tioners familiar with their adverse effects and experiencedin their use [30].

The two most commonly used antiobesity agents in chil-dren are orlistat and metformin. A third medication,sibutramine, was removed from the market by the manufac-turer in 2010 due to concerns of increased cardiovascularrisk [64]. Orlistat is currently FDA-approved for use inchildren >12 years old. It acts as an intestinal lipase inhib-itor, thereby reducing the absorption of dietary fat andcholesterol by approximately 25 % [65]. Several trials haveevaluated its efficacy and safety in obese adolescents, in-cluding two randomized, placebo-controlled trials [66–70].

The largest study with the longest follow-up was a multi-center trial of over 500 adolescents, all of whom receivedbehavioral interventions in addition to orlistat or placebo.After 1 year of treatment, subjects in the orlistat arm showeda modest decrease in BMI compared with an increase inBMI in the placebo arm [66]. A smaller, blinded trial with40 adolescents demonstrated a larger, though non-significant, decrease in BMI with orlistat use after 6 months[67]. All studies had a high incidence of gastrointestinal sideeffects in those subjects taking orlistat but reported low ratesof medication discontinuation [66–70].

While not FDA-approved for use in treating obesity,metformin is frequently prescribed and has been studiedfor its weight loss effects. The mechanism of action forweight loss is not fully understood, but likely involveseffects on glucose metabolism as well as lipogenesis, par-ticularly in the liver [71]. Numerous small trials have beenconducted in obese or hyperinsulinemic children and ado-lescents, with follow up typically up to 6 months. Thelargest trial followed 120 obese, hyperinsulinemic childrenand adolescents ages 9 to 17 years for 6 months. The in-vestigators found a significant decrease in BMI with low-dose metformin treatment compared to placebo, but nochanges in blood pressure or serum lipids [72]. Wilson andcolleagues conducted a long-term, multicenter trial lookingat extended release metformin versus placebo; all subjectsreceived lifestyle intervention. After a 12-month treatmentperiod, the mean BMI of those in the treatment arm de-creased by 0.9 while the mean BMI of those in the placeboarm increased by 0.2 (p=0.03). The difference between thetwo groups persisted for 4 to 6 months after treatmentdiscontinuation, but disappeared at 12 months post-treatment [73•]. The most recent trial was conducted in100 obese children ages 6 to 12 years and found similarresults after 6 months of treatment with metformin:greater decreases in BMI and improved markers ofinsulin resistance [74].

Perhaps the most dramatic reductions in body weighthave been reported in studies looking at surgical in-terventions for obesity. Bariatric surgery has become awidely-available therapy for obesity in adults and isincreasingly used in adolescents with severe obesity aswell. A study reviewing national trends in adolescentsundergoing bariatric surgery reported an increase from328 procedures in 2000 to 1009 procedures in 2009. Allsurgeries were performed at either adult hospitals orpediatric units within adult hospitals. The most commonprocedure was Roux-en-Y gastric bypass (RYGB)followed by laparoscopic adjustable gastric banding(LAGB) [75]. Data from a single center study of 61adolescents demonstrated a reduction in BMI by about35 % at one year after RYGB surgery, regardless ofbaseline BMI [76].

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In addition to weight loss, studies following adolescentsundergoing bariatric surgery have documented improvementor resolution in co-morbid conditions, including hypertension.One prospective study of 20 patients undergoing LAGBreported normalization of blood pressure in all 9 patientswho were hypertensive prior to surgery [77]. A systematicreview of bariatric surgery in adolescents found a total of 6studies reporting information on hypertension, with docu-mented rates of resolution ranging from 50–100 %, thoughthese were all small, single-center studies [78]. Significantimprovements in sleep apnea, diabetes, dyslipidemia, gastro-esophageal reflux, asthma, and musculoskeletal complaintshave also been reported [77–79]. Interestingly, one compara-tive study found rates of resolution of hypertension to besignificantly better in adolescents than adults (75 % vs.35 %) following LAGB surgery, despite similar reductionsin BMI [80]. This finding underscores the importance of earlyprevention and treatment of childhood obesity in improvingthe outcomes of co-morbid conditions.

Weight loss surgery is not without complications, how-ever, and long-term outcomes of adolescents who undergosuch procedures are currently unknown, though at leastthree longitudinal studies are underway, both in the USand abroad. The surgical approach is not without critics,both in the medical community and in the lay press [81].Complication rates are not insignificant and patients must takesupplements for life to avoid nutritional deficiencies [82]. TheInternational Pediatric Surgery Group published clinicalcriteria for bariatric procedures in adolescents in 2009. Allpatients must be physically mature and demonstrate commit-ment to post-operative nutritional guidelines. They recom-mend bariatric surgery for adolescents with a BMI >35 andsevere comorbidities (diabetes, severe obstructive sleep apneaor pseudotumor cerebri) or BMI≥40 and other obesity-relatedcomorbidities (including hypertension) [83].

Conclusions

Obesity-associated hypertension is no longer a rare entity inchildhood and adolescence. The primary care practitionerand specialist alike must become accustomed to routinelyscreening overweight and obese pediatric patients for ele-vated blood pressure and other complications of obesity.Lifestyle changes, recommended for all children and ado-lescents with obesity-associated hypertension, can be diffi-cult to institute and maintain, and more evidence is neededregarding how to most effectively accomplish lastingchanges that will assist in weight loss and lowering BP.Treatment of obesity-associated hypertension will, in manycases, require antihypertensive medication. While there isgrowing evidence of the short-term efficacy and safety ofthese medications in children and adolescents, comparative

studies to aid in the choice of first line therapy are needed.Pharmacologic and surgical treatment of obesity is still in itsinfancy and much work is needed in determining long-termoutcomes and risks. Preventive strategies that decrease orslow the onset of obesity have the potential for an evengreater impact on the long-term cardiovascular morbiditythat these patients are expected to face.

Conflict of Interest S. M. Halbach declares that she has no conflictof interest.

J. Flynn has received payment for serving as a consultant fromNovartis and Pfizer, and payment for the development of CME lecturesfrom the American Society of Hypertension.

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