Artigo Acesso aberto Revisado por pares

Cardiovascular Risk Associated With White-Coat Hypertension

2017; Lippincott Williams & Wilkins; Volume: 70; Issue: 4 Linguagem: Inglês

10.1161/hypertensionaha.117.08903

ISSN

1524-4563

Autores

Giuseppe Mancia, Michele Bombelli, Cesare Cuspidi, Rita Facchetti, Guıdo Grassı,

Tópico(s)

Cardiovascular Health and Disease Prevention

Resumo

HomeHypertensionVol. 70, No. 4Cardiovascular Risk Associated With White-Coat Hypertension Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBCardiovascular Risk Associated With White-Coat HypertensionPro Side of the Argument Giuseppe Mancia, Michele Bombelli, Cesare Cuspidi, Rita Facchetti and Guido Grassi Giuseppe ManciaGiuseppe Mancia From the University of Milano-Bicocca, Italy (G.M.); Department of Medicine and Surgery, University of Milano-Bicocca, Italy (M.B., C.C., R.F., G.G.); Istituto Auxologico Italiano, IRCCS, Milan, Italy (C.C.); and IRCCS Multimedica, Sesto San Giovanni, Milan, Italy (G.G.). , Michele BombelliMichele Bombelli From the University of Milano-Bicocca, Italy (G.M.); Department of Medicine and Surgery, University of Milano-Bicocca, Italy (M.B., C.C., R.F., G.G.); Istituto Auxologico Italiano, IRCCS, Milan, Italy (C.C.); and IRCCS Multimedica, Sesto San Giovanni, Milan, Italy (G.G.). , Cesare CuspidiCesare Cuspidi From the University of Milano-Bicocca, Italy (G.M.); Department of Medicine and Surgery, University of Milano-Bicocca, Italy (M.B., C.C., R.F., G.G.); Istituto Auxologico Italiano, IRCCS, Milan, Italy (C.C.); and IRCCS Multimedica, Sesto San Giovanni, Milan, Italy (G.G.). , Rita FacchettiRita Facchetti From the University of Milano-Bicocca, Italy (G.M.); Department of Medicine and Surgery, University of Milano-Bicocca, Italy (M.B., C.C., R.F., G.G.); Istituto Auxologico Italiano, IRCCS, Milan, Italy (C.C.); and IRCCS Multimedica, Sesto San Giovanni, Milan, Italy (G.G.). and Guido GrassiGuido Grassi From the University of Milano-Bicocca, Italy (G.M.); Department of Medicine and Surgery, University of Milano-Bicocca, Italy (M.B., C.C., R.F., G.G.); Istituto Auxologico Italiano, IRCCS, Milan, Italy (C.C.); and IRCCS Multimedica, Sesto San Giovanni, Milan, Italy (G.G.). Originally published28 Aug 2017https://doi.org/10.1161/HYPERTENSIONAHA.117.08903Hypertension. 2017;70:668–675Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2017: Previous Version 1 This article will support the view that white-coat hypertension (WCH), that is, the association of an elevated office with a normal ambulatory or home blood pressure (BP),1 is not an innocent condition but a condition associated with an increased cardiovascular risk. This will be based on the evidence that compared with normotensive controls, subjects with WCH (1) have an increased prevalence of metabolic risk factors and asymptomatic organ damage; (2) more frequently progress to high cardiovascular risk states such as sustained hypertension, diabetes mellitus, and left ventricular hypertrophy; and (3) exhibit, over the mid and long term, a greater risk of cardiovascular morbid and fatal events. It will also be mentioned, however, that important clinical and mechanistic aspects of WCH remain incompletely clarified: the contribution of office versus out-of-office BP to the increased risk; the biomarkers that may allow to distinguish, within the WCH population, subjects at greater versus those at normal risk; and the effect of antihypertensive drug administration on patients' prognosis. Clarification of these aspects represents a priority for medical research because WCH is common in all hypertension grades, its prevalence accounting for more than one third of the hypertensive population when the office BP elevation is mild.2Cross-Sectional EvidenceMetabolic Risk FactorsEvidence is available that subjects with WCH have an unfavorable metabolic profile. This was already observed many years ago3 and has since been confirmed by virtually all studies that have addressed this matter. A pertinent example is the PAMELA study (Pressioni Arteriose Monitorizzate e Loro Associazioni) on a population living in the north-east outskirt of Milan, in which measurements included a large number of metabolic variables. As shown in Figure 1, compared with normotensive controls, individuals with WCH (identified by an office BP ≥140/90 mm Hg and a 24-hour or home BP, respectively, <125/80 and 135/85 mm Hg) showed higher blood glucose, cholesterol, and triglycerides; a lower high-density lipoprotein cholesterol; and a greater prevalence of an impaired fasting glucose state, diabetes mellitus, metabolic syndrome, and hypercholesterolemia.4 For several variables, values approached those found in sustained hypertension, an observation that applied also to serum uric acid, that is, metabolic variable that has been found to also have a continuous relationship with cardiovascular risk.5 Although in the normotensive subjects of the PAMELA population, serum uric acid was on average 4.5±1.2 mg/dL (mean±SD), in WCH and sustained hypertension, it was 5.2±1.3 and 5.4±1.4 mg/dL, respectively, the difference from normotensive subjects being in either case statistically significant (P<0.05 for both).Download figureDownload PowerPointFigure 1. Metabolic variables in normotension (NT), white-coat hypertension (WCH), and sustained hypertension (HT). Data from the PAMELA population. Patients' categories were identified based on office vs 24-h mean blood pressure (BP) or office vs home BP. BMI indicates body mass index; Chol, cholesterol; MS, metabolic syndrome; DM, diabetes mellitus; and IFG, impaired fasting glucose. Reprinted from Mancia et al4 with permission of the publisher. Copyright © 2006, American Heart Association, Inc.Asymptomatic Organ DamageAfter few initial studies with variable results,6 evidence has been repeatedly obtained that, compared with normotensive controls, asymptomatic organ damage with documented prognostic significance has a greater prevalence in WCH, although remaining less frequent in this condition that in subjects with sustained hypertension. Although some individual studies have continued to be negative,7 this has been reported for several organs, that is the kidney (urinary protein excretion),8 the brain (silent infarcts),9 the vessels, and the heart,10 for which meta-analyses of the available studies have also been made available.11,12 In subjects with WCH, left ventricular mass index, left atrial diameter, and carotid intima–media thickness all showed values that were less than those of subjects with sustained hypertension, but greater than those seen in the normotensive group (Figure 2). White-coat (WC) hypertensives also showed E/A values intermediate between those of the normotensive and sustained hypertensive groups, thereby including in the damage seen in subjects with a selective office BP elevation also diastolic dysfunction (Figure 2). Finally, compared with normotensive controls, subjects with WCH have been shown to exhibit increased levels of plasma renin activity, a higher plasma norepinephrine, and a higher sympathetic nerve traffic to muscle circulation3,13,14 (Figure 3). Thus, WCH individuals seem to be characterized also by a neurohumoral activation, which may favor muscle and connective tissue growth15,16 and mechanistically contribute to their cardiac and vascular structural abnormalities.15,16 The arterial baroreflex has also shown some impairment, which may explain why in WCH BP variability, a phenomenon that has an independent adverse effect on outcome,17 is also abnormal.18Download figureDownload PowerPointFigure 2. Cardiac and vascular alterations in (1) white-coat hypertension (WCH) vs normotension (NT; top) and (2) WCH vs sustained hypertension (SH; bottom). Data from meta-analyses of available studies. A indicates atrial dependent ventricular filling; E, early ventricular filling; IMT, intima–media thickness; LAD, left atrial diameter; LVMI, left ventricular mass index; and SMD, standardized mean difference between groups. Adapted from Cuspidi et al11,12 with permission of the publisher. Copyright © 2015, Wolters Kluwer Health, Inc. Authorization for this adaptation has been obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.Download figureDownload PowerPointFigure 3. Individual and mean muscle sympathetic nerve activity (MSNA) values in normotensives (NT), white-coat hypertensives (WCH), and sustained essential hypertensives (EH). Data are shown as number of sympathetic bursts per min or per 100 beats. Adapted from Grassi et al13 with permission of the publisher. Copyright © 2007, American Heart Association, Inc. Authorization for this adaptation has been obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.Longitudinal EvidenceProgression to High Cardiovascular Risk StatesBecause data were collected also 10 years after the initial measurements, the PAMELA population has allowed to compare normotensive and WCH subjects for their progression to conditions characterized by a higher or an absolute high cardiovascular risk, such as sustained hypertension, type 2 diabetes mellitus, and new-onset left ventricular hypertrophy.19–22 Compared with normotensive controls, subjects with a high office and a normal ambulatory BP showed a significant increase in the risk of progression to sustained hypertension, that is, an elevation above normal of ambulatory BP as well.19–22 They also showed a greater risk of progressing to diabetes mellitus from an initially normal or prediabetic blood glucose value.20 They finally showed a significantly greater risk of moving from an initially normal left ventricular mass index to left ventricular hypertrophy (echocardiographic detection), the increase amounting to about twice the risk seen in normotensive individuals21 (Figure 4). For both new-onset diabetes mellitus and new-onset left ventricular hypertrophy, the increase in risk was similar or only slightly less than that seen in the sustained hypertension group (hazard ratio, 2.23 and 2.73, respectively; P 200 strokes,26 the risk of which became greater in WCH than in normotensive subjects after several years of follow-up, suggesting that a selective office BP elevation may adversely affect cerebral vascular integrity over the long term. It has been further documented in the large meta-analyses recently published by Briasoulis et al27 and Huang et al.28 In the meta-analysis of Briasoulis et al,27 WC hypertensives showed, during an average follow-up of 8 years, a significant increase in the risk of cardiovascular events (hazard ratio, 1.73; 95% confidence intervals, 1.27–2.36; 722 events) and cardiovascular mortality (hazard ratio, 2.79; 95% confidence intervals, 1.62–4.80; 153 events) compared with normotensive controls. A significant, albeit smaller, risk increase has also been found in the similarly large meta-analysis of Huang et al,19 which has shown the risk of cardiovascular events (follow-up 9.6 years) to be 38% and 19% greater in WC hypertensives than in normotensives (P<0.0006 and 0.04) when assessed in untreated or mixed (treated and untreated) cohorts, respectively. In this meta-analysis, the greater risk of WC hypertensives over the normotensive population included a 20% increase of all-cause mortality as well (P<0.02; Figure 5).Download figureDownload PowerPointFigure 5. Risk of cardiovascular outcomes in white-coat hypertension vs normotension. Data are separately shown as meta-analyses from cohorts of subjects under no antihypertensive treatment (8656 subjects), cohorts under antihypertensive treatment, and mixed (untreated and treated) cohorts. CI indicates confidence intervals. Reprinted from Huang et al28 with permission of the publisher. Copyright © 2017, Wolters Kluwer Health, Inc.Muntner et al29 have criticized the meta-analysis of Briasoulis et al27 because, at variance from other meta-analyses, the results were not adjusted for demographic and clinical covariates that may contribute to the overall risk. We agree that adjustment for demographic covariates is necessary because WCH tends to be more common as age advances30 with an obvious impact on the WCH risk, which was thus presumably overestimated in the meta-analysis of Briasoulis et al.27 We do not share the view, however, that adjustment should be necessarily extended to concomitant risk factors and indeed think that presenting the main results after adjustment for concomitant metabolic risk factors may be somewhat misleading. This is the case because neutralizing the contribution to the risk of concomitant metabolic and other risk factors prevents a correct appreciation of the clinical significance of WCH in its natural multifactorial phenotype, favoring the erroneous conclusion that it does not prognostically differ from normotension, as it has happened in some guidelines.31 We also do not agree that in WCH adjustments for concomitant cardiovascular risk factors is needed to decide about the use of antihypertensive treatment29 because the adjustment procedure represents an attempt to approximately ascribe the overall risk to individual variables, with no possibility to determine risk reversibility by treatment.Heterogeneity of Cardiovascular Risk in WCHPooling data from several cohorts, the International Database of Ambulatory Blood Pressure in relation to Cardiovascular Outcome group has provided evidence of an increased cardiovascular risk in patients in whom WCH was limited to a systolic BP elevation32 and in elderly WCH individuals at high cardiovascular risk.33 On the contrary, no cardiovascular risk increase was seen in younger WCH patients33 and, somewhat inconsistently, in WC patients with diabetes mellitus,34,35 generating the hypothesis that this condition may have a different prognostic significance in different demographic and clinical circumstances.36 An alternative explanation, however, is that documenting the adverse clinical significance of WCH is easier when the risk of the population at study is greater. This is supported by the results of the large meta-analysis by Huang et al,28 which has shown WCH to be accompanied by an increased risk of cardiovascular events in various subgroups, including those above or below 55 years of age and with or without a history of cardiovascular disease. It, thus, seems likely that patients with an increase of office but not of out-of-office BP are exposed to a greater outcome risk regardless their demographic and clinical characteristics.Treated patients with an uncontrolled office but a normal ambulatory or home BP represent a special case because either individual studies32 or data provided by large meta-analyses28 have reported their cardiovascular risk not to differ significantly from that of the treated population in which both office and out-of-office BP achieved control. The significance of these results is unclear, however. First, in absence of any information on their original BP and cardiovascular risk pattern, the category to which patients in whom control is limited to out-of-office BP cannot be determined. Furthermore, given the persisting uncertainty of the optimal office BP target in different clinical conditions,37 the possibility exists that what is regarded as an uncontrolled office BP actually represents the optimal (or maximally protective) value for this group. Finally, it should be emphasized that studies on WCH have a limitation that is particularly relevant for treated individuals. Namely, they are usually based on a single temporal out-of-office and office BP assessment, which can hardly provide a precise estimate of the prevailing BP value over prolonged (years!) treatment periods usually characterized by multiple treatment changes and a low and variable adherence to the prescribed treatment regimens.38,39Unmet NeedsFactors Responsible for Increased Risk of WCHIn the earliest meta-analyses, adjusting the data for metabolic variables led to an attenuation or a disappearance of the extrarisk exhibited by WC hypertensives.23–26 As shown by the more recent large meta-analysis of Huang et al,28 however, even after extensive covariate adjustment, the risk of WCH individuals remained higher than that of normotensive controls, suggesting that their BP pattern is also involved. The question remains whether this BP contribution is because of the office BP elevation, the ambulatory and home BP values, or both. In this context, it is important to mention that, although confined by definition to the normal range, in WCH, both ambulatory and home BP values are few mm Hg higher than in the control normotensive population.4,28 Because both pressures have a clear-cut relationship with cardiovascular events40–45 even when their value is in the normal range42 (Figure 6), this speaks in favors of their involvement.46 A contribution of office BP should by no means be excluded, however. In the WCH patients of the PAMELA study, for example, office rather than out-of-office BP showed the ability to predict progression to sustained hypertension or diabetes mellitus.19,20,22 Furthermore, for a similar 24-hour BP value, the cardiovascular risk of WCH subjects was greater when office BP was higher.47Cardiovascular Risk Discrimination in the WCH PopulationAn important practical issue is to distinguish, within the overall WCH category, patients in whom the cardiovascular risk is higher to decide about the closeness of the follow-up, the intensity of the lifestyle interventions, and perhaps also the need of cautionary drug treatment. A careful history, a thorough assessment of metabolic risk factors, and a precise identification of structural and functional organ alterations can obviously be of help together, however, with 2 other diagnostic approaches. One is to measure either ambulatory and home BP because evidence has been obtained that cardiovascular risk is less in WCH subjects in whom both these pressures are within the normal range,48 an observation that incidentally suggests that these 2 out-of-office BP may have a complementary prognostic value.4 The other is to measure office BP at different visits because subjects with a persistent office BP elevation have been found to be at greater risk than those in whom the elevation has been inconsistent from one visit to another.47 Future studies will have to also investigate the possibility for the WCH-related risk to have a genetic background. This has been suggested in an early investigation by Julius et al49 who found patients with WCH (high office and normal home BP) to have parents with office BP elevations as well.Antihypertensive TreatmentUnfortunately, no evidence is available on whether the risk of WCH is reduced by antihypertensive drugs, possibly with a return to the risk level of the normotensive population. To date, data can count on a 4-year follow-up of the patients recruited for the European Lacidipine Study on Atherosclerosis, which has shown antihypertensive drugs to (1) persistently lower office BP almost as much in WCH (high office and normal ambulatory BP) and sustained hypertensive patients18 and (2) have a strikingly different effect on ambulatory BP, which was effectively reduced in sustained but unchanged or slightly increased in WC hypertensives. They can also count on the follow-up of patients with WC systolic hypertension recruited for the SYSTEUR trial (Systolic Hypertension in Europe) in which drug treatment did not reduce cardiovascular outcomes more than placebo.50 Unfortunately, in this study, the number of events was so small as to make the results inconclusive and leave the question whether BP should be lowered in WCH unanswered. It should be mentioned, however, that based on epidemiological data,2 in the large number of randomized trials that have documented the protective effect of antihypertensive treatment,51 the prevalence of WCH was far from marginal. This might have been particularly the case in the trials that have shown BP reduction to lower cardiovascular outcomes in grade 1, low-to-moderate risk hypertensives,52–54 ≤40% of whom may have a WCH condition.2 It was definitively the case in patients (aged ≥80 years) with an office BP elevation recruited for the HYVET (Hypertension in the Very Elderly Trial),55 in whom treatment was accompanied by a marked reduction of cardiovascular events, despite a documented (55%) high prevalence of WCH.56 Thus, it can be argued that, until evidence for the contrary is obtained, WCH patients share the benefit of treatment of the overall hypertensive population and should not be denied a BP-lowering intervention. A randomized properly powered outcome-based trial will be necessary to give this important question a conclusive answer.Understanding the Nature of WCHA better understanding of the factors involved in the difference between office and out-of-office BP will also be desirable and perhaps helpful in designing the proper trials to perform. To date, this difference is ascribed to the alerting response to the environmental conditions where office BP is taken, but several arguments suggest that this may not be the only factor involved.44 One, the alerting response to office BP measurements is accompanied by a marked tachycardia,57 which is hardly compatible with the regularly reported similarity of office and daytime heart rates.30 Two, the difference between office and out-of-office BP increases markedly with patient's age, which should imply a hyperreaction of elderly patients to office BP measurements or, more in general, stress. This has not been found in studies that have addressed the patients' BP response to laboratory-elicited emotional stimuli. Furthermore, in patients under intra-arterial ambulatory BP monitoring, the BP increase seen during a physician's visit (ie, the directly quantified WC effect) has shown no relationship with patients' age.58 Three, the difference between office and out-of-office BP is directly related to office, but it exhibits a steep inverse relationship with out-of-office values, thereby being under the influence of emotional factors but also of factors that govern daily life BP and have little or no relationship with the emotional response to the physician's visit.59 Indeed, years ago, we showed the office daytime BP difference to bear no significant relationship with the WC effect as directly quantified by beat-to-beat BP monitoring before, during, and after the physician's visit,60 suggesting that the alerting component of this effect may not even be the most important one. This may perhaps be especially the case in elderly patients in whom an impairment of the mechanisms involved in BP homeostasis might lead to frequent daytime hypotensive episodes, lowering the mean ambulatory value. According to these arguments, the term WCH may be not entirely correct, favoring its replacement with a more neutral descriptive term such as isolated office hypertension. However, history provides multiple examples that trying to change popular names is an exercise in futility. Use of the term WCH for defining the condition of selective office BP elevation should not imply, however, that its mechanistic nature has been clarified, and no further studies in this direction are needed.Download figureDownload PowerPointFigure 6. Eleven-year increase in risk of cardiovascular mortality for 10 mm Hg increase in office, home, 24-h mean systolic blood pressure (SBP) and different baseline SBP values. Reprinted from Sega et al42 with permission of the publisher. Copyright © 2005, American Heart Association, Inc.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.This paper was sent to Theodore A. Kotchen, Guest Editor, for review by expert referees, editorial decision, and final disposition.Correspondence to Giuseppe Mancia, University of Milano-Bicocca, Piazza dei Daini 4, 20126 Milano, Italy. E-mail [email protected]References1. Pickering TG, Harshfield GA, Devereux RB, Laragh JH. What is the role of ambulatory blood pressure monitoring in the management of hypertensive patients?Hypertension. 1985; 7:171–177.LinkGoogle Scholar2. 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A review and meta-analysis.Blood Press Monit. 2015; 20:57–63. doi: 10.1097/MBP.0000000000000094.CrossrefMedlineGoogle Scholar13. Grassi G, Seravalle G, Trevano FQ, Dell'oro R, Bolla G, Cuspidi C, Arenare F, Mancia G. Neurogenic abnormalities in masked hypertension.Hypertension. 2007; 50:537–542. doi: 10.1161/HYPERTENSIONAHA.107.092528.LinkGoogle Scholar14. Mancia G, Grassi G. The autonomic nervous system and hypertension.Circ Res. 2014; 114:1804–1814. doi: 10.1161/CIRCRESAHA.114.302524.LinkGoogle Scholar15. Schlaich MP, Kaye DM, Lambert E, Sommerville M, Socratous F, Esler MD. Relation between cardiac sympathetic activity and hypertensive left ventricular hypertrophy.Circulation. 2003; 108:560–565. doi: 10.1161/01.CIR.0000081775.72651.B6.LinkGoogle Scholar16. Bevan RD. Trophic effects of peripheral adrenergic nerves on vascular structure.Hypertension. 1984; 6(6pt 2):III19–III26.AbstractGoogle Scholar17. Mancia G. Short- and long-term blood pressure variability: present and future.Hypertension. 2012; 60:5

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