Use of ambulatory and home blood pressure (BP) measurements

Long-Term Risk of Mortality Associated With Selective and Combined Elevation in Office, Home, and Ambulatory Blood Pressure Giuseppe Mancia, Rita Facchetti, Michele Bombelli, Guido Grassi, Roberto Sega Abstract In the Pressioni Arteriose Monitorate e Loro Associazioni (PAMELA) study, office, home, and ambulatory blood pressure (BP) values were measured contemporaneously between 1990 and 1993 in a large population sample (n 2051). Cardiovascular (CV) and non-cv death certificates were collected over the next 148 months, which allowed us to assess the prognostic value of selective and combined elevation in these 3 BPs over a long follow-up. There were 69 CV and 233 all-cause deaths. Compared with subjects with normal office and 24-hour BP, the hazard ratio for CV death showed a progressive increase in those with a selective office BP elevation (white-coat hypertension), a selective 24-hour BP elevation (masked hypertension), and elevation in both office and 24-hour BP. This was the case also when the above conditions were identified by office versus home BP values. Selective elevation in home versus ambulatory BP or vice versa also carried an increased risk. There was indeed a progressive increase in both CV and all-cause mortality risk from subjects in whom office, home, and ambulatory BP were all normal to those in whom 1, 2, or all 3 BPs were elevated, regardless of which BP was considered. The trends remained significant after adjustment for age and gender, as well as, in most instances, after further adjustment for other cardiovascular risk factors. Thus, white-coat hypertension and masked hypertension, both when identified by office and ambulatory or by office and home BPs, are not prognostically innocent. Indeed, each BP elevation (office, home, or ambulatory) carries an increase in risk mortality that adds to that of the other BP elevations. (Hypertension. 2006; 47:846-853.) Key Words: blood pressure monitoring, ambulatory hypertension, white-coat cardiovascular diseases Use of ambulatory and home blood pressure (BP) measurements has allowed us to discover 2 conditions that were unknown when BP was mainly measured in the clinic environment, that is: (1) isolated office (or white-coat) hypertension (HT), in which BPs obtained in the office are 140 mm Hg systolic or 90 mm Hg diastolic, whereas ambulatory or home BP values remain within their normal range; and (2) masked HT, in which office BP is normal, whereas ambulatory or home BPs are elevated. 1 The clinical significance of these conditions is still a matter of debate, because cross-sectional studies aimed at examining whether white-coat HT is accompanied by a greater incidence of HT-related organ damage have not provided univocal results. 2 4 In addition, and more importantly, the results have not been univocal in the few studies that have addressed this issue prospectically and have reported white-coat HT (as diagnosed by office BP elevation and ambulatory BP normality) to carry no increase in the incidence of cerebral or cardiovascular (CV) disease 5 9 or to have a greater or delayed CV risk as compared with that of normotensive subjects. 10 13 Furthermore, masked HT has been reported to have a greater prevalence of organ damage 14 16 and a prognostically greater risk than that of normotensive individuals and possibly of white-coat hypertensives. 13,17,18 However, the evidence is largely confined to a few studies based on ambulatory BP in populations with selected ages, limited follow-up periods, and variable definitions of ambulatory BP normality over 24 hours or the day only. Finally, limited evidence is available as to the prognostic significance of the 2 above-mentioned clinical conditions, when identified by home BP measurements, that is, procedures of large and growing use in clinical practice. The Pressioni Arteriose Monitorate e Loro Associazioni (PAMELA) study examined cross-sectionally a large sample representative of the population of Monza (a town in the northeast outskirt of Milan) from 1990 to 1993 to establish the normality range of ambulatory and home BPs. 19 From recruitment to October 2004, contact with participants was maintained by mail and phone, and a copy of the death certificate was obtained for all of the subjects who died. This allowed a number of issues to be examined (some for the first time) in the context of a population and over a long follow-up. First, it allowed the prognostic value of white-coat or masked HT to be assessed over a long observational period Received November 21, 2005; first decision December 21, 2005; revision accepted February 14, 2006. From the Clinica Medica (G.M., R.F., M.B., G.G., R.S.), Università Milano-Bicocca, Ospedale San Gerardo; Centro Interuniversitario di Fisiologia Clinica e Ipertensione (G.M., R.F., M.B., G.G., R.S.), and Centro Auxologico Italiano (G.M., G.G.), Milan, Italy. Correspondence to Giuseppe Mancia, Clinica Medica, Ospedale S. Gerardo dei Tintori, Via Pergolesi 33, 20052, Milan, Italy. E-mail giuseppe.mancia@ unimib.it 2006 American Heart Association, Inc. Hypertension is available at http://www.hypertensionaha.org DOI: 10.1161/01.HYP.0000215363.69793.bb 846

Mancia et al Mortality and Blood Pressure 847 in a general population rather than in selected cohorts of subjects, as in most previous studies. Second, it studied the prognostic value of white-coat or masked HT when the diagnosis is based on home BP vis a vis that based on ambulatory BP. Third, it studied the prognosis of individuals in whom a discrepancy exists between home and ambulatory BP, that is, one is elevated, whereas the other is normal and vice versa. Last, it studied whether and how the elevation of 1, 2, or all 3 BPs has a progressively adverse impact on prognosis, independent of their in-office or out-of-office nature. Methods The methodology used in the PAMELA Study has been reported in detail elsewhere. 19 Briefly, 3200 individuals were randomly selected from the residents of the town of Monza to be representative of the population for gender and age decades (25 to 74 years), according to the criteria used in the World Health Organization-MONItoring trends and determinants on CArdiovascular diseases (MONICA) Study conducted in the same geographic area. The overall participation rate was 64% (n 2051) consistently in each age and sex stratum. The demographic characteristics of nonparticipants were similar to those of participants. This was also the case for CV risk factors based on information collected via phone interviews. Entry Data Participants were invited to come to the outpatient sector of the local hospital (San Gerardo) in the morning of a working day (Monday through Friday), where several data were collected. Those relevant to the present study are (1) 3 sphygmomanometric BP measurements with the subject in the sitting position, starting 10 minutes after the beginning of the medical visit, (2) a 24-hour ambulatory BP monitoring through an oscillometric device (Spacelabs 90207, Spacelabs) with TABLE 1. Baseline Demographic and Clinic Variables According to Office vs 24-Hour or Home BP Office 3 Office 1 Office 3 Office 1 Variable 24-Hour 3 24-Hour 3 24-Hour 1 24-Hour 1 No. of subjects 1001 356 172 495 CV deaths, % 1.1 3.7 4.1 7.3 All-cause deaths, % 5.7 15.5 12.8 19.2 Male prevalence, % 43 48 73 60 Age, y 45 (12.7) 56.6 (11.9) 49.1 (12.9) 59.3 (10.68) Smokers, % 30 20 41 23 BMI, kg/m 2 24.1 (3.7) 27.2 (4.17) 25.9 (3.7) 27.2 (5.1) SBP office, mm Hg 117.9 (10.3) 144.2 (14.2) 126.6 (7.6) 156.8 (18.3) DBP office, mm Hg 76.8 (6.9) 89.9 (6.8) 82.1 (5.2) 94.2 (9.3) SBP home, mm Hg 113.1 (13.0) 128.3 (15.0) 127.8 (12.2) 144.5 (17.2) DBP home, mm Hg 71.0 (8.8) 79.1 (8.9) 79.6 (7.0) 85.1 (9.3) SBP 24 hour, mm Hg 112.7 (6.6) 117.3 (5.4) 127.2 (5.7) 135.2 (10.1) DBP 24 hour, mm Hg 70.2 (4.9) 72.4 (4.6) 80.0 (4.8) 82.5 (6.9) Serum cholesterol, mmol/l 5.5 (1.0) 6.1 (1.0) 5.8 (1.1) 6.1 (1.0) Blood glucose, mmol/l 4.8 (0.7) 5.1 (0.9) 5.3 (1.8) 5.4 (1.5) Office 3 Office 1 Office 3 Office 1 Variable Home 3 Home 3 Home 1 Home 1 No. of subjects 909 242 184 528 CV deaths, % 0.9 1.2 4.4 7.4 All-cause deaths, % 4.7 9.1 13.6 19.7 Male prevalence, % 43 53 68 58 Age, y 43.7 (11.9) 51.8 (11.1) 52.8 (13.2) 60.0 (10.1) Smokers, % 27 24 42 21 BMI, kg/m 2 24.0 (3.6) 26.5 (4.5) 26.1 (3.6) 27.5 (4.8) SBP office, mm Hg 117.7 (10.2) 140.2 (10.9) 126.2 (8.0) 156.6 (18.3) DBP office, mm Hg 76.9 (7.0) 90.4 (6.5) 81.0 (5.2) 93.7 (9.5) SBP home, mm Hg 111.4 (10.2) 119.9 (7.8) 134.2 (12.6) 146.2 (15.3) DBP home, mm Hg 69.8 (6.9) 75.1 (5.2) 84.4 (9.1) 86.0 (9.2) SBP 24 hour, mm Hg 113.5 (7.5) 120.4 (7.8) 121.8 (8.8) 131.2 (12.4) DBP 24 hour, mm Hg 70.8 (5.5) 75.5 (6.1) 76.0 (6.3) 80.0 (8.2) Serum cholesterol, mmol/l 5.5 (1.0) 5.9 (1.1) 5.9 (1.0) 6.1 (1.0) Blood glucose, mmol/l 4.8 (0.7) 5.2 (1.3) 5.2 (1.6) 5.4 (1.3) Data are shown as mean (SD) or %. SBP indicates systolic BP; DBP, diastolic BP; BMI, body mass index; office 24 hour 1 or office 1 home 3, white-coat HT; office 3 24 hour or office 3 home 1, masked HT.

848 Hypertension May 2006 Figure 1. Percentage incidence of CV (f) and all-cause death ( ) over an average follow-up of 148 months in subjects with various combinations of normality or elevation in office, home, and 24-hour BP. Data are adjusted for age and gender. Numbers refer to 2 trends and related P values. the BP readings set at 20-minute intervals (the subjects were sent home after checking for the device accuracy with the instruction to attend at their usual activities and to come back the next morning for the device removal), (3) 2 home BP measurements (approximately at 7:00 AM and 7:00 PM) through a validated semiautomatic device (Model HP 5331, Philips) using the arm contralateral to that used for ambulatory monitoring, (4) 3 additional sphygmomanometric sitting BP measurements, after removal of the ambulatory BP device, and (5) information (history and physical examination) on CV risk factors including overweight, smoking habit, serum cholesterol, blood glucose, diabetes mellitus, and history of previous CV morbid events. Total serum cholesterol and blood glucose levels were measured in all of the subjects by standard radioenzymatic method. Follow-Up From the time of the medical visit to October 1, 2004, a copy of the death certificate was obtained for all of the subjects who died. The causes of death reported in the certificate were coded according to the Tenth International Classification of Diseases. Over an average follow-up period amounting to 148 months, there were 233 deaths, of which 69 were of a CV nature. Data Analysis The 3 office and the 2 home BP measurements obtained at the initial visit were separately averaged. As reported in detail in the article describing the PAMELA data, 19 ambulatory BP values were edited from artifacts according to preselected criteria 20 and averaged for the 24 hours, the day (7:00 AM to 11:00 PM), and the night (11:00 PM to 7:00 AM). Valid ambulatory BP readings were 95.9% of those planned (ie, 72 readings over 24 hours) with an homogeneous distribution (2.9 per hour) throughout the entire recording period and a similar percentage of valid readings compared with the expected ones over the day (95.7%) and the night (96.5%). Based on office (pooled data) and 24-hour ambulatory BP values, subjects were divided into 4 groups: (1) normal office ( 140/90 mm Hg) and 24-hour ( 125/79 mm Hg) systolic and diastolic BP; (2) elevation in office systolic or diastolic BP with normal 24-hour ambulatory BP, that is, isolated office or white-coat HT; (3) normal office BP with elevation in 24-hour home systolic or diastolic BP, that is, masked HT; and (4) elevated office and 24-hour systolic or diastolic BP. A similar subdivision into 4 groups was made based on office versus home BP values normality ( 135 mm Hg systolic or 83 mm Hg diastolic) or elevations ( 135 mm Hg systolic or 83 mm Hg diastolic). Subjects were divided into 4 groups also according to the normal and/or elevated 24-hour and home BP values. The upper normality values of 24-hour and home BPs were derived from the cross-sectional data obtained in the whole PAMELA population based on their correspondence with office BPs equal to 140/ 90 mm Hg on the regression line linking the 3 BPs. 19 These values are superimposable to the normality values reported by other studies using different approaches and mentioned by international guidelines as the most likely cutoffs dividing out-of-office HT from normoten-

Mancia et al Mortality and Blood Pressure 849 Figure 2. Hazard ratios (HR, 95% confidence intervals) for CV death in subjects with white-coat HT, masked HT, or elevations in both in-office and out-of-office BP versus subjects with in-office and out-of-office BP normality, as defined in Figure 1. HRs are also shown for subjects with elevation in 1, 2, or all 3 available BPs versus those in whom all 3 BPs were normal (D) regardless of whether the elevation involved office, home, or ambulatory BP., unadjusted data;, data adjusted for age and gender. Symbols and explanations as in the preceding figure. sion. 1,21 The incidence of events was calculated via a logistic model. The hazard ratio was calculated by the Cox proportional hazard model, the assumption of BP proportionality being assessed by proper statistical test. The 2 test was used to evaluate the trends in death incidence or hazard ratio: (1) from the normotensive to white-coat hypertensive, masked hypertensive, and in-office and out-of-office hypertensive group; (2) from the group with normal 24-hour and home BP, the group with selective 24-hour BP elevation, the group with selective home BP elevation, and the group with elevation in both 24-hour and home BP; and (3) from the group with no BP elevation to the groups with elevation in 1, 2, or all 3 of the BPs, regardless of whether they were measured. Groups were ordered in the above fashion because of the suggestion from previous studies that: (1) in white-coat HT, CV damage and risk may be greater than in true normotension but less in true HT 2,3,5,6 13 ; (2) masked HT may be clinically worse than white-coat HT because of the superior prognostic significance of ambulatory versus office BP 14 ; and (3) the ability of home BP to predict the risk of death compares favorably with that of ambulatory BP. 14 Data were adjusted for age and gender. Further adjustments were also made for history of CV disease, smoking prevalence, blood glucose, and serum total cholesterol, which were included as covariates into the model. Throughout the text, values in parentheses refer to the SD of the mean. A 2-tailed P value 0.05 was considered to be statistically significant. Results As shown in Table 1, compared with normotensive subjects, subjects with white-coat HT, masked HT, and elevation, both in-office and out-of-office BP showed a greater male prevalence, age, body mass index, serum total cholesterol, and blood glucose. This was the case either when BP normality and elevation were identified by office versus 24-hour and by office versus home BP criteria (Table 1, bottom). As shown in Figure 1A and 1B, compared with normotensive subjects, age- and gender-adjusted incidence of CV and all-cause death were usually greater in the remaining 3 groups. There was a statistically significant trend toward a progressively greater unadjusted and age- and gender-adjusted risk of CV from the entirely normotensive to the white-coat HT, masked HT, and entirely hypertensive group, regardless of whether BP normality or elevation was identified by office versus ambulatory or by office versus home BP criteria (Figure 2A and 2B). A similar trend was observed for unadjusted hazard ratios for all-cause mortality (Figure 3A and 3B), as well as for further adjustment of the risk of CV mortality and history of CV disease, smoking, serum total cholesterol, and blood glucose (Table 2). Table 3, top, shows the baseline values of 4 groups characterized by 24-hour and home BP normality, selective elevation in 24-hour BP, selective elevation in home BP, and elevation in both 24-hour and home BP. Compared with the first group, male prevalence, age, body mass index, and lipid and glucose variables were invariably greater in the remaining 3 groups. This

850 Hypertension May 2006 TABLE 2. Risk of CV or All-Cause Death in Subjects With Various Combinations of Office, Home, and 24-Hour BP Normality or Elevations Cardiovascular Death All-Cause Death Blood Pressure 2 Trend P 2 Trend P Office BP vs home BP Unadjusted 39.43 0.0001 76.85 0.0001 After adjustment for age/gender 6.94 0.008 3.65 0.056 (NS) After further adjustment for serum 5.81 0.015 2.51 0.11 (NS) cholesterol, blood glucose, and smoking Office BP vs 24-hour BP Unadjusted 35.34 0.0001 57.52 0.0001 After adjustment for age/gender 6.02 0.014 2.25 0.133 (NS) After further adjustment for serum 4.21 0.040 0.92 0.33 (NS) cholesterol, blood glucose, and smoking Home BP vs 24-hour BP Unadjusted 36.50 0.0001 61.42 0.0001 After adjustment for age/gender 6.3 0.012 3.35 0.07 (NS) After further adjustment for serum 4.88 0.027 1.92 0.16 (NS) cholesterol, blood glucose, and smoking 0 vs 1, 2, or 3 BP elevations Unadjusted 41.25 0.0001 75.70 0.0001 After adjustment for age/gender 7.34 0.007 3.98 0.046 After further adjustment for serum 5.57 0.018 2.38 0.12 (NS) cholesterol, blood glucose, and smoking For each BP pair, trend was calculated for normality of both BPs, selective increase in 1 BP, selective increase in the other BP, and increase in both BPs. Trend was also calculated for subjects with no increase in BP or increase in 1, 2, or all 3 BPs. Data were always adjusted for history of CV disease. NS indicates not significant. was associated with a statistically significant trend toward a progressively greater CV and all-cause mortality (Figure 1C). A similar trend was observed for the unadjusted and age- and gender-adjusted hazard ratios for CV, although not for all-cause mortality (Figure 2C, Figure 3C, and Table 2). The trend toward a progressive increase in CV mortality remained significant after further adjustment for history of CV disease, smoking, serum cholesterol, and blood glucose (Table 2). Table 3 (bottom) shows baseline values of subjects in whom office, 24-hour, and home BPs were all normal versus those in whom 1, 2, or all 3 BPs were elevated, regardless of which BP was considered. Male prevalence, age, body mass index, serum total cholesterol, and blood glucose were less in subjects in whom all 3 of the BPs were normal with a progressive increase from the first to the fourth group. This was associated with a statistically significant trend toward a progressively greater ageand gender-adjusted incidence of CV and all-cause mortality (Figure 1D). A similar trend was observed for the unadjusted and age- and gender-adjusted hazard ratios for CV and all-cause mortality (Figures 2D and 3D and Table 2). In both instances, the trend remained significant also after further adjustment for history of CV disease, smoking, serum cholesterol, and blood glucose (Table 2). Discussion Our study allows several conclusions to be made. First, in the PAMELA population, the incidence and risk of CV death showed a progressive increase from subjects in which in-office and out-of-office BPs were both normal to subjects with whitecoat HT, masked HT, and in-office and out-of-office HT, independent of age and gender. Second, the progressive increase in mortality from the entirely normotensive to the entirely hypertensive group occurred regardless of whether the above conditions were identified based on office versus ambulatory or office versus home BP. Thus, white-coat and masked HT are not clinically innocent conditions, but they rather indicate a transition toward a greater risk that reached the maximum when in-office and out-of-office BP are both increased. This has 2 implications for the practice of medicine. First, physicians should not lightly decide to dismiss treatment in patients with white-coat HT. Second, normal office BP values should not be taken as a guarantee that there is no increase in risk because of the possibility of an elevation in out-of-office BP. This implies that out-of-office BP values should be more frequently collected than is recommended by current guidelines. 1 The noticeable prevalence of masked HT in the normotensive fraction of the PAMELA population (14.5% and 15.5% when assessed by ambulatory and office BP, respectively; Reference 14 ) scores in this direction. Our study provides new evidence on other clinically relevant issues. Although in our subjects only 2 home BP measurements were available, a selective elevation in home BP increased the age- and gender-adjusted risk of CV and all-cause mortality to an extent that was, if anything, greater

Mancia et al Mortality and Blood Pressure 851 TABLE 3. Baseline Demographic and Clinic Variables According to 24-Hour vs Home BP or to No. of BP Elevations 24-Hour 3 24-Hour 1 24-Hour 3 24-Hour 1 Variable Home 3 Home 3 Home 1 Home 1 No. of subjects 991 155 258 453 CV deaths, % 0.8 2.6 5 7.5 All-cause deaths, % 4.9 11 16.7 19.2 Male prevalence, % 42 65 57 63 Age, y 45.0 (12.2) 48.3 (11.7) 56.7 (12.4) 58.8 (10.8) Smokers, % 28 31 26 27 BMI, kg/m 2 24.3 (3.8) 26.0 (4.3) 27.0 (3.9) 27.2 (4.9) SBP office, mm Hg 120.7 (13.2) 134.0 (12.5) 138.6 (16.9) 154.3 (20.9) DBP office, mm Hg 78.6 (8.4) 87.3 (7.6) 86.2 (8.3) 92.8 (10.4) SBP home, mm Hg 111.9 (10.5) 121.3 (6.9) 136.6 (13.7) 146.6 (15.4) DBP home, mm Hg 70.1 (6.9) 75.9 (4.4) 84.3 (9.8) 86.3 (8.7) SBP 24 hour, mm Hg 113.0 (6.6) 127.2 (5.5) 117.2 (5.6) 135.3 (9.9) DBP 24 hour, mm Hg 70.4 (4.9) 80.7 (4.1) 72.6 (4.5) 82.6 (7.2) Serum cholesterol, mmol/l 5.6 (1.0) 6.0 (1.1) 5.9 (1.2) 6.1 (1.1) Blood glucose, mmol/l 4.8 (0.8) 5.1 (1.0) 5.1 (1.5) 5.5 (1.6) Variable N BP 1 0 N BP 1 1 N BP 1 2 N BP 1 3 No. of subjects 825 347 306 373 CV deaths, % 0.7 2.3 4.3 8.3 All-cause deaths, % 4.1 11.0 15.0 20.4 Male prevalence, % 40 59 59 61 Age, y 43.7 (11.9) 50.4 (12.7) 55.8 (11.5) 60.0 (10.0) Smokers, % 29 28 30 22 BMI, kg/m 2 23.9 (3.6) 25.9 (4.0) 27.2 (4.0) 27.4 (5.2) SBP office, mm Hg 117.0 (10.1) 131.9 (12.0) 141.2 (14.9) 160.0 (18.2) DBP office, mm Hg 76.4 (6.9) 85.2 (7.2) 88.6 (7.8) 95.0 (9.8) SBP home, mm Hg 110.5 (10.4) 123.4 (11.8) 133.9 (13.3) 149.0 (15.1) DBP home, mm Hg 69.3 (6.9) 77.4 (8.7) 82.6 (7.8) 86.7 (9.2) SBP 24 hour, mm Hg 112.3 (6.6) 118.7 (6.6) 123.4 (8.01) 136.6 (10.0) DBP 24 hour, mm Hg 69.9 (4.8) 74.2 (5.2) 76.9 (6.4) 83.0 (7.4) Serum cholesterol, mmol/l 5.5 (1.0) 5.9 (1.1) 6.1 (1.1) 6.1 (1.0) Blood glucose, mmol/l 4.7 (0.7) 5.0 (1.0) 5.3 (1.6) 5.5 (1.4) Data are shown as mean (SD) or %. N BP 1 indicates No. of elevated BPs. SBP, systolic BP; DBP, diastolic BP; BMI, body mass index; office 24 hour 1 or office 1 home 3, white-coat HT; office 3 24 hour or office 3 home 1, masked HT. than the increase associated with a selective elevation in 24-hour BP. This confirms the importance of BP values self-measured in the home environment 9,18 of which the prognostic significance may favorably compare with that of 24-hour BP even when the potential of this approach (daily measurements for weeks) is only partially used. The above, however, does not mean that home BP should be considered just as a substitute of ambulatory BP monitoring, because, in our study, an elevation in only 1 of these out-of-office BPs was accompanied by a risk of CV or all-cause death, which was less than that seen when both of these out-of-office BPs were elevated. Thus, home and ambulatory BP do not represent a duplicate of the same type of information. This is also made clear by the observation that age- and genderadjusted risk of CV and all-cause death increased progressively in subjects in whom office, home, and 24-hour BP were all normal to subjects in whom 1, 2, or all 3 of these BPs were elevated, regardless of which BP showed the elevation. This leads to the conclusion that office, home, and 24-hour BPs have an individual prognostic value that may add to the prognostic value of the others BPs. Thus, obtaining information on office, home, and 24-hour BP may represent the ideal clinical procedure. Confirming previous findings, 22 26 white-coat hypertensives, masked hypertensives, and hypertensives with in-office and out-of office BP elevations of the PAMELA study all showed body mass index, serum total cholesterol, and blood glucose values that were greater the those of individuals with

852 Hypertension May 2006 Figure 3. Unadjusted and age- and gender-adjusted HR for all-cause death in the subjects of Figure 2. Symbols and explanations as in Figure 2. in-office and out-of-office BP normality. In addition, however, they show that body mass index, total serum cholesterol, and plasma glucose all displayed a progressive increase from individuals in whom office, home, and ambulatory BPs were all normal to those in which 1, 2, or all 3 BPs were elevated (Table 1, P 0.0001 for all trends). This emphasizes that there is a close quantitative relationship between metabolic and BP abnormalities, regardless of where and how BP is measured, with each BP offering a specific contribution to the overall dysmetabolic profile. It also makes it obvious that the progressive increase in risk from normotension to white-coat HT, masked HT, and true HT, as well as from subjects with no elevation to subjects with 3 BP elevations may have a multifactorial nature, that is, it may also be because of alterations in glucose and lipid metabolism. BP alterations, per se, however, are likely to be involved, because in all of the above conditions, the progressive increase in CV mortality remained significant after adjustment for differences in metabolic, as well as other risk factors between groups, suggesting that in-office and out-of-office BPs, per se, play a role. This role may be accounted for by the data shown in Tables 1 and 3. That is, in white-coat HT, the office BP elevation was accompanied by ambulatory or home BP values that, although normal, were higher than the values seen in subjects without white-coat HT. Conversely, in masked HT, office BP values, although normal, were higher than those observed in subjects without masked HT. Finally, moving from the condition of no BP elevation to that of 1, 2, or all 3 BP elevations was associated with a progressive increase in all of the BPs, that is, both in the BPs that reached the HT range and in those that remained in the normotensive range (Table 3, bottom). This may have prognostic relevance, because office, home, and 24-hour BP have all been shown to have a continuous relationship with CV risk. 1,2,9,10 Our study has a number of favorable characteristics but also 2 limitations. The favorable characteristics include the long follow-up, as well as the objective nature (death) of the events. One limitation is that the number of CV events was small, given the low CV risk of Mediterranean populations, leading to hazard ratios with large confidence limits. However, the results were often supported by the data on all-cause death, which was 3 times as large as CV death. This was, for example, the case for age- and gender-adjusted risk of all-cause death in subjects with no or 1, 2, or 3 BP elevations. The other limitation is that the observational nature of our study did not allow us to assess the effect on the prognosis of antihypertensive treatment and therapeutic corrections of glucose and lipid abnormalities. Antihypertensive treatment, for example, might have been more common in white-coat than in masked hypertensives, because in the clinical practice treatment is usually guided by office BP elevations, contributing to the better prognosis of the former versus the latter condition.

Mancia et al Mortality and Blood Pressure 853 Perspectives Our study provides long-term prognostic evidence that whitecoat or masked HT are not innocent conditions. It also provides evidence that office, home, and 24-hour BP may each have an adverse prognostic value, which adds to that of the other BPs. References 1. Guidelines Committee. 2003 European Society of Hypertension/ European Society of Cardiology Guidelines for the management of arterial hypertension. J Hypertens. 2003;21:1011 1053. 2. Pickering TG, Coats A, Mallion JM, Mancia G, Verdecchia P. Blood pressure monitoring. Task force V: white-coat hypertension. Blood Press Monit. 1999;4:333 341. 3. Mancia G, Zanchetti A. White-coat hypertension: misnomers, misconceptions and misunderstandings. What should we do next? J Hypertens. 1996;14:1049 1052. 4. Verdecchia P, Schillaci G, Boldrini F, Zampi I, Porcellati C. Variability between current definitions of normal ambulatory blood pressure. Implications in the assessment of white coat hypertension. Hypertension. 1992;20:555 562. 5. Verdecchia P, Reboldi GP, Angeli F, Schillaci G, Schwartz JE, Pickering TG, Imai Y, Ohkubo T, Kario K. Short-and long-term incidence of stroke in white-coat hypertension. Hypertension. 2005;45:203 208. 6. Celis H, Staessen JA, Thijs L, Buntinx F, De Buyzere M, Den Hond E, Fagard RH, O Brien ET for the Ambulatory Blood Pressure and Treatment of Hypertension Trial Investigators. Cardiovascular risk in white-coat and sustained hypertensive patients. Blood Press. 2002;11: 352 356. 7. Verdecchia P, Schillaci G, Borgioni C, Ciucci A, Porcellati C. Prognostic significance of the white-coat effect. Hypertension. 1997;29:1218 1224. 8. Khattar RS, Swales JD, Banfield A, Dore C, Senior R, Lahiri A. Prediction of coronary and cerebrovascular morbidity and mortality by direct continuous ambulatory blood pressure monitoring in essential hypertension. Circulation. 1999;100:1071 1076. 9. Fagard RH, Van Den Broeke C, De Cort P. Prognostic significance of blood pressure measured in the office, at home and during ambulatory monitoring in older patients in general practice. J Hum Hypertens. 2005; 19:801 807. 10. Verdecchia P. Prognostic value of ambulatory blood pressure: current evidence and clinical implications. Hypertension. 2000;35:844 851. 11. Strandberg TE, Salomaa V. White coat effects, blood pressure and mortality in men: a prospective cohort study. Eur Heart J. 2000;21: 1714 1718. 12. Gustavsen PH, Hoegholm A, Bang LE, Kristensen KS. White-coat hypertension is a cardiovascular risk factor: a 10-year follow-up study. J Hum Hypertens. 2003;17:811 817. 13. Ohkubo T, Kikuya M, Metoki H, Asayama K, Obara T, Hashimoto J, Totsune K, Hoshi H, Satoh H, Imai Y. Prognosis of masked hypertension and white-coat hypertension detected by 24-h ambulatory blood pressure monitoring 10-year follow-up from the Ohasama study. JAm Coll Cardiol. 2005;46:508 515. 14. Sega R, Trocino G, Lanzarotti A, Carugo S, Cesana G, Schiavina R, Valagussa F, Bombelli M, Giannattasio C, Zanchetti A, Mancia G. Alterations of cardiac structure in patients with isolated office, ambulatory, or home hypertension: data from the general population (Pressioni Arteriose Monitorate E Loro Associazioni [PAMELA] Study). Circulation. 2001; 104:1385 1392. 15. Liu JE, Roman MJ, Pini R, Schwartz JE, Pickering TG, Devereux RB. Cardiac and arterial target organ damage in adults with elevated ambulatory and normal office blood pressure. Ann Intern Med. 1999;131: 564 572. 16. Lurbe E, Torro I, Alvarez V, Nawrot T, Paya R, Redon J, Staessen JA. Prevalence, persistence, and clinical significance of masked hypertension in youth. Hypertension. 2005;45:493 498. 17. Bjorklund K, Lind L, Zethelius B, Andren B, Lithell H. Isolated ambulatory hypertension predicts cardiovascular morbidity in elderly men. Circulation. 2003;107:1297 1302. 18. Bobrie G, Chatellier G, Genes N, Clerson P, Vaur L, Vaisse B, Menard J, Mallion JM. Cardiovascular prognosis of masked hypertension detected by blood pressure self-measurement in elderly treated hypertensive patients. JAMA. 2004;291:1342 1349. 19. Sega R, Cesana G, Milesi C, Grassi G, Zanchetti A, Mancia G. Ambulatory and home blood pressure normality in the elderly data from the PAMELA population. Hypertension. 1997;30:1 6. 20. Groppelli A, Omboni S, Parati G, Mancia G. Evaluation of non-invasive blood pressure monitoring devices Spacelabs 90202 and 90207 versus resting and ambulatory 24 hour intraarterial blood pressure. Hypertension. 1992;20:227 232. 21. O Brien E, Asmar R, Beilin L, Imai Y, Mancia G, Mengden T, Myers M, Padfield P, Palatini P, Parati G, Pickering T, Redon J, Staessen J, Stergiou G, Verdecchia P; European Society of Hypertension Working Group on Blood Pressure Monitoring. Practice guidelines of the European Society of Hypertension for clinic, ambulatory and self blood pressure measurement. J Hypertens. 2005;23:697 701. 22. Weber MA, Neutel JM, Smith DH, Graettinger WF. Diagnosis of mild hypertension by ambulatory blood pressure monitoring. Circulation. 1994;90:2291 2298. 23. Eastern Stroke and Coronary Heart Disease Collaborative Research Group. Blood pressure, cholesterol and stroke in eastern Asia. Lancet. 1998;532:1801 1807. 24. Lewington S, MacMahon S. Blood pressure, cholesterol and common causes of death: a review. Prospective studies collaboration. Am J Hypertens. 1999;12:96S 98S. 25. Stamler J, Daviglus ML, Garside DB, Dyer AR, Greenland P, Neaton JD. Relationship of baseline serum cholesterol levels in 3 large cohorts of younger men to long-term coronary, cardiovascular and all-cause mortality and longevity. JAMA. 2000;284:311 318. 26. Mancia G, Facchetti R, Bombelli M, Friz HP, Grassi G, Giannattasio C, Sega R. Relationship of office, home, and ambulatory blood pressure to blood glucose and lipid variables in the PAMELA population. Hypertension. 2005;45:1072 1077.