Target-Organ Damage in Stage I Hypertensive Subjects With White Coat and Sustained Hypertension
Results From the HARVEST Study
Abstract—Controversy remains on whether white coat hypertension is a benign clinical condition or carries an increased risk of target-organ damage. Nine hundred forty-two stage I hypertensive subjects enrolled in the HARVEST trial underwent 24-hour ambulatory blood pressure monitoring and urine collection for albumin measurement. Reliable echocardiographic data were obtained in 722 subjects. White coat hypertensive subjects were defined on the basis of three different partition values: mean daytime blood pressure <130/90 mm Hg, <135/85 mm Hg, or <140/90 mm Hg. Ninety-five normotensive subjects with similar age and sex distribution were studied as controls. With all threshold levels, left ventricular mass index and wall thicknesses were greater in the sustained hypertensive subjects than in the white coat hypertensive subjects, also when these differences were adjusted for blood pressure readings taken in the office. Relative wall thickness was similar in the two hypertensive groups. All echocardiographic dimensional data were greater in the white coat hypertensive subjects than in the normotensive subjects. Urinary albumin and the prevalence of microalbuminuria were also greater in the sustained hypertensive subjects than in the white coat hypertensive subjects. No significant differences in urinary albumin were found between the white coat hypertensive and the normotensive subjects. These results show that within a population of subjects with stage I hypertension, subjects with white coat hypertension have a smaller degree of hypertensive complications than those with sustained hypertension, irrespective of their blood pressure levels taken in the office. However, in comparison with normotensive subjects, white coat hypertensive subjects seem to be at greater risk. Cardiac involvement seems to precede glomerular damage in the early stage of hypertension.
- ambulatory monitoring
- hypertension, white coat
- hypertrophy, left ventricular
The clinical significance and the prognostic implications of the so-called white coat effect, eg, the pressor response triggered by BP measured by the doctor in the office, have not yet been well established. In the past few years there has been much debate over whether white coat hypertension is a benign condition or it is associated with increased degree of hypertensive complications.1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Usually, echocardiographic left ventricular structure and function were studied to assess the effect of BP on target organs,1 5 6 8 9 15 16 18 19 20 but some authors studied low-level urinary albumin,14 a funduscopic-ECG score,20 or even metabolic abnormalities10 17 to highlight differences between subjects with white coat and sustained hypertension. About 50% of the authors claimed that white coat hypertension is not a harmful condition,1 5 6 12 15 19 whereas the other 50% concluded that it carries an increased risk of target-organ damage.8 9 10 11 13 14 16 18 20 However, virtually no study was performed following the same methodological procedures, and several reasons account for the different results obtained by the various authors.
The presence of previous antihypertensive treatment, the lack of a normotensive control group, the relatively small number of subjects in some studies, the range of age and BP, the different ambulatory BP partition values used to define white coat hypertension, and the methods used to assess end organs are all factors that may have influenced the results of the aforementioned studies. In the present article, we report on the relationship between white coat hypertension and target-organ damage in the patients enrolled in the HARVEST study.21 The HARVEST participants are stage I young hypertensive patients who have never been treated for hypertension. In these subjects early end-organ involvement is assessed by echocardiography and dosage of low-level urinary albumin. Three different partition values for ambulatory BP were used (from 130/80 mm Hg up to 140/90 mm Hg) to define subjects with white coat and sustained hypertension.
The study was carried out in 942 subjects who took part in the multicenter HARVEST study, an ongoing investigation on the predictive value of 24-hour ambulatory blood pressure monitoring for the development of fixed hypertension in subjects with borderline to mild hypertension.21 Subjects 18 to 45 years old with diastolic BP from 90 to 99 mm Hg or systolic BP between 140 and 159 mm Hg, who never took antihypertensive therapy, were enrolled in the HARVEST study. The study was approved by the HARVEST Ethics Committee, and informed consent was given by the participants. Mean±SEM age of the participants was 33±0.3 years, and their mean office BP at entry was 146±0.4/94±0.2 mm Hg.
The baseline data included a medical and family history and a questionnaire of current use of alcoholic beverages and tobacco and physical activity habits. Subjects were considered smokers if they reported smoking 1 or more cigarettes per day. They were classified into four categories of alcohol consumption and of physical activity according to the criteria reported elsewhere.22
All subjects underwent physical examination, anthropometry, blood chemistry, urine analysis, office BP and 24-hour BP measurement, resting ECG, echocardiography, and 24-hour urine collection for low-level albumin measurement. BMI was related as a measure of adiposity and determined as weight (kg) divided by height (m) squared.
Ninety-five normotensive subjects with the same age and sex distribution as those of the hypertensive (men: n=71, 74.7%; women: n=24, 25.3%) were taken as control subjects (Table 1⇓). They were recruited from the medical staff and their relations. All were asymptomatic, had no history of cardiovascular disease, and were normal at physical examination. Standard ECG, M-mode and 2-dimensional echocardiogram, blood chemistry, and urinalysis were normal in all of the subjects. Their BP measured six times over a 2-week period was always lower than 140/90 mm Hg.
Office BP was measured according to the recommendations of the British Society of Hypertension.23 The mean of six readings taken in the supine position during two separate visits performed 2 weeks apart was defined as office BP. Phase V Korotkoff sounds was considered as diastolic BP, except in subjects with sounds tending to zero, in whom phase IV was taken.
Twenty-four-hour ambulatory BP monitoring was performed with the A&D TM-2420 model 7, which uses a microphone to detect Korotkoff sounds, or with the ICR Spacelabs 90207, which uses an oscillometric method. Both devices were previously validated.24 25 A recent analysis of 24-hour BP recorded with the two devices in the HARVEST population proved that they provide comparable results.26
The procedures used for the validation and the application of the devices have been described elsewhere.27 During the recordings subjects were asked to follow their ordinary daily activities, to keep a diary of them, and to go to bed not later than 11:00 pm. BP was measured every 10 minutes during the waking hours and every 30 minutes during the nighttime.
Twenty-four-hour BP measurements were stored in a personal computer and screened for editing of artifactual values according to Kennedy criteria.27 Only recordings containing less than 20% of error measurements were considered eligible for evaluation.28 The arithmetic average of the edited pressures was used as the ambulatory measurement for each period of recording. As standard deviation from the mean ambulatory BP is strictly related to the BP level,27 to measure BP variability the coefficient of variation of daytime systolic and diastolic BP was calculated for each individual.
Subjects were defined as white coat hypertensive subjects on the basis of three different partition values: mean daytime BP<130/80 mm Hg, <135/85 mm Hg, or <140/90 mm Hg. These cutoffs cover the entire range of BP levels previously used by other investigators. In particular, with the lowest threshold level we could identify a group of white coat hypertensive subjects having similar ambulatory BP values to those of the normotensive control subjects (Table 1⇑).
Echocardiography was obtained in 796 subjects. In 74 of them the echocardiographic images were technically unsatisfactory. Thus, the analysis was performed in 722 subjects (533 males, 73.8%, and 189 females, 26.2%). The echocardiographic methods used in this study have been described previously.29 Subjects were studied with M-mode and two-dimensional echocardiography. LV internal diameter and wall thicknesses were measured at end diastole, according to the recommendations of the American Society of Echocardiography.30 LV mass was calculated according to the following formula: 0.8[1.04(IVS+LVDD+PWT)3−LVDD3]+0.6g,31 where IVS is interventricular septum thickness in diastole; LVDD is LV end-diastolic diameter; and PWT is posterior wall thickness in diastole. To correct for differences in body size, LV mass was normalized for body surface area. LV wall thickness (h) was defined as the sum of interventricular septum end-diastolic thickness+posterior wall end-diastolic thickness and relative wall thickness as the ratio of h to LV end-diastolic diameter (h/r). h/r ≥0.45 was considered as an index of LV concentric remodeling. LV systolic function was assessed by measurement of ejection fraction (percentage) calculated as end-diastolic volume−end-systolic volume/end-diastolic volume×100. LV diastolic filling was assessed by Doppler analysis of transmitral flow, using the procedure described elsewhere.29 All measurements were made by two experienced physicians at the Coordinating Center, according to the previously described methods.29
Twenty-Four-Hour Urine Collection
During the 24-hour recordings, urine was collected for AER measurement. Immediately after completion, volumes were measured and urine specimens were frozen (−20°C) and sent to the Coordinating Office in Padova.32 Here, the urinary albumin level was measured by a commercially available radioimmunoassay kit (H ALB kit-double antibody, Sclavo SpA, Cinisello Balsamo, Italy). The detection limit of the method was 0.5 mg/L and the between-batch coefficient of variation was ±5%. Results were expressed in milligrams per 24 hours and were transformed logarithmically to correct for skewing in distribution. Albuminuria was estimated also as albumin-creatinine ratio.
The difference between means was assessed using two-tailed Student’s t test for unpaired observations. χ2 Analysis and Fisher’s exact test were used for the categorical variables. Significant differences in Student’s t test were checked by entering control variables (see “Results”) into an ANCOVA. Differences between normotensive subjects, white coat hypertensive subjects, and sustained hypertensive subjects were assessed from F-ratios by 1-way ANCOVA and by the Tukey’s post hoc test, controlling for BMI. Data are presented as mean±SEM unless specified. A value of P<.05 was considered statistically significant. The SAS statistical program was used for statistical analysis (SAS Institute).
Characteristics of the Participants and the Controls
The main clinical characteristics of the 942 hypertensive subjects divided according to whether they had white coat or sustained hypertension and the controls are reported in Table 1⇑. As the results obtained with the 135/85 mm Hg and 140/90 mm Hg cutoffs were similar, only the data related to the 130/80 mm Hg and 135/85 mm Hg cutoffs are given. Age and sex distribution were similar in the three groups of subjects, whereas BMI was a little lower in the normotensive subjects. Thus, all comparisons were adjusted for BMI. By definition office BP was lower in the normotensive subjects than in either hypertensive group. Among the hypertensive subjects office BP was slightly lower in the subjects with white coat than in those with sustained hypertension. The ambulatory BP values in the three groups are reported in Table 1⇑. In the white coat hypertensive subjects, ambulatory BP was close to that of the normotensive subjects.
When the 130/80 mm Hg threshold was used to identify the white-coat hypertensive subjects, the 24-hour BP, daytime BP, and nighttime BP differences with the normotensive subjects were minimal and nonsignificant. The coefficient of variation of daytime BP, taken as a measure of BP variability, was greater in the white coat hypertensive subjects than in the other two groups. For systolic BP, the coefficient of variation was 9.3±2.5 mm Hg in the normotensive subjects, 9.5±2.6 mm Hg in the sustained hypertensive subjects, and 11.0±3.9 mm Hg in the white coat hypertensive subjects (P<.001 versus normotensive and sustained hypertensive subjects). For diastolic BP, the corresponding values were 12.6±3.4 mm Hg, 11.5±2.7 mm Hg, and 13.7±4.9 mm Hg (P=.07 versus normotensive subjects and <0.001 versus sustained hypertensive subjects), respectively.
The echocardiographic data of the three groups of subjects are reported in Table 2⇓. In both hypertensive groups, LV mass index (Fig 1⇓) and wall thicknesses were greater than in the normotensive controls, and among the hypertensive subjects they were smaller in the white coat hypertensive subjects, either for the 130/80 mm Hg or the 135/85 mm Hg threshold level. The differences between the two hypertensive groups persisted after adjustment of the data for systolic BP and diastolic BP. Systolic BP adjusted data are reported in Table 3⇓. Relative wall thickness was also smaller in the normotensive subjects than in the two groups of hypertensive subjects but did not differ between the white coat and the sustained hypertensive subjects either for unadjusted (Fig 2⇓) or adjusted data (Table 3⇓). No significant difference in end-diastolic diameter was observed between the three groups. Indices of LV systolic function and diastolic filling were also similar in the three groups.
With all threshold levels, subjects with sustained hypertension had greater values of AER than the other two groups, either for data expressed in milligrams per 24 hours (Table 1⇑) or adjusted for creatinine output. However, for the 130/80 mm Hg cutoff the difference was not significant, probably because of the smaller number of subjects in the white coat hypertensive group. After adjustment for office BP the difference between the white coat and the sustained hypertensive subjects found with the higher threshold remained significant (Table 3⇑). The differences in AER between the white coat hypertensive and the normotensive subjects were negligible and nonsignificant. In the sustained hypertensive subjects, the prevalence of microalbuminuria (AER ≥30 mg/24 h) was 6.7 and 7.7%, respectively, for the 130/80 mm Hg and the 135/85 mm Hg cutoffs. These frequencies were higher than those observed in either the white coat hypertensive subjects (1.3%, P=.007, and 2.4%, P=.001, respectively) or the normotensive subjects (2.8%, P=.08 for both cutoffs).
There is still controversy over whether pharmacological treatment is beneficial in subjects with stage I hypertension. According to the ISH/WHO guidelines subjects with mild hypertension should be followed up for a long time before a decision on whether to treat them or not can be made, especially when young subjects with no other important risk factors for cardiovascular disease are considered.33 A potentially useful approach to more rational therapeutic decisions is to evaluate BP by means of ambulatory monitoring, which allows the identification of patients with white coat hypertension. These subjects are characterized by having a high BP at office measurement and a “normal” BP in ambulatory conditions. However, whether or not white coat hypertension implies a worse prognosis is still a matter of debate.1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Some authors reported that white coat hypertensive subjects do not show target-organ damage,1 5 6 12 15 19 whereas others documented initial end-organ abnormalities in these subjects.8 9 10 11 13 14 16 18 20
The present results show that within a population of stage I hypertensive subjects, subjects with white coat hypertension have less echocardiographic structural abnormalities and lower prevalence of microalbuminuria than subjects with sustained hypertension. These differences might merely reflect the higher office BP in the sustained hypertensive subjects but persisted after adjustment for office BP, confirming that ambulatory monitoring is useful in identifying those subjects who are mostly at risk. However, echocardiographic dimensional indices were significantly greater in the white coat hypertensive subjects than in the normotensive subjects of control, also when the 130/80 mm Hg threshold level was used to identify the white coat hypertensive subjects. Although the normotensive and the white coat hypertensive subjects had similar values of ambulatory BP, relative wall thickness was well above the values found in the normotensive subjects and close to those of the sustained hypertensive subjects. Also, LV wall thickness and mass were greater in the white coat hypertensive subjects than the normotensive subjects of control. On the contrary, no statistical difference in AER was found between these two groups. In this respect, our data are in keeping with those of Hoegholm et al,14 obtained with measurement of albumin in early morning urine samples. These authors found that in 111 white coat hypertensive subjects, AER was lower than in 173 sustained hypertensive subjects and only slightly higher than in a group of 127 normotensive subjects of control.
At variance with previous reports, in the present study only subjects with office BP between 140 and 159 mm Hg for systolic BP and between 90 and 99 mm Hg for diastolic BP were included. This difference represents a “gray zone” between what is currently considered a normal and definitely abnormal office BP. The 160/100 mm Hg is considered the threshold value for office BP above which treatment should always be started, and 140/90 mm Hg the BP level below which treatment can safely be withheld. Thus, this is the BP range in which ambulatory BP monitoring appears particularly useful.34
The conflicting results of previous reports on subjects with white coat hypertension could be partially due to differences in the methods used to identify these patients. Labeling a subject as a white coat hypertensive implies the arbitrary identification of upper normal limits of ambulatory BP, which differed markedly from author to author, ranging from 80 (Reference 55 ) to 95 (Reference 1818 ) mm Hg for diastolic BP and from 130 (Reference 55 ) to 140 (Reference 88 ) mm Hg for systolic BP. Obviously, the use of higher upper limits of normality for ambulatory BP results in higher frequencies of white coat hypertension, so more individuals with target-organ damage are likely to be included. To evaluate the effect of different cutoffs, in the current study three partition values (from 130/80 mm Hg up to 140/90 mm Hg), which virtually covered the whole BP range used by previous investigators, were used to identify subjects with white coat and with sustained hypertension. Although the frequency of white coat hypertension varied from 16% to 60% using the three different threshold levels, the differences in the echocardiographic data did not vary substantially between the three groups. In particular, it is noteworthy to observe that lowering the cutoff to a level that isolated a group of white coat hypertensive subjects with similar ambulatory BP values to those of the normotensive subjects did not substantially alter the between-group differences. This finding highlights the clinical importance of office BP in hypertension and suggests that subjects with hyperreaction to stressful situations may develop initial changes of the left ventricle, even though their 24-hour BP load is normal. In agreement with our previous results20 and those by other authors,13 subjects with white coat hypertension also exhibited a greater short-term BP variability throughout the daytime hours in comparison with either the normotensive or sustained hypertensive individuals, suggesting that patients with high reactivity to the doctor’s BP measurement have increased BP responsiveness also to the stressors of daily life.
Several factors can account for the lack of association between target-organ damage and white coat hypertension reported by previous studies. Some authors who concluded that white coat hypertension is innocuous did not even include a normotensive control group in their study.6 15 Previous antihypertensive treatment may have influenced the results, minimizing or eliminating the possible differences with the normotensive subjects of control. Moreover, in several studies, small samples of patients were taken into account. Cavallini et al19 found a 4 g/m2 difference in LVMI (not significant) between 24 white coat hypertensive subjects and 24 normotensive subjects of control. Similar nonsignificant results were obtained by Pierdomenico et al16 in 25 white coat hypertensive subjects and 25 normotensive subjects.
Also in the present study, the LV mass difference between the white coat hypertensive and the normotensive subjects was small (6 to 8 g/m2 for the different cutoffs), but it was highly significant for all threshold levels. Moreover, white coat hypertensive subjects also showed a clear tendency to the concentric remodeling of the left ventricle, a situation that implies a worse prognosis.35
A different relationship between BP and degree of target-organ damage was found for AER. In fact, no demarcation was observed between the white coat hypertensive subjects and the normotensive subjects. AER was higher in the sustained than the white coat hypertensive subjects. The difference ceased to be significant when the 130/80 cutoff was used, probably due to the low number of subjects in the white coat hypertensive group. However, the prevalence of microalbuminuria was greater in the sustained hypertensive subjects for both threshold levels. AER is a surrogate end point in hypertension, whose importance has not been fully established as yet. However, low level urinary albumin has been shown to be an important predictor of morbidity and mortality in several clinical conditions and even in the general population.36 37 38 Our results indicate that the glomerular escape of albumin occurs only if BP is constantly elevated during the 24 hours, whereas the LV changes can occur also in subjects who are normotensive during daily life but respond to stressful situations with an exaggerated increase in BP. On the other hand, Julius et al39 demonstrated that periods of neurogenic pressor episodes without permanent hypertension can cause LV hypertrophy in dogs.
In conclusion, in keeping with our previous results obtained in subjects with mild to severe hypertension,20 these data from the HARVEST study show that young stage I hypertensive subjects with ambulatory BP in the “normal” range display less target-organ involvement than subjects with high ambulatory BP. However, in comparison with normotensive subjects of control, white coat hypertensive subjects seem to be at greater risk. Cardiac involvement seems to precede glomerular damage in the early stage of hypertension.
Selected Abbreviations and Acronyms
|AER||=||albumin excretion rate|
|BMI||=||body mass index|
|HARVEST||=||Hypertension and Ambulatory Recording Venetia Study|
|LVMI||=||left ventricular mass indexed by body surface area|
The following is a list of centers participating in the study. Belluno: G. Catania, S. Gregori (Cardiologia); Conegliano V: M. Santonastaso, D. Piccolo (Div. Lungodegenza); Cremona: G. Garavelli (Div. Medica); Dolo: L. Borsato, F. Pegoraro (Div. Medica); Mirano: D. D’Este (Cardiologia); Padova: P. Palatini, C. Canali, F Dorigatti (Clin. Med. 1); Padova: G. Maraglino, E. Roman (Servizio Cardiologia); Piove di Sacco: C. Martines, R. Businaro (Cardiologia); Pordenone: G. Cignacco, G. Zanata (Centro Cardioreumatologico); Portogruaro: L Virgolini, R. Gelisio (Div. Medica); Rovereto: M. Mattarei, T. Biasion (Ala - Div. Medica); Rovigo: P. Zonzin, A. Bortolazzi (Cardiologia); San Daniele del Friuli: L. Mos, D. Ovan, F. Graniero (Area di Emergenza); San Donà di Piave: A. Sanson, L. Milani (Cardiologia); Trento: G. Devenuto, M. Dal Follo (Div. Medica); Treviso: P. Gatti (Div. Nefrologia); Treviso: P. Stritoni, F. Perissinotto (Div. Cardiologia); Vittorio Veneto: F. Sanzuol, E. Cozzutti, C Mognol (Div. Medica); President: C. Dal Palù; Vice President: A.C. Pessina; Trial Coordinator: P. Palatini.
- Received May 28, 1997.
- Revision received July 3, 1997.
- Accepted August 12, 1997.
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