Reverse white-coat effect as an independent risk for left ventricular concentric hypertrophy in patients with treated essential hypertension

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Abstract

Recent studies have shown that the converse phenomenon of white-coat hypertension called ‘reverse white-coat hypertension' or ‘masked hypertension' is associated with poor cardiovascular prognosis. We assessed the hypothesis that this phenomenon may specifically influence left ventricular (LV) structure in treated hypertensive patients. A total of 272 outpatients (mean age, 65 years) with chronically treated essential hypertension and without remarkable white-coat effect were enrolled. Patients were classified into two groups according to office and daytime ambulatory systolic blood pressure (SBP); that is subjects without (Group 1: office SBP daytime SBP, n=149) and with reverse white-coat effect (Group 2: office SBP<daytime SBP, n=123). LV mass index and relative wall thickness were echocardiographically determined. In all subjects, LV mass index and relative wall thickness were positively correlated with daytime and 24-h SBP, but not with office SBP. In addition, these two indices were inversely correlated with office – daytime SBP difference. LV mass index (136±31 and 115±28 g/m2, mean±s.d.) and relative wall thickness (0.49±0.09 and 0.46±0.07) were significantly greater in Group 2 than in Group 1. As for LV geometric patterns, Group 2 had a significantly higher rate of concentric hypertrophy compared with Group 1 (48 and 28%). Multivariate analyses revealed that the presence of reverse white-coat effect was a predictor for LV concentric hypertrophy, independent of age, sex, hypertension duration, antihypertensive treatment and ambulatory blood pressure levels. Our findings demonstrate that reverse white-coat effect is an independent risk factor for LV hypertrophy, especially concentric hypertrophy, in treated hypertensive patients.

Introduction

Ambulatory blood pressure (BP) is an important determinant of target organ damage and a significant predictor for cardiovascular morbidity and mortality in hypertensive patients.1, 2, 3, 4, 5, 6 There is often a discrepancy between office and ambulatory BPs, such as white-coat hypertension, a normal ambulatory but elevated office BP. On the other hand, the converse phenomenon of white-coat hypertension called ‘reverse white-coat hypertension' or ‘masked hypertension', that is, a high ambulatory but normal (or well-controlled) office BP, has received little attention.7 Whereas, some studies have revealed that the proportion of subjects with reverse white-coat condition reaches 20–40% of the general population and hypertensives.8, 9 In treated hypertensive patients with this phenomenon, particularly, the chance of active and sufficient antihypertensive treatment may be lost by an apparent well-controlled BP in the office. Recent studies suggested that an elevated ambulatory or home BP despite a well-controlled office BP is associated with poor cardiovascular prognosis in treated hypertensive patients.10, 11 However, it remains unclear what mechanism is involved in the association of reverse white-coat phenomenon with cardiovascular prognosis.

Left ventricular hypertrophy (LVH), which is a common cardiac consequence of hypertension, is well known to be an independent risk factor for cardiovascular complications and death.12, 13 In addition, left ventricular (LV) morphologic alteration in hypertensive patients is not uniform, and concentric hypertrophy among various LV geometric patterns is shown to be most closely related to poor cardiovascular prognosis.13

Thus, we hypothesized that the presence of reverse white-coat effect may promote LV hypertrophy, especially concentric hypertrophy, in treated hypertension. To assess the hypothesis, the present study investigated the influence of reverse white-coat effect on LV mass and geometry in treated hypertensive patients.

Methods

Subjects

From consecutive patients with essential hypertension who were chronically treated and underwent a 24-h ambulatory BP monitoring at an outpatient clinic of our hospital between May 2000 and December 2003, 272 subjects (142 men and 130 women; mean age, 65 years) in whom satisfactory echocardiographic data were simultaneously obtained were enrolled in the present study. Patients with secondary hypertension, stroke, ischaemic heart disease including myocardial infarction, congestive heart failure, renal failure (serum creatinine 160 μmol/l) or poorly controlled (haemoglobin A1c 8.0%) or insulin-treated diabetes mellitus were excluded from this study. Individuals with a remarkable white-coat effect (described below) were also excluded. Diabetes mellitus was diagnosed according to the American Diabetes Association criteria, such as a fasting plasma glucose of 7.0 mmol/l and/or a plasma glucose level at 2 h after a 75-g oral glucose load of 11.1 mmol/l, or when medication was taken for treatment of hyperglycaemia. A diagnosis of hyperlipidemia required a serum total cholesterol level of 5.69 mmol/l and/or a serum triglyceride level of 1.69 mmol/l or the use of lipid-lowering drugs, according to the Japan Atherosclerosis Society guidelines.14

All patients had taken antihypertensive drugs for at least 1 year (average, 12 years). One hundred and ninety-five patients (72%) were treated with Ca channel blockers, 140 (51%) with renin angiotensin system inhibitors (i.e., angiotensin II receptor blockers and angiotensin converting enzyme inhibitors), 82 (30%) with β-blockers, 53 (19%) with diuretics and 29 (11%) with other classes of agents. All subjects gave their informed consent to participate in the present study. All procedures of the present study were carried out in accordance with institutional and national ethical guidelines for human studies.

Measurement of BP

In each visit, office BP was measured twice by a physician in a hospital outpatient clinic with the patient in a sitting position after over 20 min of rest, using an appropriate-size cuff on the left arm and mercury sphygmomanometer. The first and fifth Korotkoff sounds were used to identify systolic and diastolic values, respectively, and measurements were taken to the nearest 2 mm Hg. Office BP was determined by averaging six measurements taken on three separate occasions during a 3-month period.

In the same study period, all subjects underwent 24-h ambulatory BP monitoring. BP was measured every 30 min during the day and night by the oscillometric method using an automatic monitoring device (TM-2421, A&D Co Ltd, Tokyo, Japan).15 The accuracy and performance of this device have been demonstrated previously.16 The patients were instructed to carry on with their normal daily activities during measurements and note their activity and location in a diary. According to the diary, daytime and night time were determined as the waking and sleeping periods of the patient, respectively, and mean values of daytime, night time and 24-h BP (systolic and diastolic) were calculated. Nocturnal BP dipping was determined as 100 × (daytime BP−night time BP)/daytime BP.

In the present study, all subjects were classified into two groups by the difference between office and daytime ambulatory systolic BP levels; that is, subjects without reverse white-coat effect (Group 1: office systolic BPdaytime systolic BP, and office systolic BP−daytime systolic BP<20 mm Hg) and with reverse white-coat effect (Group 2: office systolic BP⩾20 mm Hg) were excluded from the study.

Echocardiography

A comprehensive 2-dimensional and M-mode echocardiography was performed using a cardiac ultrasound unit (Sonos 5500, Philips Medical Systems, Andover, MA, USA) as described previously.17 Echocardiographic parameters were measured by the consensus of two experienced investigators who were blinded to the clinical data including office and ambulatory BP of the subjects. Interventricular septal thickness (IVSTd), posterior wall thickness (PWTd), LV diameter at end-diastole (LVDd), and LV diameter at end-systole (LVDs) were measured according to the American Society of Echocardiography recommendations.18, 19 Fractional shortening was calculated as 100 × (LVDd−LVDs)/LVDd. Relative wall thickness (RWT) was calculated as (IVSTd+PWTd)/LVDd. LV mass was estimated using the formula validated by Devereux and Reichek20: LV mass (g)=1.04 × {(IVSTd+PWTd+LVDd)3−LVDd3}−13.6. LV mass was normalized for body surface area and expressed as the LV mass index (LVMI). LVH was defined as a LVMI of 125 g/m2 in men and 110 g/m2 in women.21 The intra-observer and inter-observer coefficients of variation of LVMI were 6.7 and 9.8%, respectively.

The geometry of LV was stratified into four different patterns according to the values of LVMI (< or 125/110 g/m2, men/women) and RWT (< or 0.44). Patients with increased LVMI and increased RWT were considered to have concentric hypertrophy, and those with increased LVMI and normal RWT were considered to have eccentric hypertrophy. Those with normal LVMI and increased or normal RWT were considered to have concentric remodelling or normal geometry, respectively.

Biochemical measurement

Blood samples were obtained in the morning after an overnight fast. Total cholesterol, triglycerides, fasting plasma glucose, haemoglobin A1c and serum creatinine levels were determined by standard laboratory measurements. Creatinine clearance was calculated from the Cockcroft-Gault formula.22

Statistical analysis

Statistical analysis was performed using StatView Version 5 Software (Abacus Concepts Inc., Berkeley, CA, USA). Values are expressed as the mean±s.d. Simple correlations between variables were assessed using univariate linear regression analyses and Pearson's correlation coefficient. An unpaired Student's t-test was used for comparison between the two groups. The significance of differences among the three groups was evaluated by an unpaired ANOVA with subsequent Fisher's multiple comparison test. A multiple logistic regression analysis was performed to identify independent determinants of LV mass increase and concentric hypertrophy. A value of P<0.05 was accepted as statistically significant.

Results

Simple correlations of office and ambulatory BP levels with two indices of LV structural changes, LVMI and RWT, in all subjects are shown in Table 1. Office systolic or diastolic BP had no correlation with either LVMI or RWT. In contrast, LVMI and RWT were positively correlated with daytime and 24-h systolic BPs, and LVMI was also correlated with night time systolic BP. In addition, these two indices were significantly correlated with the difference between office BP and daytime BP. As shown in Figure 1, LVMI had a close negative correlation with office−daytime systolic BP difference (r=−0.377, P<0.001). RWT were also inversely correlated with office−daytime systolic BP difference (r=−0.170, P=0.005). These results suggested that reverse white-coat effect was significantly associated with increases in LVMI and RWT.

Table 1 Correlation of office and ambulatory blood pressure with left ventricular structure in all subjects
Figure 1
figure1

Correlation of the difference between office and daytime systolic BP levels with LVMI (a, r=−0.377, P<0.001) and RWT (b, r=−0.170, P=0.005) in all subjects.

Clinical characteristics of the two subject groups classified according to the difference between office and daytime ambulatory systolic BP levels are summarized in Table 2. One hundred and twenty-three (45%) patients were identified as having reverse white-coat effect (Group 2), and the other 149 (55%) patients belonged to Group 1. The proportion of men and the rate of habitual drinkers were significantly higher in Group 2 than in Group 1. Age, body mass index, hypertension duration, the prevalence of diabetes mellitus and hyperlipidemia, the rate of current smokers, renal function and glucose and lipid parameters did not differ between the two groups. In addition, there were no inter-group differences in the period of medication, the use of any class of antihypertensive agent and the total number of classes of antihypertensive drugs.

Table 2 Clinical characteristics of two study groups

Office and ambulatory BP levels had clear differences between the two groups. That is, Group 2 had significantly lower office systolic and diastolic BPs than Group 1, but daytime, night time, and average 24-h ambulatory BPs in Group 2 were significantly elevated compared with those in Group 1. The degree of nocturnal BP dipping, an index of circadian BP variation, did not differ between the two groups.

The comparison of echocardiographic parameters between the two groups is shown in Table 3. Group 2 had a significantly greater LVMI than Group 1, resulting from more increased LV wall thickness and internal dimension. RWT was also significantly increased in Group 2 compared with Group 1. In addition, the prevalence of LVH, defined as an increased LVMI by sex, was significantly higher in Group 2. There was no difference in fractional shortening between the two groups.

Table 3 Comparison of ecchocardiographic parameters between the two groups

To assess the impact of reverse white-coat effect on LVH, Group 2 was divided into two sub-groups by the extent of its phenomenon. As shown in Figure 2, both LVMI and prevalence of LVH were significantly greater in subjects with mild reverse white-coat effect (office systolic BP⩾10 mm Hg).

Figure 2
figure2

Comparison of LVMI (a) and prevalence of LVH (b) among the three groups classified by the extent of reverse white-coat effect. None, office systolic BP daytime systolic BP (i.e., Group 1, n=149); Mild, office systolic BP<daytime systolic BP, but daytime systolic BP−office systolic BP<10 mm Hg (n=63); Severe, daytime systolic BP−office systolic BP 10 mm Hg (n=60). LVH is defined as LVMI of 125 g/m2 in men and 110 g/m2 in women. Values are given as the mean±s.d. (a) or percentage (b).

Figure 3 shows the comparison of LV geometric patterns between the two groups. Group 2 had a significantly higher rate of concentric hypertrophy compared with Group 1 (48 vs 28%, P<0.001). In contrast, the rates of patients with normal geometry and concentric remodelling were significantly lower in Group 2 than in Group 1.

Figure 3
figure3

Comparison of LV geometric patterns between the two groups. NG, normal geometry (normal LVMI and RWT); CR, concentric remodelling (normal LVMI and increased RWT); EH, eccentric hypertrophy (increased LVMI and normal RWT); CH, concentric hypertrophy (increased LVMI and RWT). P<0.05, *P<0.01, and **P<0.001 vs Group 1.

To confirm whether the influence of reverse white-coat phenomenon on LV mass increase and specific geometric change was independent of various clinical parameters, we investigated possible predictive factors using a multiple logistic regression analysis in all subjects (Table 4). Although average 24-h systolic BP was the strongest predictor for both LVH and concentric hypertrophy, the presence of reverse white-coat effect (i.e., Group 2) was found to be a significant determinant for these LV structural changes, independent of age, sex, body mass index, hypertension duration, the use of any class of antihypertensive agent and 24-h systolic and diastolic BP levels (for LVH: odds ratio 2.42 vs Group 1, P=0.005; for concentric hypertrophy: odds ratio 1.89, P=0.039). The significant predictive value of reverse white-coat effect remained even when daytime systolic and diastolic BPs, instead of 24-h BPs, were adopted as independent predictors (data not shown).

Table 4 Independent predictors for left ventricular mass increase and concentric hypertrophy by multiple logistic regression analysis

Discussion

This study has demonstrated that the presence of reverse white-coat effect is one of the independent predictors for LVH, especially for LV concentric hypertrophy, in patients with treated essential hypertension. The new findings suggest that reverse white-coat phenomenon, independent of average ambulatory blood pressure levels, may have an unfavourable influence on left ventricular geometry in essential hypertension.

The present subjects with reverse white-coat effect (Group 2) had a controlled office BP in spite of elevated ambulatory BP, indicating that the group took on an aspect of masked hypertension. There have been a few studies reporting the possible association between masked hypertension and cardiac and carotid arterial structural changes in the general population. Liu et al.23 found that LV mass and carotid wall thickness in patients with masked hypertension were significantly greater than those in true normotensive subjects and similar to those in patients with sustained hypertension. The data from the PAMELA Study also showed that LVMI was increased in untreated subjects with masked hypertension and sustained hypertension than in those with true normotension.24 In addition, our recent study showed that masked hypertension was associated with advanced target organ damage in treated hypertensive patients, comparable to that in cases of sustained hypertension.25 Furthermore, prospective studies have revealed that a high ambulatory or home BP is a powerful predictor for cardiovascular morbidity and mortality in the general population and treated hypertensive patients even when their office BP is normal or well controlled.10, 11, 26, 27, 28 As for the association between LV geometry and cardiovascular prognosis, it was reported that hypertensive patients with concentric hypertrophy among four LV geometric patterns had the highest incidence of cardiovascular events and death.13 Taken together, it is likely that advanced target organ changes including LV concentric hypertrophy in patients with masked hypertension or reverse white-coat condition are linked to poor cardiovascular prognosis in such patients.

A higher level of ambulatory BP is a major determinant of target organ damage in hypertensive patients.1, 2 In the present study, however, the presence of reverse white-coat effect was a significant predictor for LVH and concentric hypertrophy, independent of average 24-h ambulatory BP levels. Other factors than a higher ambulatory BP could contribute to target organ damage in reverse white-coat hypertension. Our study has not provided the specific mechanism by which reverse white-coat effect could promote LV concentric hypertrophy in patients with treated hypertension. Therefore, further investigations are required to clarify how reverse white-coat or masked hypertension has a specific unfavourable effect on the hypertensive target organ.

There were some limitations in our study. The present findings were derived from cross-sectional data on the basis of one-time examination of ambulatory BP monitoring and echocardiography. Our subjects were divided into subgroups based on office−daytime difference only in systolic BP, not considering diastolic BP difference. In addition, cardiac magnetic resonance imaging might be more adequate than echocardiography in evaluating LV mass exactly.

All patients in the present study had received antihypertensive medication. As another limitation of this study, therefore, we must consider the possibility that different classes of antihypertensive drugs may have differently affected the development of LVH, partly independently of their BP-lowering effects. Renin angiotensin system inhibitors, particularly, are known to have BP fall-independent protective effects on hypertensive target organ. However, the percentage of patients treated with angiotensin II receptor antagonists or angiotensin converting enzyme inhibitors did not differ between the two study groups. Our multivariate analysis also showed that the association of reverse white-coat effect with LVH and concentric hypertrophy was independent of the use of any class of antihypertensive agent.

In conclusion, the present study indicates that reverse white-coat effect is a significant determinant of LVH, especially concentric hypertrophy, in patients with treated essential hypertension, independent of average ambulatory BP levels and various other clinical risk factors. Our findings suggest that the presence of this phenomenon may be an independent risk for the adverse LV geometric change in treated hypertensive patients and ambulatory BP monitoring seems to be necessary to unmask this latent risk that is not detectable by routine BP measuring in the office.

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Acknowledgements

This study was supported by the Grant for Cardiovascular Disease (11C-5) and the Health and Labor Sciences Research Grants (H14-kouka-021) from the Ministry of Health, Labor and Welfare of Japan, and the Grant from Japan Cardiovascular Research Foundation. We thank Chikako Tokudome, Yoko Oikawa, Yoko Saito, and Miho Nishibata for their secretarial assistance.

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Correspondence to T Horio.

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Keywords

  • blood pressure
  • ambulatory
  • cardiac hypertrophy
  • geometry

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