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(Hypertension. 1995;26:413-419.)
© 1995 American Heart Association, Inc.

Articles

Is White Coat Hypertension Associated With Arterial Disease or Left Ventricular Hypertrophy?

M. Chiara Cavallini; Mary J. Roman; Thomas G. Pickering; Joseph E. Schwartz; Riccardo Pini; Richard B. Devereux

From the Department of Medicine, The New York Hospital–Cornell Medical Center, New York (M.J.R., T.G.P., R.B.D.); the Institute of Gerontology and Geriatrics, University of Firenze (Italy) (M.C.C., R.P.); and the Department of Psychiatry and Behavioral Science, State University of New York–Stony Brook (J.E.S.).

Correspondence to Mary J. Roman, MD, Division of Cardiology, Box 222, The New York Hospital–Cornell Medical Center, 525 E 68th St, New York, NY 10021.

	Abstract

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Abstract Although white coat hypertension may be present in 20% or more of hypertensive individuals, its prognostic significance is unknown. We compared prognostically relevant measures of target-organ damage among 24 individuals with white coat hypertension and age- and sex-matched groups of sustained hypertensive and normotensive subjects classified by clinical and 24-hour ambulatory blood pressures. Left ventricular and carotid artery structure and function were evaluated by ultrasonography. Left ventricular mass index was similar in white coat hypertensive (82±17 g/m²) and normotensive (78±15 g/m²) subjects but was higher in sustained hypertensive subjects (97±19 g/m², P<.02 and P<.002, respectively). Similarly, carotid artery intimal-medial thickness was greater in the sustained hypertensive group (0.98±0.21 mm) than in the white coat hypertensive (0.84±0.16 mm, P<.05) and normotensive (0.76±0.18 mm, P<.001) groups. The prevalence of discrete atherosclerotic plaques was higher in the sustained hypertensive group (58%) than in the white coat hypertensive (25%, P<.05) and normotensive (21%, P<.02) groups. Cardiac and carotid structure in individuals with white coat hypertension resemble findings in normotensive subjects and differ significantly from those in age- and sex-matched sustained hypertensive subjects. These findings suggest that white coat hypertension may be a benign condition for which pharmacological intervention may not be necessary, a hypothesis that needs to be tested in longitudinal studies with clinical end points.

Key Words: hypertension, white coat • hypertrophy, left ventricular • atherosclerosis • carotid arteries

	Introduction

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The term white coat hypertension is used to describe individuals with persistently elevated clinical blood pressure (BP) but normal ambulatory BP. White coat hypertension has been estimated to occur in about 20% of mildly hypertensive patients^{1 2} or even in higher proportions when it is defined by less conservative criteria.^{3 4 5} Thus, as many as 6 to 7 million adults in the United States alone may be classified as hypertensive on the basis of elevated BP isolated to the clinic setting and consequently be subjected to the expense and side effects of pharmacological therapy.

The prognosis of individuals with white coat hypertension and hence the need for monitoring and/or treatment is uncertain. Since ambulatory BP reflects pressure through the day^{6 7 8} and better correlates with target-organ damage than clinic BP,^{9 10 11} one might predict a more benign outcome than in sustained hypertension. In a prospective study Perloff et al¹² observed that patients who had lower ambulatory than clinic BP values had a lower risk of subsequent fatal or nonfatal cardiovascular events than patients with more elevated ambulatory BP. Similarly, cardiovascular morbid events occurred in 2.1% of white coat and 4.4% of sustained hypertensive individuals among a group of 739 mildly hypertensive patients followed for 5 years by Pickering.¹³ Conversely, Alderman et al¹⁴ found that previously untreated hypertensive patients whose clinic diastolic BP was at least 4 mm Hg higher when taken by a physician than by a nurse were at higher risk of myocardial infarction during up to 14 years of follow-up than patients with less pressure "reactivity" to physician measurements.

The presence and degree of target-organ damage in hypertensive patients have proved useful in predicting prognosis.¹⁵ Thus, echocardiographic left ventricular (LV) hypertrophy is an independent predictor of cardiovascular morbid events in patients with uncomplicated essential hypertension,¹⁶ in the general population,¹⁷ and in catheterized patients with and without coronary artery disease.¹⁸ Similarly, ultrasonically detectable carotid intimal-medial thickening and discrete atherosclerotic plaque have been shown to predict subsequent myocardial infarction.¹⁹ In addition, echocardiographic LV mass predicts the risk of stroke,²⁰ and atherosclerosis of extracranial carotid arteries is independently associated with higher LV mass.²¹

Data regarding target-organ damage in patients with white coat hypertension are conflicting. Several cross-sectional studies have documented a low prevalence of target-organ damage,^{2 22 23 24} whereas others have not.^{5 25 26 27 28} We undertook the present study to evaluate cardiac and carotid artery structure in matched populations of normotensive, white coat hypertensive, and sustained hypertensive subjects to determine the extent of prognostically relevant target-organ damage in white coat hypertension.

	Methods

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Study Population
Hypertensive study participants were individuals referred from the Hypertension Center of The New York Hospital from August 1990 through November 1993. Twenty-four subjects were defined as having white coat hypertension on the basis of average clinic BP values greater than or equal to both 140 mm Hg systolic and 90 mm Hg diastolic (or 160/90 mm Hg in individuals aged 65 years or older²⁹ ), with ambulatory awake BP measurements less than 134 mm Hg systolic and less than 90 mm Hg diastolic, which represent the 90th percentile of daytime BP recordings in healthy volunteers¹ (or <142/90 mm Hg for patients older than 65 years³⁰ ). The white coat hypertensive subjects were matched for age (±5 years) and sex with 24 subjects with sustained hypertension, defined by average clinic BP values greater than or equal to both 140 mm Hg systolic and 90 mm Hg diastolic (or 160/90 mm Hg in patients aged 65 years or more) with elevated awake ambulatory BP, and a control group (n=24) with normotensive clinic and ambulatory BP measurements derived from an employed population participating in an ongoing longitudinal study.³¹ All white coat and sustained hypertensive subjects were either never medicated (50% and 33%, respectively) or off antihypertensive medications (50% and 67%, respectively) for a median of 3 months (5th to 95th percentile: 1 to 67 months) and 9.5 months (5th to 95th percentile: 1 to 60 months), respectively. None of the control subjects had ever taken antihypertensive medications. All subjects were free of clinical evidence of diabetes mellitus, coronary artery disease, or cerebrovascular disease. The presence of valvular disease was excluded by Doppler echocardiography. Subjects with isolated systolic hypertension or secondary forms of hypertension were excluded. All subjects underwent standard laboratory blood analyses. The study was performed in accordance with protocols approved by the Committee on Human Rights in Research of Cornell University Medical College.

BP Determination
Clinic BP level was determined as the average of at least two separate sets of three measurements by a physician with a mercury sphygmomanometer at an interval of at least 2 weeks, not including the first visit. In the same period 24-hour ambulatory BP was recorded in every subject during a normal day with a SpaceLabs 90207 monitor. The monitor was placed on the nondominant arm and set to take BP readings every 15 minutes during the day and every 30 minutes at night. Methods used to validate these readings have been previously described.¹ Subjects recorded their activity and location after each reading in a diary to permit calculation of systolic and diastolic 24-hour, awake, sleep, work, and home ambulatory BP values. Low-frequency BP variability was estimated using the SD and coefficient of variation [(SD/Mean Ambulatory BP)x100] of awake ambulatory pressure.

Echocardiography
All subjects underwent standard M-mode and two-dimensional echocardiography performed by a research technician using an echocardiograph equipped with 2.5- and 3.5-MHz imaging transducers. LV dimensions were derived from two-dimensionally guided M-mode tracings, as recommended by the American Society of Echocardiography,³² or if M-mode recordings were technically inadequate, by measurements obtained from the two-dimensional study.³³ M-mode measurements of blinded tracings were performed on up to six cycles with the use of a digitizing tablet and were averaged. LV mass was calculated with the use of the Penn convention and adjusted for body surface area.³⁴ LV hypertrophy (LV mass indexed by body surface area) was considered present if the LV mass index exceeded 125 g/m² in men¹⁶ or 110 g/m² in women.³⁵ LV mass adjusted by height^2.7, which reduces variability in normal-weight subjects and detects the correct magnitude of increase caused by obesity,³⁶ was also calculated, and LV hypertrophy (LV mass indexed by height^2.7) was considered present in both sexes for values greater than 51 g/m^2.7. Relative wall thickness, a measure of LV geometry, was calculated as [(2xEnd-Diastolic Posterior Wall Thickness)/LV End-Diastolic Dimension]. LV volumes were calculated with the Teichholz correction.³⁷ Fractional shortening, ejection fraction, stroke volume, cardiac output, and total peripheral resistance were calculated with standard formulas.

Carotid Ultrasonography
Carotid arteries were evaluated in all subjects with a Biosound Genesis II system (OTE Biomedica) equipped with a 7.5-MHz imaging transducer. The subject was examined in the supine position with the neck in slight hyperextension to obtain an optimal visualization of the common carotid artery, carotid bulb, and extracranial internal and external carotid arteries on both sides. Multiple projections were used for identification of any irregularity in the vessel walls. Discrete carotid atherosclerosis was defined as the presence of discrete plaques, at least 50% greater than the surrounding wall, in any segment of the arteries.³⁸ A two-dimensionally guided M-mode tracing of the distal common carotid artery, about 1 cm proximal to the carotid bulb, was obtained and recorded on 0.5-inch Super VHS videotape with simultaneous electrocardiogram. The videotape was subsequently reviewed, and suitable frames for measurements were obtained with a frame-grabber (Imaging Technology, Inc) interfaced with a high-resolution (640x480 pixel) video monitor and were stored on diskettes. The axial resolution of the M-mode system is 0.2 mm. Carotid measurements were performed on the stored images by a reader blinded to the subject data and BP values with the use of a mouse-driven computer program after calibration for depth and time. All measurements were obtained on several cycles and averaged. Intimal-medial thickness of the far wall of the distal common carotid artery was measured at end diastole. Standard wall thickness measurements were never obtained at the level of a discrete plaque. End-diastolic and peak-systolic internal dimensions of the artery were determined by continuous tracing of the intimal-luminal interface of the near and far walls of the distal common carotid artery. Relative wall thickness of the artery was calculated according to the formula [(2xEnd-Diastolic Wall Thickness)/End-Diastolic Dimension]. Ultrasound characterization of carotid wall layers and measurement of wall thicknesses have been validated with gross and histopathologic reference standards.³⁹

Statistical Analysis
Data were stored and analyzed with the Crunch 4 statistical package (Crunch Software Corp). Comparisons of continuous, normally distributed variables, expressed as mean±SD, among the three groups were performed by one-way ANOVA followed by the Scheffé test for multiple comparisons. Student's t test was used for comparison of continuous variables between two groups. Continuous, nonnormally distributed variables, reported as medians and range from the 5th to 95th percentile, were compared between groups with the Mann-Whitney test. Differences in prevalences were compared by the ² statistic with continuity correction. The 95% confidence intervals for differences in the continuous and categorical variables between the three study groups were determined. A value of P<.05 was considered statistically significant.

	Results

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Study Population
Tables 1 through 3 show descriptive data of the study groups. The three groups were similar in body surface area, body mass index, resting heart rate, and family history of cardiovascular disease as well as, by selection, age and sex. The two hypertensive groups were similar with regard to duration of hypertension and previous use of antihypertensive medications as well as with regard to the treatment withdrawal period and prevalence of subjects off treatment for less than 3 months. White coat hypertensive subjects were more likely than sustained hypertensive subjects to be former smokers (46% versus 13%, P<.05), whereas there were no differences in the duration of smoking cessation and prevalence of current smokers among the three groups. Subjects with sustained hypertension were more likely to have a family history of hypertension than normotensive subjects. No significant differences were noted in serum lipids, glucose, blood urea nitrogen, or creatinine.

View this table: [in this window] [in a new window]   Table 1. Demographics of Normotensive, White Coat, and Sustained Hypertensive Subjects

View this table: [in this window] [in a new window]   Table 2. Previous Use of Antihypertensive Medications and Duration of Hypertension in White Coat and Sustained Hypertensive Subjects

View this table: [in this window] [in a new window]   Table 3. Comparison of Laboratory Analyses in Normotensive, White Coat, and Sustained Hypertensive Subjects

Clinic and Ambulatory BP Values
Table 4 shows ambulatory and clinic BP values for the study groups. By definition, clinic systolic and diastolic BP values were significantly elevated in the two hypertensive groups, whereas ambulatory BP values were similar in the normotensive and white coat hypertensive groups and significantly lower than in sustained hypertensive subjects. The SD of awake systolic BP was greater in both hypertensive groups than in control subjects, but no other intergroup differences in BP variability attained statistical significance.

View this table: [in this window] [in a new window]   Table 4. Clinic and Ambulatory Blood Pressures of Normotensive, White Coat, and Sustained Hypertensive Subjects

LV Structure and Function
Table 5 shows data concerning LV structure and function in the study groups. Absolute LV mass and LV mass indexed either by body surface area or by height^2.7 as well as systolic wall thicknesses were higher in the sustained hypertensive than the white coat hypertensive and normotensive groups.

View this table: [in this window] [in a new window]   Table 5. Left Ventricular Structure and Function in Normotensive, White Coat, and Sustained Hypertensive Subjects

LV internal dimensions, LV absolute and relative wall thicknesses, and LV mass were similar in white coat hypertensive and normotensive subjects. The prevalence of LV hypertrophy (LV mass/body surface area) was significantly higher in the sustained hypertensive (25%) than in the normotensive (0%, P<.05) group and tended to be higher than in the white coat hypertensive group (4%, P<.1; confidence interval for difference, -40% to -2%). The prevalence of LV hypertrophy (LV mass indexed by height^2.7) tended to be higher in sustained hypertensive subjects (21%) than in white coat hypertensive subjects (0%; confidence interval for difference, -37% to -5%) or normotensive subjects (4%). LV systolic function and hemodynamic parameters were similar in the three groups.

Carotid Artery Structure
Table 6 presents data concerning carotid artery structure in the study groups. Common carotid artery intimal-medial thickness was greater in sustained hypertensive than white coat hypertensive (P<.05) and normotensive (P<.001) subjects. Carotid wall thicknesses and diameters were similar in normotensive and white coat hypertensive subjects. The prevalence of carotid artery plaques was higher in sustained hypertensive subjects (58%) than in white coat hypertensive (25%, P<.05) and normotensive (21%, P<.02) subjects. No white coat hypertensive subjects and only one normotensive subject but four sustained hypertensive subjects (17%) had diffuse carotid intimal-medial thickening (1.2 mm), which has been a proposed measure of diffuse atherosclerosis.^{38 40} When the presence of either discrete or diffuse carotid atherosclerosis was considered, prevalences were 25% in both white coat hypertensive and normotensive subjects and were significantly higher among sustained hypertensive subjects (67%, P<.01 for both comparisons).

View this table: [in this window] [in a new window]   Table 6. Carotid Structure in Normotensive, White Coat, and Sustained Hypertensive Subjects

Relation of Previous Pharmacological Treatment to Target-Organ Damage
Two subjects with sustained hypertension and four with white coat hypertension had been off medications for at least 1 month but less than 3 months. These subjects and their corresponding control subjects were excluded and comparisons performed among the remaining 20 subject triplets. LV mass/body surface area remained significantly greater in the sustained hypertensive group (96±17 g/m²) than in white coat hypertensive (81±18 g/m², P<.05) and normotensive (80±15 g/m², P<.01) subjects, as did carotid intimal-medial thickness (1.0 versus 0.84 mm, P<.05, and 0.75 mm, P<.0001) and the prevalence of atherosclerosis (65% versus 25%, P<.05 for both comparisons).

	Discussion

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The present study provides the first comprehensive assessment of cardiac and vascular target-organ damage in well-matched groups of white coat, sustained hypertensive, and normotensive individuals. It extends previous comparisons of LV findings to include examination of the conduit arteries, which provide an additional indication of hypertensive target-organ involvement.⁴¹ Our findings indicate similarly normal LV and carotid structures and a lower prevalence of ventricular hypertrophy and carotid atherosclerosis in white coat hypertensive and normotensive individuals compared with those with sustained hypertension, suggesting that white coat hypertension may be a benign condition.

LV Structure and Function
In our study population LV mass was similar in white coat hypertensive and normotensive subjects and significantly higher in the sustained hypertensive subjects. Previous evaluations of LV hypertrophy in white coat hypertension have provided conflicting results. In 1980, Sokolow et al⁴² reported that patients with no electrocardiographic or roentgenographic evidence of LV hypertrophy had a greater drop in pressure between clinic and home than patients with these findings. Subsequently, Floras et al²² found funduscopic changes or LV hypertrophy by electrocardiogram or chest radiograph in 19% of 32 clinically defined hypertensive patients in whom ambulatory mean BP was more than 10 mm Hg lower than clinic BP compared with 64% of 22 sustained hypertensive patients. Using echocardiography, radionuclide angiography, and exercise testing, White et al²³ observed similar cardiac structure and function in 18 normotensive and 18 white coat hypertensive (defined as clinic BP >140/90 mm Hg and mean awake ambulatory BP 130/80 mm Hg) individuals, whereas age- and body size–matched sustained hypertensive patients had higher LV mass. Verdecchia et al,² defining the upper limits of normal daytime ambulatory BP as 136/87 mm Hg for men and 131/86 mm Hg for women, found mean LV mass and the prevalence of LV hypertrophy to be similar in 42 white coat hypertensive and 47 healthy normotensive subjects who were not, however, matched for age and sex. Hoegholm et al²⁴ found lower LV mass and relative wall thickness in 53 patients with white coat hypertension (defined as average diastolic BP >90 mm Hg in the clinic and 90 mm Hg during daytime ambulatory monitoring) than in 90 patients with established hypertension matched for age and sex.

In contrast, Weber²⁵ found patients with white coat hypertension (average 24-hour diastolic ambulatory BP <85 mm Hg plus a clinic-ambulatory difference >15 mm Hg) and patients with sustained hypertension matched by age, weight, and clinic BP to have similar echocardiographic and metabolic findings. Among patients older than 60 years of age Kuwajima et al²⁷ found increased left atrial dimensions and LV mass in white coat (average clinic BP >160/90 mm Hg and average 24-hour ambulatory systolic BP <140 mm Hg) and sustained hypertensive individuals compared with normotensive subjects.

Conflicting results of previous studies may reflect several methodological differences. The use of higher upper limits of normal for ambulatory BP results in higher prevalences of white coat hypertension in hypertensive populations, thereby including more individuals who may be truly hypertensive and have target-organ damage.² In addition, the current study used specific age-related criteria to define white coat hypertension and excluded individuals with isolated systolic hypertension in whom the prevalence of white coat hypertension appears to be higher than in diastolic hypertension.³⁰ Further differences may be attributed to the use of average 24-hour^{25 26} or average daytime (with the daytime period arbitrarily defined)^{2 23 24 26} rather than average awake ambulatory BP to define white coat hypertension, as was done in our study. Average awake pressures, based on a large number of readings during individuals' usual activities, may represent the most reliable estimate of the usual BP level.

Despite the use of ambulatory BP partition values that were similar to those in our study, Cardillo et al²⁶ found LV mass values in the white coat hypertensive group to be intermediate between their sustained hypertensive and normotensive subjects. Although awake ambulatory BP levels and age were higher in our three groups than in the corresponding groups of Cardillo et al, LV mass index was consistently lower in our study, possibly because of the higher proportion of women (67%) in our sex-matched groups compared with the 19% to 45% who were women in their three groups.²⁶ In fact, similar to previous observations,¹ we found white coat hypertension predominantly in women (67%, which determined the gender mix of our comparison groups). Most previous studies that did not detect an association between white coat hypertension and target-organ damage^{2 23 24} had higher proportions of women in their white coat populations than in their sustained hypertensive and normotensive groups. Differences in proportions of women might also explain the contrasting results of Julius et al,⁵ since women comprised only 27% and 19% of their white coat and sustained hypertensive groups, respectively, compared with 51% of their normotensive group (P<.005 and P<.0005, respectively). Female gender also confers a better prognosis among the general population of hypertensive individuals,⁴³ underlining the importance of sex matching or of sex-specific analyses to obtain unbiased results when populations are being compared.

Carotid Artery Structure
Intimal-medial thickness of the carotid artery has been shown to be related to concurrent coronary artery disease^{44 45} and to subsequent myocardial infarction,¹⁹ possibly as a result of both atherosclerosis⁴⁰ and arterial remodeling caused by a pressure load.⁴¹ Our study provides the first evaluation of carotid artery structure in white coat hypertension. Carotid artery intimal-medial thickness was increased in our sustained hypertensive subjects and was similarly normal, compared with previous results in our laboratory,⁴¹ in the white coat hypertensive and normotensive groups. The prevalences of discrete carotid plaques and atherosclerosis (discrete plaque and/or diffuse intimal-medial thickening) were similar in the white coat hypertensive and normotensive groups and substantially higher in the sustained hypertensive group. These findings parallel the average levels of ambulatory BP in our white coat hypertensive and normotensive subjects, suggesting that sustained rather than episodic BP elevation is important in producing preclinical disease of the arterial tree.

The higher total smoking exposure of the white coat hypertensive group suggests that the differences between white coat and sustained hypertensive subjects with regard to carotid atherosclerosis may have been underestimated.

Although Floras et al²² showed normal baroreflex sensitivity, a finding that implies normal conduit arteries, in white coat hypertensive subjects, and peripheral resistance was normal in white coat hypertensive subjects in the current study, Julius et al⁵ reported elevated minimal forearm vascular resistance, a possible measure of small-artery structural changes, in white coat hypertensive individuals. However, many of the individuals classified as having white coat hypertension in that study might have been classified as having sustained hypertension by our criteria.

Relation of Previous Treatment to Target-Organ Damage
Although 17% of the white coat and 8% of the sustained hypertensive subjects were off treatment for less than 3 months (but for at least 1 month), the overwhelming majority of hypertensive subjects had never been medicated (50% and 33%, respectively, in the two groups) or had been off medication for more than 3 months (33% and 58%, respectively), thereby minimizing or eliminating the possible influence of previous antihypertensive treatment on the differences in LV and carotid artery anatomy among the three study groups. Furthermore, the fact that more than 90% of the sustained hypertensive individuals were never medicated or were off treatment for more than 3 months implies that the degree of hypertension in this group is mild, thereby blunting rather than accentuating the differences with the other two groups.

Conclusions
Although the concept of white coat hypertension is simple, its definition (using clinic and ambulatory or home BP measurements) and the establishment of the normal range of ambulatory BP are still controversial. The definition of the upper limit of "normal" ambulatory BP appears to be the major determinant of both prevalence and target-organ findings in white coat hypertension,² with additional contributions from the age and sex of study subjects. The best definition of white coat hypertension may be one that includes the minimal number of high-risk individuals. Although our study supports the hypothesis that white coat hypertensive individuals who have truly normal awake ambulatory BP values represent a low-risk group, long-term prospective studies are required to define conclusively the prognosis of white coat hypertension. At present, ambulatory BP monitoring and evaluation of target-organ damage and other cardiovascular risk factors appear to identify a substantial subset of borderline or mildly hypertensive individuals without preclinical hypertensive disease¹⁵ in whom the level of risk may be too low to mandate long-term antihypertensive medication.

	Acknowledgments

 
This study was supported in part by grants HL-18323 and HL-30605 from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md. Dr Cavallini is the recipient of a research grant from the University of Firenze (Italy). The authors wish to thank Mariane Spitzer, RDMS, for invaluable technical assistance and Virginia Burns for assistance in preparation of the manuscript.

Received April 22, 1994; first decision May 26, 1994; accepted December 16, 1994.

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