Left Ventricular Filling Profiles in Young White-Coat Hypertensive Patients Without Hypertrophy

Study Population

We surveyed 235 successive clinically hypertensive patients from our hypertensive outpatient clinic and 76 healthy normotensive volunteers. All individuals fulfilled all of the inclusion criteria for this study and underwent 2-D, pulsed Doppler, and color Doppler echocardiographic examinations and 24-hour ambulatory BP monitoring. Of the 235 clinically hypertensive patients, 151 patients had never been treated previously, and 84 patients had discontinued their previous antihypertensive drug therapy at least 6 months prior to this study. The following criteria were used to define subject eligibility for inclusion in this study: (1) age <50 years old (mean, 39.1±8.5 years; age range, 28 to 49 years); (2) a diagnosis of clinical hypertension based on the average of three office readings at 5-minute intervals, taken at each of three different occasions during a 3- to 4-week period, excluding his/her first visit. All subjects were asked not to smoke or ingest caffeine within 2 hours of each visit. All subjects were ordered not to take herb drugs within 2 months prior to enrollment. Clinical hypertension was defined when all three visits showed an average systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg, as recommended by the Fifth Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure.¹⁹ Healthy normotensive subject had average office systolic and diastolic BPs <140 and 90 mm Hg, respectively, at all three visits; (3) no evidence of cardiovascular (coronary artery disease, valvular heart disease, congestive heart failure, or rhythm abnormality) or cerebrovascular disease detected by means of history taking, physical examinations, resting electrocardiogram, treadmill exercise test, chest x-ray, and echocardiographic examination; (4) no evidence of any kind of secondary hypertension; (5) no evidence of renal and liver function abnormality or any metabolic disease; (6) normal 2-D echo: normal systolic function expressed as FS, no LVH expressed as normal LVMI and normal RWT, normal LVDd and LVDs, normal LAD (the normal limits for these measurements were established from 60 age- and sex-matched healthy volunteers. Data were considered abnormal if they were 2 SDs greater than the mean in the normal subjects), and no regional wall motion abnormality; (7) no more than a mild degree of mitral or aortic regurgitation as determined by color Doppler study; (8) no obesity, expressed by normal BMI; (9) well hydrated; and (10) subjects with adequate echocardiographic acoustic windows and well-documented 24-hour BP recordings. Among 235 clinically hypertensive patients, 183 were defined as having sustained hypertension, and 52 were classified as having white-coat hypertension (see below for definition of white-coat hypertension). The prevalence of white-coat hypertension was 22% in our study population. From all of these participants, we chose three groups balanced for sex, age, and BMI: 50 sustained hypertensives, 25 white-coat hypertensives, and 25 normotensives. These subjects were selected for a further comparative study. Subjects who could not be matched appropriately were not used for comparisons between groups, although they were used for the within-group correlation study. The study was in accordance with the Second Declaration of Helsinki. All procedures were approved by the Committee on Human Studies of our College Hospital, and informed consent was completed by all subjects.

Clinical and 24-Hour Blood Pressure Recording

Clinical BP recordings were performed on the nondominant arm, with the patient in the supine position after 10 minutes of rest. Twenty-four-hour BP recording was achieved by a portable noninvasive recorder (SpaceLabs 90207), with cuffing on the nondominant arm. Recording was done during an ordinary daily activity within 2 weeks of the last office interview. BP readings and pulse rates were recorded every 20 minutes from 6 am to 11 pm and every 30 minutes from 11 pm to 6 am. The data were edited to a 24 consecutive 1-hour average. Systolic readings of >260 or <70 mm Hg, diastolic readings of >150 or <40 mm Hg, and pulse pressure readings of >150 or <20 mm Hg were automatically deleted. The correctness of the recorder was confirmed by carrying out three simultaneous readings with a standard mercury manometer through a Y-tube at the beginning and end of the monitoring time. We measured several parameters including average 24-hour, daytime, and nighttime systolic and diastolic BPs and pulse rates. Average daytime and nighttime BPs were recalculated according to each individual’s awake and sleep periods, which were recorded in a diary. Twenty-four-hour BP recordings that had more than four measurement deficits were reexamined. All recordings were analyzed by an investigator (Z.-Y.L.) who was unaware of other data of any patient.

White-Coat Hypertension

Clinically hypertensive patients were classified as white coat if their average 24-hour BP was <127/81 mm Hg and at least 18/16 mm Hg less than their average office values. The remaining hypertensive subjects were placed into the category of sustained hypertension. Because geographic factors may contribute to the normal limits of the 24-hour BP values, we did not use the previously reported cutoff point.^{3 5 20 21} Instead, we chose the upper limit as 2 SDs above the average 24-hour systolic and diastolic BP values taken from 50 healthy clinically normotensives in our geographic area (Shin-E area, Taipei, Taiwan). These 50 subjects included 25 men and 25 women (age, 39.1±7.2 years; age range, 30 to 50 years). The resulting upper limit for the average 24-hour BP values was 127/81 mm Hg. Hence, the major criterion of white-coat hypertension was based on a clinically hypertensive patient who showed an average 24-hour systolic BP <127 and diastolic BP <81 mm Hg. The later criterion was taken from examination of our normotensives in whom the mean±SD of their average office and 24-hour systolic and diastolic differences were 10±8 and 9±7 mm Hg, respectively. The values of 18 and 16 mm Hg were measured as the mean+SD. Intraindividual reproducibilities of white-coat and sustained hypertension were determined from three successive 24-hour BP monitorings in a randomly selected subsample of 20 sustained and 20 white-coat hypertensive subjects. We arranged 5 to 18 days (mean, 12±8 days) as the interval between recordings.

Echocardiography

Echocardiographic studies were performed on an ATL (Advanced Technology Laboratories) Ultramark 7, phased-array, ultrasound system with a 2.5-MHz transducer. 2-D echo, pulsed Doppler, and color Doppler ultrasound images were recorded within 2 weeks of the 24-hour BP recording in all subjects. Mitral inflow velocity was recorded from the apical four-chamber view by the pulsed Doppler technique with patients in passive end-expiration. The sample volume was placed at the level of the mitral leaflet tips. All parameters were calculated by the averaging of at least five successive cardiac cycles. The LVMI (g/m²) was calculated as (V_epi−V_endo)×1.05/BSA, where BSA is the body surface area. The LV epicardial enclosed volume (V_epi) and endocardial enclosed volume (V_endo) were measured at end-diastole (the R-wave peak of the simultaneously recorded electrocardiogram). Volume measurements were calculated from apical four-chamber (A₁) and two-chamber (A₂) views by use of the biplane area-length formula (V=8A₁A₂/3πL), where L is the lesser of the lengths of the long axes of these two views. The RWT was calculated as 2×(PWT/LVDd). LV PWT and LVDd were measured at end-diastole from the parasternal long-axis view of the 2-D echo image. FS was calculated as (LVDd−LVDs/LVDd)×100. LVDs was measured as the shortest systolic dimension taken from the parasternal long-axis view of the 2-D echo image. LAD was measured as the largest systolic dimension taken from the parasternal long-axis view of the 2-D echo image. LV diastolic filling indexes²² included the following measurements: peak late diastolic filling velocity (A) (cm/s), peak early diastolic filling velocity (E) (cm/s), A:E ratio, atrial time-velocity integral (Ai) (cm), early time-velocity integral (Ei) (cm), Ai:Ei ratio, early filling time (EFT, ms), and deceleration time of early filling (DT, ms). In addition, isovolumic relaxation time (IVRT, ms) was also measured as the time interval from the Doppler sampling information of aortic valve closure artifacts to the onset of mitral valve flow. Echocardiography was carried out and analyzed by the same operator (N.-C.C.) throughout the study, who was blinded with regard to all other data of all subjects. Intraobserver variations in calculating all echocardiographic parameters were estimated by a randomly selected subsample of 100 sustained hypertensives, 30 white-coat hypertensives, and 40 normotensives on two occasions by one physician (N.-C.C.) with an interval of 2 months between measurements. Variability in measurement was outlined as the difference between the first and second readings divided by the first reading. Percentage variabilities for the readings of two identical echocardiograms were obtained.

Neurohumoral and Metabolic Measurements

The possible different impact of neurohumoral profiles, ie, renin-angiotensin-aldosterone profile (plasma renin activity, plasma aldosterone, and urinary aldosterone) and the sympathetic nervous system profile (plasma and urinary epinephrine and norepinephrine) on the cardiac and metabolic changes between the white-coat hypertensive group and the other two groups were evaluated. All subjects were ordered to maintain a normal diet without sodium restriction. We directed all subjects to take nothing at home after midnight before obtaining a blood sample and to sit quietly for 30 minutes in the early morning after arriving at our laboratory. Fasting blood samples were drawn for the measuring of lipid profiles, glucose, insulin level, plasma renin activity, aldosterone, norepinephrine, and epinephrine concentrations. Twenty-four-hour urine samples were also collected on the same day during which ordinary daily activities were performed for examination of urinary aldosterone, norepinephrine, and epinephrine excretion. Correlations were estimated for the relationships between plasma renin activity, plasma aldosterone, plasma norepinephrine, plasma epinephrine, 24-hour urinary aldosterone excretion, 24-hour urinary norepinephrine excretion, and 24-hour urinary epinephrine excretion, with the values of total cholesterol, triglyceride, LDL cholesterol, and left ventricular diastolic filling profiles in all subjects.

Statistics

Values were expressed as mean±1SD. All analyses were executed with the SPSS/PC+ package. For multiple comparisons, the means of continuous variables were compared with one-way ANOVA followed by Scheffé’s test. Frequencies were analyzed by Fisher’s exact test and continuity-adjusted χ² test where suitable. Study of correlations was performed by linear-regression analysis. A value of P<.05 was considered statistically significant.

Clinical Data and Blood Pressure Values

The demographic data for 50 sustained hypertensive patients, 25 white-coat hypertensive subjects, and 25 normotensive volunteers are summarized in Table 1⇓. Age, sex distribution, and BMI did not differ among the three groups (ANOVA; P=.798, P=.707, P=.905, respectively). In addition, the mean duration of hypertension was virtually identical in both hypertension groups. Table 2⇓ shows the clinical and ambulatory BP values in these three groups. The clinical systolic and diastolic BP values were not different between white-coat and sustained hypertensives. The average 24-hour, daytime, and nighttime systolic and diastolic BPs were similar in the white-coat hypertensives and normotensives. Intraindividual reproducibility among white-coat hypertensives and sustained hypertensives between the first and second and between the second and third 24-hour BP recordings were both 100% (sample size, 40).

Echocardiographic Findings

The LVMI, RWT, FS, LVDs, LVDd, LAD, and HR in 60 age- and sex-matched healthy volunteers (age, 38.6±6.9 years; range, 31 to 49 years) on 2-D echo were 76±8 g/m², 33±.03, 37±6%, 29±3 mm, 47±3 mm, 31±3 mm, and 73±6 beats/min, respectively. These data served to establish the normal reference values for 2-D echo measurements. Transmitral peak A, E, A:E ratio, Ai, Ei, Ai:Ei ratio, EFT, DT, and IVRT in healthy volunteers were 47±5 cm/s, 65±9 cm/s, .75±.09, 6±2 cm, 14±3 cm, .44±.05, 271±39 ms, 183±28 ms, and 78±10 ms, respectively. Table 3⇓ indicates the percentage variabilities for LVMI, RWT, FS, LVDs, LVDd, LAD, and Doppler indexes of two identical echocardiograms in 170 subjects. Table 4⇓ demonstrates echocardiographic data in these three groups. In our study, no remarkable changes in LVMI, RWT, FS, LVDs, LVDd, and LAD were identified among these three groups (ANOVAs are displayed in Table 4⇓), and the differences between any two of these three groups were within the range of intraobserver variability. However, compared with the normotensive group, the white-coat hypertensive group had significantly more impaired left ventricular diastolic filling profiles; it showed increased A (P=.023), decreased E (P=.004), elevated A:E ratio (P<.001), raised Ai (P=.029), reduced Ei (P<.001), heightened Ai:Ei ratio (P<.001), prolonged DT (P=.0016), and lengthened IVRT (P<.001). The diastolic filling profiles were similar in both white-coat and sustained hypertensive groups.

Laboratory Findings

Table 5⇓ is a record of the laboratory data. Compared with the normotensive group, the white-coat hypertensive group showed significantly higher values for total cholesterol (P=.001), LDL cholesterol (P<.001), plasma renin activity (P=.04), plasma and 24-hour urinary norepinephrine (P<.001 and P<.001, respectively), and plasma and 24-hour urinary aldosterone (P<.001 and P=.0017, respectively). No difference was observed between white-coat and sustained hypertensive groups. The values for triglyceride, glucose, insulin, and plasma and 24-hour urinary epinephrine excretion were approximately similar between any two of these three groups. Table 6⇓ demonstrates that 24-hour urinary aldosterone excretion correlated significantly with transmitral A:E ratio within the white-coat hypertensive group (γ=.353, P=.008) but not within either of the other two groups. Furthermore, plasma and 24-hour urinary norepinephrine correlated closely with total cholesterol value within the white-coat hypertensive group (γ=.327, P=.037 and γ=.388, P=.006, respectively), although not within either of the other two groups. There were no significant correlations between plasma renin activity, plasma aldosterone concentration, plasma epinephrine concentration, or 24-hour urinary epinephrine and any of the other metabolic measurements or LV diastolic filling indexes within any of these three groups.

When the chosen sustained and white-coat hypertensive subjects in our study were reclassified according to the reference limits suggested by the consensus document on noninvasive ambulatory BP monitoring, ie, 135/85 mm Hg,²³ two subjects with sustained hypertension were reclassified as white-coat hypertensives. If the critical point was set at 146/91 mm Hg, as derived from a meta-analysis of 23 studies²¹ using both invasive and noninvasive ambulatory recordings in clinically normotensive subjects or in general populations, four subjects with sustained hypertension were reclassified as white-coat hypertensives. However, this redistribution did not affect the results in our present study.