Abstract
The study aimed to compare arterial and echocardiographic parameters in subjects with newly diagnosed masked (MH) or white-coat hypertension (WCH) to subjects with sustained normotension or sustained hypertension, defined according to the 2014 European Society of Hypertension practice guidelines for ambulatory blood pressure (BP) monitoring. We recruited 303 participants (mean age 46.9 years) in a family-based population study. SpaceLabs monitors and oscillometric sphygmomanometers were used to evaluate ambulatory and office BP, respectively. Central pulse pressure (PP) and aortic pulse-wave velocity (PWV) were measured with pulse-wave analysis (SphygmoCor software). Carotid intima–media thickness (IMT) and cardiac evaluation were assessed by ultrasonography. Analysing participants without antihypertensive treatment (115 sustained normotensives, 41 sustained hypertensives, 20 with WCH, 25 with MH), we detected significantly higher peripheral and central PP, PWV, IMT and left ventricular mass index in hypertensive subgroups than in those with sustained normotension. The differences between categories remained significant for peripheral PP and PWV after adjustment for confounding factors, including 24 h systolic and diastolic BP. Participants with WCH and MH, defined according to strict criteria, had more pronounced arterial and heart involvement than normotensive participants. The study demonstrates a high prevalence of these conditions in the general population that deserves special attention from physicians.
Introduction
Introduction to daily practice of ambulatory blood pressure monitoring (ABPM) techniques resulted in the identification of two additional blood pressure (BP) patterns, besides sustained hypertension with elevated office and out-of-office BP or true normotension with normal BP. White-coat hypertension is defined as elevated office and normal ambulatory blood pressure (ABP) while masked hypertension is the reverse.[Citation1] ABPM is superior to conventional BP measurement in the prediction of cardiovascular events.[Citation2] Studies show that cardiovascular risk gradually increases from normotension through white-coat hypertension and masked hypertension to sustained hypertension.[Citation2,Citation3]
The great value in estimating a patient’s cardiovascular risk lies in assessing asymptomatic organ damage, which is easily evaluable in outpatient clinics.[Citation4] Several previous studies have investigated the relation between subclinical organ damage and white-coat or masked hypertension (diagnosed based on ambulatory or home BP measurements), with contradictory results.[Citation5–7] These studies have applied varying ABP thresholds during different periods of the day. Out-of-office BP was mainly defined according to 24 h, less often daytime and rarely night-time BP levels.
A recent outcome-driven study [Citation8] and practice guidelines for ABPM [Citation1] unanimously stress that for reliable diagnosis of white-coat and masked hypertension, full 24 h ambulatory recordings are required, with thresholds applied to the whole ambulatory recording including separately daytime and night-time.
In the present study, we evaluated target organ damage in randomly recruited adult Polish participants with white-coat or masked hypertension, in whom ambulatory normotension or hypertension, respectively, was established based on 24 h plus both daytime and night-time intervals of BP recordings, according to the recently published practice guidelines for ABPM of the European Society of Hypertension.[Citation1]
Methods
Study population
Recruitment to the study was conducted according to the principles outlined in the Helsinki Declaration for investigations in human subjects. The Ethics Committee of Jagiellonian University approved the protocol. Participants gave informed written consent.
From March 2012 until December 2013, we examined nuclear families of Caucasian extraction, including offspring with a minimum age of 18 years, recruited randomly from the general population living in a geographically defined area close to Krakow, Poland. Overall, the response rate was 82%. Of 303 participants, 102 were on antihypertensive drug treatment. In all participants, we employed the same standardized methods to measure BP, arterial and cardiac parameters.
Blood pressure measurement and definition of white-coat, masked and sustained hypertension
Clinic BP measurement was obtained by trained observers at a local examination centre after the subjects had rested for at least 15 min in the sitting position and had refrained from smoking, heavy exercise, and drinking alcohol or caffeinated beverages for at least 2 h before the examination. Brachial BP was the average of five consecutive readings obtained by the validated OMRON 705CP oscillometric sphygmomanometer (Omron, Kyoto, Japan).
SpaceLabs 90207 (Remond, WA, USA) ABP monitors were programmed to obtain BP readings every 15 min during daytime and every 30 min at night, starting just after the clinic visit. Daytime and night-time were defined as fixed time intervals (i.e. daytime was defined as 08:00–22:00 h and night-time as 00:00–06:00 h), discarding the transition periods between day and night. We included in the analyses ABP measurements with at least 70% of expected 24 h recordings, with at least 20 valid awake and five valid asleep measurements, and with at least two valid daytime measurements and one valid night-time measurement per hour.[Citation1] The average values of daytime, night-time and 24 h systolic and diastolic BP were then calculated.
Sustained hypertension was defined as an office BP of at least 140 mmHg systolic and/or 90 mmHg diastolic BP and elevated ABP, with thresholds as follows: for 24 h ABP ≥ 130/80 mmHg, and/or for the daytime (awake ABP) ≥ 135/85 mmHg and/or for the night-time (asleep ABP) ≥ 120/70 mmHg.[Citation1] White-coat hypertension was defined as conventional hypertension (BP ≥140/90 mmHg) with normal ABP (i.e. 24 h ABP <130/80 mmHg and awake ABP < 135/85 mmHg and asleep ABP < 120/70 mmHg). Masked hypertension was defined as a normal office BP (<140/90 mmHg) in participants with elevated ABP (i.e. 24 h ABP ≥ 130/80 mmHg and/or awake ABP ≥ 135/85 mmHg and/or asleep ABP ≥ 120/70 mmHg). In cases where systolic or diastolic BP was in a different category, participants were considered as hypertensives.
Measurement of arterial properties
Carotid ultrasonography
The ultrasound examinations were performed by two trained observers using a General Electric VIVID 7 System (GE Vingmed, Horten, Norway) with a 4.8–10.0 MHz linear transducer probe. After participants had rested for at least 10 min in the supine position, good-quality B-mode ultrasound images of the left and right common carotid arteries were recorded during five consecutive heart cycles. The intima–media thickness (IMT) of the far wall was measured offline using EchoPAC (GE Vingmed, Horten, Norway) workstation software. Automatic IMT measurement was based on a tracing of 1 cm (starting approximately 1 cm proximally from the bifurcation) of the leading edge of the intima surface and the leading edge of the adventitia surface, followed by multiple measurements between pairs of pixels located on both traces. Mean IMT was calculated as the mean of the left and right IMT dimensions.
Assessment of arterial stiffness
To ensure steady state, measurements of arterial stiffness were obtained at the examination centre after the subjects had rested for at least 15 min in the supine position. The radial arterial waveform was recorded in the dominant arm by applanation tonometry. Recordings were discarded when the systolic or diastolic variability of consecutive waveforms exceeded 5% or when the amplitude of the pulse-wave signal was less than 80 mV. The radial pulse wave was calibrated by the supine brachial BP measured in the same arm immediately before the recordings. From the radial signal, the SphygmoCor software (AtCor Medical Pty, West Ryde, NSW, Australia) calculates the aortic pulse wave and subsequently the central systolic BP. Peripheral and central pulse pressures were defined as the difference between systolic and diastolic BP derived from the brachial BP and from the aortic pulse wave, respectively. We computed the aortic pulse-wave velocity (PWV) from recordings of the arterial pressure wave at the carotid and femoral arteries simultaneously with electrocardiography. The transit time between carotid and femoral pressure waves was calculated using the foot-to-foot method. Wave “foots” are identified using intersecting tangent algorithms. We measured the distance between the site of the carotid recordings and the suprasternal notch and between the suprasternal notch and the site of the femoral recordings. Aortic PWV was calculated as the ratio of the distance travelled in metres to the transit time in seconds (SphygmoCor software).
The observers involved in the study took part in a reproducibility study of the SphygmoCor measurements. After repeated examination of 10 subjects, we computed the coefficient of variation as the ratio of the mean difference between repeat measurements to the standard deviation of the paired differences multiplied by 100.[Citation9] Intraobserver and interobserver variability were around 3% and 5%, respectively.[Citation10]
Echocardiography
The cardiac ultrasonography was performed by two experienced cardiologists using a General Electric Medical System VIVID 7 device equipped with a 2.5–3.5 MHz array transducer probe. For offline analyses, at least five consecutive cardiac cycles were recorded, according to the recommendations of the American Society of Echocardiography,[Citation11] and digitally stored on a workstation running EchoPAC software. Left ventricular mass was calculated based on the method of Devereux and co-workers [Citation12] and then adjusted for body surface area to obtain the left ventricular mass index (LVMI). The anteroposterior left atrial end-systolic dimension was measured in the parasternal long-axis view. From the transmitral flow signal, early diastolic peak flow velocity (E), late diastolic peak flow velocity (A) and their ratio (E/A) were determined. The early (e′) and late (a′) diastolic velocities of septal and lateral mitral annulus and the E/e′ ratio were obtained from tissue Doppler recordings.
Other measurements
We administered a standardized questionnaire to obtain information on each subject’s medical history, smoking and drinking habits, and use of medications. Current smoking was defined as daily use of tobacco products. Current alcohol intake was defined as an intake of more than 5 g of ethanol per day during the past 12 months. Body mass index (BMI) was the body weight in kilograms divided by the height in metres squared. Venous blood was collected after overnight fasting. We measured total serum cholesterol and blood glucose by automated enzymatic methods. Diabetes mellitus was defined as a fasting blood glucose concentration of at least 7.0 mmol/l (126 mg/dl) or the use of antidiabetic drugs.
Statistical methods
For database management and statistical analysis, we used SAS software, version 9.1 (SAS Institute, Cary, NC, USA). For comparison of proportions and means, we applied chi-squared (χ2) statistics and analysis of variance (ANOVA) with post hoc comparison (Tukey test), respectively. IMT measurements were log-transformed before analyses to remove skewness, and then geometric means were calculated by back-transformation. The differences in adjusted means of evaluated parameters between BP categories were assessed using an analysis of covariance (ANCOVA) in PROC MIXED. Multivariate regression analysis was used to evaluate the association of BP-dependent indices with subclinical organ changes. In all analyses, statistical significance was taken as a p value of 0.05.
Results
Characteristics of participants
Of the 303 participants, 105 (34.6%) had elevated office BP. Among 201 untreated participants, there were 115 (57.2%) normotensives, 20 (10%) with white-coat hypertension, 25 (12.4%) with masked hypertension and 41 (20.4%) with sustained hypertension. In the treated group (n = 102), there were 40 subjects (39.2%) with controlled hypertension, 19 (18.6%) with a white-coat effect, 18 (17.7%) with masked uncontrolled hypertension and 25 (24.5%) with uncontrolled hypertension according to both office and home BP. gives the anthropometric characteristics, risk factors and BP values of each subgroup. Untreated subjects with white-coat hypertension were older, and had higher BMI and total cholesterol levels than untreated normotensives. In the subgroup without antihypertensive treatment, the percentage of men was higher in the masked hypertension than in the white-coat hypertension group. The untreated participants with white-coat hypertension, although in the normal range by definition, had 24 h systolic BP that was higher than in normotensives. Similarly, masked hypertensive patients had higher office BP than true normotensives.
Table 1. Clinical characteristics of 201 untreated and 102 treated subjects.
Treated subjects were older than untreated subjects (58.7 vs 41.0 years), and had higher BMI (29.5 vs 25.0 kg/m2), blood glucose (5.89 vs 5.09 mmol/l) and office systolic BP (135.1 vs 125.0 mmHg). They were also less likely to smoke (6.9 vs 18.4%) and drink alcohol (16.6 vs 27.9%) than untreated participants (all p ≤ 0.031).
Taking into account participants with office BP below 140/90 mmHg, the proportion of participants with elevated ABP, i.e. masked (uncontrolled) hypertension, was higher in the treated than in the untreated subgroup (31.0 vs 17.9%; p = 0.041). Among participants with office BP ≥ 140/90 mmHg, the proportion of those with normal ABP, i.e. white-coat hypertension, was comparable between treated and untreated hypertensives (43.2 vs 32.8%; p = 0.28).
Subclinical organ changes
Treated participants had more advanced changes in the arteries and heart than untreated participants. In comparison to untreated subjects, they had higher peripheral (49.1 vs 40.7 mmHg) and central (47.1 vs 36.7 mmHg) PP, aortic PWV (9.3 vs 7.2 m/s), carotid IMT (0.74 vs 0.60 mm), left atrial diameter (40.9 vs 35.6 mm), ascending aortic diameter (26.2 vs 24.7 mm) and LVMI (94.6 vs 84.6 g/m2), and lower early to late peak mitral flow velocity (0.99 vs 1.37) (p for all < 0.001). Within treated participants, only peripheral and central PP were significantly higher in uncontrolled hypertensives than in properly treated participants. None of studied echocardiographic parameters was substantially different in the BP subgroups (data not shown).
summarizes target organ evaluation by BP category in untreated subjects. The crude averages of peripheral and central PP were significantly higher in subjects with white-coat, masked and sustained hypertension than in normotensives. The IMT was higher in masked and sustained hypertension, while the PWV was higher in white-coat and sustained hypertension than in normotensive participants. These associations remained significant for peripheral PP and PWV even after adjustment for cardiovascular risk factors and 24 h systolic and diastolic BP (). Compared with normotensives, the white-coat, masked and sustained hypertensives had higher values of left atrial diameter and LVMI in unadjusted analyses () Among the echocardiographic parameters, none remained significantly different between the study groups after adjustment for age, gender, BMI, 24 h systolic and diastolic BP, total cholesterol, smoking and alcohol use.
Figure 1. Multivariable adjusted average of peripheral pulse pressure and aortic pulse-wave velocity (PWV) according to blood pressure categories, as follows: normotensives (NT), white-coat hypertensives (HT), masked hypertensives and sustained hypertensives. Analyses were adjusted for age, gender, body mass index, 24 h systolic and diastolic blood pressure, total cholesterol, smoking and alcohol use. *p < 0.05 for differences vs normotensives.
Table 2. Subclinical organ changes in untreated participants according to blood pressure category.
summarizes the results of stepwise regression with peripheral PP and PWV as the dependent variables in untreated subjects. Classification to the white-coat hypertension group had an independent impact on peripheral PP and PWV, while categorization to masked hypertension had an impact on peripheral PP also after taking into account 24 h systolic and diastolic BP as explanatory variables in the model.
Table 3. Determinants of peripheral pulse pressure (PP) and pulse-wave velocity (PWV) in untreated participants.
Discussion
The present report focused on the advance of subclinical organ changes in the large arteries and heart depending on BP category in randomly recruited participants. In cross-sectional analysis, parameters of interest were closer to the threshold for diagnosis of target organ damage in subjects already treated with antihypertensive drug compared to those with newly diagnosed hypertension. Among participants without antihypertensive treatment, most of the measured arterial and heart parameters tended to be higher in white-coat, masked and sustained hypertensives than in normotensives. The differences between BP categories remained significant for peripheral PP and PWV after adjustment for confounding factors including 24 h systolic and diastolic BP.
Although several studies have reported associations between white-coat and masked hypertension and a greater degree of target organ changes,[Citation13,Citation14] different criteria for patient allocation to the hypertension subclasses were used each time. Studies that were based on ABPM differed in regard to whether mean awake BP or mean 24 h BP was used to define white-coat and masked hypertension.[Citation15,Citation16] The recent European Society of Hypertension practice guidelines for ABPM included night-time BP measurement as a part of the definitions.[Citation1] The prevalence of white-coat, masked or sustained hypertension differs substantially depending on the chosen definition. In our population, we diagnosed white-coat hypertension in 10%, masked hypertension in 12% and sustained hypertension in 20% of untreated participants, which is in agreement with a recent analysis of data from the International Database on Ambulatory Blood Pressure in Relation to Cardiovascular Outcome (IDACO).[Citation8] In IDACO, white-coat and masked hypertension frequencies ranged from 6.3% to 12.5% and from 9.7% to 19.6%, respectively.[Citation8] Moreover, as reported in the study by Asayama et al.,[Citation8] the applied definition of white-coat hypertension greatly influenced risk stratification in the population. In multivariable analyses with normotension during all intervals of the day as the reference, hazard ratios of cardiovascular events associated with white-coat hypertension were weakest when 24 h plus daytime and night-time were considered.[Citation8] Although the cardiovascular risk in white-coat hypertension, as defined using the most stringent definition, was comparable to the risk in normotensives, our study suggests that white-coat hypertensives have more advanced changes in target organs in comparison to normotensives. Both peripheral PP and PWV were higher in white-coat hypertension than in true normotensives. Therefore, the importance of white-coat hypertension diagnosis in the prediction of cardiovascular risk remains an open question. In previously conducted studies, the prevalence of organ damage and the incidence of cardiovascular events were similar between white-coat hypertension and true normotension.[Citation5,Citation7,Citation17] In contrast, several observations have led to partially different conclusions. It has been found that, compared with normotensives, white-coat hypertensives are more commonly characterized by the presence of organ damage such as left ventricular hypertrophy [Citation18] or carotid atherosclerosis.[Citation6,Citation13] Moreover, white-coat hypertension carries a higher risk of cardiovascular mortality than does normotension [Citation19] or prehypertension.[Citation20] Thus, further studies applying the same stringent definition of white-coat hypertension in a larger population are needed.
Masked hypertension is recognized by the recent guidelines for management of hypertension as a condition requiring pharmacological treatment.[Citation4] The large body of data supports current knowledge about ambulatory hypertension, which is characterized by a common coexistence with organ damage and greater long-term cardiovascular risk in comparison to in- and out-of-office normotension.[Citation2,Citation5,Citation7,Citation14,Citation21] In our study, while diagnosing masked hypertension according to the latest recommendation, i.e. accounting for 24 h BP as well as day and night periods, we observed more advanced structural and functional changes in large arteries in comparison to participants with sustained normotension. It seems that irrespective of the part of the day used for diagnosis of ambulatory hypertension, this high-risk condition could be reliably identified.[Citation8] The hazard ratios of cardiovascular events comparing masked hypertension, diagnosed based on ambulatory hypertension during any period of the day, with normotension were all significant, ranging from 1.76 to 2.03.[Citation8]
Observed changes in tissues and organs induced by prolonged exposure to elevated BP precede so-called target organ damage and are responsible for hypertension-related morbidity and mortality. BP values are continuously distributed in the population, and are strongly and directly related to vascular and overall mortality, without any evidence of a threshold down to at least 115/75 mmHg.[Citation22] Our study, in agreement with previous data, confirms the existence of a continuum of target organ changes ranging from normotension through white-coat hypertension and masked hypertension to sustained hypertension. It seems that both white-coat and masked hypertension are not benign conditions because they carry an increased risk of target organ damage. Thus, each BP measurement, both in and out of the office, is important not only for pure classification but also for cardiovascular risk stratification.
From a practical point of view, it cannot be omitted that the part of discussed study related to the already treated hypertensive subpopulation. The current study confirms that ABPM may prevent unnecessary intensification of antihypertensive treatment in about 40% of patients with elevated in-office BP. It also allows clinicians to optimize therapy, and thus reduce cardiovascular morbidity and mortality in more than 30% of patients with office BP within the normal range.
The present study should be interpreted within the context of its potential limitations. First, we analysed a relatively small study group, in contrast to other studies on target organ damage in white-coat and masked hypertension, which were more commonly defined using home BP measurements.[Citation6,Citation7] On the other hand, among the studies which used ABPM, ours is one of the largest according to number of participants.[Citation14] The strengths of the current study are that we used a more precise method for the measurement of out-of-office BP, i.e. 24 h ABPM, and implemented detailed procedures for all evaluated phenotypes. Moreover, ABP monitors were applied just after office BP measurement and all cardiovascular phenotypes were obtained within 48 h. This enabled us to apply a single ABP measurement. However, this did not allow for assessment of the reproducibility of the allocation to the BP classes. Secondly, this was a cross-sectional study and the prognostic significance of our results needs to be evaluated in future longitudinal studies.
In conclusion, data from the present study emphasize a high prevalence of white-coat and masked hypertension in the general population as diagnosed according to the uniform criteria. We have shown that both conditions are associated with more pronounced arterial and cardiac involvement than in normotensive participants. These findings underscore the need for the initiation of appropriate treatment in white-coat and masked hypertension that potentially may decrease cardiovascular risk. Notably, the high prevalence of masked uncontrolled hypertension and the white-coat effect in treated hypertensives highlights the need for ABPM in daily practice.
Acknowledgements
The authors gratefully acknowledge the expert assistance of Adam Bednarski, Agata Franczyk and Joanna Płatek.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding information
The data collection was supported by a grant from the National Science Centre, Poland [grant no. UMO-2011/01/B/NZ5/00341].
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