Abstract
Masked hypertension (MHT) is characterized by normal clinic and above normal 24‐hour ambulatory blood pressure (BP) levels. We evaluated clinical characteristics and CV outcomes of different nocturnal patterns of MHT. We analyzed data derived from a large cohort of adult individuals, who consecutively underwent home, clinic, and ambulatory BP monitoring at our Hypertension Unit between January 2007 and December 2016. MHT was defined as clinic BP <140/90 mm Hg and 24‐hour BP ≥ 130/80 mm Hg, and stratified into three groups according to dipping status: (a) dippers, (b) nondippers, and (c) reverse dippers. From an overall sample of 6695 individuals, we selected 2628 (46.2%) adult untreated individuals, among whom 153 (5.0%) had MHT. In this group, 67 (43.8%) were nondippers, 65 (42.5%) dippers, and 21 (13.7%) reverse dippers. No significant differences were found among groups regarding demographics, clinical characteristics, and prevalence of risk factors, excluding older age in reverse dippers compared to other groups (P < 0.001). Systolic BP levels were significantly higher in reverse dippers than in other groups at both 24‐hour (135.6 ± 8.5 vs 130.4 ± 6.0 vs 128.2 ± 6.8 mm Hg, respectively; P < 0.001) and nighttime periods (138.2 ± 9.1 vs 125.0 ± 6.3 vs 114.5 ± 7.7 mm Hg; P < 0.001). Reverse dipping was associated with a significantly higher risk of stroke, even after correction for age, gender, BMI, dyslipidemia, and diabetes (OR 18.660; 95% IC [1.056‐33.813]; P = 0.046). MHT with reverse dipping status was associated with higher burden of BP and relatively high risk of stroke compared to both dipping and nondipping profiles, although a limited number of CV outcomes have been recorded during the follow‐up.
Keywords: ambulatory blood pressure monitoring, coronary artery disease, dipping status, masked hypertension, nighttime blood pressure, stroke
1. INTRODUCTION
Masked hypertension (MHT) is a clinical condition characterized by normal blood pressure (BP) levels when measured during clinical consultation and above normal BP levels at home or during 24‐hour ambulatory BP monitoring.1, 2, 3 The presence of MHT has been initially revealed throughout the systematic evaluation of full BP profile, including home, clinic, and 24‐hour ambulatory BP levels, in large epidemiological surveys and observational clinical studies in hypertension performed during the last few years.4, 5, 6, 7 These studies have consistently shown that, despite normal clinic BP values, MHT is associated with an increased risk of developing hypertension‐related organ damage,7, 8, 9 as well as an increased risk of cardiovascular (CV) events.10, 11 However, several items related to this condition are still debated, among which are definition, diagnostic criteria, prevalence, and clinical implications in the setting of clinical practice.12, 13, 14, 15
These controversial aspects can be explained by the fact that (a) it is not clear whether the definition of MHT should be limited to untreated individuals or can be applied also to treated uncontrolled hypertensive patients16, 17, 18; (b) there is no agreement on which BP thresholds should be applied, beyond clinic BP, for defining abnormal out‐of‐office BP levels (ie, home, 24‐hour, daytime, nighttime, all periods)19; (c) there are opposing data on estimated prevalence, because of the potential selection bias related to the need of assessing 24‐hour BP levels; and (d) there is still no evidence in favor of the potential benefit obtained from treating MHT patients in terms of reduced incidence of CV events. Another aspect that has not been fully elucidated is the potential impact of nighttime BP levels on the risk of CV and cerebrovascular complications in patients with MHT.
On the basis of these considerations, and in view of the strong correlation between nighttime BP levels and increased risk of CV complications,20, 21, 22 the present analysis is aimed at evaluating clinical characteristics and CV outcomes of patients with MHT, who were stratified according to nocturnal BP pattern (dipping status).
2. METHODS
2.1. Study population
The methodology of the analysis has been previously described.23 Briefly, for the purposes of the present analysis we extracted data from our medical database, which included clinical records derived from adult individuals who were consecutively evaluated at the outpatient service of our Hypertension Unit, Division of Cardiology, Sant'Andrea Hospital in Rome, Italy, between January 2007 and December 2016. To be included in the study protocol, participants had to present the following inclusion criteria: (a) adult individuals aged more than 18 years, (b) absence of pharmacological treatment for hypertension, and (c) signature of informed consent for study participation. In addition, the following exclusion criteria were considered: (a) diagnosis of secondary forms of hypertension or resistant hypertension; (b) recent (<6 months) history of acute CV diseases, including at least one of the following — coronary artery disease, stroke, congestive heart failure, severe valve disease, or peripheral artery disease; (c) diagnosis of sleep apnea syndrome or any other pulmonary disease that may induce sleep abnormalities; and (d) any neurological or psychiatric disease that may, at least in part, affect the BP assessment or the signature of the informed consent.
Once identified, patients with MHT were stratified according to their nocturnal BP pattern into three groups, as follows: (a) dippers, (b) nondippers, and (c) reverse dippers.
2.2. Home, clinic, and 24‐hour ambulatory blood pressure measurements
All BP measurements were performed according to recommendations by European guidelines.3 Trained nurses who are active in our unit instructed each patient on the proper assessment of home BP levels the week before patients entered our Hypertension Unit. Home BP data were recorded by patients into specifically designed BP diaries, which are routinely used in our practice, and then entered by nurses into the clinical database. Home BP measurements were performed according to recommendations from European guidelines (twice in the morning and twice in the evening for 7 days before clinical consultation).3
Clinic BP measurements were performed in the hypertension clinic during the morning section (from 8:00 to 10:00 am). Sequential BP measurements were performed in a quiet room, after 10 minutes of rest, on the same arm and with the participant in the sitting position, by using an automated, oscillometric device (Omron 705 IT, Omron Healthcare Europe BV, Hoofddorp, The Netherlands). The average of three consecutive BP measurements and heart rate was considered as clinic systolic/diastolic BP levels.3
An oscillometric device (Spacelabs 90207, Spacelabs Inc., Redmond, WA) was used to perform 24‐hour ambulatory BP monitoring. According to recommendations from European guidelines,3 different cuff sizes were applied, depending on arm circumference of individual patients (small 6‐11 cm, small/medium 10‐19 cm, medium 18‐26 cm, large 22‐32 cm, and extra‐large 33‐47 cm). The device was set in the Hypertension Unit after completion of the clinic BP measurements and the monitoring was started at about 10:00 am. Automatic BP readings were obtained every 15 minutes during the daytime (from 6:00 am to 22:00 pm) and every 30 minutes during the nighttime (from 22:00 pm to 6:00 am) over the 24 hours.3 Each patient was instructed not to alter her/his usual schedule during the monitoring period and asked to avoid unusual physical activities and to maintain the arm still during BP measurements. Average values for the 24‐hour, daytime, and nighttime systolic and diastolic BP levels and heart rate were reported. In addition, BP load, defined as number of BP measurements above the normal BP thresholds, was reported for each time period (24‐hour, daytime, and nighttime) in each participant.3 Nocturnal systolic and diastolic BP profiles were defined according to difference (percentage) between daytime and nighttime BP levels, as follows: (a) dipping status (daytime/ night‐time BP difference between 10%‐20%); (b) nondipping status (daytime/ nighttime BP difference between 0%‐10%); and (c) reverse dipping status (daytime/nighttime BP difference <0%).3
2.3. Definition of masked hypertension
According to recommendations from current European guidelines,1, 3 MHT was defined for normal clinic (<140/90 mm Hg) and above normal 24‐hour (≥ 130/80 mm Hg) BP levels.
Patients with MHT were further stratified into three categories according to nocturnal BP pattern: (a) dippers (normal clinic [<140/90 mm Hg] and above normal 24‐hour [≥ 130/80 mm Hg] BP levels associated with dipping statu)s; (b) nondippers (normal clinic [<140/90 mm Hg] and above normal 24‐hour [≥ 130/80 mm Hg] BP levels associated with nondipping status); and (c) reverse dippers (normal clinic [<140/90 mm Hg] and above normal 24‐hour [≥ 130/80 mm Hg] BP levels associated with reverse dipping status). Dipping pattern was defined on the basis of systolic daytime and nighttime BP levels.
2.4. Definition of cardiovascular risk factors and comorbidities
Development of treated hypertension during the clinical observation was defined in the presence of stable (>6 months) antihypertensive drug treatment in two subsequent visits.3 The decision to start antihypertensive treatment was based on the recommendations proposed by current guidelines.3
Diagnosis of hypercholesterolemia was made in the presence of total cholesterol levels ≥ 190 mg/dL or low‐density lipoprotein (LDL) cholesterol levels ≥ 130 mg/dL and hypertriglyceridemia for triglyceride levels ≥ 150 mg/dL or stable lipid‐lowering drug treatment in both conditions.24 Diabetes was defined in the presence of plasma glucose levels ≥ 126 mg/dL or in the presence of glucose‐lowering therapy.25
Coronary artery disease (CAD), including nonfatal myocardial infarction (MI), was defined according to the presence of two of the following three items: symptoms (eg, chest pain) lasting longer than 15 minutes, transient increase in serum concentrations of enzymes indicating cardiac damage (more than twice the upper limit of normal), and electrocardiographic changes typical of myocardial ischemia (new persistent ST‐segment elevation or pathological Q waves in two contiguous leads).26, 27 The diagnosis of CAD may also include other coronary events, for example, acute coronary syndrome, recurrent angina, and coronary revascularization.28
Nonfatal stroke was defined as a neurological deficit with sudden onset and persistence of symptoms for more than 24 hours or leading to death with no apparent causes other than vascular ones.29 Transient ischemic attack (TIA) was defined as a neurological event with the signs and symptoms of stroke that go away within a short period of time (typically lasts 2‐30 minutes).30
Hospitalization due to hypertension was defined in the presence of sustained BP rise above 180/110 mm Hg with or without signs of acute organ damage (hypertension emergency or urgency, respectively).3 Hospitalization due to heart failure was defined in the presence of any of the following signs or symptoms: effort or rest dyspnea, pulmonary congestion, lower limb edema, or venous congestion.31
2.5. Definition of cardiovascular events
As described in our previous analysis,23 a systematic search was performed for each subject included in the present study in the medical database for drug prescriptions provided by regional health care system (Regione Lazio, Italy) and available online. All citizens who are residents in this area must be included in this database, independently by gender, ethnic group, or referring physicians. Access to this database is strictly limited to prescribing physicians, who have been endorsed by the regional health care system. A unique patient code includes demographic data, prescription information, clinical diagnoses, and death. All the diagnoses are coded using the ninth revision of the International Classification of Diseases (ICD‐9). Compared to baseline observation, the occurrence of CAD, including MI (ICD‐9 410 and 412), stroke or TIA (ICD‐9 434.9, 435), heart failure (ICD‐9 428), dyslipidemia (ICD‐9 027), and diabetes (ICD‐9 250) was determined.
2.6. Statistical analysis
All data were entered into Microsoft Access for Windows (Microsoft Office, Microsoft Corp, Redmond, WA). Baseline characteristics of patients are presented as number and percentage for dichotomous variables and mean ± standard deviation of the mean for continuous variables. Normal distribution of data was assessed using histograms and Kolmogorov‐Smirnov test. Differences between continuous variables were assessed using ANOVA test. Differences for systolic/diastolic BP levels among various statin groups were also adjusted for potential confounding factors, including age, gender, body mass index (BMI), diabetes, and presence of antihypertensive therapy, by adopting a univariate general linear model with least‐squares deviation for multiple comparisons. Categorical variables were compared among groups by the chi‐square test. To evaluate the association between dipping status and CV outcomes, OR and 95% CI were derived from logistic regression analysis. A multivariable model was fitted with baseline covariates, which showed differences at the <0.05 significance level. All tests were two sided, and a P value of <0.05 was considered statistically significant. All calculations were generated using SPSS, version 20.0 (SPSS Inc., Chicago, IL).
3. RESULTS
3.1. Study population
The flowchart for patients’ selection is reported in Figure S1 (available online). From an overall sample of 6695 individuals who underwent full BP assessment at our Hypertension Unit during the predefined observational period, we excluded 150 (2.2%) subjects aged <18 years, 46 (0.7%) pregnant women, 534 (8.0%) records because of poor quality of the data, and 376 (5.6%) records because of partial or missing BP data, thus leading to a remaining sample of 5684 adult individuals, which represents 84.9% of the original study population. Among these, 3056 (53.8%) were under pharmacological therapy for hypertension and, thus, were excluded from the analysis; among untreated adult individuals (n = 2628), 153 (5.0%) had a diagnosis of MHT. In this subgroup, 65 (42.5%) were dippers, 67 (43.8%) nondippers, and 21 (13.7%) reverse dippers. General characteristics of patients with MHT are reported in Table 1.
Table 1.
General characteristics of untreated outpatients with masked hypertension stratified according to their dipping profile
| Parameters | Overall | Dippers | Nondippers | Reverse dippers | P value |
|---|---|---|---|---|---|
| Outpatients (%) | 153 (100.0) | 65 (42.5) | 67 (43.8) | 21 (13.7) | – |
| Female (%) | 63 (41.2) | 28 (43.1) | 27 (40.3) | 8 (38.1) | 0.905 |
| Age (y) | 54.7 ± 14.5 | 50.8 ± 12.1*° | 55.2 ± 15.0* | 65.3 ± 14.6 | <0.001 |
| Height (cm) | 167.7 ± 18.7 | 77.6 ± 20.0 | 83.5 ± 26.0 | 74.4 ± 12.3 | 0.182 |
| Weight (kg) | 79.8 ± 22.3 | 167.3 ± 16.0 | 168.2 ± 22.7 | 167.1 ± 10.3 | 0.949 |
| BMI (kg/m2) | 26.4 ± 4.4 | 26.5 ± 4.6 | 26.1 ± 4.2 | 26.7 ± 4.7 | 0.820 |
| Age >65 y (%) | 44 (28.8) | 9 (13.8) | 20 (29.9) | 15 (71.4) | <0.001 |
| Smoking (%) | 84 (54.9) | 35 (53.4) | 37 (55.2) | 12 (57.1) | 0.671 |
| Obesity (%) | 27 (17.6) | 13 (20.0) | 9 (13.4) | 5 (23.8) | 0.446 |
| Dyslipidemia (%) | 11 (7.2) | 4 (6.2) | 4 (6.0) | 3 (14.3) | 0.399 |
| Diabetes (%) | 11 (7.2) | 2 (3.1) | 6 (9.0) | 3 (14.3) | 0.170 |
BMI, body mass index; MHT, masked hypertension.
* P < 0.05 vs reverse dippers; °P < 0.05 vs non dippers.
There were no differences among groups with regard to anthropometric parameters, as well as distribution of CV risk factors, with the only exception of age, which is significantly higher in reverse dippers (65.3 ± 14.6 years) compared to nondippers (55.2 ± 15.0 years) or dipping patterns (50.8 ± 12.1 years; P < 0.001).
3.2. Home, clinic, and 24‐hour ambulatory blood pressure levels
Average BP levels in outpatients stratified into different MHT groups are reported in Table 2. There is a trend toward increase of both systolic and diastolic home BP levels from patients with dipping to those with nondipping toward reverse dipping status; in particular, systolic home BP levels were significantly higher in this latter group compared to other groups. Conversely, there were no significant differences among groups with regard to clinic BP levels (both systolic and diastolic), which resulted within the normal range of BP stratification.
Table 2.
Average home, clinic, 24‐h, daytime, and nighttime systolic and diastolic blood pressure levels, pulse pressure, and heart rate in untreated outpatients with masked hypertension stratified according to their dipping profile. Adjustments were made for the following covariates: age, gender, body mass index, and diabetes
| Parameters | Overall | Dippers | Nondippers | Reverse dippers | P value | |
|---|---|---|---|---|---|---|
| Unadjusted | Adjusted | |||||
| Home SBP (mm Hg) | 134.3 ± 16.6 | 129.2 ± 15.25*° | 137.8 ± 17.15* | 139.0 ± 16.9 | 0.089 | 0.578 |
| Home DBP (mm Hg) | 83.9 ± 10.0 | 82.2 ± 10.4 | 84.5 ± 10.1 | 86.8 ± 8.4 | 0.402 | 0.319 |
| Clinic SBP (mm Hg) | 130.3 ± 6.9 | 129.9 ± 6.6 | 131.0 ± 6.7 | 128.9 ± 8.2 | 0.424 | 0.516 |
| Clinic DBP (mm Hg) | 83.8 ± 5.2 | 84.6 ± 4.5 | 83.7 ± 4.8 | 81.8 ± 7.5 | 0.087 | 0.897 |
| Clinic PP (mm Hg) | 46.4 ± 8.4 | 45.3 ± 8.8 | 47.3 ± 7.6 | 47.2 ± 9.1 | 0.357 | 0.571 |
| Clinic HR (bpm) | 77.5 ± 12.2 | 74.5 ± 11.2 | 79.6 ± 10.2 | 80.5 ± 18.5 | 0.071 | 0.050 |
| 24‐h SBP (mm Hg) | 130.2 ± 7.1 | 128.2 ± 6.85*° | 130.4 ± 6.0 | 135.6 ± 8.5 | <0.001 | 0.016 |
| 24‐h DBP (mm Hg) | 80.8 ± 4.9 | 81.5 ± 4.1 | 80.5 ± 4.7 | 79.8 ± 7.1 | 0.274 | 0.667 |
| 24‐h PP (mm Hg) | 49.3 ± 8.7 | 46.6 ± 8.15*° | 49.9 ± 7.55* | 55.7 ± 10.5 | <0.001 | 0.027 |
| 24‐h HR (bpm) | 74.5 ± 8.7 | 75.4 ± 9.0 | 74.3 ± 8.9 | 72.2 ± 6.6 | 0.321 | 0.789 |
| Daytime SBP (mm Hg) | 133.3 ± 6.7 | 133.4 ± 6.9 | 132.7 ± 5.9 | 134.5 ± 8.3 | 0.573 | 0.638 |
| Daytime DBP (mm Hg) | 83.8 ± 5.8 | 85.8 ± 5.45*° | 82.9 ± 5.1 | 80.3 ± 7.0 | <0.001 | 0.003 |
| Daytime PP (mm Hg) | 49.5 ± 8.6 | 47.6 ± 8.45* | 49.8 ± 7.6 | 54.2 ± 10.2 | 0.008 | 0.322 |
| Daytime HR (bpm) | 77.5 ± 9.4 | 78.7 ± 9.7 | 77.3 ± 9.7 | 74.3 ± 6.8 | 0.171 | 0.713 |
| Nighttime SBP (mm Hg) | 122.4 ± 10.8 | 114.5 ± 7.75*° | 125.0 ± 6.35* | 138.2 ± 9.1 | <0.001 | <0.001 |
| Nighttime DBP (mm Hg) | 73.0 ± 6.4 | 69.5 ± 4.75*° | 74.7 ± 5.45* | 78.9 ± 7.6 | <0.001 | <0.001 |
| Nighttime PP (mm Hg) | 49.3 ± 9.5 | 45.0 ± 8.15*° | 50.3 ± 7.5* | 59.3 ± 11.3 | <0.001 | <0.001 |
| Nighttime HR (bpm) | 67.2 ± 9.1 | 67.9 ± 9.5 | 66.4 ± 8.7 | 67.9 ± 9.6 | 0.635 | 0.663 |
bpm, beats per minute; DBP, diastolic blood pressure; HR, heart rate; MHT, masked hypertension; PP, pulse pressure; SBP, systolic blood pressure.
* P < 0.05 vs reverse dippers; °P < 0.05 vs non dippers.
Systolic BP levels were significantly higher in patients with reverse dipping status compared to those with nondipping or dipping status at both 24‐hour (135.6 ± 8.5 mm Hg vs 130.4 ± 6.0 mm Hg vs 128.2 ± 6.8 mm Hg, respectively; P < 0.001) and nighttime (138.2 ± 9.1 mm Hg vs 125.0 ± 6.3 mm Hg vs 114.5 ± 7.7 mm Hg; P < 0.001) periods, whereas diurnal systolic BP levels did not show significant differences among groups.
Also diastolic nighttime BP levels were significantly higher in reverse dippers compared to nondippers and dippers at nighttime (78.9 ± 7.6 mm Hg vs 74.7 ± 5.4 mm Hg vs 69.5 ± 4.7 mm Hg, respectively; P < 0.001) periods. On the other hand, daytime diastolic BP levels were significantly higher in dippers compared to nondippers or reverse dippers (85.8 ± 5.4 mm Hg vs 82.9 ± 5.1 mm Hg vs 80.3 ± 7.0 mm Hg, respectively; P < 0.001), whereas no significant differences were found for 24‐hour diastolic BP among groups.
Pulse pressure was significantly higher in patients with reverse dipping compared to nondipping or dipping status at both 24‐hour (55.7 ± 10.5 mm Hg vs 49.9 ± 7.5 mm Hg vs 46.6 ± 8.1 mm Hg, respectively; P < 0.001), daytime (54.2 ± 10.2 mm Hg vs 49.8 ± 7.6 mm Hg vs 47.6 ± 8.4 mm Hg, respectively; P = 0.008), and nighttime periods (59.3 ± 11.3 mm Hg vs 50.3 ± 7.5 mm Hg vs 45.0 ± 8.1 mm Hg; P < 0.001).
There were no significant differences among groups with regard to 24‐hour and daytime, systolic and diastolic BP loads. At the same time, however, reverse dippers showed significantly higher systolic (Figure 1) and diastolic (Figure 2) nighttime BP loads compared to other groups. As expected, this was paralleled by significantly different nocturnal systolic and diastolic BP reductions among groups (Figure 3).
Figure 1.
24‐h, daytime, and nighttime systolic blood pressure loads in untreated outpatients with masked hypertension stratified according to their dipping profile. Blood pressure loads were defined as number of blood pressure measurements above the normal blood pressure thresholds reported for each time period (24‐h, daytime, and nighttime) in each participant. BP, blood pressure; MHT, masked hypertension
Figure 2.
24‐h, daytime, and nighttime diastolic blood pressure loads in untreated outpatients with masked hypertension stratified according to their dipping profile. Blood pressure loads were defined as number of blood pressure measurements above the normal blood pressure thresholds reported for each time period (24‐h, daytime, and nighttime) in each participant. BP, blood pressure; MHT, masked hypertension
Figure 3.
Systolic and diastolic blood pressure reduction in untreated outpatients with masked hypertension stratified according to their dipping profile. BP, blood pressure; MHT, masked hypertension
3.3. Cardiovascular events
During an average follow‐up of 9.8 ± 6.6 years (median 7.9 years [confidence interval: 8.7‐10.8 years]), we recorded only a few predefined CV outcomes in this selected group of adult MHT patients; thus any speculation on the predictive role of this clinical condition in our study sample should be considered with caution. In particular, 57 patients developed sustained hypertension, 11 experienced CAD, and 17 had hospitalizations for hypertension and 5 for heart failure without significant differences among groups, with the only exception being stroke events, which were significantly more frequent in reverse dippers compared to other groups (Table S1, available online). Indeed, MHT with reverse dipping status was associated with increased risk of stroke as indicated by univariate analysis (OR 21.833; 95% IC [2.154‐21.322]; P = 0.009) and maintained borderline significance even after correction for age, gender, BMI, dyslipidemia, and diabetes (OR 18.660; 95% IC [1.056‐33.813]; P = 0.046; Table 3), although the limited number of predefined CV outcomes that occurred during the follow‐up period in tested groups does not allow any definite conclusion nor clinical speculation.
Table 3.
Univariate and multivariate analyses for the risk of predefined cardiovascular outcomes in patients with masked hypertension stratified according to their dipping profile. Composite cardiovascular outcome was a composite of new‐onset hypertension, myocardial infarction, stroke, hospitalization due to hypertension or heart failure. In multivariate analysis, the following covariates were considered: gender, age, body mass index, smoking status, hypercholesterolemia, diabetes
| Parameters | CV events | Univariate analysis | Multivariate analysis | ||
|---|---|---|---|---|---|
| OR (95% CI) | P value | OR (95% CI) | P value | ||
| Dippers | |||||
| New‐onset hypertension | 24 (36.9) | 0.976 (0.503‐1.894) | 0.942 | – | – |
| Myocardial infarction | 7 (10.8) | 0.2534 (0.709‐9.054) | 0.152 | – | – |
| Stroke | 1 (1.5) | 0.443 (0.045‐4.356) | 0.485 | – | – |
| HT hospitalization | 6 (9.2) | 0.712 (0.249‐2.036) | 0.526 | – | – |
| HF hospitalization | 3 (4.6) | 2.081 (0.338‐12.825) | 0.430 | – | – |
| Nondippers | |||||
| New‐onset hypertension | 24 (35.8) | 0.896 (0.462‐1.738) | 0.997 | – | – |
| HT hospitalization | 6 (9.0) | 0.671 (0.235‐1.918) | 0.456 | – | – |
| Reverse dippers | |||||
| New‐onset hypertension | 9 (42.9) | 1.312 (0.516‐3.341) | 0.568 | – | – |
| Myocardial infarction | 4 (19.0) | 4.202 (1.113‐15.868) | 0.034 | 4.317 (0.757‐24.621) | 0.100 |
| Stroke | 3 (14.3) | 21.833 (2.154‐22.322) | 0.009 | 18.660 (1.056‐33.813) | 0.046 |
| HT hospitalization | 5 (23.8) | 3.125 (0.973‐10.033) | 0.056 | – | – |
| HF hospitalization | 2 (9.5) | 4.526 (0.710‐28.870) | 0.110 | – | – |
CV, cardiovascular; HF, heart failure; HT, hypertension.
4. DISCUSSION
Despite the wide availability of accurate and validated tools for measuring BP levels, MHT remains a complex clinical condition that has not been fully elucidated from pathophysiological, clinical, diagnostic, and therapeutic points of view.32, 33 In fact, because of heterogeneous methodological approaches and no uniform definitions of the disease, both prevalence and prognostic implication of MHT have been questioned. Whereas some studies used home BP thresholds, others applied the ambulatory BP monitoring (either 24‐hour or daytime periods, or both) for identifying individuals with elevation of out‐of‐office BP levels.
Independently of the way out‐of‐office BP levels have been assessed, however, MHT has been associated with higher risk of having hypertension‐related organ damage, mostly including left ventricular hypertrophy and carotid atherosclerosis,12, 13, 14, 15 as well as higher BP variability and increased risk of developing major CV complications.16, 17, 18 Although these correlations have been demonstrated in several clinical studies, which applied the same protocol used in the present analysis to larger population samples, it should be also noted that there is still no evidence demonstrating beneficial effects in terms of reduction of organ damage after pharmacological therapy in MHT patients. At the same time, there is no interventional, randomized, controlled clinical trial demonstrating the effectiveness of a given antihypertensive therapy in lowering out‐of‐office BP levels and reducing risk of CV complications in patients with MHT.
Our study confirmed the relatively low prevalence of MHT in a large sample of adult outpatients who underwent systematic BP assessment. Prevalence of MHT recorded in our analysis was substantially similar to that of other clinical studies, performed in different populations.34, 35, 36, 37 In all these studies, which often included both treated and untreated patients, a higher risk of major CV outcomes in MHT patients compared to patients with normal BP values has been consistently and independently reported.34, 35, 36, 37 As applied in a previous study from the same database,23 in order to avoid the potential confounding impact of antihypertensive treatment on the diagnosis of MHT, all treated hypertensive patients have been systematically excluded from the present analysis, thus leading to a relatively small population sample of adult untreated individuals in whom the independent prognostic role of this condition can be tested.
Indeed, in our analysis we were able to demonstrate that stratifying MHT patients according to their dipping status may provide additional information on their CV risk profile and susceptibility of developing CV outcomes. In fact, we observed substantially higher BP levels and BP loads in patients with a specific pattern of MHT, that is, MHT with reverse dipping status, which has been also associated with higher risk of having a stroke during the follow‐up period, even after correction for potentially confounding factors. In addition, subjects with reverse dipping showed significant higher pulse pressure than subjects with nondipping or dipping circadian pattern. This may, at least in part, help to explain the relatively higher risk of major CV outcomes (mostly stroke) observed in those MHT patients with reverse dipping pattern compared to those with dipping or nondipping patterns.
The present study has some potential limitations that should be acknowledged. First, data have been retrospectively extracted from our medical database and not prospectively collected during clinical consultations. In addition, the relatively small sample of the study population, as well as the limited number of predefined CV outcomes recorded during the follow‐up period, cannot allow any definite conclusion on the potential implication of different forms of MHT in terms of long‐term CV prognosis.38 In fact, only 1 (out of 65) masked hypertensive patients with dipping pattern and 3 with reverse dipping (out of 21) developed stroke during the follow‐up period. At the same time, however, it should be also noted that the relatively small number of CV outcomes may be due to the retrospective nature of this observational study as well as to the rigorous selection of the study population, which included only untreated individuals with true MHT. Also, lack of information on fatal CV and/or non‐CV events, as well as the limited proportion of patients who were lost during follow‐up (<3% of the overall population sample) may have, at least in part, affected the observed results. We do not have data on sleeping quality nor on prevalence of sleep disorders, which have been reported to affect 24‐hour and mostly nighttime BP levels during ambulatory BP monitoring. In regard to the latter, information on work activities as well as circadian pattern of involved patients may also have had potential impact on the observed results. In particular, times of sleeping and waking may have influenced the prevalence of MHT, as well as dipping status of these individuals. Finally, data on metabolic and renal parameters as well as markers of organ damage and other non‐CV comorbidities have not been addressed, being beyond the intention of the present analysis.
5. CONCLUSIONS
Our present analysis confirmed that, although not frequent, MHT can be considered a potentially harmful condition, being associated with substantially higher 24‐hour BP levels and increased BP loads. Among different forms of this condition, as defined by our study protocol, MHT with reverse dipping status seems to be related to higher burden of CV risk, being associated with significantly higher probability of having a stroke during the follow‐up period. However, the strict selection criteria applied for identifying our study population as well as the relatively limited number of CV outcomes recorded during the follow‐up do not allow any definite conclusion on the predictive role of this clinical condition. Further studies are needed with larger population sample and higher number of CV events to better evaluate the potential prognostic impact of different forms of true (untreated) MHT in the clinical practice.
CONFLICT OF INTEREST
Authors have no conflict of interest to disclose on the contents of the present manuscript.
ETHICAL APPROVAL
This article does not contain data derived by any current studies with human participants performed by any of the authors. The clinical studies mentioned were provided with specific ethical approval.
Supporting information
ACKNOWLEDGMENT
The preliminary results of the analysis have been discussed as oral communication at 27th congress of the European Meeting on Hypertension and Cardiovascular Prevention by European Society of Hypertension (ESH), held in Milan, June 16‐19, 2017.
Presta V, Figliuzzi I, D'Agostino M, et al. Nocturnal blood pressure patterns and cardiovascular outcomes in patients with masked hypertension. J Clin Hypertens. 2018;20:1238‐1246. 10.1111/jch.13361
REFERENCES
- 1. Parati G, Stergiou G, O'Brien E, et al. European Society of Hypertension practice guidelines for ambulatory blood pressure monitoring. J Hypertens. 2014;32(7):1359‐1366. [DOI] [PubMed] [Google Scholar]
- 2. O'Brien E, Parati G, Stergiou G, et al. European society of hypertension position paper on ambulatory blood pressure monitoring. J Hypertens. 2013;31(9):1731‐1768. [DOI] [PubMed] [Google Scholar]
- 3. Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2013;31(7):1281‐1357. [DOI] [PubMed] [Google Scholar]
- 4. Drawz PE, Alper AB, Anderson AH, et al. Masked hypertension and elevated nighttime blood pressure in CKD: prevalence and association with target organ damage. Clin J Am Soc Nephrol. 2016;11(4):642‐652. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Stergiou GS, Asayama K, Thijs L, et al. Prognosis of white‐coat and masked hypertension: International Database of HOme blood pressure in relation to Cardiovascular Outcome. Hypertension. 2014;63(4):675‐682. [DOI] [PubMed] [Google Scholar]
- 6. Omboni S, Aristizabal D, De la Sierra A, et al. Hypertension types defined by clinic and ambulatory blood pressure in 14 143 patients referred to hypertension clinics worldwide. Data from the ARTEMIS study. J Hypertens. 2016;34(11):2187‐2198. [DOI] [PubMed] [Google Scholar]
- 7. Tientcheu D, Ayers C, Das SR, et al. Target organ complications and cardiovascular events associated with masked hypertension and white‐coat hypertension: analysis from the Dallas heart study. J Am Coll Cardiol. 2015;66(20):2159‐2169. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Hanninen MR, Niiranen TJ, Puukka PJ, Kesaniemi YA, Kahonen M, Jula AM. Target organ damage and masked hypertension in the general population: the Finn‐Home study. J Hypertens. 2013;31(6):1136‐1143. [DOI] [PubMed] [Google Scholar]
- 9. Kotsis V, Stabouli S, Toumanidis S, et al. Target organ damage in “white coat hypertension” and “masked hypertension”. Am J Hypertens. 2008;21(4):393‐399. [DOI] [PubMed] [Google Scholar]
- 10. Mancia G, Bombelli M, Facchetti R, et al. Long‐term risk of sustained hypertension in white‐coat or masked hypertension. Hypertension. 2009;54(2):226‐232. [DOI] [PubMed] [Google Scholar]
- 11. Mancia G, Bombelli M, Facchetti R, et al. Increased long‐term risk of new‐onset diabetes mellitus in white‐coat and masked hypertension. J Hypertens. 2009;27(8):1672‐1678. [DOI] [PubMed] [Google Scholar]
- 12. Waeber B. What stands behind masked hypertension? J Hypertens. 2008;26(9):1735‐1737. [DOI] [PubMed] [Google Scholar]
- 13. Bobrie G, Clerson P, Menard J, Postel‐Vinay N, Chatellier G, Plouin PF. Masked hypertension: a systematic review. J Hypertens. 2008;26(9):1715‐1725. [DOI] [PubMed] [Google Scholar]
- 14. Verdecchia P, Angeli F, Gattobigio R, et al. The clinical significance of white‐coat and masked hypertension. Blood Press Monit. 2007;12(6):387‐389. [DOI] [PubMed] [Google Scholar]
- 15. Cuspidi C, Parati G. Masked hypertension: an independent predictor of organ damage. J Hypertens. 2007;25(2):275‐279. [DOI] [PubMed] [Google Scholar]
- 16. Vinyoles E, Camafort M, Domenech M, Coca A, Sobrino J, ESTHEN Group Investigators . Prevalence of masked uncontrolled hypertension according to the number of office blood pressure measurements. Rev Clin Esp. 2015;215(8):425‐430. [DOI] [PubMed] [Google Scholar]
- 17. Paripovic D, Kostic M, Spasojevic B, Kruscic D, Peco‐Antic A. Masked hypertension and hidden uncontrolled hypertension after renal transplantation. Pediatr Nephrol. 2010;25(9):1719‐1724. [DOI] [PubMed] [Google Scholar]
- 18. Obara T, Ohkubo T, Kikuya M, et al. Prevalence of masked uncontrolled and treated white‐coat hypertension defined according to the average of morning and evening home blood pressure value: from the Japan Home versus Office Measurement Evaluation Study. Blood Press Monit. 2005;10(6):311‐316. [DOI] [PubMed] [Google Scholar]
- 19. Asayama K, Thijs L, Li Y, et al. Setting thresholds to varying blood pressure monitoring intervals differentially affects risk estimates associated with white‐coat and masked hypertension in the population. Hypertension. 2014;64(5):935‐942. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Metoki H, Ohkubo T, Kikuya M, et al. Prognostic significance of night‐time, early morning, and daytime blood pressures on the risk of cerebrovascular and cardiovascular mortality: the Ohasama Study. J Hypertens. 2006;24(9):1841‐1848. [DOI] [PubMed] [Google Scholar]
- 21. de la Sierra A, Gorostidi M, Banegas JR, Segura J, de la Cruz JJ, Ruilope LM. Nocturnal hypertension or nondipping: which is better associated with the cardiovascular risk profile? Am J Hypertens. 2014;27(5):680‐687. [DOI] [PubMed] [Google Scholar]
- 22. Friedman O, Logan AG. Can nocturnal hypertension predict cardiovascular risk? Integrated Blood Pressure Control. 2009;2:25‐37. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Tocci G, Presta V, Figliuzzi I, et al. Prevalence and clinical outcomes of white‐coat and masked hypertension: analysis of a large ambulatory blood pressure database. J Clin Hypertens (Greenwich). 2018;20:297‐305. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults . Executive Summary of the Third Report of The National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III). JAMA. 2001;285(19):2486‐2497. [DOI] [PubMed] [Google Scholar]
- 25. Ryden L, Standl E, Bartnik M, et al. Guidelines on diabetes, pre‐diabetes, and cardiovascular diseases: executive summary. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). Eur Heart J. 2007;28(1):88‐136. [DOI] [PubMed] [Google Scholar]
- 26. Van de Werf F, Bax J, Betriu A, et al. Management of acute myocardial infarction in patients presenting with persistent ST‐segment elevation: the Task Force on the Management of ST‐Segment Elevation Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J. 2008;29(23):2909‐2945. [DOI] [PubMed] [Google Scholar]
- 27. Bassand JP, Hamm CW, Ardissino D, et al. Guidelines for the diagnosis and treatment of non‐ST‐segment elevation acute coronary syndromes. Eur Heart J. 2007;28(13):1598‐1660. [DOI] [PubMed] [Google Scholar]
- 28. Thygesen K, Alpert JS, White HD. Universal definition of myocardial infarction. Eur Heart J. 2007;28(20):2525‐2538. [DOI] [PubMed] [Google Scholar]
- 29. Goldstein LB, Adams R, Alberts MJ, et al. Primary prevention of ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council: cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: the American Academy of Neurology affirms the value of this guideline. Stroke. 2006;37(6):1583‐1633. [DOI] [PubMed] [Google Scholar]
- 30. Easton JD, Saver JL, Albers GW, et al. Definition and evaluation of transient ischemic attack: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association Stroke Council; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Nursing; and the Interdisciplinary Council on Peripheral Vascular Disease. The American Academy of Neurology affirms the value of this statement as an educational tool for neurologists. Stroke. 2009;40(6):2276‐2293. [DOI] [PubMed] [Google Scholar]
- 31. Haider AW, Larson MG, Franklin SS, Levy D. Systolic blood pressure, diastolic blood pressure, and pulse pressure as predictors of risk for congestive heart failure in the Framingham Heart Study. Ann Intern Med. 2003;138(1):10‐16. [DOI] [PubMed] [Google Scholar]
- 32. Franklin SS, O'Brien E, Thijs L, Asayama K, Staessen JA. Masked hypertension: a phenomenon of measurement. Hypertension. 2015;65(1):16‐20. [DOI] [PubMed] [Google Scholar]
- 33. Parati G. Clinical relevance of masked hypertension. Am J Hypertens. 2006;19(9):887‐888. [DOI] [PubMed] [Google Scholar]
- 34. Mancia G, Facchetti R, Bombelli M, Grassi G, Sega R. Long‐term risk of mortality associated with selective and combined elevation in office, home, and ambulatory blood pressure. Hypertension. 2006;47(5):846‐853. [DOI] [PubMed] [Google Scholar]
- 35. Mancia G, Bombelli M, Brambilla G, et al. Long‐term prognostic value of white coat hypertension: an insight from diagnostic use of both ambulatory and home blood pressure measurements. Hypertension. 2013;62(1):168‐174. [DOI] [PubMed] [Google Scholar]
- 36. Banegas JR, Ruilope LM, de la Sierra A, et al. High prevalence of masked uncontrolled hypertension in people with treated hypertension. Eur Heart J. 2014;35(46):3304‐3312. [DOI] [PubMed] [Google Scholar]
- 37. Ohkubo T, Kikuya M, Metoki H, et al. Prognosis of “masked” hypertension and “white‐coat” hypertension detected by 24‐h ambulatory blood pressure monitoring 10‐year follow‐up from the Ohasama study. J Am Coll Cardiol. 2005;46(3):508‐515. [DOI] [PubMed] [Google Scholar]
- 38. Katz MH. Multivariable analysis: a primer for readers of medical research. Ann Intern Med. 2003;138(8):644‐650. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials