Circadian profile of 24-hour ambulatory blood pressure monitoring in healthy young adults

INTRODUCTION

High blood pressure (BP) or hypertension is a major public health concern affecting around 1.4 billion people worldwide.¹ It is an important risk factor for ischaemic heart disease, stroke, and chronic kidney disease, and constitutes a major disease burden globally.^2–6

The Asian population is more likely to be associated with adverse cardiovascular events associated with hypertension than the western population.⁷ The risk of adverse cardiovascular events like heart failure, stroke, and myocardial infarction can be reduced by timely antihypertensive therapy.⁸ Therefore, accurate BP measurement is an important task for clinicians for diagnosis and management of hypertension. It is crucial to select the most appropriate method for measurement of BP. Office BP readings are only a surrogate measure of true BP, while true BP may be defined as mean BP over a prolonged period.⁹ Out-of-office BP measurements are superior in identifying white coat and masked hypertension and predicting future cardiovascular risk.^10,11 In view of the current European guidelines, the future risk of cardiovascular events should be considered while prescribing antihypertensive treatment, and therefore, out-of-office BP measurement becomes more crucial.¹²

Many studies have provided evidence that 24-hour ambulatory BP monitoring (ABPM) is better than traditional office BP recording.^13,14 Some studies have attempted to explore the crucial period for 24 hours, which determines the prognosis, and they have concluded that night-time BP is more important in this regard.^15–17 Thus, 24-hour ABPM is valuable because, apart from recording the BP in a natural setting, it can also record BP while the subject is asleep.

International bodies responsible for formulating guidelines have advocated ABPM as a gold standard for BP measurement.^18–22 Despite having much evidence regarding its utility, it is not widely utilized by clinicians, particularly in India. Lack of studies in India may be attributed to several reasons. These include a lack of awareness among physicians and the general population, scarcity of devices, shortage of physicians with adequate interpretation skills, concerns over patient dis-comfort, and lack of normative data specific to the Indian population.

To address these issues, we did a pilot study to assess feasibility, identify barriers, and generate preliminary normative data specific to the Indian population.

METHODS

We recruited 60 healthy subjects (36 males and 24 females) aged 18–30 years from the university population (King George’s University, Lucknow), based on clinical history and examination. Their BP was measured on the non-dominant arm using a mercury sphygmomanometer with an appropriate cuff based on mid-arm circumference. Informed consent was obtained. The study was approved by the institutional ethics committee.

ABPM was done using an automated ABPM device, TM-2430 (A and D Company Limited, Japan). Subjects were instructed to record all routine activities in an activity record sheet, including their waking, retiring, and meal times. After providing detailed instructions, they were asked to wear the ABPM device, and the selection of cuff size was based on mid-arm circumference. The standard 12×24 cm adult cuff size was appropriate for all subjects. Recording was started in the morning between 9 a.m. and 11 a.m. and continued for 24 hours. Recordings were done on the working day to ensure that the routine remained unaltered. The device was programmed to record every 30 minutes over 24 hours. Subjects were instructed to follow their ordinary daily routine and to avoid strenuous physical activity. They were asked to go to bed before 11 p.m. as far as possible. To minimize erroneous readings, subjects were requested to keep their arm still during inflation and deflation of the cuff. Their feedback was taken for discomfort level, sleep quality, and effect on daily activities on a scale of 1 to 5.

RESULTS

Of 60 subjects, 57 were able to complete the 24-hour recording, and an additional 4 subjects could not follow the sleep-wake cycle. All recordings from the remaining subjects met or exceeded the quality requirements recommended by the European Society of Hypertension.²³ Each recording had uninterrupted 24-hour coverage with > 90% of the expected valid measurements during waking as well as sleep hours. Data from only 53 subjects were analysed (Table 1).

The BP and heart rate time series data followed a sinusoidal pattern with a 24-hour period (Fig. 1), and almost all subjects had significant rhythms on the zero-amplitude test (Table 2). Other harmonics at 12-, 6-, and 3-hour cycles did not reveal significant rhythms. Population Cosinor rhythm parameters (MESOR, amplitude, and acrophase) were determined by fitting a population Cosinor model on the individual rhythms of all subjects (Table 2). Heart rate, systolic BP (SBP), diastolic BP (DBP), and mean BP had statistically significant (p<0.05) circadian variations. The MESOR values represent the average levels, with the amplitude values signifying the extent of daily fluctuations. The acrophase values show the time of day when the peak of each parameter occurs, and all the parameters had peaks around mid-noon (~14 hours).

Close

FIG 1. Circadian profile of systolic, diastolic, mean blood pressure (BP), and heart rate with fitted cosine curve. Mean sleep time was 22.4 clock hours, and mean awake time was 6.4 clock hours. The solid line represents the average values of all subjects, with error bars representing standard errors; the dashed line represents the fitted cosine curve, and the dotted line represents the midline estimating statistic of rhythms

Export to PPT

Circadian rhythm parameters, which include 24-hour average, awake hours weighted average, and sleep hours weighted average for SBP and DBP. The actual time of sleep and awakening time was considered for determining average awake hours BP, and sleep hours BP.

SBP measures variability in terms of per cent dip, average real variability pre-awakening BP surge, and sleep-trough BP surge (Table 3). The percentage dip was determined by taking the difference between the awake and sleep hours’ SBP average. Average real variability was determined from the difference of successive blood pressure values. BP surge was determined in two ways. Pre-awakening BP surge was determined as a difference of 2-hour mean BP before and after awakening. Sleep-trough BP surge was determined by taking the minimum of 3 values: the moving average, the 2-hour mean pressure after awakening. Per cent dip was found to correlate well with pre-awakening and sleep-trough BP surge (r=0.42 and 0.46).

Subgroup analysis was done by gender, and males exhibited higher values for MESOR SBP and MESOR mean BP. Females had a higher MESOR heart rate as compared to males (Table 4). All SBPs (24-hour average, awake hours, and sleep hours) were higher in males as compared to females. The BP surge was also higher in males, but not statistically significant (Table 5).

In our study group, 13 subjects had a positive family history of hypertension. Rhythm parameters did not differ significantly between subjects with positive family history and those with negative family history (Tables 6 and 7).

The feedback from subjects indicated that the mean discomfort was low 1.34 (0.6) on a Likert scale of 1–5. The mean sleep quality reported by subjects was good, 4.11 (0.5) on a Likert scale of 1–5, indicating that the ABPM did not have a significant impact on sleep quality. Subjects reported some restriction in their daily activities 1.91 (0.6) on a Likert scale of 1–5. Subjective feedback also reflected similar issues and confirmed these findings.

DISCUSSION

Despite evidence for the superiority of ABPM in the diagnosis and management of hypertension, it is not in common use in clinical practice, particularly in India, and the majority of physicians use ABPM in <5% of patients.²⁵ Most studies using ABPM have been conducted on patients, and there is a scarcity of normative data in the Indian population. In addition to commonly used ABPM parameters like 24-hour BP, daytime BP, and night-time BP, various other novel parameters are being described for their better prognostic value, like percent dip, pre-awakening, and sleep-trough morning BP.

We recorded BP by ABPM in healthy young adults. The BP profile of each subject was modelled with a single Cosinor analysis, and it was found that almost all subjects had significant rhythms. MESOR closely matched the 24-hour average values.

Cosinor analysis has an advantage as it can estimate rhythm parameters even at non-equidistant and fewer sampling data points. None of our subjects were hypertensive on casual BP measurement, and none of them were found to have masked hypertension with ABPM as well. In a multicentric study, 12.0% and 19.3% of Indians visiting primary care physicians had white coat and masked hypertension, respectively. 11.9% of subjects also had isolated nocturnal hypertension.²⁶ In our study, only healthy individuals were recruited.

The values of 24-hour mean, awake time mean, and sleep time mean are similar in range to the values published for British, African-American, and other populations^27,28 while the Danish population had marginally higher values.²⁹

In Ohasama’s study (in the Japanese population), in subjects who were labelled as normotensive based on their screening BP, 24-hour mean (SD) SBP (at a sampling rate of 30 minutes) was 118 (11.1) and DBP was 69.4 (6.8) mmHg.³⁰ In the same study in normal adults above 40 years of age, 24-hour mean (SD) SBP was 123.3 (13) and DBP was 72 (7.7) mmHg.³¹ The 24-hour average BP results in our study are closer to the former study.³⁰

In the European population, 24-hour mean SBP was 141 mmHg and DBP was 89 mmHg³² while the American white population’s 24-hour mean SBP was 138 mmHg and DBP was 88 mmHg.³³ Both these studies had higher values of BP than in our group of subjects. These studies were conducted on subjects with a wide age range (20–75 and 20–84 years, respectively).

In African-American, Anglo, and Hispanic young adults (17 to 25 years) studied together, 24-hour ambulatory mean SBP (at a sampling rate of every 30 minutes during the day and every 1 hour at night) were 124, 121, and 117 mmHg, respectively. Moreover, BP values in males were, in general, higher than those of females in all study groups.³⁴ In our study also, males had a higher value for SBP for 24 hours, awake hours, as well as sleep hours, while the difference in DBP was not significant.

In school children having a family history of hypertension, it was found that they had significantly higher values of 24-hour mean SBP and DBP (116 v. 101 and 66 v. 59). However, there was no significant difference in dipping (9.3% v. 9.4%).³⁵ Differences in the studied age group, ethnicity, sample size, and/or method of recording family history may have led to differences from this study. However, our study did not find any difference in circadian parameters with respect to family history of hypertension.

Another important parameter that is studied is the steep rise in BP at the time of awakening, which is known as the morning BP surge (MBPS). Exaggerated MBPS is associated with adverse cardiovascular events like cardiac hypertrophy, stroke, subarachnoid haemorrhage, cardiac infarcts, and carotid artery thickening.^36–38 MBPS is defined in terms of either sleep-trough MBPS or pre-awakening MBPS. Sleep-trough MBPS is calculated as the difference between the average SBP 2 hours after awakening and the average of three nocturnal readings centred on the lowest sleep SBP. Similarly, pre-awakening MBPS was calculated as the difference between average SBP 2 hours after awakening and average SBP just 2 hours before awakening.

In hypertensive subjects, higher MBPS values indicate a higher risk for adverse cardiovascular events than those with lower MBPS.³⁶ Of 519 elderly hypertensives (upper decile high MBPS group), 53 had sleep-trough morning BP surge and pre-awakening BP surge of 34 mmHg and 17 mmHg, respectively. At the same time, the other group had corresponding values of 17 mmHg and 6.5 mmHg, respectively. In our group of normotensive subjects, sleep-trough and pre-awakening BP surge (25 mmHg and 16 mmHg) are both higher than in the above-mentioned study. On one hand, BP surge may depict higher variability, thus higher risk, but on the other hand, its value seems to be dependent on the degree of per cent dip, as is being reflected by positive correlation (r=0.42 and 0.46) between the per cent dip and pre-awakening surge and per cent dip and sleep-trough surge, respectively. Therefore, MBPS values should be interpreted cautiously in healthy and hypertensive subjects, and it is important to gather more data for MBPS values in normotensive as well as hypertensive subjects.

Sample-to-sample BP variability has been proposed as a prognostic marker for the stratification of cardiovascular risk. In treated elderly hypertensives, higher ARV (>12.8 mmHg) was associated with higher values of SBP, indicating a higher risk.³⁹ In our study, ARV was found to be 12.8 mmHg. ARV may be important in subjects having hypertension or any autonomic imbalance.

The feedback from subjects indicated that they did not experience major discomfort during monitoring. The study also found that ABPM did not have a significant impact on sleep quality. However, the results showed that some subjects reported restriction in their daily activities while wearing the ABPM device. These results suggest that ABPM can be tolerated well by the subjects, with only minor discomfort. In other studies, too, ABPM has been reported to have minimal effect on the sleep quality of subjects.⁴⁰

Some subjects reported feeling self-conscious while wearing the ABPM device in public, which suggests that privacy concerns should be addressed in future studies. Subjects also reported difficulty adjusting to wearing the ABPM device for the first time, suggesting that a longer habituation period may be needed to improve patient comfort and compliance. In addition to discomfort, some subjects also reported that wearing the ABPM device restricted their exercise schedule and limited their participation in sports activities, which they did not like. The discomfort was due to the hot weather and the cuff created discomfort, startling response during the start of recording, and some subjects reported feeling awkward and uncomfortable when they needed to stop midway through an activity to accommodate the ABPM recording.

With the increasing popularity of ABPM and technological advancements, ABPM devices are becoming more reliable, cheaper, comfortable, and user-friendly. However, we suggest that the cuffless option of measuring BP reliably, along with the facility of wireless capturing of the data, can be explored to address the few subjective limitations of the ABPM device.

Our study did not investigate the repeatability of ambulatory blood pressure monitoring (ABPM) recordings. However, existing guidelines suggest that 24-hour ABPM is adequate for clinical purposes.²³ Our sample size was relatively small and limited to a university population. Therefore, while our findings are valuable, caution should be exercised when extrapolating them to a general population. Our study strictly adhered to established guidelines and protocols, ensuring a standardized methodology and the utilisation of a 24-hour protocol.²³ We used Cosinor analysis for modelling time series data due to its wide acceptance in circadian research.

Our study had well-defined objectives, focusing on feasibility assessment, the generation of normative data, and the identification of limitations and logistical issues. Our findings provide essential insights into the feasibility of conducting such studies, subject compliance, and the performance of ABPM devices. Moreover, the normative data and variance derived from our study can serve as valuable inputs for designing larger investigations. Regarding the cost considerations, our primary expenses were associated with equipment and consumables. Nevertheless, large-scale studies may entail multifaceted cost factors, including logistic support and manpower requirements based on the characteristics of the target population.