Determinants of Blood Pressure Variability in Individuals with Essential Hypertension: A Survey-Based Study

Background: Blood pressure variability (BPV) in hypertensive patients is implicated as a remarkable feature leading to additional cardiovascular complications. The aim of the study was to identify the determinants influencing BPV among patients with essential hypertension seen at the Cardiology department of the faculty of medicine, University of Alexandria, Egypt. Methods: This was a descriptive cross-sectional hospital-based study conducted from August 2019 to November 2019. All the eligible patients were made to fill out a standard questionnaire to obtain family and personal clinical history and undergo routine physical examination, laboratory tests and 24-hour ambulatory blood pressure monitoring. BPV was summarized as the standard deviation (SD) of all-day systolic and diastolic BP in both normal patients (with SD < 11) and abnormal patients (with SD ≥ 11). Results: Out of a total of 114 patients, 18 (15.8%) non-hypertensive patients were included in the control group and the remaining 96 (84.3%) were classified based on the degree of hypertension. BPV in all these patients was found to be significantly related to the male gender, a mild or moderate degree of hypertension, high prevalence of non-dipping, diabetes, use of beta-blockers as antihypertensive medication, heart rate variability, BMI, and increased day-time variability. Conclusion: Variability in blood pressure influenced by different intrinsic and extrinsic factors plays an important role in the management of hypertension. In order to reduce the burden of disease and for a better quality of life for hypertensive patients, it is important that physicians start considering lowering BPV in addition to reducing physiological BP levels.


Introduction
Several studies have revealed that blood pressure variability (BPV) is a major risk factor that independently contributes to the development of cardiovascular diseases (CVD). It may also lead to target organ damage (especially involving blood vessels, kidneys, and heart), increased mortality, and morbidity in people with hypertension [1] [2] [3] [4]. BPV is a dynamic variable, which can be simply defined as spontaneous fluctuations in BP over a period of time [5] and may be categorized as 1) short-term (estimated as beat-to-beat, minute-to-hour daytime/night-time changes), 2) mid-term (day-to-day), and 3) long-term (over a period of months, and seasons) variability. BPV is generally expressed as a standard deviation (SD) of 24-hour mean BP (systolic or diastolic). Various intrinsic and extrinsic factors influence BPV, and the magnitude of these variations differs among different individuals. These can be classified as a) physiological factors, including different cardiovascular control mechanisms such as autonomic, neural, humoral mechanisms, and alterations in regulatory mechanisms mainly related to arterial stiffness; b) behavioral factors such as physical and/or mental activity, body posture, and exercise; c) demographic, lifestyle, and environmental factors such as gender, age, race, body mass index (BMI), high salt diet, smoking, alcohol, antihypertensive medications, temperature, and seasonal variations; d) comorbidities such as primary and secondary hypertension, diabetes, chronic kidney disease, stroke, autonomic neuropathy, and others Hano and Koike 2022, [2] [5] [6] [7] [8] [9]. One of the best tools that enable the measurement of BPV precisely is 24-hour ambulatory blood pressure monitoring (ABPM) [10]. This helps in evaluating even short-term BP variability with a measurement gap of fewer than 15 minutes, or any abnormal BP patterns, over a period of 24 hours. Moreover, identifying white-coat or masked hypertension in an individual (with large discrepancies between home BP and clinic BP readings) and assessing the efficacy of antihypertensive treatment are rendered easy with ABPM [11] [12].
The therapeutic management for hypertension should be well-planned and considered for evaluating BP fluctuations within a patient in addition to mean BP. Furthermore, the therapy should not only focus on reducing elevated BP but also help decrease BPV. Different drug agents available to date for treating hypertension include calcium channel blockers (CCBs), angiotensin receptor blockers (ARBs), angiotensin-converting enzyme inhibitors (ACEIs), beta-blockers (BBs), and diuretics [13] [14] [15]. Despite these therapies, it is difficult to achieve controlled BP in clinical practice. Understanding the various variables or factors that can potentially affect BPV in hypertensive patients in a hospital setting could help improve patient outcomes, thereby reducing the overall burden of the disease. Therefore, a real-world evidence-based study was designed to evaluate the determinants of BPV in patients with essential hypertension presented to the cardiology department of our hospital.

Subjects and Methods
A total of 114 patients presenting with symptoms of essential hypertension to the cardiology department of Alexandria University Hospital, Egypt, either as outpatients or during hospitalization, were enrolled in the present cross-sectional study. Essential hypertension was defined as a systolic BP (SBP) ≥ 140 mmHg and diastolic BP (DBP) ≥ 90 mmHg. The inclusion/exclusion criteria for the selection of patients have been provided in Table 1.
Informed consent was received from all the patients participating in the study. Thereafter, all the eligible patients underwent the following procedures [16]: 1) Completing a standard questionnaire to obtain family and personal clinical histories, along with confirmation from medical records at the hospital with particular attention to: a) previous levels and time-duration of high BP; b) indications of secondary hypertension; c) risk factors, including lifestyle and dietary habits d) any history or current symptoms of organ damage; e) current and previous antihypertensive therapy; f) personal, family and environmental factors; 2) General physical check-up for assessing secondary hypertension, organ damage, and visceral obesity included in-clinic BP measurement done twice in each visit, for two visits being one weak apart; 3) Laboratory examination included routine tests such as complete blood count, blood glucose level, serum electrolytes (sodium, potassium, and magnesium), serum urea, creatinine and creatinine clearance; standard 12 lead ECG for evidence of left ventricular hypertrophy; conventional transthoracic echocardiography for detection of exclusion criteria; and 24-hour Table 1. Inclusion and exclusion criteria for selecting patients.

BP Assessment
All the BP measurements (in-clinic or ambulatory) were taken in accordance with the protocol recommended by the European Society of Hypertension [17].
In-clinic BP was measured using a mercury sphygmomanometer having an appropriate-sized cuff, with the patient in a seated position. The first and fifth Korotkoff's sound was the criteria to identify systolic and diastolic values, respectively.
Twenty-four-hour ABPM was performed using a validated and calibrated oscillometric device having cuffs of appropriate sizes (Bravo CE 0413; SunTech Medical Instrument Inc. with a SunTech cuff). Subjects were instructed to take all their usual medicines, carry out their usual daily activities, but to avoid vigorous exercise. Ambulatory BP [mmHg (kPa)] was measured for a period of 24-hours with the device programmed to take BP readings at every 60-minute intervals without interfering with the subject's activity or sleep. The mean of three consecutive readings was used for further analysis. During measurements, subjects were told not to move and talk, keep their arm immobile and relaxed, and to breathe normally. They were also asked to keep a record of all their daily activities or events such as eating, exercise, time of medicine intake, emotional stress, posture, and any indications (e.g., dizziness) related to BP, and timings of sleeping and waking up [18]. Readings obtained from ABP monitoring were carefully elucidated with respect to the patient's recorded information. Reference ABP values for adults and interpretation of the results have been given in Table 2.
For minimizing the consequences of recording errors while monitoring ABP, the within-subject mean and SD were used to evaluate BP and BPV. Taking the night time dipping into account, daily mean and SD were calculated as day time mean

Results
Out of a total of 114 individuals enrolled in the study, 18 (15.8%) patients were not found to be hypertensive; therefore, they were included in the control group.
According to the inclusion criteria, the remaining 96 (84.3%) hypertensive patients were classified based on the degree of hypertension (mild, moderate, and severe) ( Figure 1).
The distribution of all these cases (N = 114) based on the types of medications [ARBs, ACEIs, CCBs, BBs, and diuretics] that they received was also studied. It was found that the majority of patients (38.6%) were on ACEI/ARBS, while only 7% were on diuretics (Table 3).

4) Based on the Presence or Absence of Diabetes
Among patients having abnormal SD SBP, 28.9% were diabetic, with 63.6% of them presented with insulin-dependent diabetes mellitus (IDDM) (Table 6(a)).
Among both diabetic and non-diabetic patients, those with hypertension showed higher values of SD all-day systolic blood pressure with a significant relation of a P wave < 0.001 (Table 7).

Discussion
ABPM is increasingly being approved for routine use in clinical practice [18] [19]. The evidence that ABPM accurately reflects information regarding BPV over cuffed blood pressure monitoring (CBPM) has been gaining importance over the past several years. Twenty-four-hour or all-day ABPM provides actual blood pressure readings of a patient during usual daily activities, rather than in an unrealistic environment of a clinic or office. This may improve the physician's ability to predict cardiovascular risk and assess the efficacy of antihypertensive medication. Additionally, this would prevent irrational prescribing based on one or a few CBPMs limited to only a short period of the diurnal pattern [20].
ABPM and, in particular, nocturnal blood pressure readings may have prognostic implications [21].  relationship between age and BPV or standard deviation of SBP or DBP. This may be because of the limited number of patients in our study or that the outcome of variability was influenced by study design, the methods used for blood pressure measurement, and statistical expression of variability.
The absence of dip in nocturnal pressure (as in non-dippers) may place patients at a high risk of CVD [28]. Among our studied individuals, a high prevalence of non-dippers was observed with 43.86% patients for systolic and 40.35% for diastolic pressure. This was quite similar to a study done by Tartan et al. (2006), which found that the majority (61.4%) of their hypertensive patients were non-dippers [29].
The pattern of circadian variability of blood pressure in diabetic patients is different from that of non-diabetics [30]. The present study showed a significant relation of DBP with IDDM than with the non-insulin-dependent group. Moreover, a higher BPV of all-day systolic SD was observed in hypertensive diabetic patients than non-diabetics, which correlated well with many studies [30] [31] [32].
Among all the antihypertensive agents, CCBs have been found to reduce BPV the most [33]. CCBs, in combination with ACE-inhibitors, have also shown to decrease BPV more in comparison to diuretics plus beta-blockers [34]. Treatment with amlodipine and indapamide sustained-release tablets have shown to significantly reduce BPV in patients, probably attributable to lowering levels of BP or enhancing the regulation of the autonomic nervous system or both [35].
Our results were also consistent with previous studies and showed that the BPV (measured as SD SBP) was least in patients on CCBs.
The current study observed a significant relationship between heart rate variability and BPV (SD systolic and diastolic BP) and found it comparable to other findings [36] [37].
Significant correlations have been seen between BMI and mean 24-hour ABP variability with confirmed hypertension found to be higher in overweight individuals than compared with normal-weight subjects [38] [39]. This is similar to the results obtained in our study with significantly higher Mean ± SD values of BMI in patients with abnormal SD SBP and DBP.
Increased variability in day-time BP, evaluated as the abnormal SD SBP and DBP in our study, has been found to be associated with severe cardiovascular complications in hypertensive patients [40]. However, there were a few limitations in our study. This was a single-center study. The proportion of data was collected from free text fields, and may be biased and as such represented an underestimate of the findings or clinical variables.

Conclusion
In hypertensive patients, cardiovascular risk and multiple organ damage are not only related to the blood pressure levels, but also to BPV. Therefore, it would be reasonable to include 24-hour ABPM as a tool for assessing BPV in the current A. Kamal diagnostic armamentarium of managing hypertension. Through this study, we could also identify several significant factors influencing BPV, such as male gender, mild or moderate degree of hypertension, high prevalence of non-dipping, diabetes, use of beta-blockers, heart rate variability, BMI, and increased day-time variability in patients with essential hypertension. A better understanding of these determinants may add to significant prognostic information about hypertensive patients.

Conflicts of Interest
The author declares no conflicts of interest regarding the publication of this paper.