Evaluation of heart rate variability using 24‐hour Holter electrocardiography in hypertensive patients

Abstract Background Hypertension (HTN) remains a serious risk factor for cardiovascular mortality across the world. Hypertensive state has been shown to be associated with autonomic nervous function. This study aimed to explore the association between autonomic nervous impairment assessed by heart rate variability (HRV) and HTN. Methods A total of 52 hypertensive and 55 non‐hypertensive patients were consecutively studied using 24‐hour Holter. The hypertensive patients were grouped into controlled blood pressure (BP) and uncontrolled BP. This study compared HRV in non‐hypertensive and hypertensive patients; and hypertensive patients with controlled and uncontrolled BP. HRV parameters include time and frequency domain. Results Mean age for hypertensive and non‐hypertensive patients were 53.58 ± 14.31 and 44.89 ± 16.63 years old, respectively. Median (IQR) SDNN for hypertensive and non‐hypertensive group were 109.00 (90.00‐145.00) and 129.00 (107.00‐169.00), respectively. SDNN, ASDNN, rMSSD, pNN50, BB50, VLF, and HF values were significantly lower in the hypertensive group compared to non‐hypertensive group (all P < .05). A multiple regression analysis showed that HRV parameters: SDANN, ASDNN, rMSSD, and LF values were independent risk factors of HTN. SDNN, SDANN, ASDNN, VLF, LF, and HF values were significantly lower in the uncontrolled BP compared to controlled BP group (all P < .05). A multiple regression analysis showed that HRV parameters: SDNN, SDANN, rMSSD, and HF values were independent risk factors of uncontrolled BP in hypertensive patients. Conclusions Our study showed that cardiac autonomic nervous impairment, as demonstrated by reduced HRV, is significantly associated with HTN. Decreased HRV was more evident in uncontrolled BP than in controlled BP group.


| INTRODUC TI ON
Hypertension (HTN) remains a serious risk factor for cardiovascular mortality across the world. 1 The asymptomatic nature of HTN may hinder diagnosis and prompt initiation of appropriate therapies. 2 Essential hypertensive disorders can be identified not only by reduced parasympathetic tones but also by a severe sympathetic overdrive, resulting in an increase in resting heart rate values. 3,4 Another literature summarises sympathetic dysregulation in the differentiation risk in stages of HTN (mild, moderate, severe), form of hypertension in young, middle-aged, and elderly, white-coat HTN, masked HTN, and gestational HTN. 5 Heart rate variability (HRV) influences the autonomic control of cardiac function. HRV reflects the autonomous nervous system response to external stimuli. Abnormal HRV represented autonomous imbalance and was associated with worse cardiovascular outcome. 6 One of the major studies that found reduced HRV in males and females with systemic HTN was the Framingham Heart Study. This study also found that LF (low frequency) power of HRV was correlated with new-onset HTN in men. The assessment of HRV using 24-hour Holter Electrocardiography (ECG) is a simple and reliable tool to assess autonomic imbalance in HTN patients. 7 Analyzing HRV may be beneficial in improving our understanding of underlying pathophysiology, optimizing treatment modalities for hypertensive patients subsets with signs of autonomic impairment, and predicting future major adverse cardiovascular events (MACE) in patients at risk. 3 This study aimed to explore the association between HRV in non-hypertensive and hypertensive patients and between controlled and uncontrolled BP of hypertensive patients.

| Study design and study setting
This was an observational study using a retrospective cross-sectional design. This study was held at Cardiac Center-Dr Soetomo General Hospital, Surabaya, Indonesia.

| Data collection
All participants were subjected to 24-hour Holter ECG monitoring (MARS PC Holter Monitoring and Review System software and SEER Light Digital Holter Recorder; GE). Each patient was given a detailed explanation of how the test was done and how to handle the recorder. Holter ECG was placed in the patient's waist, and the electrode leads were placed appropriately on the chest. The patients were instructed to go home, recommence normal daily activities, and return to hospital after 24 hours.  Characteristic (ROC) curve was used to determine the optimal cutoff of HRV parameters. P values less than .05 were considered statistically significant.

| Baseline characteristics of study population
Characteristics of study population are summarized in Table 1.
There was no difference in distribution of sex between two groups. Mean age for hypertensive and non-hypertensive patients were 53.58 ± 14.31 and 44.89 ± 16.63 years old, respectively. Mean heart rate for hypertensive and non-hypertensive patients were 76.67 ± 14.03 and 74.27 ± 12.49 bpm, respectively.
Diabetes mellitus (DM) was found in 3.8% of hypertensive patients and 3.6% of non-hypertensive patients. History of arrhythmia became the most common comorbidity in both groups: 50.0% in hypertensive patients and 81.8% in non-hypertensive patients.
The use of ACE-i/ARB and CCB was higher in hypertensive group, while the use of anti-arrhythmic drug amiodarone was higher in non-hypertensive group. Note: Data are presented as mean ± SD, median (IQR), n (%).

| Multivariate adjusted factors related to HTN
Multiple regression analysis showed that HRV parameters: SDANN, ASDNN, rMSSD, and LF values were independent risk factors of HTN after adjusting for age, sex, BMI, amiodarone use, beta-blockers use, ACE-i/ARB use, CCB use, and diuretic use (Table 4).

| Multivariate adjusted factors related to uncontrolled blood pressure of hypertensive patients
Multiple regression analysis showed that HRV parameters: SDNN, SDANN, and rMSSD values were independent risk factors of uncontrolled blood pressure in hypertensive patients after adjusting for age, sex, BMI, amiodarone use, beta-blockers use, ACE-i/ARB use, CCB use, and diuretic use ( Table 6).

| D ISCUSS I ON
This study showed that decreased HRV level has significant asso-  Table S1 which was expressed in lower entropy and correlation dimension. 12 A similar study in India involving 30 hypertensive patients and 30 non-hypertensive patients showed significantly reduced HFnu, SDNN, rMSSD, pNN50, and significantly increased LFnu and LF-HF ratio in hypertensive individuals. The study also used five-minutes of ECG recording. 10 A study from Japan showed parasympathetic nervous system activity impairment were associated with increased ambulatory mean arterial pressure in the morning. 11 Another study suggested that HRV reflects diastolic BP better than systolic BP levels and that alcohol intake strongly affected systolic BP levels in men, which may had weakened the association with HRV. 9 In Chinese population, a study showed that reduced HRV and HRT were present in hypertensive patients, particularly in hypertensive patients with uncontrolled BP. 7 HRV can be used to evaluate cardiac autonomic activity. It shows us the oscillation of heart rate which reflect the sympathetic and vagal function that regulates the heart rate response to any stimuli. 7,14,15 Apart from external stimuli, HRV is also affected by internal stimuli, including circadian rhythms, core body temperature, metabolism, the sleep cycle, and the renin-angiotensin system. Using 24-hour HRV recordings is the "gold standard" of clinical HRV assessment because it provides greater predictive power than short-term measurements. 16 Deviation of HRV from the normal range is associated with various cardiovascular diseases. The 24-hour recording of SDNN is the "gold Some studies reported the effect of BP medication, including beta-blocker, ACE inhibitor, ARB, and diuretic to HRV. Betablockers users had equal or greater HRV than non-users, whereas those using diuretics or ACE inhibitors had a lower HRV. 14 Captopril medication increased HRV expressed as total power and LF power in the frequency domain. 19 Anti-arrhythmic drug amiodarone also affected HRV. Amiodarone administration showed a reduction of pNN50 and rMSSD. 20 In this study, we performed multivariate regression to confounding factors, including anti-arrhythmic and blood pressure medication use.It showed a significant association between several HRV parameters and hypertension, particularly in hypertensive patients with uncontrolled BP. There was considerable effect modification by antihypertensive medication use, with stronger associations among individuals not using antihypertensive medications. Abbreviations: BMI, body mass index; HF, high-frequency power; rMSSD, root mean square of the difference of successive R-R intervals; SDANN, standard deviation of five-minute mean R-R interval; SDNN, standard deviation of intervals of all normal beat.

TA B L E 6
Multivariate logistic regression for risk of uncontrolled blood pressure in hypertensive group

| Study limitation
Several limitations of this study should be considered. First, we could not confirm the presence of a causal relationship between cardiac autonomic nervous impairment and HTN due to the cross-sectional design of the study with a relatively small sample size. Second, age of patients in the HTN group was significantly higher than those in the non-HTN group. HRV parameters in an elderly population are usually lower than those of a younger population; therefore, this result is possibly biased in terms of age. After adjusting for age as one of risk factors of HTN in multivariate model, we found that HRV is an independent risk factor for HTN. Third, we could not exclude the effects of medication that affect autonomic cardiac function. Fourth, most subjects recruited in this study were patients with arrhythmia indicated for Holter study. This might cause population bias, and the result of this study only represent a population of patient with arrhythmia and HTN.

| CON CLUS ION
Our study showed that cardiac autonomic nervous impairment, as demonstrated by reduced HRV, is significantly associated with HTN.
Decreased HRV was also significantly associated with uncontrolled blood pressure in hypertensive patients.