The autonomic nervous system is vital for regulating blood pressure (BP) and heart rate (HR), making it a significant factor in hypertension development  [1]. Numerous studies on plasma catecholamines in essential hypertension have consistently shown elevated levels in hypertensive individuals  [2]. Additionally, disruptions in autonomic HR and BP control have been evidenced in various studies using HR variability (HRV) and baroreceptor reflex sensitivity (BRS) [3].

Baroreceptor reflex sensitivity (BRS) refers to the responsiveness of the baroreceptors, specialized sensory receptors located in the walls of blood vessels, particularly in the carotid sinuses and aortic arch [4]. These receptors detect changes in blood pressure (BP) and transmit this information to the brain, specifically to the cardiovascular control center in the medulla oblongata. The brain then initiates appropriate adjustments in heart rate, vascular tone, and fluid balance to maintain BP within a narrow range, thereby ensuring adequate perfusion to vital organs  [5].

BRS is a measure of how effectively the baroreceptor reflex system responds to changes in BP. It is typically expressed in units of milliseconds per millimeter of mercury (ms/mm Hg) and quantifies the degree of change in heart rate or vascular resistance in response to alterations in BP. A higher BRS indicates a more sensitive and effective baroreceptor reflex, capable of rapidly modulating cardiovascular responses to maintain BP homeostasis [6].

Heart rate variability (HRV) refers to the variation in the time interval between consecutive heartbeats, known as R-R intervals, as measured from an electrocardiogram (ECG) signal  [7]. It reflects the dynamic interplay between the sympathetic and parasympathetic branches of the autonomic nervous system, which regulate heart rate in response to physiological and environmental stimuli  [8]. HRV analysis provides valuable insights into the autonomic nervous system function and cardiovascular health. Reduced HRV is associated with various pathological conditions, including cardiovascular diseases, diabetes, and psychological stress  [9]. Conversely, higher HRV is generally indicative of better cardiovascular health and adaptability to stressors [10].

There are several metrics used to quantify HRV, including time domain, frequency domain, and nonlinear measures. Time domain measures include parameters such as the standard deviation of normal-to-normal intervals (SDNN) and the root mean square of successive differences (RMSSD). Frequency domain analysis involves decomposing HRV signals into different frequency bands, such as low frequency (LF) and high frequency (HF), using spectral analysis techniques. Nonlinear measures assess the complexity and irregularity of HRV patterns, providing additional information about autonomic regulation [11].

HRV, which reflects tonic HR control, is typically diminished in hypertensive patients, as indicated by reductions in standard deviation of all R-R intervals (SDNN) and total power (TP) of heart period spectrum  [12]. Some studies have reported heightened markers of sympathetic predominance, although not consistently across all studies [13].

BRS, reflecting reflex vagal HR control, is found to be decreased in hypertensive individuals [14]. Both BRS and HRV parameters generally decline with age in both healthy and hypertensive subjects, with suggestions that BRS stabilizes after middle age  [15].

Gender differences may exist in the pathophysiology of essential hypertension. Previous observations indicate that hypertensive women tend to have low-renin hypertension and exhibit less cardiovascular reactivity to stress compared to hypertensive men[16]. While limited studies have explored gender differences in HRV in hypertension, more research is available in healthy subjects, showing lower SDNN, LF/HF ratio, and LF normalized units in women compared to men  [17]. Moreover, BRS tends to be reduced in women, although not significantly in those aged 60 years and above  [10].

Studies suggest higher tonic parasympathetic activity in women than in men, yet paradoxically propose decreased reflex vagal responses in healthy women compared to healthy men [12]. However, the correlation between HRV and BRS remains weak [4].

Despite extensive research on gender differences in HRV and BRS in healthy subjects, specific investigations on gender differences in BRS in hypertensive patients compared to normotensive controls are lacking. This article introduces new findings suggesting a potentially more pronounced role of autonomic dysfunction in female hypertension compared to male hypertension [5].

Participants over 18 years old with mild hypertension (systolic BP  130 - 140 , diastolic BP 80 - 90 mm Hg) were considered eligible. Exclusion criteria included secondary hypertension, recent cardiovascular events, organ failure, diabetes mellitus, autoimmune disease, or Parkinson’s disease. Medications such as neuroleptics, antidepressants, lithium, antiarrhythmics, and cimetidine were prohibited. Normotensive controls had BP levels <129/80 mm Hg. All participants provided written informed consent, and baseline characteristics are summarized in Tables 1 and 2.

The study involved two visits. During the first visit, hypertensive patients were instructed to discontinue antihypertensive medications, followed by weekly BP monitoring. The final eligibility assessment occurred two weeks later. All examinations were conducted in the morning in a controlled environment (temperature 23±2°C), after an overnight fast and abstention from tobacco for at least 24 hours. Blood pressure and heart rate were measured after 10 minutes of rest.

HRV Analysis: Heart rate variability (HRV) was assessed by the following  method:  POWERLAB 26T (AD Instrument, Sydney, Australia): An analysis was performed using the POWERLAB 26T, where HRV was measured in a supine position for 20 minutes. This system analyzed both time-domain (e.g., RMSSD, PNN50) and frequency-domain (e.g., LF, HF, LF/HF ratio) HRV metrics, providing insights into the sympathetic and parasympathetic regulation of heart rate. Data were processed and reviewed for accuracy, ensuring the reliability of HRV metrics.

BRS Measurement (Ambulatory Blood Pressure Monitoring Performed Using Meditech ABPM-05) : To measure Baroreflex Sensitivity (BRS), we first extracted Systolic Blood Pressure (SBP) and Heart Rate (HR) values from the 24-hour Ambulatory Blood Pressure Monitoring (ABPM) data. Since BRS is the relationship between blood pressure changes and heart rate adjustments, we converted HR into RR intervals (the time between consecutive heartbeats) using the formula RR Interval (ms) = 60000 / HR (bpm). Then, we performed a linear regression analysis between SBP and RR intervals, where the slope of the regression line represents BRS in milliseconds per mmHg (ms/mmHg). This method quantifies how effectively the autonomic nervous system adjusts heart rate in response to blood pressure fluctuations, providing insights into autonomic function and cardiovascular regulation.

Statistical Analysis: Data were analyzed to identify potential differences in autonomic function between hypertensive and normotensive groups, with a focus on gender differences. Multiple regression analysis was used to determine the independent effects of variables such as age, gender, HDL cholesterol, and hypertension status on BRS and HRV.

Baroreceptor Reflex Sensitivity (BRS):

Differences Between Hypertensive and Normotensive Subjects:

BRS was significantly lower in hypertensive patients compared to normotensive controls (7.6±0.6 vs. 10.4±0.8 ms/mm Hg; P=0.005).

Gender Differences: 

Hypertensive women exhibited significantly lower BRS than normotensive women, whereas the difference between hypertensive and normotensive men was not statistically significant. Female hypertensives also had lower BRS than male hypertensives. No significant BRS differences were noted between the normotensive men and women. In hypertensive and normotensive male groups, BRS correlated negatively with age (r=−0.65 and r=−0.61; P≤0.01), while a significant correlation between systolic BP and BRS was found only in hypertensive women (r=−0.51; P=0.04).

Multiple Regression Analysis: 

Gender, age, and hypertension status emerged as significant independent predictors of BRS. BRS decreased with age and was lower in females and hypertensive individuals compared to males and normotensive individuals.

Heart Rate Variability (HRV):

HRV was assessed using:  20-minute analysis with POWERLAB 26T.

Differences Between Hypertensive and Normotensive Subjects: 

 Both methods revealed lower PNN50, RMSSD, TP, LF, and HF values in hypertensive patients compared to normotensive controls. There were no significant differences in normalized units or LF/HF ratio, although a tendency for a higher LF/HF ratio in the hypertensive group was noted.

Gender Differences:

Hypertensive women showed higher HF normalized units and lower LF normalized units and LF/HF ratio compared to hypertensive men. These gender differences persisted in the normotensive groups as well. Additionally, hypertensive women had significantly lower TP and LF than hypertensive men. No significant differences were observed between hypertensive and normotensive men in any HRV parameters.

Multiple Regression Analysis:

Age, gender, HDL cholesterol, and hypertension status were significant independent predictors of HRV. HRV decreased with age and was lower in hypertensive individuals and women compared to normotensive individuals and men. Higher HDL cholesterol was associated with increased HRV, except for LF normalized units and LF/HF ratio, which were inversely correlated with HDL cholesterol. LF/HF ratio decreased with both higher HDL and age.

Blood Parameters (Hemoglobin, Hematocrit, Creatinine, and Lipids):

Differences Between Hypertensive and Normotensive Subjects:

HDL cholesterol was higher in the hypertensive group. No significant differences were found in hematocrit,

creatinine, total cholesterol, or triglycerides.

Gender Differences:

Hypertensive men had higher HDL cholesterol than normotensive men, while no significant differences were observed between the two female groups. Normotensive women had higher HDL cholesterol levels than normotensive men. Creatinine and hematocrit levels were higher in males compared to females. No significant gender differences were noted for total cholesterol and triglyceride levels.
 

TABLE 1. Basal parameters in normotensive and hypertensive participants

TABLE 2.Basal parameters in Normotensive females versus Hypertensive females and Normotensive Males versus Hypertensive Males

Data are mean ± SEM

Figure 1: Baroreceptor Reflex Sensitivity (BRS)

BRS was measured in 16 normotensive females (NT), 20 hypertensive females (HT), 20 normotensive males (NT), and 24 hypertensive males (HT).

BRS was significantly lower in the female hypertensive group compared to the female normotensive group (P < 0.0005).

There was no significant difference in BRS between male hypertensive and male normotensive groups (NS).

However, BRS was significantly lower in the female hypertensive group compared to the male hypertensive group (P < 0.01).

No significant difference was observed between normotensive males and normotensive females (NS).

**P < 0.0005; P < 0.01.

Table 3. Results of Stepwise Multiple Regression Analysis with Gender, Blood Pressure Category, Age, HDL Cholesterol, BMI, Total Cholesterol, Triglycerides, and Smoking Status as Predictors for Dependent Variables: BRS, Mean R-R, SDNN, PNN50, RMSSD, TP, LF, HF, LF/HF Ratio, and Normalized LF and HF Units.

Figure 2: HRV Frequency Domain Parameters

HRV parameters were analyzed in 16 normotensive females (NT), 20 hypertensive females (HT), 20 normotensive males (NT), and 24 hypertensive malelevels.

Total Power (TP) and Low Frequency (LF) were significantly lower in hypertensive women than in normotensive women (P < 0.01 and P < 0.05, respectively).

High Frequency (HF) was lower in hypertensive women compared to normotensive women, but this difference did not reach significance (P = 0.075).

LF normalized units (LF nu), HF normalized units (HF nu), and LF/HF ratio differed significantly between male and female hypertensive groups (P < 0.05).

LF nu, HF nu, and LF/HF ratio also differed significantly between male and female normotensive groups (P < 0.05).

**P < 0.05; P < 0.01.

TABLE 4. HRV in Normotensive vs Hypertensive Subjects

Data are mean ± SEM

Figure 3: HRV Time Domain Parameters

HRV parameters were analyzed in 16 normotensive females (NT), 20 hypertensive females (HT), 20 normotensive males (NT), and 24 hypertensive males (HT).

PNN50 and RMSSD were significantly lower in hypertensive women compared to normotensive women (P < 0.05 and P < 0.01, respectively).

No significant differences were observed for Mean RR and SDNN across the groups.

RMSSD was lower in hypertensive women compared to normotensive women (P < 0.05).

PNN50 was significantly lower in hypertensive women compared to normotensive women (P < 0.01).

**P < 0.05; P < 0.01.

The present study confirms that baroreceptor sensitivity (BRS) is significantly lower in hypertensive subjects compared to normotensive controls, with the reduction being more pronounced in females. This finding is consistent with prior research that also demonstrated a pronounced decrease in BRS among hypertensive individuals, particularly women [6,10]. The significant reduction in BRS observed in hypertensive women compared to hypertensive men suggests that gender-specific factors, such as hormonal influences or differential cardiovascular control mechanisms, may contribute to greater autonomic dysfunction in female hypertension [12,15].

Moreover, BRS was significantly correlated with systolic blood pressure in the female hypertensive group, but not in males, indicating that hypertension-related autonomic dysfunction may be more closely linked to blood pressure regulation in women. This finding is supported by the hypothesis that female sex hormones might modulate arterial properties, influencing both arterial compliance and baroreceptor function [11,15]. Previous studies have shown that estrogen replacement therapy increases BRS in postmenopausal women, which further suggests the potential role of hormonal regulation in autonomic function [16].

Our study also demonstrated significantly reduced heart rate variability (HRV) parameters, including PNN50, RMSSD, TP, LF, and HF in hypertensive patients compared to normotensive controls. The reductions were more substantial in women, supporting the notion that autonomic dysfunction plays a more prominent role in female hypertension [12]. Interestingly, while hypertensive women showed higher HF normalized units and lower LF normalized units and LF/HF ratio compared to hypertensive men, these differences were not observed between hypertensive and normotensive men, suggesting a unique autonomic profile in hypertensive women characterized by increased parasympathetic withdrawal and sympathetic dominance [3,13]. These findings align with those of previous studies that reported similar reductions in HRV among hypertensive patients, with variations depending on gender [3,13].

The gender differences in HRV observed in this study are also consistent with findings that suggest women generally exhibit higher parasympathetic activity and lower sympathetic activity than men [16]. However, this balance appears to shift more dramatically in hypertensive women, leading to greater autonomic imbalance. The observed HRV patterns in hypertensive women—characterized by lower LF/HF ratios and normalized units—could reflect a more pronounced autonomic withdrawal in response to hypertensive pathology. This differential autonomic response could potentially contribute to the increased cardiovascular risk observed in hypertensive women, as suggested by the increased susceptibility to arrhythmias and cardiac events in this group [17].

Multiple regression analysis in our study identified gender, age, HDL cholesterol, and hypertension status as significant independent determinants of both BRS and HRV values. Higher HDL cholesterol was associated with higher HRV values, except for LF normalized units and LF/HF ratio, which were inversely correlated. This finding suggests that lipid metabolism may also play a role in modulating autonomic function, potentially offering a protective mechanism against autonomic decline in women. These results are in line with studies showing that HDL cholesterol is associated with improved endothelial function and vascular health, which could enhance autonomic regulation [15].

While our study provides valuable insights into the autonomic dysfunction in hypertensive individuals, particularly women, several limitations should be acknowledged. The cross-sectional nature of the study prevents us from establishing causality or observing changes in autonomic function over time. Additionally, although we controlled for certain variables, potential confounders such as medication use, physical activity, and psychological stress were not fully accounted for, which could have influenced our findings. Future studies should employ longitudinal designs and include a larger and more diverse sample to better understand the long-term interactions between hypertension, age, gender, and autonomic function [1,14].

Moreover, the study did not account for potential differences in comorbid conditions or stages of hypertension, which could provide further insight into the variability of autonomic dysfunction within hypertensive and normotensive populations. These factors warrant further investigation to elucidate their roles in gender-specific autonomic regulation and cardiovascular risk [9,16].

This study underscores significant gender-specific differences in autonomic regulation among hypertensive individuals, with a particular emphasis on the pronounced autonomic dysfunction observed in hypertensive women. The findings reveal that hypertensive patients, especially women, exhibit markedly lower baroreceptor sensitivity (BRS) and reduced heart rate variability (HRV) compared to both their normotensive counterparts and hypertensive men. The pronounced reduction in BRS among hypertensive women, alongside significant correlations between BRS, age, and systolic blood pressure, highlights the influence of gender and age on autonomic function. Additionally, the distinct patterns of HRV observed in hypertensive women suggest that autonomic dysfunction may play a more substantial role in female hypertension.

Multiple regression analyses further confirm that gender, age, and hypertension status are critical determinants of both BRS and HRV. These findings point to the importance of considering gender-specific differences in the pathophysiology of hypertension and support the need for targeted management strategies that address the unique autonomic challenges faced by hypertensive women. Ultimately, recognizing these differences could enhance the effectiveness of therapeutic interventions and improve cardiovascular outcomes for hypertensive patients.

CONFLICT OF INTEREST: Nil

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