Rheumatoid arthritis (RA) is a chronic systemic inflammatory autoimmune disorder that impacts between 0.5-1.0% of the worldwide population [1]. Rheumatoid arthritis (RA) is predominantly marked by symmetric polyarthritis, but it also entails considerable extra-articular symptoms and heightened cardiovascular morbidity and mortality [2]. Epidemiological studies indicate that cardiovascular disease constitutes roughly 40-50% of premature fatalities in RA patients, with standardized mortality ratios between 1.5 and 3.0 relative to the general population [3]. The heightened cardiovascular risk cannot be entirely attributed to conventional risk factors, indicating that rheumatoid arthritis-specific processes, such as persistent systemic inflammation, significantly contribute to cardiovascular pathology [4]. The autonomic nervous system is crucial for cardiovascular homeostasis via intricate regulation mechanisms that involve both sympathetic and parasympathetic branches. Cardiac autonomic dysfunction, marked by an imbalance in sympathovagal tone, is acknowledged as an independent predictor of cardiovascular events and sudden cardiac death across diverse groups [5]. Heart rate variability (HRV) analysis offers a non-invasive, quantitative evaluation of cardiac autonomic function by assessing beat-to-beat variations in heart rate, which illustrate the dynamic interaction between sympathetic and parasympathetic impulses on the sinoatrial node.[6] Recent evidence indicates that chronic inflammation in RA may impair autonomic cardiovascular regulation via various mechanisms, including cytokine-mediated effects on autonomic centers, endothelial dysfunction, and changes in baroreceptor sensitivity [7]. Numerous studies have reported reduced HRV parameters in RA patients relative to healthy individuals, signifying autonomic dysfunction [8]. Moreover, autonomic dysfunction has been correlated with markers of disease activity, indicating a possible connection between systemic inflammation and cardiovascular autonomic regulation [9]. Although there is increasing awareness of cardiovascular problems in RA, cardiac autonomic dysfunction is still insufficiently defined in this population. Many current researches are constrained by limited sample sizes, heterogeneous methodologies, or insufficient complete examination of HRV. The correlation between particular illness characteristics, including disease duration, activity level, and autonomic indicators, necessitates additional clarification to enhance clinical risk classification. The current study sought to thoroughly assess cardiac autonomic function in RA patients through standardized heart rate variability analysis, compare results with age- and sex-matched healthy controls, and examine correlations between autonomic dysfunction and disease-related parameters such as disease duration and activity scores.

Study Design and Participants This case-control study was conducted in the Department of General Medicine in a tertiary teaching institute in Kerala from December 2020 to June 2021. Written informed permission was acquired from all participants. The study comprised 80 consecutive RA patients who met the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for RA. Eighty healthy volunteers, matched for age and sex, were recruited as controls via hospital personnel and neighborhood advertisements. Criteria for Inclusion and Exclusion The inclusion criteria for RA patients were: age between 18 and 65 years, a confirmed diagnosis of RA for a minimum of 6 months, and a stable drug regimen for at least 3 months. The exclusion criteria for both groups encompassed: established cardiovascular disease (coronary artery disease, heart failure, arrhythmias), hypertension, diabetes mellitus, chronic kidney disease, thyroid disorders, neurological diseases affecting autonomic function, use of medications influencing heart rate (beta-blockers, calcium channel blockers, anticholinergics), active infection, pregnancy, and any contraindication to Holter monitoring. Clinical Evaluation A comprehensive medical history and physical examination were conducted for all subjects. In RA patients, disease duration was documented, and disease activity was evaluated utilizing the Disease Activity Score in 28 joints with erythrocyte sedimentation rate (DAS28-ESR). The clinical examination comprised a tender joint count, a swollen joint count, and a patient global assessment utilizing a visual analog scale. Laboratory examinations encompassed a complete blood count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and rheumatoid factor. Analysis of Heart Rate Variability The assessment of cardiac autonomic function was conducted using 24-hour ambulatory electrocardiographic monitoring (Holter monitoring) with a three-channel digital recorder. Participants were directed to continue their regular daily routines while refraining from vigorous activity. Recordings were examined with computerized HRV analysis software, accompanied by manual verification of automated QRS detection and the editing of artifacts and ectopic beats. The time-domain HRV parameters assessed were: standard deviation of all normal-to-normal RR intervals (SDNN), root mean square of successive RR interval differences (RMSSD), and the percentage of successive RR intervals deviating by more than 50 ms (pNN50). Frequency-domain metrics comprised low-frequency power (LF: 0.04-0.15 Hz), high-frequency power (HF: 0.15-0.40 Hz), and the LF/HF ratio. SDNN signifies total heart rate variability, RMSSD and pNN50 denote parasympathetic activity, whereas the LF/HF ratio illustrates sympathovagal balance. Cardiac autonomic dysfunction was characterized by SDNN < 100 ms or RMSSD < 27 ms, according to established normative values. Statistical Analysis Statistical analysis was conducted utilizing SPSS version 26.0. Continuous data were presented as mean ± standard deviation (SD), whereas categorical variables were represented as frequencies and percentages. The Kolmogorov-Smirnov test was employed to evaluate the normality of the distribution. Independent sample t-tests were employed to compare continuous variables across groups, whereas chi-square tests were utilized for categorical variables. Pearson correlation coefficients were computed to evaluate the correlations between HRV parameters and illness features. A p-value less than 0.05 was deemed statistically significant.

Baseline Characteristics The study comprised 80 RA patients (64 females, 16 males) with a mean age of 48.6 ± 10.2 years, alongside 80 age- and sex-matched healthy controls (mean age 47.8 ± 9.8 years). The baseline characteristics are illustrated in Table 1. RA patients exhibited a mean disease duration of 6.8 ± 4.2 years. According to DAS28-ESR values, 26 patients (32.5%) exhibited low disease activity, 38 (47.5%) had moderate disease activity, and 16 (20.0%) presented high disease activity. No significant differences were observed between groups regarding age, sex distribution, body mass index, or smoking status (p > 0.05). Table 1. Baseline Characteristics of Study Participants Parameter RA Patients (n=80) Controls (n=80) p-value Age (years) 48.6 ± 10.2 47.8 ± 9.8 0.614 Female, n (%) 64 (80.0) 64 (80.0) 1.000 BMI (kg/m²) 24.8 ± 3.4 24.2 ± 3.1 0.238 Current smokers, n (%) 18 (22.5) 16 (20.0) 0.692 Disease duration (years) 6.8 ± 4.2 - - DAS28-ESR score 4.2 ± 1.3 - - ESR (mm/hr) 32.4 ± 18.6 12.2 ± 6.4 <0.001 CRP (mg/L) 14.8 ± 12.2 2.6 ± 1.8 <0.001 Rheumatoid factor positive, n (%) 62 (77.5) - - Medications: - Methotrexate, n (%) 68 (85.0) - - - Hydroxychloroquine, n (%) 52 (65.0) - - - Prednisolone, n (%) 44 (55.0) - - BMI: body mass index; DAS28-ESR: Disease Activity Score-28 with erythrocyte sedimentation rate; CRP: C-reactive protein Parameters of Heart Rate Variability The comparison of HRV characteristics between RA patients and controls is presented in Table 2. RA patients had markedly reduced time-domain characteristics in comparison to controls. In RA patients, SDNN measured 98.4 ± 24.6 ms, compared to 142.3 ± 28.4 ms in controls (p < 0.001). RMSSD was significantly reduced in RA patients (24.8 ± 8.2 ms) relative to controls (38.6 ± 10.4 ms, p < 0.001). In a comparable manner, pNN50 was markedly reduced in RA patients (8.6 ± 4.8%) compared to controls (16.2 ± 6.4%, p < 0.001). Frequency-domain analysis demonstrated substantial differences between groups. LF power was decreased in RA patients (452.6 ± 186.4 ms²) relative to controls (687.8 ± 224.6 ms², p < 0.001). HF power was markedly reduced in RA patients (162.4 ± 68.2 ms²) compared to controls (412.6 ± 142.8 ms², p < 0.001). The LF/HF ratio was markedly increased in RA patients (2.8 ± 0.9) relative to controls (1.6 ± 0.5, p < 0.001), signifying sympathetic dominance and sympathovagal imbalance. Table 2. Comparison of Heart Rate Variability Parameters HRV Parameter RA Patients (n=80) Controls (n=80) p-value Time-domain SDNN (ms) 98.4 ± 24.6 142.3 ± 28.4 <0.001 RMSSD (ms) 24.8 ± 8.2 38.6 ± 10.4 <0.001 pNN50 (%) 8.6 ± 4.8 16.2 ± 6.4 <0.001 Frequency-domain LF power (ms²) 452.6 ± 186.4 687.8 ± 224.6 <0.001 HF power (ms²) 162.4 ± 68.2 412.6 ± 142.8 <0.001 LF/HF ratio 2.8 ± 0.9 1.6 ± 0.5 <0.001 Mean heart rate (bpm) 78.6 ± 10.4 72.4 ± 8.6 <0.001 SDNN: standard deviation of all normal RR intervals; RMSSD: root mean square of successive RR interval differences; pNN50: percentage of successive RR intervals differing by >50 ms; LF: low frequency; HF: high frequency; bpm: beats per minute Prevalence of Cardiac Autonomic Dysfunction Cardiac autonomic dysfunction was observed in 50 RA patients (62.5%) against 15 controls (18.8%), indicating a statistically significant difference (p < 0.001, odds ratio 7.2, 95% CI 3.6-14.4). Correlation with Disease Parameters Correlation study demonstrated significant relationships between HRV measures and disease features in RA patients (Table 3). The duration of the disease had strong negative correlations with SDNN (r = -0.52, p < 0.001), RMSSD (r = -0.48, p < 0.001), and HF power (r = -0.44, p < 0.001), alongside a positive correlation with the LF/HF ratio (r = 0.46, p < 0.001). The DAS28-ESR score exhibited strong negative relationships with SDNN (r = -0.48, p < 0.001), RMSSD (r = -0.51, p < 0.001), and HF power (r = -0.49, p < 0.001), alongside a positive correlation with the LF/HF ratio (r = 0.52, p < 0.001). ESR and CRP levels exhibited substantial inverse correlations with parasympathetic indices and positive correlations with the LF/HF ratio. Table 3. Correlation between HRV Parameters and Disease Characteristics in RA Patients Disease Parameter SDNN RMSSD HF power LF/HF ratio Disease duration (years) r = -0.52*** r = -0.48*** r = -0.44*** r = 0.46*** DAS28-ESR score r = -0.48*** r = -0.51*** r = -0.49*** r = 0.52*** ESR (mm/hr) r = -0.42*** r = -0.46*** r = -0.44*** r = 0.48*** CRP (mg/L) r = -0.38** r = -0.41*** r = -0.39** r = 0.43*** Tender joint count r = -0.36** r = -0.42*** r = -0.38** r = 0.40*** Swollen joint count r = -0.34** r = -0.38** r = -0.36** r = 0.37** **p < 0.01; ***p < 0.001. r: Pearson correlation coefficient

The present investigation indicates considerable cardiac autonomic dysfunction in RA patients compared to healthy controls, characterized by lower HRV values and sympathovagal imbalance. These findings provide crucial insights into cardiovascular risk factors in RA and underline the potential benefit of autonomic function testing in this population. The observed decline in time-domain HRV measures, particularly SDNN and RMSSD, demonstrates general autonomic dysfunction with predominant parasympathetic withdrawal in RA patients. SDNN indicates overall heart rate variability and encompasses both sympathetic and parasympathetic effects, whereas RMSSD primarily represents parasympathetic regulation [10]. Our observations of diminished SDNN (98.4 ± 24.6 ms compared to 142.3 ± 28.4 ms in controls) are consistent with prior research indicating lower HRV in RA patients. A meta-analysis by Adlan et al. revealed similar decreases in HRV indicators across many investigations of RA patients, substantiating autonomic dysfunction as a defining trait of the disease [11]. The increased LF/HF ratio in RA patients (2.8 ± 0.9 compared to 1.6 ± 0.5) signifies sympathetic dominance and an impaired sympathovagal equilibrium. This sympathetic overactivity may lead to cardiovascular problems via several pathways, such as increased myocardial oxygen demand, facilitation of arrhythmias, endothelial dysfunction, and prothrombotic effects [5]. The frequency-domain changes identified in our investigation, specifically the decreased HF power indicating reduced parasympathetic activity, align with the findings of Syngle et al., who showed notable autonomic dysfunction in RA patients employing same methodology [12]. Our study reveals a significant finding: the prevalence of cardiac autonomic dysfunction in RA patients is 62.5%, in contrast to 18.8% in controls, resulting in a sevenfold increased odds ratio. This prevalence exceeds that reported in several prior studies but aligns with recent research employing stringent diagnostic criteria [8]. The significant impact of autonomic dysfunction in RA patients, even without evident cardiovascular illness, indicates that autonomic evaluation could operate as an early indicator of cardiovascular risk. The notable connections between HRV measures and disease activity markers offer mechanistic insights into autonomic dysfunction in RA. The significant negative associations between the DAS28-ESR score and parasympathetic indicators (r = -0.51 for RMSSD) indicate that systemic inflammation directly influences autonomic function. Chronic elevation of pro-inflammatory cytokines, including tumor necrosis factor-alpha and interleukin-6, can influence autonomic centers within the central nervous system and peripheral autonomic nerve function. Moreover, inflammatory mediators exacerbate endothelial dysfunction, which may hinder baroreceptor sensitivity and autonomic cardiovascular regulation.[13] The duration of the disease exhibited substantial inverse associations with HRV values, signifying a steady decline in autonomic function over time. This temporal association indicates the cumulative impact of chronic inflammation on autonomic structures and underscores the necessity of early illness management to potentially maintain autonomic function.[14] The association between inflammatory markers (ESR, CRP) and autonomic dysfunction reinforces the inflammation-autonomic dysfunction axis in the pathogenesis of rheumatoid arthritis (RA) [15]. Our findings possess significant clinical ramifications. The proven correlation between reduced HRV and adverse cardiovascular outcomes across diverse populations suggests that autonomic dysfunction may partially account for the increased cardiovascular mortality in people with RA. Regular HRV evaluation may function as a non-invasive instrument for cardiovascular risk stratification in RA, augmenting conventional risk assessments.[16]. Moreover, stringent management of disease activity may enhance joint results, safeguard autonomic function, and diminish cardiovascular risk.[17] The parasympathetic withdrawal noted in our RA patients has therapeutic implications. Recent evidence indicates that vagal nerve activation and cholinergic anti-inflammatory pathways may regulate immunological responses [18]. Comprehending autonomic dysfunction in rheumatoid arthritis may unveil novel therapeutic strategies aimed at addressing both disease activity and cardiovascular complications. [19,20] This study has several flaws that require attention. The cross-sectional approach prohibits causal inferences and the evaluation of temporal relationships. Longitudinal studies are essential to assess temporal variations in autonomic function and their correlation with cardiovascular events. Despite excluding patients with established cardiovascular illness and drugs influencing heart rate, subclinical cardiovascular disease cannot be entirely ruled out. Furthermore, although we evaluated disease activity by DAS28-ESR, other aspects of the disease, such as radiographic progression, were not investigated. Future research should integrate comprehensive cardiovascular imaging and extended follow-up to evaluate the prognostic significance of autonomic dysfunction.

This study reveals significant cardiac autonomic dysfunction in patients with RA, marked by reduced heart rate variability, parasympathetic withdrawal, and sympathetic dominance. The incidence of autonomic dysfunction is significantly greater in RA patients than in healthy individuals. The activity and duration of disease are significant factors influencing autonomic dysfunction, indicating inflammatory processes in autonomic cardiovascular dysregulation. These findings underscore the necessity for an extensive cardiovascular risk evaluation in the management of RA, encompassing the assessment of autonomic function. Heart rate variability analysis may function as an effective non-invasive method for the early detection of cardiovascular risk in this population. Future research should concentrate on the longitudinal evaluation of autonomic function, its predictive significance for cardiovascular events, and the possible advantages of targeted therapies aimed at preserving autonomic integrity and reduce cardiovascular morbidity in rheumatoid arthritis.

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