Heart Rate Variability in Patients of Ankylosing Spondylitis: A Systematic Review and Meta-Analysis

Patients with ankylosing spondylitis (AS) have a significantly higher risk of cardiovascular morbidities. The participation of the autonomic nervous system (ANS) in AS is still unknown and inconclusive. Heart rate variability (HRV) is defined as the variability of the time interval between two consecutive heartbeats. This meta-analysis aims to detect the association of HRV and its various parameters with AS patients by comparing them to healthy controls. Research literature was searched in PubMed, Embase, and Cochrane Library databases from inception to April 2022. The Review Manager 5 (RevMan) Version 5.4 software was used to analyze the data. In addition, the protocol of systematic review is registered in the PROSPERO database with ID CRD42022336484. This study includes a total of nine case-control studies with a total of 923 patients; 409 with AS and 514 healthy controls. The root mean square of successive differences between normal heartbeats (RMSSD) [standardized mean difference (SMD); -0.47, 95% CI: -0.69 to -0.25, p < 0.0001], proportion of NN50 (pNN50) (SMD; -0.89, 95% CI: -1.74 to -0.04, p = 0.04) and HRV (SMD; -1.11, 95% CI: -1.53 to 0.69, P < 0.00001) were significantly low in AS cases compared to healthy controls. The HRV value was also significantly low in patients with high Bath ankylosing spondylitis disease activity (BASDAI) index (SMD: -1.45, 95% CI: -2.45 to -0.36, p < 0.009). HRV (parasympathetic activity) was significantly lowered in AS patients compared to healthy controls.


Introduction And Background
Ankylosing spondylitis (AS) is a chronic autoimmune inflammatory disorder of the axial skeleton that mainly affects spinal joints, sacroiliac joints, and adjacent tendons and ligaments [1].It clinically manifests as back pain, progressive stiffness of the spine, peripheral arthritis, and enthesopathy [2].AS tends to develop more in young adults and occurs twice more often in males than females [3].Cardiovascular morbidity and mortality are increased in AS patients, mainly due to the presence of chronic inflammation [4,5].Diseases of the aortic root are the known cardiac complication of AS.At the same time, fibrosis-related conduction defects, arrhythmia, and left ventricular diastolic function abnormalities are rare complications of AS [6][7][8].Furthermore, many studies reported that patients with AS were significantly associated with an increased risk of cardiovascular mortality [9,10] and many non-atherosclerotic cardiovascular morbidities [11].
Heart rate variability (HRV) is defined as the variability of the time interval between two consecutive heartbeats [12].The more significant the difference in HRV, the greater the parasympathetic activity of the heart.A high HRV indicates that a person can continuously adapt to the microenvironment variations [13].Consequently, a low HRV is associated with an increased risk of cardiovascular disease [14].
HRV was found to be lower in AS patients, and their values were negatively correlated with the blood level of C-reactive protein (CRP) and the score of Bath ankylosing spondylitis disease activity index (BASDAI) [15,16].However, the non-significant result of HRV has also been reported in AS patients [17].Thus, various studies reported inconclusive and conflicting results between AS and the autonomic nervous system [15,16,18].Furthermore, the relationship between autonomic dysfunction and clinical characteristics, CRP, erythrocyte sedimentation rate (ESR), HLA B-27, and activity score of AS have not been explained comprehensively.
The autonomic nervous system (ANS) is vital in regulating cardiac functions.Several rheumatologic diseases, including AS, are characterized by the involvement of the central nervous system (CNS), peripheral nervous system (PNS), as well as autonomic nervous system (ANS) [19][20][21][22].The involvement of the ANS has been evaluated earlier in AS by HRV and cardiovascular reflex tests.However, the role of the ANS in AS is still not fully understood, and results are inconclusive [23].All parameters of HRV are influenced by the ANS and are primarily controlled by the PNS [24].It is challenging to diagnose cardiac involvement in patients with AS because of aortic incompetence and bradycardia [25].Even though standard cardiovascular reflex testing remains the gold standard [26], measuring HRV is the most reliable, simple, painless, repetitive, and non-invasive method of detecting autonomic cardiac dysfunction or autonomic neuropathy of the heart [27,28].This meta-analysis aims to detect the association of HRV and its various parameters with the AS by comparing them to healthy controls.

Literature Search
We summarized all published studies that measured HRV in patients of AS and healthy controls.The research literature was searched in databases such as PubMed, Embase, and Cochrane Library, using the following MeSH keywords of the English language: 'Ankylosing Spondylitis' and ('Heart Rate Variability or 'HRV') from inception to August 2022 (see Supplementary Table in the Appendix).Furthermore, the reference lists of all publications were searched manually to incorporate any additional studies that were not identified through the preliminary literature search.This study included observational case-control studies that measured HRV in patients with AS and healthy controls as a primary objective.In addition, studies that measured any non-linear HRV parameters or frequency and HRV times to assess autonomic cardiac regulation in AS patients were also included.The protocol of systematic review is registered in the PROSPERO database with ID CRD42022336484.The systematic review was performed as per the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) statement [29].

Ethical Considerations
Ethical approval was not taken for this study because the data used in this study has already been published, and there was no direct engagement of patients.

Extraction of Data
One author (SD) was involved in the literature search, article collection, and data extraction.Next, two authors (GS and RS) independently revised the abstracts and determined whether the article met the inclusion criteria for systematic review.When agreement on appropriateness could not be obtained, the disputed articles were reviewed by the other authors (DP and VC).All of the authors then reviewed the eligible articles.Finally, the following data were extracted from the selected articles: name of the authors, publication year, place of the study, sample size, and various parameters of the HRV and their association or correlation with other clinical and biochemical variables.

Assessment of the Quality
The quality assessment was performed according to the modified form of the Newcastle Ottawa Scale [30].This scale includes three assessment domains: the selection of participants, comparability, and outcome procedures utilized in the included observational studies.Further, domains contain six subdomains, each receiving a score of one.Results with lower scores of ≤ 3 were interpreted as having a more significant potential for bias [31].

Parameters of HRV and Heart Rate Turbulence
HRV parameters measured in both the time domain and spectral domain were included in this study (Table 1).The following parameters were mainly reviewed in the time domain: RR intervals, root mean square of successive differences between normal heartbeats (RMSSD), standard deviations of the RR intervals (SDNN), and the percentage of adjacent NN intervals differ by more than 50 milliseconds (pNN50).SDNN is associated with low-frequency (LF) power, whereas pNN50 and RMSSD are related to high-frequency (HF) power, hence with parasympathetic activity.The following parameters were reviewed in the spectral domain: very low frequency (VLF; 0.003 to 0.04 Hz), Low Frequency (LF: 0.04 to 0.15 Hz), High Frequency (HF: 0.15 to 0.4 Hz), and LF/HF ratio.VLF reflects an alteration in renin-angiotensin system activity, the mechanism of thermoregulation, and the function of peripheral chemo-receptors.Furthermore, LF indicates the activity of both sympathetic and parasympathetic activity; HF indicates the parasympathetic activity of the Sinoatrial (SA) node, and LF/HF ratio represents the sympathovagal balance [32][33][34].Heart rate turbulence (HRT) which includes turbulence onset (TO) and turbulence slope (TS), is also used to assess heart rate variability [35].

Data Synthesis and Statistical Analysis
This study was conducted to determine the HRV difference between AS cases and healthy controls.HRV parameters were reported in mean and standard deviation.The HRV parameters mentioned as the median and interquartile ranges were changed to their respective mean and standard deviation [36].The standard mean differences (SMDs) with 95% confidence intervals were used to assess effect size in continuous data.
The I2 statistic was used to calculate the extent of the inconsistency.The I2 values of 25%, 25-50%, and >50% were considered low, moderate, and a high degree of heterogeneity, respectively.In the absence of statistical heterogeneity, a fixed-effect model was employed.In contrast, a random-effect model was applied in the existence of statistical heterogeneity (defined by an I2 value > 50% or a chi-square p-value of < 0.05) [37].As the number of selected studies was less than 10, a funnel plot to evaluate publication bias was not included.The Review Manager 5 (RevMan) version 5.4 software was used to evaluate all observed data [38].

Results
We primarily retrieved a total of thirty-nine studies from various databases.Finally, after excluding duplicates, case reports, letter to editors and case series, we included nine observational case-control studies for this systematic review and meta-analysis to reach a conclusion.Figure 1 represents the flow of the PRISMA-recommended process [29] for selecting the eligible studies.A total of 923 participants were examined from the selected nine observational case-control studies that compared HRV parameters analysis in AS cases and healthy controls.Most of the included studies reported a low risk of bias (none of the studies reported a score of ≤ 3) according to the modified NOS scale, as shown in Table 2. Table 3 depicts the included studies with their place, sample size, method of HRV assessment, and main results or outcomes.The baseline characteristics of the included studies and the value of measured HRV parameters are shown in Table 4 and Table 5, respectively [16][17][18]23,25,[39][40][41][42].The methods used for HRV analysis and included HRV parameters were different among the included studies.In qualitative analysis, most studies have reported an overall decrease in measured HRV parameters except LF/HF ratio, which was elevated in AS [17,18,39].Studies that measured similar HRV parameters were further included in the meta-analysis to derive the final outcome [16][17][18]23,25,[40][41][42].

Discussion
According to our knowledge and various database searches, this is the first meta-analysis to evaluate HRV parameters in AS patients compared to healthy controls.We observed an overall decrease in HRV parameters in patients with AS compared to healthy controls, revealing the consequence of AS on the cardiovascular system by affecting ANS.It was found that ANS dysfunction in patients with AS is predominantly associated with PNS, and this dysfunction was associated with the severity or activity of AS [16,41].We reported high heterogeneity across the included observational studies during the meta-analysis of HRV parameters.Hence, we measured SMD in a random-effect model for the studies with a heterogeneity of >50.0% during assessing specific HRV parameters.
The most commonly evaluated parameters were SDNN, RMSSD, pNN50, LF, HF, LF/HF ratio, and HRV value in the included studies.We found significant low value of RMSSD in AS patients compared to healthy controls (SMD: -0.47, 95% CI: -0.69 to 0.25, Z = 4.15, p < 0.0001).RMSSD is the main time domain that indicates beta-to-beat difference and is found to be associated with heart rhythm by affecting vagal nerve changes.Furthermore, the PNS significantly impacts the RMSSD compared to the SDNN [12].Similarly, pNN50 was reported low in AS patients compared to healthy control in this meta-analysis (SMD: -0.89, 95% CI: -1.74 to -0.04, Z = 2.06, p < 0.04).The pNN50 also indicated PNS activity, and its value was correlated with HF and SDNN [12].In addition, the HRV value was also significantly low in AS patients compared to healthy controls (SMD: -1.11, 95% CI: -1.53 to -0.69, Z = 5.20, p < 0.00001).Thus, reduced RMSSD, pNN50, and HRV values suggest that AS might cause a significant decrease in parasympathetic activity or vagal regulation of the heart rate.
But, the LF/HF ratio was elevated in patients with AS compared to controls (SMD: 0.15, 95% CI: -0.45 to 0.74).It might be due to the alteration of the sympathetic system in response to sympathovagal balance [18].The low HRV was significantly associated with the AS patients with high BASDAI scores (SMD: -1.45, 95% CI: -2.45 to -0.36, Z = 2.83, p < 0.009).It suggests the association of parasympathetic dysfunction with the severity and active course of the AS.Most of the included studies have not reported a significant association of HRV parameters according to age and gender distribution.Hence, subgroup analysis of HRV concerning age and gender distribution was not performed.Similarly, subgroup analysis of HRV with CRP, erythrocyte sedimentation rate, and disease duration was not conducted due to the unavailability of required data in the included studies.
The impairment of the ANS in AS supports the hypothesis that an excessive inflammatory response is generated in many inflammatory disorders and autoimmune disorders due to the disturbance of the cholinergic pathway for anti-inflammation.This ANS impairment was mainly attributed to subsequent consequences of inflamed nerves resulting in inhibited nerve conduction [43,44].In support of this view, various studies have reported deranged autonomic functions in diseases like rheumatoid arthritis, Behcet, lupus, and other inflammatory diseases, including Crohn's disease [45,46].Another possible explanation for deranged autonomic functions can be explained by the theory of cytokines, where it is suggested that overproduction and expression of various cytokines in autoimmune diseases, including ankylosing spondylitis, may lead to changes in HRV [47,48].Furthermore, the systematic inflammation in AS seriously influences the autonomic regulation of cardiac function and decreases parasympathetic activity.Therefore, subnormal HRV parameters might contribute to the development of cardiovascular disease in AS.

Limitations and future perspectives
Firstly, one of the most important limitations is that different techniques or modalities were used to measure HRV parameters.Secondly, the cross-sectional design of the included studies with limited patients is the main limitation of this study.Due to the lack of prospective design, altered HRV parameters could not determine the actual prognostic significance.In addition, the limited sample size of study participants, duration and activity of AS, position of patients, and time of assessment may affect the values of HRV parameters.
The RMSSD and pNN50 accurately identify the parasympathetic activity and also correlate the survival in the presence of cardiac insufficiency.Considering the prognostic relevance of HRV, individuals with AS should be actively monitored for unfavorable cardiovascular events by conducting the prospective study.HRV should be recorded as per the guidelines laid down by the Task Force of The European Society of Cardiology and The North American Society of Pacing and Electrophysiology [49].
The Next-generation HRV (Next-gen HRV) integrates the parasympathetic, sympathetic, and output of Bayevsky's tension index [50].Next-gen HRV or immune autonomics could provide a novel approach to combat how the ANS stress level seems to exaggerate AS and possibly other autoimmune disorders.Next-gen HRV records ECG at a frequency of 8000 Hz, which minimizes inaccuracy in heartbeat separation and estimates the time across beats.Thus, HRV has progressed in hardware, software, and implementations to provide a dramatic transformation in integrating ANS stress response as a crucial personalized, new therapeutic component to deliver superior treatment for AS and other rheumatic disorders.

Conclusions
HRV parameters were significantly disturbed in the patients of AS, indicating impairment of the cardiac autonomic nervous system.This meta-analysis stated that there is considerable evidence for an overall decrease in HRV in patients of AS.Therefore, HRV analysis can be used as a non-invasive tool to access and monitor disease activity or severity in patients of AS.

Additional Information
no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work.Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.
, the calculated mean of the 5minute SD of NN intervals Measurement of variability because of a short cycle of less than 5 minutes VLF (ms)2  Very low-frequency power, 0.003 to 0.04 Hz Indicates an activity of renin-angiotensin system activity, the mechanism of thermoregulation, and the function of peripheral chemo-receptors LF (ms) 2 Low-frequency power, 0.04 to 0.15 Hz Indicates parasympathetic and sympathetic activity and baroreceptors functioning LF (nU) Normalized low-frequency power Indicates sympathetic activity HF (ms) 2 High-frequency power, 0.15 to 0.4 Hz Indicates parasympathetic activity and heart rate changes due to respiratory sinus arrhythmia HF (nU) Normalized high-frequency power Indicates parasympathetic activity LF/HF ratio The ratio of low-frequency to highin the two normal NN intervals following a premature ventricular contraction Indicates acceleration of sinus rhythm after premature ventricular contraction

FIGURE 1 :
FIGURE 1: The flow chart of the PRISMA-recommended process for selecting research literature in the systematic review.

TABLE 1 : Definition and importance of various parameters of HRV, electrocardiogram, and heart rate turbulence
NN -Normal RR intervals

TABLE 2 : Assessment of risk of bias by modified Newcastle-Ottawa scale
0 = No, 1 = Yes.Total score of less than or equal to 3 is a high risk of bias.AS -Ankylosing Spondylitis; HRV -Heart Rate Variability 2024 Sharma et al.Cureus 16(1): e51717.DOI 10.7759/cureus.51717Author

of study Place of study Sample size Method of assessment of HRV parameter Observation and results
of R-R interval and heart rate response to standing were significantly low in cases of AS compared to controls.HRV parameters were significantly correlated with CRP and BASDAI index.
Decreased LF, VLF, HF, SDNN, RMSSD, SDANN, and pNN50.Increased TS and TO in cases of AS compared to controls.Holter parameters were negatively correlated with the duration of AS.

TABLE 3 : Method of HRV assessment, observation, and main results of the included studies
AS -Ankylosing Spondylitis; BASDAI -Bath Ankylosing Spondylitis Disease Activity Index; CRP -C-Reactive Protein; ECG -Electrocardiography; ESR -Erythrocyte Sedimentation Rate; HF -High Frequency; HRV -Heart Rate Variability; LF -Low Frequency; pNN50 -the division of the number of interval differences of successive NN intervals of more than 50 ms by the total number of NN intervals; RMSSD -Root mean square of successive differences between normal heartbeats; SDANN -Average standard deviation of the averages of all normal-to-normal R-R intervals; SDNN -Standard deviation of the normal-to-normal (NN) interval; SDSD -Standard deviation of successive RR interval differences.2024Sharma et al.Cureus 16(1): e51717.DOI 10.7759/cureus.51717

TABLE 5 : Values of different parameters of HRV in AS cases and healthy controls
LF -Low Frequency; HRV -Heart Rate Variability; HF -High Frequency; pNN50 -percentage of beats in which the change in successive normal sinus (NN) intervals exceeds 50 ms; SDNN -Standard deviation of the normal-to-normal (NN) interval; RMSSD -Root mean square of successive differences between normal heartbeats.