Baroreflex-dependent Cardiovascular Autonomic Reactivity is Deranged in Young Adult Mild COVID-19 Survivors

Abstract

Background

COVID-19 has subacute as well as long-term effects defined as long COVID on multiple organ systems. Emerging literature suggests long-term effects of COVID-19 on the autonomic nervous system in survivors, the mechanistic basis of which is currently not delineated.

Purpose

The study aimed to assess the cardiovascular autonomic functions in mild COVID-19 survivors and compare them with age- and sex-matched healthy controls.

Methods

We recruited 34 young adult mild COVID-19 survivors. Autonomic function was assessed by cardiovascular autonomic reactivity tests at least 1 month after clinical recovery from acute COVID-19 infection. The responses were compared with those of 34 age- and sex-matched pre-COVID era healthy controls.

Results

Mild COVID-19 survivors had significantly lower Valsalva ratio (1.578 ± 0.2747 vs 1.773 ± 0.3459; p = .0156) and displayed a greater fall in systolic blood pressure during head-up tilt test (−9.206 ± 7.121 vs 1.147 ± 8.457; p < .0001) in comparison to the healthy controls. Haemodynamic cardiovascular autonomic abnormalities were seen in 47% of COVID-19 survivors. Haemodynamic criteria of orthostatic hypotension were met in 12% of COVID-19 survivors, and postural orthostatic tachycardia syndrome haemodynamic criteria were met in 35% of COVID-19 survivors. Autonomic reflex responses to deep breathing, handgrip test and cold pressor test were found to be comparable between the two groups.

Conclusion

Young adult mild COVID-19 survivors show lower cardiovagal and cardiovascular adrenergic responses to baroreflex-dependent autonomic reactivity as medium- to long-term autonomic sequelae. They have an intact non-baroreflex-dependent autonomic reactivity.

Introduction

COVID-19 has subacute as well as long-term effects defined as long COVID on multiple organ systems. Long COVID is defined as symptoms and/or delayed or long-term effects of SARS-CoV-2 infection beyond 4 weeks of SARS-CoV-2 infection. ¹ It is further divided into two categories: subacute or ongoing symptomatic COVID-19, which includes symptoms and abnormalities present 4–12 weeks after acute COVID-19, and chronic or post-COVID-19 syndrome, which includes symptoms and abnormalities persisting or present beyond 12 weeks after the onset of COVID-19 and are not attributable to an alternative diagnosis.^{2, 3}

Many COVID-19 survivors present with fatigue, arrhythmia, labile blood pressure (BP), orthostatic symptoms like headache and palpitations during standing, which are symptoms of autonomic nervous system dysfunction. Previous case reports and case series have reported postural orthostatic tachycardia syndrome (POTS) as the most common presentation of autonomic dysfunction in COVID-19 survivors. Orthostatic hypotension (OH) has also been reported in COVID-19 survivors.^4–6

Studies on COVID-19 survivors with autonomic function evaluation with the help of complete standard cardiovascular autonomic reactivity tests (CART) to evaluate cardiovagal function and cardiovascular adrenergic function are limited.^{7, 8} Shouman et al. investigated autonomic function in 27 individuals who had recovered from COVID-19 and found that the majority exhibited abnormalities, including orthostatic intolerance and POTS. However, the study lacked a control group of healthy individuals for comparison, and the severity of acute COVID-19 illness among participants was not reported. 51.5% of severe and 78% of mild COVID-19 survivors exhibited autonomic dysfunction, according to another study by Milovanovic et al. on COVID-19 survivors where investigators compared survivors’ and controls’ percentages of abnormal CART results, such as abnormal BP or heart rate changes. In their study, most (60%) of the survivors were of severe COVID-19, and only 40% were of mild COVID-19. There are no reports currently available comparing the responses to CART in young adult mild COVID-19 survivors with controls. Also, the mechanistic basis of abnormal autonomic function is currently not delineated.

In our study, we aimed to evaluate autonomic functions in young adult mild COVID-19 survivors using standard CART (head-up tilt test [HUT], deep breathing test [DBT], Valsalva manoeuvre [VM], handgrip test [HGT] and cold pressor test [CPT]) and compared with age- and sex-matched historical control data from the pre-pandemic time. We also assessed the prevalence of haemodynamic cardiovascular autonomic abnormalities (CAA) in young adult mild COVID-19 survivors.

Methods

Patients

The study was an observational cross-sectional study on 34 young adult mild COVID-19 survivors conducted in the Autonomic Function Laboratory. The study procedures were approved (ref. no. IECPG-743/23.12.2021, RT-27/27.01.2022) by the institute’s ethics committee for research on human subjects, and the study was performed in compliance with the Declaration of Helsinki, 1964 and its later amendments. Informed consent was obtained from all participants included in the study.

COVID-19 survivors were included in the study who were clinically stable for at least 4 weeks post-recovery from the acute phase of reverse transcription-polymerase chain reaction (RT-PCR)-positive mild COVID-19. COVID-19 survivors with resting oxygen saturation less than 93%, requirement for oxygen supplementation, history of cardiovascular or neurological disorders, chronic kidney disease, collagen vascular diseases, type 1/2 diabetes mellitus and history of postural giddiness or palpitations, syncopal attacks or resting palpitations anytime during the 6-month period before the diagnosis of COVID-19 were excluded. Age- (±5 years) and sex-matched healthy volunteers who had undergone the assessment of cardiovascular autonomic functions at the Autonomic Function Laboratory at AIIMS, New Delhi before November 2019 were included as the control group. It was ensured that the historical controls and COVID-19 survivors were recorded using identical equipment and analysed using the same protocol.

Study Protocol

All participants were subjected to CART. Subjects were asked to visit the Autonomic Function Laboratory to evaluate autonomic functions, where they were made to lie down and rest for 15 min to allow cardiovascular parameters to come to baseline. Electrocardiogram (ECG) electrodes were then placed in Lead II configuration, and a finger cuff was applied for non-invasive beat-to-beat BP recording using Finometer MIDI^®. The ECG was recorded using a Bio Amp module connected to a Power Lab 4/26T system (AD Instruments, Australia). ECG waveform was acquired and analysed using the LabChart Pro 8.0™ software. Beat-to-beat BP was recorded using the finger photoplethysmographic technique using Finometer™ (Finometer MIDI^® Finapres Medical Systems, Amsterdam, The Netherlands), which operates on the principle of volume clamp.

Acquisition of ECG and non-invasive beat-to-beat BP recording was continued throughout the course of the tests. After 15 min of supine rest, HUT, DBT, VM, HGT and CPT were done in the stated order with an interval of 5 min of recovery time between consecutive tests (Figure 1).

Figure 1. Schematic Representation of the Sequence of the Administration of Various Tests.

Cardiovascular Autonomic Reactivity Tests

It included the assessment of cardiovagal function and cardiovascular adrenergic function. Cardiovagal function was assessed in the study by heart rate responses to VM and deep breathing. Cardiovascular adrenergic function was assessed in the study by BP responses to HUT, VM, HGT and CPT.^{9, 10}

Head-up Tilt Test

In the lying down position, subjects were fastened to the table using straps for support, and the table was tilted from 0° to 70° (within a time span of 15–20 s) and was tilted back after 5 min. ECG and BP were recorded continuously throughout the test. Parameters quantified were changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP) in response to the test. ¹⁰ BP responses are measures of cardiovascular adrenergic function. ¹¹

Assessment of Haemodynamic Cardiovascular Autonomic Abnormalities

CAA haemodynamic criteria were assessed from BP and heart rate changes during HUT. Haemodynamic criteria of OH (OH₂₀) are defined by a drop in BP of at least 20 mmHg for SBP and/or at least 10 mmHg for DBP within 3 min of upright posture. Haemodynamic criteria of POTS (POTS_HR) are defined by an increase in heart rate of ≥30 beats per minute (bpm) within 10 min following an upright posture and in the absence of OH (BP fall ≥20/10 mmHg). ¹²

Deep Breathing Test

In a sitting posture, a respiratory belt transducer was placed around the subject’s chest to record respiratory movements with Lead II ECG. Subjects were asked to breathe smoothly and deeply with 5 s of inspiration and 5 s of expiration in each cycle, at 6 cycles per minute. Parameters quantified were change in heart rate, which is the difference in the peak heart rate during inspiration and the lowest heart rate during expiration averaged over 6 cycles, and expiration-to-inspiration ratio (E:I), which is the ratio of the peak RR interval during expiration to the lowest RR interval during inspiration averaged over 6 cycles. ¹⁰ Both parameters are measures of cardiovagal function. ¹¹

Valsalva Manoeuvre

In a sitting position, subjects were asked to blow into a 10 mL syringe barrel (needle and syringe plunger removed from syringe barrel) connected to a pressure transducer and maintain the pressure at 40 mmHg for 15 s. ¹⁰ Pressure on the transducer, Lead II ECG and continuous non-invasive beat-to-beat BP were acquired during the course of the test. Parameters quantified were Valsalva ratio, which is the longest RR interval during phase IV/shortest RR interval during phase II (a measure of cardiovagal function), and the BP responses during VM (a measure of cardiovascular adrenergic function). ¹¹

Handgrip Test

In a sitting position, the subject was briefed about the test and was shown the procedure to use the grip force transducer. After the instructions, the subjects were told to voluntarily apply grip force maximally for a few seconds with their dominant hand. The value was noted down, and the procedure was repeated three times. Their maximal voluntary contraction (MVC) was noted by taking the maximum value of the three readings. The subject was then instructed that they would have to keep a sustained pressure on the grip force transducer for 4 min at 30% of MVC. The real-time grip force values were displayed on the computer screen to guide the subject. BP was continuously acquired using a non-invasive beat-to-beat BP monitor during the conduct of the test and until 2 min after the cessation of the test. ¹⁰ The parameter quantified was an increase in DBP, which is a measure of cardiovascular adrenergic function.^{9, 10}

Cold Pressor Test

In a sitting position, the subject was briefed about the test. Cold water at 10 °C was prepared in an insulated container and was placed on the couch where the subject was seated (at the Autonomic Function Laboratory, cold water at 10 °C is used for administering CPT). ¹³ The subject subsequently dipped the hand up to the wrist in water for 1 min with fingers spread out. After removing the hand from the water, it was covered by a towel. Beat-to-beat BP was continuously acquired during the course of the test and until 4 min after the removal of the hand from the water. ¹⁴ The parameter quantified was an increase in DBP, which is a measure of cardiovascular adrenergic function. ¹¹

Cardiovagal Index and Adrenergic Index

The cardiovagal index and adrenergic index were calculated based on the recent consensus guidelines provided by the American Autonomic Society, the American Academy of Neurology and the International Federation of Clinical Neurophysiology. ¹¹ Cardiovagal index was calculated from analysing heart rate responses to VM and deep breathing. BP responses to HUT and BP responses, pressure recovery time (PRT) and absence or presence of phase IV and/or late phase II (Phase II_L) during VM were analysed to quantify the adrenergic index (Figure 2).

Figure 2. Blood Pressure (BP) and Heart Rate Changes During Valsalva Manoeuvre (VM).

Statistical Analysis

Data of each outcome variable were tested for normality of distribution using the D’Agostino–Pearson test. Summary statistics of normally distributed outcome variables are expressed as mean ± standard deviation (SD) and for those not normally distributed as median (25th percentile–75th percentile). Quantitative variables and calculated indices of autonomic reactivity were compared between the two groups using an unpaired t-test or its non-parametric variant as appropriate. p < .05 was considered statistically significant. All statistical analyses were performed using GraphPad Prism version 8.0.2 (GraphPad Software, San Diego, USA).

Results

The study was done on 34 young adult mild COVID-19 survivors. The demographic profile and baseline characteristics of COVID-19 survivors and healthy controls are shown in Table 1 and Figure 3. The age of the COVID-19 survivors and healthy controls was comparable, and both groups consisted of 16 males and 18 females. All COVID-19 survivors were young adults with a median age of 27 years (24.75–28). None of the COVID-19 survivors included in the study had symptoms at the time of assessment. The SBP and pulse pressure were significantly higher in COVID-19 survivors (p = .0297 for SBP and p < .0001 for pulse pressure) in comparison to healthy controls. The resting heart rate and DBP were not significantly different between COVID-19 survivors and healthy controls.

Table 1. Demographic Profile and Baseline Characteristics of COVID-19 Survivors and Healthy Controls.

Parameter	Healthy Controls	COVID-19 Survivors	p Value
Age (years)	27 (25–28.25)	27 (24.75–28)	.9779
Sex (male:female)	(16:18)	(16:18)
Time interval between COVID-19 diagnosis and autonomic assessment (weeks)	–	65 (29–103)
Severity of COVID-19	–	Mild
Resting heart rate (beats per minute)	71.03 ± 10.31	72.03 ± 9.27	.6755
Systolic blood pressure (mmHg)	110.60 ± 11.15	116.80 ± 11.55	.0297*
Diastolic blood pressure (mmHg)	71.91 ± 7.96	69.59 ± 7.44	.2183
Pulse pressure (mmHg)	38.74 ± 8.01	47.18 ± 8.41	<.0001*

Notes: Values are expressed as mean ± standard deviation for normally distributed data and median (25th percentile–75th percentile) for non-normally distributed data. *Statistically significant (if p < .05).

Figure 3. Baseline Characteristics of the COVID-19 Survivors and Healthy Controls. (a) Resting Heart Rate in Beats Per Minute (bpm), (b) Systolic Blood Pressure (SBP), (c) Diastolic Blood Pressure (DBP), (d) Pulse Pressure.

Notes: ns: Not significant. Statistically significant if p < .05.

Cardiovagal Function

The results of heart rate responses to deep breathing and VM, reflecting the cardiovagal function, are shown in Table 2 and Figure 4. Heart rate responses to deep breathing (delta heart rate) and E:I ratio were not significantly different between the COVID-19 survivors and the controls. Valsalva ratio was found to be significantly lower in the COVID-19 survivors (p = .0156) in comparison to the controls.

Table 2. Comparison of Cardiovagal and Cardiovascular Adrenergic Function Between COVID-19 Survivors and Healthy Controls.

Parameter	Healthy Controls	COVID-19 Survivors	p Value
Heart Rate Response to Deep Breathing
Delta heart rate (beats per minute)	27.76 ± 7.75	28.29 ± 8.30	.7867
Expiration to inspiration ratio (E:I)	1.43 ± 0.13	1.45 ± 0.18	.5643
Heart Rate Response to Valsalva Manoeuvre
Valsalva ratio	1.77 ± 0.34	1.57 ± 0.27	.0156*
Diastolic blood pressure response to handgrip test (mmHg)	13.50 (12–23.50)	18 (10.25–24.50)	.7868
Diastolic blood pressure response to cold pressor test (mmHg)	15.88 ± 5.64	16.77 ± 10.59	.7052
Systolic blood pressure response to head-up tilt test (mmHg)	1.147 ± 8.457	−9.206 ± 7.121	<.0001*

Notes: Values are expressed as mean ± standard deviation for normally distributed data and median (25th percentile–75th percentile) for non-normally distributed data. *Statistically significant (if p < .05).

Figure 4. Comparison of Cardiovagal and Cardiovascular Adrenergic Function Between COVID-19 Survivors and Healthy Controls. (a) Heart Rate (in Beats Per Minute [bpm]) Changes to Deep Breathing Test (DBT), (b) Expiration to Inspiration Ratio (E:I), (c) Valsalva Ratio, (d) Diastolic Blood Pressure (DBP) Response to Handgrip Test (HGT), (e) Diastolic Blood Pressure (DBP) Response to Cold Pressor Test (CPT), (f) Systolic Blood Pressure (SBP) Response to Head-up Tilt (HUT) Test.

Notes: ns: Not significant. Statistically significant if p < .05.

Cardiovascular Adrenergic Function

The results of HUT, HGT and CPT, representing the cardiovascular adrenergic function, are shown in Table 2 and Figure 4. Fall in SBP during HUT was significantly greater in the COVID-19 survivors (p < .0001) than in the controls. DBP responses to HGT and CPT were not significantly different between the COVID-19 survivors and the controls.

Haemodynamic Cardiovascular Autonomic Abnormalities

Haemodynamic CAA was seen in 47% (16 out of 34) of COVID-19 survivors. Among them, OH₂₀ was present in 12% (4 out of 34) of COVID-19 survivors, and POTS_HR was present in 35% (12 out of 34) of COVID-19 survivors.

Cardiovagal Index and Adrenergic Index

The cardiovagal index was found to be abnormal in 12% (4 out of 34) of COVID-19 survivors (Table 3). The adrenergic index was found to be abnormal in 6% (2 out of 34) of COVID-19 survivors (Table 3).

Table 3. Cardiovagal and Adrenergic Index of COVID-19 Survivors.

	n (%)
Cardiovagal Index
0	30 (88%)
1	4 (12%)
2	0
3	0
Adrenergic Index
0	32 (94%)
1	2 (6%)
2	0
3	0
4	0

Notes: Values expressed as number (percentage). n: Number.

Discussion

The present study was conducted to assess the autonomic functions in young adult mild COVID-19 survivors. The assessment was comprehensively done, encompassing cardiovagal and cardiovascular adrenergic functions. We also assessed the incidence of haemodynamic CAA in young adult mild COVID-19 survivors.

Tests for cardiovagal function used in the study included VM and DBT. It was found that the values of the Valsalva ratio in COVID-19 survivors were significantly lower than those of healthy controls. However, no significant differences were observed in the heart rate response to deep breathing between COVID-19 survivors and the control group. Reduced cardiovagal function was previously reported by Shouman et al. and Milovanovic et al., both of whom found abnormal heart rate responses to DBT as well as the VM.^{7, 8} In contrast, Salem et al. found no significant differences in heart rate response to deep breathing between the COVID-19 survivors and the controls, agreeing with the findings of the present study with reference to the cardiovagal response to DBT. ¹⁵

The apparent disagreement of the present study with reference to the heart rate response to deep breathing as reported by Milovanovic et al. could be linked to the differences in the demographics, the severity of COVID-19 and the presence or absence of comorbidities. The COVID-19 survivors in the study of Milovanovic et al. were older (mean age was more than 40 years), 60% had severe COVID-19 and had comorbidities like hypertension and diabetes mellitus, whereas the present study comprised only young mild COVID-19 survivors without comorbidity. Severe COVID-19 and the presence of comorbidities may explain the abnormal heart rate response reported by Milovanovic et al. The median age of the COVID-19 survivors in the study of Shouman et al. was 30 years, similar to our study group, and both studies reported abnormal heart rate response to VM, suggesting that heart rate response to VM is more likely to be impaired in younger adults surviving COVID-19.

Salem et al. showed similar heart rate response to deep breathing between the COVID-19 survivors and the controls, agreeing with the findings of the present study. The COVID-19 survivor group in the study of Salem et al. was younger, with a mean age of 30.3 years, similar to the present study. This might indicate that the cardiovagal response to DBT is preserved in younger adults surviving COVID-19.

Tests for cardiovascular adrenergic function used in the study included HUT, HGT and CPT. In our study, we found a significantly greater fall in SBP during HUT in the COVID-19 survivors than the controls, consistent with findings by Salem et al. DBP response to HGT did not differ between groups in our study, whereas Milovanovic et al. and Salem et al. reported abnormal DBP response to HGT in a sizeable proportion of COVID-19 survivors. Hilz et al. in their study mentioned that many patients during the HGT perform a Valsalva-like straining manoeuvre, causing bias in HGT. ¹⁶ This can explain the different findings in HGT in our study from previous studies. DBP response during CPT did not differ between groups in our study, which is similar to the findings of the study by Stute et al. ¹⁷

Pathophysiological Mechanisms of OH₂₀

In our study, haemodynamic CAA were seen in 47% of COVID-19 survivors. CAA has also been reported in 73% of COVID-19 survivors in a study by Hira et al. ¹⁸ 12% of the COVID-19 survivors in our study had OH₂₀. Salem et al. reported 39.3%, and Hira et al. reported 30% of the COVID-19 survivors developing OH. OH in COVID-19 survivors can be caused by direct effects of SARS-CoV-2 on autonomic centres, immune-mediated persistent inflammation, hypoxia and renin–angiotensin system (RAS) imbalance, all of which can cause impairment in orthostatic BP control. ¹⁹

Pathophysiological Mechanisms of POTS_HR

In our study, 35% of COVID-19 survivors had POTS_HR, similar to 35% reported by Sharma et al. and 22% reported by Shouman et al. ²⁰ Several mechanisms have been proposed for POTS in COVID-19 survivors, including autoimmunity, autonomic neuropathy, hypovolaemia, deconditioning and persistent inflammation, among which autoimmunity is prominent, where autoantibodies form against A/B adrenoceptors and muscarinic acetylcholine receptors.^{19, 21}

It was found in our study that adrenergic index was abnormal in 6% of the COVID-19 survivors, the same (6%) as reported by Shouman et al. In our study, we found an abnormal cardiovagal index in 12% of COVID-19 survivors, while Shouman et al. also reported an abnormal cardiovagal index in COVID-19 survivors (27%). This pattern of cardiovagal and cardiac adrenergic dysfunction is not unique to SARS-CoV-2, as similar post-viral autonomic dysfunction has been described after other viral illnesses, including hepatitis and Epstein–Barr virus infection, supporting a shared post-viral immune-mediated pathway of autonomic dysfunction. ¹⁵

Mechanistic Explanation of the Pattern of Autonomic Dysfunction

The salient findings of the present study were significantly lower heart rate response to the VM and significantly greater fall in SBP in the COVID-19 survivors in comparison to the controls. None of the other autonomic tests revealed any significant difference between the COVID-19 survivors and the controls. The fact that the autonomic responses to the VM and HUT are baroreflex-dependent invokes the possibility that the characteristic autonomic abnormality in COVID-19 survivors could be an impaired baroreceptor reflex and the consequent impact on baroreflex-dependent autonomic reactivity. The study by Srivastava et al. corroborates this proposal as they report impaired baroreflex sensitivity in the survivors of mild COVID-19 at 3–6 months of clinical recovery. ²² This suggests that non-baroreflex-dependent autonomic reactivity is intact in mild COVID-19 survivors.

Several mechanisms have been proposed to explain this selective impairment of baroreceptor reflex. First, direct neuro-invasion: SARS-CoV-2 receptor ACE-2 and TMPRSS2 are highly expressed on afferent fibres of the vagus and the glossopharyngeal nerve, which relay signals from carotid sinus and aortic arch receptors to the brainstem; through these pathways, possibly viruses enter the nucleus tractus solitarius, causing baroreflex dysfunction.^{19, 23} Second, immune-mediated injury: SARS-CoV-2 can cause an exaggerated inflammatory response in COVID-19 survivors with high levels of cytokine release like tumour necrosis factor (TNF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-12 (IL-12) and interferon (IFN). These cytokines may sensitise or injure baroreceptor afferents and brainstem autonomic centres independently of direct viral invasion. ²⁴ Third, autoimmunity: autoantibodies directed against adrenergic and muscarinic receptors are detected in COVID-19 survivors and can affect both afferent baroreceptor signalling and efferent sympathetic or parasympathetic outflow. Fourth, RAS imbalance: SARS-CoV-2 binding downregulates ACE-2 receptors, shifting RAS towards the pro-inflammatory state, which can further destabilise baroreceptor reflex. These mechanisms—direct neuro-invasion, immune-inflammatory injury, autoimmunity and RAS dysregulation may act individually or in combination to cause baroreceptor reflex dysfunction while sparing autonomic pathways that do not depend on the baroreceptor reflex arc. ¹⁹

The major strength of the present study is that we have performed a comprehensive evaluation of cardiovagal and cardiovascular adrenergic functions along with assessment of haemodynamic CAA. Unlike most of the previous studies, our COVID-19 survivor group was free of comorbidities that could independently influence autonomic functions. Additionally, we included a historical control group to ensure that COVID-19 had no influence on our age- and sex-matched control data. We found autonomic dysfunction even in COVID-19 survivors with no symptoms at the time of assessment, whereas most of the studies found autonomic dysfunction in COVID-19 survivors with symptoms at the time of assessment.^{7, 18}

The wide variation in the interval between the time of COVID-19 diagnosis and autonomic assessment in the present study is one limitation which might have induced variability in the outcome variables at the time point of assessment. The second limitation is the absence of detailed documentation of prior viral infections in the control group, which could potentially influence autonomic function. The third limitation is that during HUT, tilt was done for 5 min instead of 10 min, therefore we may have missed some POTS.

Conclusion

Young adult mild COVID-19 survivors show lower cardiovagal and cardiovascular adrenergic responses to baroreflex-dependent autonomic reactivity tests in comparison to age- and sex-matched healthy controls. Young adult mild COVID-19 survivors have an intact non-baroreflex-dependent autonomic reactivity.

Abbreviations

CAA: Cardiovascular autonomic abnormalities; CART: Cardiovascular autonomic reactivity tests; CPT: Cold pressor test; DBT: Deep breathing test; E:I: Expiration to inspiration ratio; HGT: Handgrip test; HUT: Head-up tilt; OH: Orthostatic hypotension; POTS: Postural orthostatic tachycardia syndrome; PRT: Pressure recovery time; VM: Valsalva manoeuvre.

Authors’ Contributions

Conceptualisation: Dinu S. Chandran, Ashok Jaryal, Manish Soneja, Ambuj Roy, Kishore Kumar Deepak; data curation: Ayan Roy; formal analysis: Ayan Roy, Dinu S. Chandran; investigation: Ayan Roy; methodology: Dinu S. Chandran; resources: Dinu S. Chandran, Ashok Jaryal, Manish Soneja, Ambuj Roy, Kishore Kumar Deepak; supervision: Dinu S. Chandran, Ashok Jaryal, Manish Soneja, Ambuj Roy, Kishore Kumar Deepak; writing – original draft: Ayan Roy; writing – reviewing and editing: Ayan Roy, Dinu S. Chandran.

Data Availability

Data are available from the corresponding author upon request.

ICMJE Statement

The ICMJE disclosure form has been submitted with the article.

Patient Consent

Informed consent was obtained from all participants included in the study.

Statement of Ethics

The study procedures were approved (ref. no. IECPG-743/23.12.2021, RT-27/27.01.2022) by the institute’s ethics committee for research on human subjects, All India Institute of Medical Sciences (AIIMS), New Delhi, India and the study was performed in compliance with the Declaration of Helsinki, 1964 and its later amendments.