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Abstract

Background:

Cardiotoxicity is a commonly observed adverse effect seen in breast cancer (BC) patients undergoing chemotherapy with attributes toward cardiac autonomic dysfunction (CAD). Yoga, a mind-body system of medicine that has been shown to improve cardiac autonomic nervous system (ANS) activity in various health conditions, could be an effective adjuvant approach in addressing CAD.

Objective:

This study aims to investigate the protective effects of Integrated Yoga Therapy (IYT) on ANS functioning, assessed using Heart rate variability (HRV) in breast cancer patients undergoing chemotherapy.

Methods:

A total of 68 (stage I-III) BC patients were randomly assigned into 2 groups: Treatment as Usual group (TAU) and TAU with Yoga Therapy group (TAUYT). All patients underwent anthracycline-based adjuvant chemotherapy for a total of 6 cycles with 21 days/cycle. During chemotherapy, the TAUYT group received IYT 5 days a week for 18 weeks, compared with usual care alone in the TAU group. Resting heart rate (RHR) and HRV, measured in both the time and frequency domains, were used to assess the cardiac ANS function of each patient before and after 6 cycles of chemotherapy.

Results:

A total of 30 subjects in the TAU group and 29 subjects in the TAUYT group were included in the analysis. At baseline (before chemotherapy), there were no significant differences between the TAU and TAUYT groups in terms of RHR and HRV indices. However, after chemotherapy, patients in the TAU group had a significantly higher average RHR (P < .02) and lower HRV indices with reduced parasympathetic indices: RMSSD (P < .01), pNN50% (P < .04), high-frequency power (P < .001) and increased sympathetic indices: low-frequency power (P < .001) with sympathovagal imbalance: LF/HF (P < .001) compared with patients in the TAUYT group.

Conclusion:

The study showed the protective effects of yoga therapy on CAD in patients receiving anthracycline-based chemotherapy for BC, proposing yoga as a potential adjuvant intervention in improving cardiac health and preventing cardiovascular-related morbidities.

Trial Registration:

This trial is registered with the Clinical Trials Registry-India (CTRI) database (CTRI/2020/10/028446; October 16, 2020).

Keywords

breast cancer yoga chemotherapy heart rate variability autonomic dysfunction resting heart rate

Introduction

Breast cancer is the most common form of cancer affecting women globally.¹ Anthracyclines, such as doxorubicin and epirubicin, are clinically effective chemotherapeutic drugs used to treat patients with breast cancer. However, one of the significant drawbacks of administering anthracyclines as chemotherapy is their cardiotoxicity. Anthracycline-induced cardiotoxicity is a cumulative, dose-dependent effect that can manifest as acute symptoms and can lead to irreversible heart failure due to pericarditis and late cardiomyopathy.^2,3 In addition to directly damaging cardiomyocytes, anthracyclines can also cause dysfunction of the cardiac autonomic nervous system, independent of the decline in cardiac contractility.^4,5

Disruptions in vagal tone, also known as autonomic dysfunction (AD), can be assessed by increased resting heart rate (RHR) and/or a detrimental change in heart rate variability (HRV).^6,7 Heart rate refers to the number of heartbeats per minute, while HRV represents the fluctuations in time intervals between heartbeats. These changes in heart rate occur as a result of complex, nonlinear interactions among various physiological systems. However, the irregularities in heartbeats can be easily observed when examining HR beat-by-beat, making HRV a measure of neurocardiac regulation that reflects heart–brain interactions and autonomic nervous system (ANS) dynamics.⁸ Optimal levels of HRV are associated with good health, self-regulatory capacity, and resilience, while reduced HRV serves as a marker of adverse cardiovascular consequences and signifies the onset and progression of AD.^9,10

Various anti-cancer chemotherapeutic agents cause dysfunction of the ANS, leading to decreased parasympathetic activity and increased sympathetic overdrive, which can greatly impact cardiac health by increasing cardiovascular strain and the risk for early mortality.^4,11 Moreover, the High-Frequency band in HRV, also known as the respiratory band, which represents HR variations related to the respiratory cycle and reflects parasympathetic or vagal activity, is typically lower in patients undergoing chemotherapy.¹² Therefore, measuring cardiac autonomic activity through HR and HRV provides valuable prognostic information for cancer patients. However, the prevention or reduction of anthracycline-induced cardiotoxicity and the expansion of the therapeutic window for breast cancer patients undergoing chemotherapy has been an intriguing area of research for both oncologists and cardiologists. Hence, techniques that modulate vagal tone and improve cardiovascular health in breast cancer patients undergoing chemotherapy are recommended.

Yoga, a mind-body practice comprising physical postures, breathing techniques, meditation, and relaxation, is believed to be a promising intervention that could improve physical health, calm the mind, and provide relaxation.¹³ The therapeutical application of yoga for adults with or without a history of cancer has shown improved cardiac autonomic regulation with increased HRV and vagal dominance.^14,15 Regular yoga practices also improved psychosocial outcomes, including anxiety, depression, and stress, with enhanced markers of ANS functioning, including heart rate, increased exercise capacity, and reduced cardiovascular disease risk.^16,17 Furthermore, among breast cancer patients, yoga has been widely used as an adjuvant approach in managing the disease and treatment-related side effects, including mood, quality of life (QOL), and sleep.¹⁸ However, the evidence on the effects of yoga on cardiac autonomic dysfunction in breast cancer patients undergoing chemotherapy remains limited.

However, studies conducted on exercise programs have shown that administering exercise training during chemotherapy positively affects autonomic modulation with improvements in peak oxygen uptake (VO₂peak), fatigue, quality of life, and other measures of cardiorespiratory fitness.^19,20 Accordingly, yoga, which has an added benefit over exercise concerning breath coordination (emphasis on slow and regulated breathing) during practices, might substantially reduce autonomic dysfunction in breast cancer patients undergoing chemotherapy. Hence, depending on the preliminary evidence available on the beneficial effects of yoga on various health-related issues, including cardiovascular health. The present study hypothesizes that yoga could help prevent or mitigate autonomic dysfunction in BC patients undergoing chemotherapy and exploit its therapeutic benefits.

Materials and Methods

Selection of Subjects

A total of 68 patients diagnosed with stages I, II, and III breast cancer were recruited for the study from a tertiary care cancer hospital in Bangalore, India. The study is a two-arm, parallel-group randomized controlled trial in which subjects were randomly assigned to 1 of 2 study groups: Treatment as Usual (TAU) (n = 34) or Treatment as Usual with Yoga Therapy (TAUYT) (n = 34) (Figure 1). All patients received epirubicin cyclophosphamide (EC) chemotherapy, consisting of 80 mg/m² epirubicin plus 500 mg/m² cyclophosphamide. Yoga therapy was given to the TAUYT group during 6 chemotherapy cycles, whereas the TAU group was given only the usual care while they were under their 6 cycles of chemotherapy. All patients underwent assessment at 2-time points, before and after 6 cycles of chemotherapy. All subjects signed informed consent forms. The study is approved by the ethics committee of the HealthCare Global Enterprises Ltd. Hospital (EC/434/19/01) and National Institute of Mental Health and Neurosciences (NIMH/DO/ETHICS SUB-COMMITTEE (BS&NS) 9th MEETING/2018).

Figure 1.

Subject recruitment CONSORT flow diagram.

Inclusion and Exclusion Criteria

Women who meet the following criteria were included in the study: (1) 18 to 60 years of age; (2) diagnosed with stage I to III breast cancer as confirmed by the pathological diagnosis of the surgically removed tumor; (3) normal liver and kidney function (4) scheduled to receive at least 6 cycles of adjuvant chemotherapy; (5) normal sinus rhythm; and (6) have Left Ventricular Ejection Fraction ≥55 on the echocardiography before randomization.

Patients who match the following exclusion criteria were excluded from the study: (1) prior exposure to chemotherapy or radiotherapy; (2) a history of hypertension, diabetes mellitus, kidney disease, hyperthyroidism or hypothyroidism; (3) a history of cardiac coronary disease or congestive heart failure, existing cardiovascular symptoms, cardiomyopathy, or valvular disease; (4) abnormal electrocardiography, such as ischemic ST-T changes, pathological Q wave, a complete left bundle branch block, atrioventricular block, persistent atrial flutter, atrial fibrillation, atrial tachycardia, and/or paced rhythm; (5) severe anxiety or mood disorder (eg, major depressive disorder) diagnosed within the past year; (6) substance use disorder (eg, alcohol, narcotics); (7) regular participation in an active behavioral intervention/yoga in last 6 months; (8) injuries or illnesses (eg, orthopedic injury, acute arthritis) that prevent stretching while practicing asanas.

Randomization and Blinding

Subjects satisfying the selection criteria and consenting to participate in the study were randomly assigned with an allocation ratio of 1:1 to the TAU group or TAUYT group. Allocation concealment was done using opaque envelopes with group assignments by personnel not involved in the study. Following randomization, a single-blind method is employed, that is, the study staff who did the assessment and the statistician who analyzed the data were blinded to group allocation. However, blinding was not possible among subjects as it was a yoga intervention.

Research Protocol

All patients received Epirubicin Cyclophosphamide (EC) chemotherapy, consisting of 80 mg/m² Epirubicin plus 500 mg/m² Cyclophosphamide. EC chemotherapy was administered intravenously once every 3 weeks for 6 cycles (18 weeks total). During their 6 chemotherapy cycles, the yoga intervention was given to participants in the TAUYT group and usual care alone to TAU group. Yoga intervention is based on earlier protocols employed by the study team for breast cancer patients and was found to have good patient adherence.^21,22 The intervention consists of loosening exercises, asanas (postures), breathing exercises, pranayama (voluntarily regulated nostril breathing), meditation, and imagery-based yogic relaxation techniques. All the practices were done with breath coordination in a ratio of 1:2 (exhalation time is double the time on inhalation). The sessions were conducted every morning for 40 minutes, 5 days a week, for a total of 18 weeks in both hospital and home settings. The initial 1-week yoga session was delivered in person as a one-to-one session in the hospital setting. After they were discharged from the hospital following their first chemotherapy cycle, they were instructed to continue practising yoga at home using a documented video provided by the study team. When they returned to the hospital for subsequent chemotherapy cycles, which occured every 21 days for a total of 6 cycles, they received in-person yoga sessions and the necessary adjustments to their practices. The study team used a patient compliance registry to monitor adherence to the practice time. Over 80% of the participants completed a minimum of 3 sessions per week at home, while all participants attended the in-person sessions owing to their perception of the benefits of yoga in managing symptoms related to cancer and its treatments. The intensity of the protocol remained constant throughout the 18-week period. However, patients were given prior instructions to stop if they experienced any exertion, fatigue, or difficulty in following the practice.

All patients underwent general physical examinations to determine their height, weight, and blood pressure. The general physical examinations and blood test data were obtained from the patients’ medical records as they are routinely performed as part of their oncology care. Cardiac function was evaluated using HRV at 2-time points, that is, before and after 6 cycles of chemotherapy. At the end of the study, out of 68 subjects, 59 subjects completed the study; 4 subjects from the TAU group and 5 subjects from the TAUYT group withdrew from the study. In the TAU group, out of 4 withdrawn subjects, 2 were lost to follow-up due to the COVID-19 outbreak, and 2 discontinued the study due to a shift to another hospital. In the TAUYT group, out of 5 withdrawn subjects, 3 subjects were lost to follow-up due to the COVID-19 outbreak, and 2 discontinued the yoga intervention due to excess fatigue and pain (Figure 1).

Heart Rate Variability

HRV is a non-invasive marker of health used to assess neurocardiac regulation of the heart by measuring the R-R interval (QRS peak) of an electrocardiogram (ECG). HRV reflects the balance between the sympathetic and parasympathetic activity of the heart.²³ For HRV recording an artifact-free, lead II electrocardiogram (ECG) was recorded for 20 minutes in all subjects at rest in the supine position, and signals were conveyed through the analog-to-digital converter (Power Lab, 16-channel data acquisition system, AD Instruments, Australia) with a sampling rate of 1024 Hz. The raw ECG was converted into consecutive RR intervals for analysis. The data was analyzed offline using an automatic program that allows visual checking of the raw ECG and breathing signals.

Data extraction

An artifact-free 5 minutes ECG segment was taken for analysis to obtain both time domain and frequency domain parameters of the HRV using HRV Analysis Software (Lab chart pro version 8, AD instruments, Australia). The time-domain analysis included the following measurements: average heart rate beats per minute, the mean of the intervals between adjacent QRS complexes or the instantaneous HR (RR Intervals), SD of RR Intervals (SDNN) in milliseconds, the square root of the mean of the sum of the squares of differences between adjacent normal-to-normal intervals (RMSSD) in milliseconds, the number of interval differences of successive NN intervals >50 ms (NN50), and the percentage of such NN50 over the recorded segment of 5 minutes (pNN50). Frequency domain parameters were total power, low frequency (LF), 0.04 to 0.15 Hz; high frequency (HF), 0.15 to 0.40 Hz; and LF/HF, the ratio of the LF band to the HF band.

Sample Size

The submitted manuscript reports interim findings of the secondary variable (HRV) from an ongoing larger trial investigating the effect of yoga intervention on cognitive impairment and cardiac autonomic dysfunction in breast cancer patients undergoing chemotherapy. The optimal sample size for the larger trial was estimated based on an earlier study by Vadiraja et al,²⁴ which reported an effect size of 0.49, with a 95% confidence interval and 80% power for the cognitive function variable. The larger trial requires a sample size of 67 subjects in each arm (TAU and TAUYT), with a two-tailed type I error of 5%. While the larger trial continues to recruit patients, this article reports an interim analysis of 30 and 29 subjects in the TAU and TAUYT groups, respectively, showing improvements in cardiac autonomic function as assessed using HRV and resting heart rate. In the present study, the effect size was computed as 0.78 based on the descriptive statistics of the variable SDNN and considering an alpha of 0.05, the post hoc power for our study showed 81% for the sample analyzed (n1 = 30 and n2 = 29).

Statistical Analysis

The data were analyzed using IBM SPSS (IBM Corp. Released 2013. IBM SPSS Statistics for Windows, Version 22.0. Armonk, NY: IBM Corp). A total of 59 subjects who completed the study were included in the analysis, with 30 subjects in the TAU group and 29 subjects in the TAUYT group. Normality of the data was assessed using the Shapiro-Wilk test. Since the data did not follow a normal distribution, Mann-Whitney U test was used to compare baseline characteristics between the 2 groups. To assess changes within each group over time, Wilcoxon signed rank test was performed. Furthermore, the Mann-Whitney U was employed to compare the delta change in scores (post-pre) between TAU and TAUYT groups. Additionally, the Rank Biserial Correlation Coefficient (rbs) and Cohen’s d was used to quantify the effect size (degree of association) between the ranks of TAU and TAUYT in the Mann-Whitney U test.

Results

Comparison of Demographics, and Baseline Characteristics

There were no significant differences in patient demographics or baseline characteristics between the TAU and TAUYT groups, including age, duration of observation, body mass index, and tumor staging. Also, there were no significant differences observed in the cumulative dosages of chemotherapeutic agents such as epirubicin and cyclophosphamide between the patients of the 2 groups (Table 1). When assessed for baseline (before chemotherapy) characteristics between groups using Mann-Whitney U test, there were no significant differences between the TAU and TAUYT groups in terms of RHR and HRV indices (Table 1).

Table 1.

Comparison of Demographics, and Baseline Characteristics of Participants Between TAU and TAUYT Groups.

Characteristics	TAU (n = 30)	TAUYT (n = 29)	U/χ²	P
Characteristics	Mean ± SD or n (%) or Median (IQR)	Mean ± SD or n (%) or Median (IQR)	U/χ²	P
Age (y)	46.3 ± 6.1	45.4 ± 7.7	428	.92
BMI (kg/m²)	23.96 ± 1.09	24.14 ± 1.21	356	.81
Marital status
Married	27	25	0.08	.78
Single	2	3	0.2	.65
Others	1	1	0	1.0
Stage, n, %
I	6 (20)	6 (21)	0	1.0
II	22 (73)	21 (72)	0.02	.9
III	2 (7)	2 (7)	0	1.0
Resting heart rate	81.6 (17.5)	80.1 (7.4)	385	.46
Average RR	739.8 (173.8)	750.9 (72.4)	382	.42
SDNN (ms)	27.5 (25.4)	33.9 (9.6)	347	.19
RMSSD (ms)	18.6 (20.3)	26 (13.2)	319	.08
pNN50%	2.8 (8.6)	6 (9.5)	315	.07
Total power (ms²)	870.1 (1457.1)	1023 (747.3)	352	.21
LF power (nu)	39.7 (18.7)	46.1 (16.6)	332	.12
HF power (nu)	54.6 (20.4)	48.8 (13.9)	332	.12
LF/HF	0.8 (0.6)	1 (0.6)	330	.11

Abbreviations: U, Mann-Whitney U test; χ², chi-square test; TAU, treatment as usual group; TAUYT, treatment as usual group with yoga therapy; BMI, body mass index; Others in marital status denote: widowed or divorced/separated; HRV, heart rate variability; SDNN, standard deviation of all normal-to-normal intervals; RMSSD, root mean square of differences between adjacent normal-to-normal intervals; pNN50, percentage of the number of pairs of adjacent normal-to-normal interval difference by >50 ms; Average RR, average time interval between normal-to-normal intervals; HF (nu), high frequency normalized units; LF (nu), low frequency normalized units.

Yoga Attenuated the Increase in RHR of Participants in the TAUYT Group

RHR was recorded in all patients both before and after chemotherapy to ascertain whether the treatment had any adverse effects on the cardiac ANS. RHR is a well-recognized predictor for ANS functioning.²⁵ Before chemotherapy, patients in both groups showed comparable baseline RHR (Table 1). After chemotherapy, patients in the TAU group had a higher RHR (P < .05; Table 2), suggesting that chemotherapy significantly increased RHR. However, when subjects in the TAUYT group were compared to those in the TAU group using the Mann-Whitney U test, subjects in the TAUYT group had a significantly lower RHR than those in the TAU group (P < .05; Table 2), indicating that yoga intervention prevents the increase in RHR of patients caused by chemotherapy.

Table 2.

Comparison of Participants Between TAU and TAUYT Groups During Chemotherapy.

Variable	TAU (n = 30)					TAUYT (n = 29)					Between group
	Pre	Post	Difference (Post − Pre)	W	P-value	Pre	Post	Difference (Post − Pre)	W	P-value	U	P-value	Effect size
	Median (IQR)					Median (IQR)							r_rb	Cohen’s d
	Mean ± SD					Mean ± SD							r_rb	Cohen’s d
Resting heart rate	81.6 (17.5)	92.4 (6.6)	9.51 (15.02)	59	<.001	79.9 (7.4)	75.9 (9.5)	−2.87 (8.95)	298	.08	193	<.001	0.556	1.087
Resting heart rate	82.7 ± 9.82	91 ± 10.19	8.27 ± 9.9	59	<.001	80.1 ± 8.02	78.2 ± 9	−1.93 ± 9.24	298	.08	193	<.001	0.556	1.087
Average RR	739.8 (173.8)	648.5 (41.8)	−60.5 (132)	359	.009	750.9 (72.4)	790.3 (89.6)	29.10 (92.70)	135	.07	237	.003	0.455	0.849
Average RR	729 ± 98.2	673 ± 81.6	−53.7±99.3	359	.009	756 ± 76.8	775 ± 87	18.9 ± 84.4	135	.07	237	.003	0.455	0.849
SDRR (ms)	27.5 (25.4)	20.7 (17)	−5.32 (18.99)	350	.01	33.9 (9.6)	33 (13.1)	1.01 (10.95)	223	.91	300	.041	0.310	0.553
SDRR (ms)	28.8 ± 15	21.8 ± 12.9	−7.01 ± 14.5	350	.01	35.6 ± 13.6	35.2 ± 15.2	−0.38 ± 9.06	223	.91	300	.041	0.310	0.553
RMSSD (ms)	18.6 (20.3)	9.2 (7.6)	−5.12 (16.9)	425	<.001	26 (13.2)	29.4 (14.5)	4.72 (9.36)	125	.05	158	<.001	0.637	1.306
RMSSD (ms)	21.7 ± 12.8	11.8 ± 8.8	−9.90 ± 11.7	425	<.001	28.7 ± 15.2	31.7 ± 18.2	3.05 ± 12.4	125	.05	158	<.001	0.637	1.306
pNN50%	2.8 (8.6)	0 (0.4)	0 (8.13)	169	.003	6 (9.5)	7.9 (10.8)	1.50 (7.76)	159	.21	231	.002	0.469	0.88
pNN50%	5.9 ± 8.5	1.2 ± 2.8	−4.70 ± 8.35	169	.003	9.3 ± 11.2	11.8 ± 15.9	2.50 ± 12	159	.21	231	.002	0.469	0.88
Total power (ms²)	870.1 (1457.1)	288.1 (618.3)	−158.99 (783.35)	368	.004	1023 (747.3)	995.9 (783.3)	−114.91 (834.73)	236	.7	331	.12	0.239	0.42
Total power (ms²)	1026 ± 936	699 ± 1144	−327 ± 1099	368	.004	1412 ± 1295	1365 ± 1354	−47.5±680	236	.7	331	.12	0.239	0.42
LF power (nu)	39.7 (18.7)	75.1 (9.8)	31.6 (14.64)	0	<.001	46.1 (16.6)	38.1 (13.6)	−8.83 (15.48)	357	.002	52	<.001	0.880	2.31
LF power (nu)	42.6 ± 12.7	73.5 ± 6.7	30.9 ± 11.7	0	<.001	48.1 ± 13.1	39.7 ± 12.1	−8.4 ± 18.2	357	.002	52	<.001	0.880	2.31
HF power (nu)	54.6 (20.4)	24.7 (6.6)	−28.61 (18.03)	465	<.001	48.8 (13.9)	60 (13.1)	13.16 (14.95)	75	.001	48	<.001	0.890	2.368
HF power (nu)	54.9 ± 12.8	26 ± 6.5	−28.9±12.5	465	<.001	50 ± 12.3	58.8 ± 11.6	8.75 ± 17.5	75	.001	48	<.001	0.890	2.368
LF/HF	0.8 (0.6)	3.1 ± 1	2.06 (1.06)	0	<.001	1 (0.6)	0.6 (0.4)	−0.41 (0.44)	365	<.001	30	<.001	0.931	2.661
LF/HF	0.9 ± 0.5	3 ± 1	2.17 ± 0.9	0	<.001	1.1 ± 0.5	0.8 ± 0.6	−0.3 ± 0.85	365	<.001	30	<.001	0.931	2.661

Abbreviations: W, Wilcoxon sing rank test to assess change in the intra group; U, Mann-Whitney U test to assess the distribution of the delta change between groups (inter group); RBS (r_rb), Rank Biserial Correlation Coefficient; IQR, interquartile range; SD, standard deviation; TAU, treatment as usual group; TAUYT, treatment as usual group with yoga therapy; SDNN, standard deviation of all normal-to-normal intervals; RMSSD, root mean square of differences between adjacent normal-to-normal intervals; pNN50, percentage of the number of pairs of adjacent normal-to-normal interval difference by >50 ms; Average RR, average time interval between normal-to-normal intervals, HF (nu), high frequency normalized units; LF (nu), low frequency normalized units.

Yoga Helps Maintain Sympathovagal Balance During Chemotherapy

Next, we assessed the time and frequency domains of HRV, as changes in HRV may provide insight into the severity of cardiac ANS dysfunction.²⁶ Patients in both groups exhibited comparable baseline HRV measures before chemotherapy (Table 1). However, after chemotherapy, the subjects in TAU groups had significantly lower HRV indices, including average normal-to-normal intervals, SD of all normal-to-normal intervals (SDNN), root mean square of differences between adjacent normal-to-normal intervals (RMSSD), per cent of number of pairs of adjacent normal-to-normal interval difference by >50 ms (pNN50%), High Frequency, and higher LF with raised LF/ HF ratio, compared with those before chemotherapy (P < .05 for all indices; Table 2). When compared between groups, subjects in the TAUYT group exhibited significantly higher HRV indices and lowered LF/ HF ratios than those in the TAU group (P < .05; Table 2), proposing that yoga prevents the decline in HRV induced by chemotherapy.

Safety/Adverse Events

All yoga practices were taught by expert yoga therapists, with participants being advised to practice with caution at home. For patients experiencing significant physical limitations during the chemotherapy treatment phase, appropriate modifications were made to alleviate physical discomfort. No adverse events were reported throughout the study. Additionally, the relaxation techniques employed in the same session were sufficient in addressing any issues that arose.

Discussion

In this prospective study, we examined cardiac ANS activity to assess the protective effects of yoga on cardiac health in anthracycline-treated breast cancer patients. The study findings revealed that yoga significantly improved cardiac ANS activity in these patients, as measured by RHR and HRV indices. HRV, which measures the variability of heart rate from one beat to the next, is widely used to assess cardiovascular ANS activity and its regulatory function.²⁶ Abnormal HRV is a risk factor for cardiovascular mortality, irrespective of conventional indicators such as left ventricular ejection fraction, the frequency of ventricular premature beats, late potential, and average heart rate.²⁷ HRV is a measure of the heart’s sympathetic and parasympathetic activity, and the cardiac sympathovagal balance can be examined using various measurement methods.²⁸ In the present study, we used the 2 most commonly used types of HRV measurement, time domain and frequency domain measurements. A decline in HRV denotes impaired cardiac autonomic activity with sympathovagal imbalance. Consistent with previous findings that have shown damaged cardiac sympathovagal balance by anthracyclines,^29-31 our present study also revealed that patients in the TAU groups exhibited reduced HRV after epirubicin treatment, suggesting that epirubicin impaired cardiac ANS activity. However, this decrease was prevented in TAUYT group patients, suggesting that yoga improved the epirubicin-induced ANS dysfunction.

In the present investigation, we evaluated RHR to determine the degree of cardiac ANS dysfunction caused by epirubicin and the cardioprotective impact of yoga. Since RHR indicates the final output of both the limbs of ANS activity, an abnormal increase in RHR is a risk factor for adverse cardiovascular events.²⁵ An earlier study has shown that increasing RHR by 10 beats/min was comparable to increasing systolic blood pressure by 10 mm Hg, resulting in an 8% increase in major cardiovascular events and an 11% increase in the risk of heart failure.³² We found that after chemotherapy, patients in the TAU group had higher RHR, suggesting impaired ANS activity. In contrast, the implementation of yoga sessions during chemotherapy significantly reduced the increase in RHR (Table 2).

Furthermore, studies have shown that reduced HRV reflecting autonomic dysfunction is a risk factor for cardiovascular diseases and a marker for all-cause mortality.^33,34 A decreased HRV is concerning as it signifies an inability to lower sympathetic activation of the heart, which can render the heart vulnerable to arrhythmia, direct to sudden death, and accelerate the development of atherosclerotic coronary artery disease.³⁵ Beyond being implicated in the risk for cardiovascular disease and survival, a lowered HRV is also associated with stress, depression, and fatigue among adults with a history of cancer.³⁶ In our study, HRV parameters such as SDNN, RMSSD, pNN50, LF Power (nu), HF Power (nu), and LF/HF were significantly worse after chemotherapy administration than at baseline. Our findings are comparable with those of other studies, which observed a drop in HRV parameters,³⁷ suggesting the probability of a worsened sympathetic activity following TAU infusion. Similarly, fatigue following chemotherapy can also reduce sympathetic activity, further deteriorating HRV measures.³⁸ On the other hand, physical activities such as exercise and yoga have shown improved HRV indices with reduced long-term mortality.^39,40

Longitudinal studies on the autonomic function of cancer patients have shown that treatment-related factors, such as chemotherapy and radiation therapy, can lead to changes in heart rate variability (HRV) and autonomic nervous system activity.⁴¹ After the completion of treatment, HRV measurements in cancer patients can show persistent autonomic dysfunction, including decreased HRV, decreased vagal activity, and increased sympathetic activity, with reduced overall health and quality of life.⁴² The extent and timing of recovery are influenced by various factors, such as the type and stage of cancer, the type and intensity of treatment received, the presence of comorbidities, and the individual’s baseline HRV and autonomic function. Some studies have suggested that interventions such as exercise training may help improve HRV and autonomic function with improved cardiorespiratory fitness in cancer patients.^19,20

According to the National Institutes of Health, Yoga is one of the most commonly used complementary therapies, with emerging evidence supporting its use among adults diagnosed with cancer.⁴³ Yoga practice has been shown to increase the heart rate variability (HRV) by increasing activity of the parasympathetic nervous system (PNS) and reducing stress and anxiety. By improving physical fitness, yoga can increase HRV, which can help reduce the risk of cardiovascular disease and improve overall heart health. Controlled breathing practices in yoga, such as pranayama, have also increased respiratory function and improved endurance and strength.²³ Similar to these studies, in the present study, following 18-weeks of yoga therapy, HRV analysis showed that the time-domain (RMSSD, RMSSD, pNN50%) and frequency-domain parameters (HF power) had increased significantly with reduced HF power and LF/HF. These findings are consistent with those of other studies showing that yoga enhances PNS activity.⁴⁴ Although the mechanism by which yoga influences autonomic activity is not well comprehended, the practices appear to directly stimulate the vagus nerve and enhance parasympathetic output via the nature of breathing practices involved in yoga.⁴⁵

HRV has a direct relationship with breathing rate.⁴⁶ The breathing rate plays a crucial role in regulating the ANS by modulating the activity of the PNS. Controlled, slow, and deep breathing stimulates the PNS, leading to an increase in HRV and a shift toward greater vagal (parasympathetic) activity.¹⁴ This results in a decrease in heart rate and other physiological changes that promote relaxation and restoration of the body. Also, the bidirectional flow of the vagus nerve allows for adaptive and flexible interaction between the brain and the peripheral organs.⁴⁷ Thus, breathing rate is a significant factor in regulating the ANS through its effects on HRV,¹⁴ and it can be utilized as a tool to modulate ANS activity for promoting relaxation, restoration, or activation as needed. Hence, HRV appears well placed to reflect the cardiac influence and the mind-body integration that occurs with yoga practices by directly linking the input and output of the central nervous system.⁴⁸ Therefore, agreeing with the abovementioned RHR and HRV data, yoga enhanced cardiac ANS function in epirubicin-treated breast cancer patients.

We acknowledge a few limitations in the study: First, we measured HRV with an ECG over a 5-minute period, rather than using 24-hour monitoring. However, the Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology (1996)²⁸ recommends this short-term HRV method which is the most widely used approach in cancer patients.⁴⁹ Secondly, we did not control for the respiratory rate. The influence of respiratory rate is currently under debate, given that consciously controlled breathing may affect HF values by inhibiting cardiac parasympathetic-nerve activity.⁵⁰ Third, HRV measurements may represent only partial vagal-nerve activity while primarily reflecting cardiac vagal activity, although there is evidence of a strong correlation between HRV and vagal activity.⁵¹ Furthermore, the use of the LF/HF ratio as a measure of sympatho-vagal balance is a topic of debate in the scientific community, as this balance is a complex and dynamic phenomenon that is influenced by multiple factors, including breathing patterns, baroreceptor sensitivity, thermoregulation, and other physiological processes. Finally, a multicenter study with large samples and an active control group is required to establish conclusive results on yoga as a protective approach for cardiac health in cancer patients. Also, a control group without chemotherapy needs to be studied to strengthen the cardiotoxic effect of chemotherapy.

Conclusion

In conclusion, we demonstrated that yoga protects the cardiac ANS from epirubicin-induced impairment in breast cancer patients, as evidenced by improved RHR and HRV. Therefore, we recommend implementing regular yoga sessions while the patient undergoes chemotherapy to effectively prevent/reduce the event of cardiotoxicity in anthracycline-treated breast cancer patients.

Footnotes

Acknowledgements

We acknowledge the Central Council for Research in Yoga and Naturopathy (CCRYN), Ministry of AYUSH, and the Department of Science and Technology, Government of India, New Delhi, for providing support.

Author Contributions

This work is a collaborative effort in which all authors have an equal contribution. The final manuscript was read, revised, and approved by all of the authors.

Availability of Data and Materials

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Credit Authorship Contribution Statement

All authors approved the final manuscript as submitted and agree to be obliged for all aspects of the work.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethical Clearance

The study is approved by the ethics committee of the HealthCare Global Enterprises Ltd. Hospital (EC/434/19/01) and National Institute of Mental Health and Neurosciences (NIMH/DO/ETHICS SUB-COMMITTEE (BS&NS) 9th MEETING/2018).

Consent for Publication

Not applicable

ORCID iDs

Kaviraja Udupa

Talakad N Sathyaprabha

Data Availability

The data supporting this study’s findings are available from the corresponding author upon reasonable request.

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Effects of an 18-Week Integrated Yoga Program on Cardiac Autonomic Function in Breast Cancer Patients Undergoing Adjuvant Chemotherapy: A Randomized Controlled Trial

Abstract

Background:

Objective:

Methods:

Results:

Conclusion:

Trial Registration:

Keywords

Introduction

Materials and Methods

Selection of Subjects

Inclusion and Exclusion Criteria

Randomization and Blinding

Research Protocol

Heart Rate Variability

Data extraction

Sample Size

Statistical Analysis

Results

Comparison of Demographics, and Baseline Characteristics

Yoga Attenuated the Increase in RHR of Participants in the TAUYT Group

Yoga Helps Maintain Sympathovagal Balance During Chemotherapy

Safety/Adverse Events

Discussion

Conclusion

Footnotes

Acknowledgements

Author Contributions

Availability of Data and Materials

Credit Authorship Contribution Statement

Declaration of Conflicting Interests

Funding

Ethical Clearance

Consent for Publication

ORCID iDs

Data Availability

References