Effect of Yoga on Endothelial Function: A Systematic Review and Meta-Analysis

Abstract

Introduction:

Endothelial dysfunction is the initial step in the pathogenesis of atherosclerosis; and it plays a central role in the development of cardiovascular diseases and many types of human diseases (diabetes, kidney failure, cancer, and viral infections). Strategies that are effective in protecting vascular endothelial function and retard or reversing endothelial dysfunction in the early stage appear to be potential in the prevention of vascular, cardiac, and many human diseases. Several studies have been carried out on the effects of yoga on endothelial function, but the results of these studies have not been synthesized. This study aimed at conducting a systematic review and meta-analysis to determine the effectiveness of yoga on endothelial function.

Methods:

A systematic review and meta-analysis of studies that assessed the effect of yoga practice on vascular endothelial function was done as per the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The PubMed, Scopus, Google Scholar, and Cochrane controlled register of trials (CENTRAL) were searched from inception to August 2022. The search strategy was constructed around yoga-based techniques and endothelial function. All the yoga-based interventional studies on endothelial function or dysfunction were included in this review. A narrative synthesis and descriptive analysis were done due to the diverse methodology of selected studies. We carried out a formal meta-analysis of controlled trials that assessed the effect of yoga on flow-mediated dilatation (FMD), a measure of endothelial function.

Results:

A total of 18 studies were included for review involving 1043 participants. Yoga training showed improved endothelial function in 12 studies, whereas 6 studies did not find any statistically robust effect. Meta-analysis (n = 395 participants, 6-studies, 7 comparisons) showed an increase in brachial FMD by yoga practice (mean difference = −1.23%; 95% confidence interval −2.23 to −0.23; p = 0.02). The heterogeneity between the studies was 43% (Tau² = 0.70, χ² = 10.49). The risk of bias was low to moderate in these studies. No adverse effects were reported.

Conclusions:

Yoga practice improved endothelial function. Yoga could be a safe and potential integrative medicine to improve endothelial function. However, as the statistical heterogeneity, that is, variation in the FMD among the studies was moderate, large clinical trials are necessary for its clinical recommendations.

Introduction

Endothelial dysfunction is a well-documented predictor of atherosclerosis and plays a central role in the development of cardiovascular (CV) diseases and many types of human diseases (diabetes, kidney failure, cancer, and viral infections).^1,2 It is mainly characterized by a disturbance in the balance between vasodilators and vasoconstrictors; impairment in endothelial-dependent relaxation, and the induction of a proinflammatory and prothrombic state.³

The endothelium is involved in a multitude of physiological functions and plays a critical role in controlling vascular tone, blood pressure, vascular permeability, blood fluidity, fibrinolysis, and angiogenesis; inhibiting platelets aggregation, leukocyte adhesion, and migration; preventing inflammatory response and thrombogenesis; suppressing vascular smooth muscle cell proliferation; and maintaining CV integrity and homeostasis of different organs and systems.⁴ The endothelium regulates these functions by synthesizing and releasing several factors such as vasodilators, vasoconstrictors, antithrombotic factors, growth factors, and inflammatory mediators.^5,6

Nitric oxide is recognized as the most essential endothelial-derived relaxation factor (EDRF) and a key molecule in the maintenance of vascular tone, integrity, and homeostasis. Reduction in the bioavailability of nitric oxide results in endothelial dysfunction.⁷ Impaired endothelial-dependent vasodilation, which is mediated by nitric oxide, is a hallmark of endothelial dysfunction.⁸

The endothelium is the primary site of dysfunction in CV and metabolic diseases. Factors that impair endothelial function and subsequently damage vasculature are common CV risk factors such as hypertension, diabetes, insulin resistance, dyslipidemia, homocysteine, hypercholesterolemia, oxidative stress, inflammatory factors, aging, obesity, smoking, estrogen deficiency, menopause, chronic inflammatory diseases, environmental stressors (noise and air pollution), and mental stress.^1,4,7

Currently, there are several methods to measure endothelial function. Ultrasound assessment of endothelial-dependent flow-mediated vasodilation (flow-mediated dilatation [FMD]) of the brachial artery is the gold-standard clinical measure of endothelial function.⁹ Other measures are cardiac catheterization, venous occlusion plethysmography pulse wave analysis (PWA), flow-mediated magnetic resonance imaging (MRI), laser Doppler skin-flowmetry, and digital pulse amplitude tonometry (PAT).¹⁰

Biomarkers of endothelial function include endothelial progenitor cells, endothelial microparticles, asymmetric dimethyl arginine (ADMA), adhesion molecules, selectins, nitric oxide concentration (NOx), and endothelins.¹¹

There is convincing evidence that endothelial dysfunction predicts future CV events. Strategies that are effective in improving or reversing endothelial dysfunction in the early stage appear to be potential in the prevention and control of vascular, cardiac, and many human diseases.² Several interventions (lifestyle and pharmacological treatment) have been shown to improve endothelial function and reduce CV risk.¹² Statins,^13,14 angiotensin-converting enzyme inhibitors,¹⁵ and aspirin¹⁶ improve endothelial function and reduce CV morbidity and mortality. Favorable responses of the endothelium to lifestyle changes have also been reported.¹²

Yoga is a mind–body exercise rooted in Vedas and ancient Indian literature is beneficial for physical, mental, and spiritual well-being. Yoga is associated with a significant reduction in CV risk and diseases.¹⁷ Several studies have been carried out on the effects of yoga on endothelial function, where a few studies reported an improvement in endothelial function^{18

–29} whereas a few showed no effects;^30

–35 but the results of these studies have not been synthesized. Therefore, this study aimed at conducting a systematic review and meta-analysis to determine the effectiveness of yoga practice on endothelial function.

Methods

This systematic review has been registered prospectively in the PROSPERO (CRD42020195995). The guidelines of the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) were followed for reporting this systematic review and meta-analysis.

Data sources and search strategy

Four electronic databases: PubMed, SCOPUS, Cochrane Controlled Register of trials (CENTRAL), and Google Scholar were searched for eligible studies that are published in English language through August 2022.³⁶ Google Scholar was used to search academic and gray literature.³⁷ The keywords used for the searches are: “Yoga,” “Meditation,” “Pranayama,” “yogic breathing exercise,” “Yogasanas,” “asanas,” “endothelial,” “endothelium,” “flow-mediated vasodilation,” “endothelial-dependent vasodilation,” “vascular reactivity,” “nitric oxide,” and “endothelial markers.”

The Boolean operators “AND,” and “OR” were used to capture relevant and related articles (four reviewers). The references were also searched manually to find articles for review (two reviewers). Independently, two reviewers (V.K., R.C.) screened the titles and abstracts in the databases as per the eligibility criteria, whereas a third reviewer (S.G.P.) was consulted whether any disagreement existed between them.

Study selection

Types of participants: Studies including human participants of any age or gender.

Types of interventions: Yoga-based interventions: asanas (stretching and maintaining postures), pranayama (breathing exercises), meditation, relaxation techniques, yoga diet, yoga lifestyle; either of these used as a single technique or combined/integrated were included.

Type of Comparator: Active control, passive control, and single group studies without comparator were included.

Main outcome and measures of effect: Changes in the endothelial function assessed by FMD was the primary outcome. However, other measures and biomarkers of endothelial function were also considered for review.

Types of studies: All the interventional studies (i.e., controlled, uncontrolled, randomized, non-randomized, and cross-over) that assessed the effect of yoga on endothelial function were included in this review. There were no restrictions on language while searching or filtering the studies. Those studies whose full text was not available were excluded from the review.

Data extraction

The data were extracted and analyzed by two independent reviewers (E.C., V.K.). The third reviewer (R.M.D.) was consulted whether there was any discrepancy or no consensus between the two authors. A narrative synthesis was done due to the diverse methodology (study design, study quality, and measures of outcomes) of all selected studies.

Data extraction proforma of the current review included the following items: details of eligibility criteria, number of participants, participant characteristics (age, sex, diagnosis, duration of illness and eligibility criteria), type of yoga intervention and comparator, details of yoga-based intervention (duration of each session, frequency, type of yoga techniques, total duration of intervention), adherence to the intervention, outcome measures and method of measurement, results and conclusions, and adverse events. Details of the control group intervention were also recorded.

Mean change in FMD and standard deviation (SD) were recorded from only those studies that have FMD as an outcome. Missing SDs were imputed from the provided data as either 95% confidence interval (CI) or standard error or p-value according to the Cochrane statistical methods.³⁸ Authors were contacted for missing data and any additional information if required.

Quality assessment

The quality of the method of individual studies was assessed independently by two reviewers (H.S.V., A.M.C.) using the Cochrane risk of bias (RoB) tool. The third reviewer (R.R.) was consulted for any discrepancy between the two authors or whether there is no consensus between the two authors. The RoB tool includes the following items: Randomization sequence generation, allocation concealment, blinding of participants and investigators, the blindness of outcome assessments, incomplete outcome data, selective outcome reporting, and other biases. The quality of the studies was divided into three categories: low risk, high risk, and unclear bias according to the guidelines of Cochrane systematic review.³⁹

Data analysis

Meta-analysis of the results (FMD %) of the eligible studies was done using Review Manager (RevMan 5.4) software produced by Cochrane Collaboration. Mean change and SD values were added into RevMan 5.4. Statistical heterogeneity between the studies was assessed using the χ² test and I ² value. Based on the I ² value, heterogeneity between studies was categorized as low risk of heterogeneity (<25% of I ² value), moderate risk of heterogeneity (25%–75% I ² value), and high risk of heterogeneity (>75% I ² value).

We have selected mean difference and 95% CIs for estimating the effect size of individual studies (as the measure of the primary outcome was the same in all studies). A fixed-effects model was used if there was homogeneity between studies or a random-effects model for heterogeneity.⁴⁰ A p-value <0.05 was considered as statistically significant. A result of the meta-analysis was shown in the form of a forest plot. A sensitivity analysis was performed to identify any undue influence of an individual study with a bias on the overall meta-analysis.

Results

Study selection process and search results

The study selection process and results are depicted in detail in Figure 1. The database search resulted in 399 titles and abstracts, out of that 21 studies were reviewed for eligibility. Of these, five studies were excluded: two had no yoga-based intervention,^41,42 one was an observational study,⁴³ and the measures of two were imprecise.^44,45 The full details and data of two conference abstracts were obtained by contacting the authors. Finally, 18 articles were included in the qualitative synthesis. Of these, six studies that assessed FMD were included for quantitative synthesis, that is, meta-analysis.^{21,23,27,28,33,35}

FIG. 1.

Flow diagram showing the results of database search.

Study characteristics and participants

A descriptive summary and study characteristics including study outcomes and results were provided in Table 1. There were 10 randomized controlled trials,^{19,21,23

–26,28,30,32,33} 1 randomized cross-over design,³⁵ 4 non-randomized studies,^18,20,22,27 and 3 single group (without control group/comparator) studies with pre-post design.^29,31,34

Table 1.

General Characteristics of Included Studies

First author (year)^Ref.	Design of study	Number/age/sex and characteristics of participants	Experimental intervention	Control group intervention	Measures of endothelial function	Results
Boroujeni (2015)³⁰	RCT, procedure of randomization is not clear. No blinding.	Women patients with migraine (n = 32). Two groups: (1) Yoga group (n = 18, age = 35.4 ± 7.9 years); (2) Control group (n = 14, age = 34.9 ± 8.37 years).	Yoga training: 3 sessions/week for 12 weeks, duration of each session was 75 min plus usual medical care.	Usual medical care.	Serum total NOx (reduction by nitrate reductase and Griess assay using kits from R&D Systems, Minneapolis, MN).	No significant difference in total nitric oxide levels between two groups.
Chen (2016)¹⁹	RCT, equal participant allocation (1:1), no blinding.	Healthy female Chinese subjects (n = 30). Two groups: (1) Yoga group (n = 15, age = 18–25 years); (2) Control group (n = 15, age = 18–25 years).	Hatha yoga: 2 times a week for 8 weeks. Duration of each session was 60 min.	No intervention.	Circulating endothelial microparticles (platelet-poor plasma by flow-cytometry).	Yoga practice significantly reduced circulating CD31⁺/CD42b⁻ endothelial microparticles compared with the control group (change between groups).
Chien (2013)²⁰	Community based pre-post design study on subjects with dysmenorrhea and healthy controls, no blinding.	Women participants (n = 60) with primary dysmennorrhea and healthy. Novice never practiced yoga. Two groups: (1) Women with dysmenorrhea (n = 30; age = 17.24 ± 0.12 years); (2) Healthy women control (n = 30; age = 17.61 ± 0.10 years).	Yoga twice a week 30 min/session for 8 weeks.	Yoga twice a week 30 min/session for 8 weeks.	Serum total NOx (ELISA Kit for Humans; Assay Designs, Inc.) and homocysteine (ELISA Kit; Diazyme Laboratories) at 0 and 2 months.	Yoga intervention significantly reduced serum homocysteine levels in both dysmenorrheal and control groups, but there was no change between two groups. However, there was no change in NOx.
Christa (2018)²¹	RCT (Outcome assessment blinded).	Patients with acute myocardial infarction (n = 80). Two groups: (1) Yoga group (n = 40; age = 50.12 ± 9.76 years; M/F = 38/2); (2) Standard care group (n = 40; age = 50 ± 9.22 years; M/F = 38/2).	Yoga-based cardiac rehabilitation program for 3 months with standard care. A total of 13 in-hospital sessions spread over 3 months with encouragement to practice regularly at home using instruction booklet and video in the local language. Each session lasted for about 75 min.	Enhanced standard care (3 educational sessions) spread over for 3 months.	FMD using brachial artery reactivity test.	FMD was significantly improved with yoga-care program than enhanced standard care (change between groups).
Dod (2010)¹⁸	Non-randomized controlled study.	Subjects with stable CHD (n = 47). Two groups: Experimental group (n = 27; age = 56.0; M/F = 14/13). Control group (n = 20; age = 56.6 years; M/F = 11/9).	Multisite Cardiac Lifestyle Intervention Program for 12 weeks, which includes Yoga/Meditation (1 h/day), nutrition, aerobic exercise (3 h/week), smoking cessation, and group psychosocial support.	Usual standard of care.	FMD using brachial artery reactivity test (two-dimensional gray-scale and color flow Doppler vascular imaging by a Philips Sonos 7500 ultrasound machine; HP, Andover, MA), ICAM (mg/L), VCAM (mg/L), E-selectin (ng/mL) at 0 and 3 months.	Significant improvement in FMD with intervention given to experimental group. No change in serum markers: ICAM, VCAM, and E-selectin (change between groups).
Hunter (2013)³¹	Single group: Pre-post design (includes cross-sectional study also).	Sedentary middle-aged and older healthy subjects (n = 13; age = 51 ± 7 years; M/F = not given).	Hatha yoga for 75 min/session twice a week for 3 months.	No control group.	Brachial artery FMD at 0 and 3 months (iE33; Philis Medical; and Medical Imaging Applications, Coralville, IA).	No change in FMD with the hatha yoga intervention (Within-group change).
Hunter (2017)²²	Pre-post design.	Healthy sedentary subjects (n = 36). Two groups: (1) Young healthy group (n = 17, age = 31 ± 2 years, M/F = 3/14); (2) Middle aged and elderly group (n = 19, age = 50 ± 2; M/F = 6/13).	Bikram Yoga: 3 times a week for 8 weeks. Duration of each session was 90 min. Yoga training was given in a room with heat (41°C) and humidity (40%–60% relative humidity).	No control group.	Brachial artery FMD at 0 and 2 months (Vascular tools; Medical Imaging Applications).	Brachial artery FMD was significantly increased with yoga training in middle-aged and older but not in young healthy subjects (within-group change).
Hunter (2018)²³	RCT, blinding of participants and key study personnel ensured till baseline data collection. No blinding of outcome assessment.	Healthy sedentary adults (n = 52). Three groups: (1) Yoga group at 40.5°C (n = 19, age = 47 ± 5, M/F = 4/15); (2) Yoga group at 23°C (n = 14, age = 49 ± 5, M/F = 4/10); (3) Control group (n = 19, age = 49 ± 6, M/F = 6/13).	Bikram Yoga: 3 times a week for 12 weeks. Duration of each session was 90 min.	No intervention.	Brachial artery FMD at 0 and 3 months (Philips iE33 Ultrasound System, Bothell, WA and Vascular tools; Medical Imaging Applications).	Improvement in FMD was significantly better with yoga practiced in thermoneutral condition than heated condition (change between groups). No change within the control group.
Lim (2015)³²	RCT, no blinding.	Young healthy subjects (n = 25). Two groups: (1) Yoga group (n = 12, age = 21.0 years, M/F = 6/6); (2) Control group (n = 13, age = 22.0, M/F = 5/8).	Twelve sessions of yoga classes, one session of 90 min/week spread over 12 weeks and practice at home for at least three times a week by watching a 40-min video provided by the instructor.	Usual social life and physical exercise activities during each session for the equivalent of the yoga group under the supervision of the physical trainer.	Serum nitric oxide level (Griess method).	Significant reduction in nitric oxide levels with yoga practice (change between groups).
Naji-Esfahani (2014)²⁴	RCT, blinding of outcome assessment.	Women patients with migraine (n = 32). Two groups: (3) Yoga group (n = 18, age = 35.4 ± 7.9 years); (4) Control group (n = 14, age = 34.9 ± 8.37 years).	Yoga training: 3 sessions/week for 12 weeks, duration of each session was 75 min plus usual medical care.	Usual medical care.	Blood levels of ICAM and VCAM at 0 and 3 months (method of measurement was not given).	Significant reduction in VCAM levels with yoga training and usual care than only usual care. No change in ICAM levels between groups (change between groups).
Patil (2015)²⁵	RCT, blinding of outcome assessment.	Elderly individuals with increased PP ≥60 mmHg (n = 60). Two groups: (1) Yoga group (n = 30; age = 68.5 ± 4.85 years; M/F = 30/0); SBP = 146.87 ± 5.72; DBP = 74.2 ± 4.6; PP = 72.17 ± 6.018); (2) Walking group (n = 30; age = 69.3 ± 5.93; M/F = 30/0; SBP = 145.83 ± 6.33; DBP = 75.57 ± 5.685; PP = 70.33 ± 6.32).	Integrated yoga for 1 h/day for 5 days in a week for 3 months.	Walking-exercise for 1 h/day for 5 days in a week for 3 months.	Total NOx (cadmium reduction, Griess assay).	Significant increase in total NOx with yoga intervention (change between groups).
Patil (2020)²⁶	RCT (Outcome assessment blinded).	Patients with acute myocardial infarction (n = 82). Two groups: (3) Yoga group (n = 43; age = 51.9 ± 10.7 years; M/F = 36/7); (4) Standard care group (n = 39; age = 53.1 ± 10.6 years; M/F = 30/9).	Yoga-based cardiac rehabilitation program (Yoga CaRe) for 3 months with standard care. A total of 13 in-hospital sessions spread over 3 months with encouragement to practice regularly at home using instruction booklet and video in the local language. Each session lasted for about 75 min.	Enhanced standard care (3 educational sessions) spread over for 3 months.	Endothelial biomarkers: ADMA, total NOx, eNOS, ET-1, E-Selectin, P-selectin, VCAM, ICAM-1.	Significant improvement in endothelial function with Yoga CaRe program than standard care (change between groups).
Paul-Labrador (2006)³³	Randomized, single blind, attention controlled trial.	Patients with CHD (n = 103). Two groups: (1) Transcendental meditation group (n = 52; age = 67.7 ± 9.0 years; M = 79%); (2) HE group (n = 51; age = 67.1 ± 10.5 years; M = 84%).	Transcendental meditation for 16 weeks. 1.5 h twice per week for the first 4 weeks and weekly thereafter.	Active HE.	FMD using brachial artery reactivity test at 0 and 16 weeks.	No change in Brachial artery FMD (change between groups).
Sivasankaran (2006)²⁷	Pre-post design.	Patients with CAD (n = 33). Two groups: (1) Patients with CAD (n = 10; age = 63 ± 6 years; M = 80%); (2) Subjects with or without CAD risk factors (n = 23; age = 52 ± 11 years; M = 52%).	Yoga and meditation for 90 min a day for three times a week for 6 weeks.	Yoga and meditation for 90 min a day for three times a week for 6 weeks.	FMD using brachial artery reactivity test at 0 and 6 weeks.	Yoga and meditation improved FMD in patients with CAD but not in subjects without CAD (within group change).
Sarvottam (2013)³⁴	Single group: pre-post design.	Overweight and obese male subjects aged between 18 and 55 years (n = 51, BMI = 26.26 ± 2.42 kg/m²).	Yoga-based lifestyle intervention for 2 h/day for 10 days.	No control group.	Serum ET-1 (ELISA method; Biomedica Medizinprodukte, Vienna, Austria).	No change in plasma ET-1 with yoga intervention (within-group change).
Udhan (2020)²⁹	Single group: pre-post design.	Healthy subjects (n = 200, age = 39 ± 0.95 years, M/F = 120/80).	Yoga training for 1 h/day for 6 days in a week for 6 months.	No control group.	Plasma total NOx (method of measurement not given).	Plasma total NOx increased significantly with yoga practice for 6 months (within-group change).
Vaccarino (2013)²⁸	RCT (block randomization, allocation by sequentially numbered, sealed envelopes.) Outcome assessment blinded.	Black Americans with metabolic syndrome aged between 30 and 65 years (n = 68). Two groups: (1) Meditation group (n = 33, age = 51.5 ± 7.5 years, M = 25%); (2) HE group (n = 35, age = 25.1 ± 7.6, M = 17.1%).	CRM, mantra-based meditation, 21 sessions lasting for 1–1.5 h spread over 12 months. Home practice of CRM twice a day for 20 min.	HE on lifestyle modification by professional health educator in 21 sessions spread over 12 months. Home practice twice a day on diet, exercise, and lifestyle habits.	Brachial artery FMD, Endothelial-independent, nitroglycerin-mediated vasodilation at 0, 6, and 12 months (Acuson 10-mHz linear-array transducer and Acuson Aspen ultrasound system).	CRM and HE significantly improved FMD but no change between groups. No change in endothelial-independent dilatation in either group (change within- and between-groups).
Wooten (2020)³⁵	Randomized cross-over study. No Blinding of outcome assessment.	Young healthy subjects (n = 20, age = 23 ± 4, M/F = 10/10).	Twenty yoga poses for 30 sec each (without blood flow restriction).	Twenty yoga poses for 30 sec each (with blood flow restriction).	Brachial artery FMD (automated diagnostic ultrasound system, UN-EXEF-38G; UNEX Corp.).	Yoga poses with or without blood flow restriction did not induce any significant change in FMD (within-group change).

Age is given as mean ± SD; M/F indicates number of males/females.

ADMA, asymmetric dimethyl arginine; CAD, coronary artery disease; CHD, coronary heart disease; CRM, consciously resting meditation; DBP, diastolic blood pressure; ELISA, enzyme-linked immunosorbent assay; eNOS, endothelial nitric oxide synthase; ET-1, endothelin-1; FMD, flow-mediated dilatation; HE, health education; ICAM, intercellular cell-adhesion molecule; NOx, nitric oxide concentration; PP, pulse pressure; RCT, randomized controlled trial; SBP, systolic blood pressure; SD, standard deviation; VCAM, vascular cell-adhesion molecule.

Most of the studies originated in USA (n = 8).^{18,22,23,27,28,31,33,35} Five studies were from India,^{21,25,26,29,34} one each from Iran (two papers from the same project),^24,30 Taiwan,²⁰ Korea,³² and China.¹⁹ Type of participants were healthy,^{19,22,23,29,31,32,35} overweight, and obese;³⁴ patients with coronary artery disease,^18,27,33 myocardial infarction,^21,26 metabolic syndrome,²⁸ dysmenorrhea,³⁰ migraine,^23,29 and elderly hypertension.²⁵

The total number of participants was 1043 (ranging from 13 to 200 subjects in each study) in the 18 included studies. Most of the studies included both genders,^{18,21
–23,26–29,32,33,35} whereas a few had only females^19,20,24,30 or males,^25,34 and one study did not provide any information on gender.³¹ Age of the participants was ranging from 17 to 70 years.

Details of interventions

The yoga programs used in the included studies are given in detail in Table 2. The total duration of yoga intervention was ranging from 10 days to 52 weeks. One study assessed the immediate effects of several yoga postures.³⁵ The minimum duration of each session was 40 min and the maximum was 120 min; and the frequency of sessions was 2–7 times/week. Dod et al. evaluated the Ornish program, which is a multicomponent intervention including yoga, increasing physical activity, dietary approaches, and tobacco cessation.¹⁸

Table 2.

Details of Intervention: Yoga Programs

First author (year)^Ref.	Session duration, frequency/week, total period	Yoga program
Boroujeni (2015)³⁰	75 min/session, 3 times/week, 12 weeks	Yoga training: 75 min/session, 3 sessions/week for 12 weeks plus usual medical care. Hatha yoga program included (1) Asanas (Eye-related exercises, Pawanmuktasana, standing-sitting and lying out screw position, palming, (2) Suryanamaskara, (3) Neti exercises, (4) Pranyama, (5) Shavasana.
Chen (2016)¹⁹	60 min/session, 2 times/week, 8 weeks	Hatha yoga: 60 min/session, 2 times a week for 8 weeks. Each session included breathing exercise (6 min); loosening exercise (i.e., corn tree pose; 10 min); standing poses (i.e., warrior pose and mountain pose; 8 min); supine poses (i.e., bridge pose and dolphin plank pose; 8 min); prone poses (i.e., hare pose and locust pose; 8 min); sitting poses (i.e., staff pose and hero pose; 8 min); relaxation/corpse pose (6 min); and seatedmeditation (6 min). Approximately 32 min was spent in active poses.
Chien (2013)²⁰	30 min/session, 2 times/week, 8 weeks	Yoga twice a week for 30 min/session for 8 weeks. The yoga program included a warm-up period followed by a series of static yoga postures with regular breathing and ended with a 10-min relaxation in the horizontal position. Asanas/poses included were Half-Tortoise pose (Ardhakurmasana), Cobra Pose (Bhujangasana), Reverse table Pose (ArdhaPurvottanasana), Bridge pose (SetubandhaSarvangasana), and Cobbler's Pose (Baddhakonasana). Emphasis was given to attention to respiration and upper body alignment while practicing asanas.
Christa (2018)²¹	75 min/session, daily, 12 weeks	Yoga-based cardiac rehabilitation program for 3 months with usual standard care. A total of 13 in-hospital sessions spread over 3 months with encouragement to practice regularly at home using instruction booklet and video in the local language. Each session was lasted for about 75 min. The intervention given in 13 sessions are as follows: (1) Educational session (1 session in week 1), (2) Pranayam, relaxation and meditation techniques (1 session in week 3), (3) Health rejuvenating exercises, Asanas, Pranayam, relaxation, and meditation techniques (2 sessions/week for weeks 5–7 then followed by 1 session/week for weeks 8–12) and (4) group session—discussion on long-term maintenance of Yoga, dietary and lifestyle changes at home (week 13). Yoga program included (1) shoulder, chest, and abdomen exercises (3 min each)—total of 3 exercises (10 min); (2) Yogasanas- two core poses and one elective pose from each group (standing, sitting, lying)—total of nine poses (25 min); standing asanas included were Kati-chakrasana, Tadasana, Urdhva-hastottanasana (core poses), and Ardhakati-Chakrasana or Trikonasana (elective poses); sitting asanas included were Gomukhasana, Janushirsasana, Vakrasana (core poses) and Ardha-padmasana or Vajrasana (elective poses); lying asanas included were Ekpadottanasana, Naukasana, Ardha-pavanamuktasana (core poses) and Markatasana or Merudandasana (elective poses); (3) Pranayama or controlled breathing exercises (two core and one elective practice for 5 min each for 15 min)—total of three practices were included, they are Anulomvilom/Nadishodhana Pranayama, Bhramari Pranayama, Ujjayi Pranayama (core pranayama) and Sitali Pranayama or Sitkari Pranayama (elective pranayama); and (4) Meditation and relaxation techniques (two core and one elective practice for 5 min each for 15 min)—a total of three techniques were practiced, they were Chanting, Mindfulness meditation, Shavasana (core practices), and Dirghasvasapreksha or Antarangatrataka (elective practices).
Dod (2010)¹⁸	60 min/session, daily, 12 weeks	Multisite Cardiac Lifestyle Intervention Program for 12 weeks, which includes Yoga/Meditation (1 h/day), nutrition (10% fat, whole foods, vegetarian diet), aerobic exercise (3 h/week), smoking cessation, and group psychosocial support.
Hunter (2013)³¹	75 min/session, 2 times/week, 12 weeks	Hatha yoga for 75 min/session twice a week for 3 months. Hatha yoga included floor postures (cow, cat, and child's pose), forward bends (head-to-knee, and wide-leg forward bending), lateral bends (triangle and extended side-angle pose), hips and balancing postures (tree-pose and downward-facing dog), backbend (bridge and camel poses), inversion poses and sun salutation postures.
Hunter (2017)²²	90 min/session, 3 times/week, 8 weeks	Bikram Yoga for 90 min/session for 3 times a week for 8 weeks. Yoga training was given in a room with heat (41°C) and humidity (40%–60% relative humidity). Bikram yoga included 26 postures: standing and supine postures-that improve balance, strength, and flexibility. Practices included were: standing deep breathing, awkward pose, half-moon pose, eagle pose, standing head to knee, standing bow, balancing stick, standing separate leg stretching, triangle pose, standing separate leg head to knee pose, tree pose, toe stand, dead body pose, wind removing pose, sit-up, cobra, locust pose, full locust pose, bow pose, fixed firm pose, half tortoise, camel, rabbit pose, head to knee and stretching pose, spine-twisting pose, blowing in firm pose and dead body pose (savasana). Breathing exercises were practiced before and after the practice of postures.
Hunter (2018)²³	90 min/session, 3 times/week, 12 weeks	Bikram Yoga for 90 min/session for 3 times a week for 12 weeks. Yoga training was given in a room with heat (40.5°C and 23°C). Postures/Asanas included were standing deep breathing, Half Moon pose, Awkward pose, Eagle pose, Standing head to knee, Standing bow, Balancing stick, Standing separate leg stretching, Triangle pose, Standing separate leg head to knee pose, Tree pose, Toe stand, Dead body pose (Savasana), Wind removing pose, Sit-up, Cobra pose, Locust pose, Full Locust pose, Bow pose, Fixed firm pose, Half Tortoise, Camel pose, Rabbit pose, Head to knee and stretching pose, Spine-twisting pose, Blowing in firm pose, and Dead body pose (savasana). All the postures were practiced twice except Spine-twisting pose.
Lim (2015)³²	90 min/yoga class, 40 min at home, 3 times/week, 12 weeks	Twelve sessions of yoga classes, one session of 90 min/week spread over 12 weeks and practice at home for at least three times a week by watching a 40-min video provided by the instructor. Each session included (1) Yogasanas (35 min) included were Sukhasana, Vajrasana, Yoga mudra, Paschimottanasana, Ardhamatsyendrasana, Shavasana, Naukasana, Bhujangasana, ArdhaShalabhasana, Chakrasana, Vriksasana, and Sarvangasana; (2) Pranayama or controlled breathing practices (30 min) included were Bhastrika, Ujjayi, Suryabhedana, Chandra bhedana, Nadishodhana, and Kapalbhati; (3) Meditation (25 min) included were Budhist meditation, which involves paying sustained attention to sensations, perceptions, and thoughts with suspension of judgment (for 12.5 min) and Compassion meditation (karuna for 12.5 min).
Naji-Esfahani (2014)²⁴	75 min/session, 3 times/week, 12 weeks	Yoga training: 3 sessions/week for 12 weeks, duration of each session was 75 min plus usual medical care. Hatha yoga program included (1) asanas (Eye-related exercises, Pawanmuktasana, standing-sitting and lying out screw position, palming, (2) Suryanamaskara, (3) Neti exercises, (4) Pranyama, (5) Shavasana.
Patil (2015)²⁵	60 min/session, 5 times/week, 12 weeks	Integrated yoga program: 60 min/session for 5 days in a week for 3 months. Yoga program included (1) Prayer at beginning and closing of session (2 min); (2) Loosening Practices for 10 min (loosening of fingers, wrist, shoulder, and ankle), breathing practices (hands in and out breathing, Ankle stretch breathing, straight leg raising breathing, lumbar stretch breathing); (3) Yogasanas for 15 min (Utkatasana, Padhastasana, Ardhachakrasana, Shashankasana, ArdhaUstrasana, Bhujangasana, ArdhaSalabasana, Trikonasana); (4) Pranayama for 5 min (AnulomaViloma Pranayama, Brahmari Pranayama); (5) Cyclic Meditation (23 min); and (6) Devotional Session (5 min).
Patil (2020)²⁶	75 min/session, daily, 12 weeks	Yoga-based cardiac rehabilitation program for 3 months with usual standard care. A total of 13 in-hospital sessions spread over 3 months with encouragement to practice regularly at home using instruction booklet and video in the local language. Each session lasted for about 75 min. The interventions given in 13 sessions are as follows: (1) Educational session (1 session in week 1), (2) Pranayam, relaxation, and meditation techniques (1 session in week 3), (3) Health rejuvenating exercises, Asanas, Pranayam, relaxation, and meditation techniques (2 sessions/week for weeks 5–7 then followed by 1 session/week for weeks 8–12), and (4) group session—discussion on long-term maintenance of Yoga, dietary, and lifestyle changes at home (week 13). Yoga program included (1) shoulder, chest, and abdomen exercises (3 min each)—total of 3 exercises (10 min); (2) Yogasanas—two core poses and one elective pose from each group (standing, sitting, lying)—total of nine poses (25 min); standing asanas included were Kati-chakrasana, Tadasana, Urdhva-hastottanasana (core poses), and Ardhakati-Chakrasana or Trikonasana (elective poses); sitting asanas included were Gomukhasana, Janushirsasana, Vakrasana (core poses), and Ardha-padmasana or Vajrasana (elective poses); lying asanas included were Ekpadottanasana, Naukasana, Ardha-pavanamuktasana (core poses), and Markatasana or Merudandasana (elective poses); (3) Pranayama or controlled breathing exercises (two core and one elective practice for 5 min each for 15 min)—total of three practices were included, they are Anulomvilom/Nadishodhana Pranayama, Bhramari Pranayama, Ujjayi Pranayama (core pranayama), and Sitali Pranayama or Sitkari Pranayama (elective pranayama); and (4) Meditation and relaxation techniques (two core and one elective practice for 5 min each for 15 min)—total of three techniques were practiced, they were Chanting, Mindfulness meditation, Shavasana (core practices), and Dirghasvasapreksha or Antarangatrataka (elective practices).
Paul-Labrador (2006)³³	90 min/session, 2 times/week, 16 weeks	Transcendental meditation for 16 weeks. 1.5 h twice per week for the first 4 weeks and weekly once thereafter.
Sivasankaran (2006)²⁷	90 min/session, 3 times/week, 6 weeks	Yoga and meditation for 90 min a day for three times a week for 6 weeks. Each 90-min session included meditation (15 min), Pranayama (15 min), Shavasana/deep relaxation following instructions of instructor (20 min) and Asanas/yoga postures (40 min). Pranayama involved slow deep inhalation, breath holding, full exhalation with a closed glottis, and breath holding in a time ratio of 4:2:5:2. Type of asanas and meditation included in the program is not mentioned or given in detail in the article.
Sarvottam (2013)³⁴	120 min, daily, 10 days	Yoga-based lifestyle intervention for 2 h/day for 10 days. The program included asanas/poses and breathing exercises but the details were not provided in the article. This program also included vegetarian diet recommendation, which involves cereals and pulses (preferably unrefined) as staple foods, moderate amounts of judiciously chosen fat, about 500 g of vegetables and fruits daily, with vegetables being predominantly leafy greens and at least some eaten raw, moderate amounts of milk and milk products (yogurt was suggested) and spices in moderation.
Udhan (2020)²⁹	60 min/session, 6 times/week, 6 months	Yoga training for 1 h/day for 6 days in a week for 6 months. Yoga program included Asanas, Pranayama, and Meditation. But the details of these were missing in the article.
Vaccarino (2013)²⁸	60–90 min/yoga class, 21 times/year, 20 min twice a day daily at home, 1 year	CRM, mantra-based meditation, 21 sessions lasting for 1–1.5 h spread over 12 months. Home practice of CRM twice a day for 20 min. The intervention program involved a four-step course for 4 consecutive days (sessions 1–4) and a follow-up program for 12 months (sessions 5–21). Most sessions lasted 1–1.5 h, and the general format was group meditation plus a lecture/discussion. All sessions were taught by an experienced teacher.
Wooten (2020)³⁵	10 min	Twenty yoga poses for 30 sec each. The yoga poses or asanas were performed in the following sequential order: Warrior 1, Warrior II, Reverse warrior, Extended Slide Angle, Forward fold, Halfway lift, High plank, Up Dog, Down Dog, Wide-legged forward chair pose, Mountain pose, Camel pose, Easy pose, Bridge pose, Happy baby, and Savasana.

Method of assessment of endothelial function

The method used for the assessment of endothelial function in the included studies is given in Table 1. The measure used in most studies was brachial FMD (which is a gold-standard measure of endothelial function).^{18,22,23,27,28,31,33,35} However, others evaluated the biomarkers of endothelial function such as ADMA,²⁵ NOx,^{20,25,26,29,30,32} endothelin-1 (ET-1),^26,34 endothelial nitric oxide synthase (eNOS),²⁶ cell-adhesion molecules,^24,26 and endothelial microparticles.¹⁹

Effect of yoga practice

Meta-analysis of effect of yoga on FMD

The results of the meta-analysis were presented in a forest plot (Fig. 2). Among the 15 controlled trials, 7 assessed FMD whereas the other studies evaluated different biomarkers of endothelial function such as circulating endothelial microparticles, ADMA, nitric oxide, or ET-1. One of the studies (Dod et al.) included aerobic exercise (3 h/week) along with yoga and meditation (1 h daily) in its intervention program, so it was excluded from the meta-analysis.¹⁸

FIG. 2.

Forest plot.

Hence, the results of six controlled trials assessing FMD were included in the meta-analysis, which showed a significant increase in brachial FMD with yoga practice (Mean difference −1.23%, 95% CI −2.23 to −0.23, p = 0.02). Hunter et al.'s study included two yoga groups where participants practiced yoga at two temperatures: yoga at 23°C and 40.5°C, respectively; and one control group. Hence, the data of this study in the forest plot are shown as Hunter 2018a (Yoga at 23°C) and Hunter 2018b (Yoga at 23°C).²⁴ These 6 studies included 7 comparisons and a total of 395 participants (188 in the yoga group and 207 in the control group). The heterogeneity between the studies was 43% (Tau² = 0.70, χ² = 10.49). The RoB was low to moderate in these studies.

Narrative review

The results of the effect of yoga on endothelial function have been summarized in Table 1. Out of 18 studies, 12 had reported a significant favorable change in the measures of endothelial function with yoga intervention,^{18

–29} whereas 6 studies did not find any significant effect.^30

–35 Yoga intervention has improved endothelial function in healthy subjects^19,22,23,29 and in patients with coronary heart disease,^18,27 myocardial infarction,^21,26 metabolic syndrome,²⁸ hypertension,²⁵ migraine,²⁴ and dysmenorrhea.²⁰ Among the three studies on patients with coronary heart disease, two studies showed an improvement in endothelial function with yoga^18,27 whereas one study did not find any significant effect.³³

Among healthy subjects, four studies showed an improvement in endothelial function^19,22,23,29 whereas three studies observed no significant change.^31,34,35 Chen et al. showed an improvement in female healthy participants.¹⁹ One study reported a favorable change in endothelial function by yoga in middle-aged and older subjects but not in young healthy.²² The comparator and the type of data analysis (i.e., between-groups or within-group) have been given in detail in Table 1. Most of the studies did both between-groups and within-group data analysis,^{18
–20,24–26,28,30,32,33} whereas a few used only within-group data analysis.^{23,27,29,31,34,35}

Studies have reported significant favorable changes in circulating endothelial microparticles,¹⁹ ADMA,²⁶ and homocysteine.²⁰ Among the six studies that evaluated NOx, there were increased NO levels in two studies,^25,29 decreased levels in one study,³² and no significant difference in the other three studies.^20,26,29 One study showed a significant decrease in ET-1 levels in patients with acute myocardial infarction²⁶ whereas the other study found no change in healthy obese individuals.³⁴

There was no significant effect of yoga on intercellular cell-adhesion molecule (ICAM),^18,24,26 vascular cell-adhesion molecule (VCAM),^18,24,26 E-selectin,^18,26 eNOS,²⁶ and P-selectin.²⁶ Naji-Esfahani et al. found a favorable change in VCAM in patients with migraine.²⁴

Quality assessment and potential bias

The summary and graphical representation of the assessment of RoB of the included studies is shown in Figures 3 and 4. Out of 18 studies, 10 studies reported appropriate generation of random allocation of sequence. Five studies presented the concealment of the allocation sequence.^{19,21,26,28,33} Two studies masked the participants about interventions either by presenting it as health-promoting to minimize expectation bias/performance bias²⁸ or till baseline data collection.²³

FIG. 3.

Risk-of-bias summary.

FIG. 4.

Risk-of-bias graph.

However, we believe that the outcomes of lifestyle modification studies are not likely to be influenced by lack of blinding. Blinding of assessment outcomes was done by seven studies. All the studies presented complete outcome data except two where the information was unclear,^24,30 There was no reporting bias in 17 studies, of which 1 study split the outcomes of a single study into 2 publications.^24,30

However, it is to be noted that very few studies have either registered in clinical trial registries or published the protocol. We found a high RoB in the design of a few studies; either the participant's condition of the comparator group was not similar to the study group^20,27 or no comparator^22,27 or single-group studies.^29,31,34

Sensitivity analysis

A sensitivity analysis of the studies included in the meta-analysis did not show any significant influence of an individual study on the overall meta-analysis.

Adverse events

Among the included studies, only two studies had reported adverse events.^23,33 Of these, one had reported a pulling hamstring during the practice of asana (Half-moon pose/Ardha-chandrasana)²³ whereas other studies had no adverse events.³³

Discussion

We believe that this is the first systematic review and meta-analysis of the effect of yoga on endothelial function. We have included 18 studies involving 1043 participants for review and narrative synthesis; and 6 studies (that assessed FMD) involving 395 participants for meta-analysis.

Yoga training showed an improvement in endothelial function in 12 studies whereas 6 studies did not find any statistically robust difference. The meta-analysis of six studies showed a significant increase in brachial FMD in the yoga group, indicating an improvement in endothelial function with yoga practice. A moderate (43%) heterogeneity was found between the studies.

The variability in the duration, frequency, and type of yoga techniques among the intervention programs of the reviewed studies may be attributed to the differences in the results (effect size) of the studies. The duration of yoga intervention ranged from 6 weeks to 12 months, except in one study that evaluated the immediate effect of 20 selective yoga postures practiced for 30 sec each.³⁵

Studies with yoga intervention for ≥12 weeks have shown better beneficial changes in endothelial function (77%; 10 out of 13 studies) than those with ≤12 weeks of yoga intervention (40%; 2 out of 5 studies). Duration of each session did not affect much but studies that delivered the intervention for ≥5 times a week (frequency; 87.5%; 7 out of 8 studies) showed greater response than those using intervention ≤5 times a week (62.5%; 5 out of 8 studies).

In one study by Sarvottam et al., the frequency of intervention was 7 times/week but the total duration of yoga training was only 1.5 weeks³⁴ whereas in another study immediate effects were observed.³⁵ These findings suggest that higher frequency and duration of yoga intervention is associated with greater endothelial response. However, the adequate dosage (duration and frequency) of yoga intervention for endothelial protection or improvement remains unclear and needs to be determined.

The RoB was low in 50% of the studies, moderate in 30%, and high in 20% of the studies included in the narrative syntheses (n = 18). However, the quality of the methodology of the six studies included in the meta-analysis was good with low to moderate RoB.

The intervention program of most of the studies of this review included only yoga-based techniques except one study by Dod et al., where apart from yoga and meditation (1 h daily), aerobic exercise (3 h/week) was also part of their Multisite Cardiac Lifestyle Intervention Program.¹⁸ Hunter et al. compared the effect of yoga training at two temperatures on FMD, in which they reported a significantly better improvement in FMD with yoga, practiced in a thermoneutral condition (23°C) than heated condition (40.5°C).²³

Limitations

There are several limitations to this review. The search strategy was focused only on studies published in the English language, so we may have missed studies published in other languages. Instead of focusing on one clinical condition, all studies that assessed the effects of yoga on endothelium were included. There was both clinical and methodological diversity that may affect and vary the intervention effects. Hence, statistical heterogeneity among the included studies was significant.

Due to fewer numbers of controlled studies that assessed the biomarkers of endothelium, it was not possible to conduct a meta-analysis of yoga effects on endothelial biomarkers. Since unpublished and non-English language studies were not searched, and the study protocols of most of the studies included for review were not published or registered prospectively, so potential for publication bias cannot be ruled out.

Implications for research and clinical practice

Despite the successful control of CV risk factors with several strategies including drugs, the reduction of CV morbidity and mortality is limited to about 20%–45%.¹² The tool that helps in monitoring the response to treatment and can predict future events will be useful in identifying the patients at risk (despite optimal treatment). A growing number of interventions that are known to reduce CV risk are found to be associated with improved endothelial function.⁴⁶

Because endothelial dysfunction predicts future events, major research efforts have been focused on the early detection of endothelial dysfunction and the identification of new treatment approaches in humans. Available evidence supports that change in endothelial function can be used in the care of patients and as a surrogate measure for assessing the effectiveness of interventions that prevent CV events.^46,47

The findings of this review are intriguing, as they showed a favorable endothelial response to yoga in people with varying health issues and during cardiac rehabilitation. The methodological quality of the controlled trials included in the meta-analysis was good and demonstrated significant improvement in endothelial function with yoga practice. This implies that yoga could be a potential clinical tool to improve endothelial function.

However, most of the studies did not assess the association between improvement in endothelial function and clinical outcomes with yoga; and were limited by small sample size. Therefore, still there is a need for clinical trials with large sample sizes; and those that can focus and provide evidence on the association of change in the endothelial function with clinical outcomes following yoga practice. Further, future studies should also focus on the underlying mechanisms through which yoga influences endothelial function.

Mechanism of yoga on endothelial function

The precise mechanism underlying the benefit of yoga on the endothelial system remains to be elucidated. Oxidative stress and vascular inflammation play a major role in the development of endothelial dysfunction. Vascular oxidative stress reduces the bioavailability of nitric oxide either by scavenging nitric oxide by superoxide or by altering the function of eNOS, where it produces superoxide instead of nitric oxide (eNOS uncoupling).

Oxidative stress also induces ET-1 synthesis in endothelial cells and human macrophages.⁴⁸ Either reduction in bioavailability of nitric oxide or increased production of ET-1 results in endothelial dysfunction and shifts the physiological endothelial balance toward vasoconstrictor dominance.⁴⁹ A few studies endeavored to explore the mechanism underlying the yoga-induced changes in the endothelial system. We have recently investigated the effect of 3 months of a yoga-based cardiac rehabilitation program on several biomarkers related to the endothelial system and oxidative stress in patients after acute myocardial infarction.

Our study found a significant reduction in ADMA, ET-1, ICAM-1, VCAM, E-selectin, and total antioxidant capacity (TAOC) with yoga CaRe program. In this study, yoga did not induce any change in eNOS, P-selectin and total NOx, oxidized low density lipoproteins (LDL) (Oxd-LDL), superoxide dismutase (SOD), and inflammatory markers: tumor necrosis factor-alpha (TNFα), C-reactive protein (CRP).²⁶ However, in the study of Dod et al., there was no significant change in cell-adhesion molecules after 3 months of lifestyle intervention program (yoga and meditation, nutrition, aerobic exercise, smoking cessation, and psychological support) in patients with coronary artery disease.¹⁸

Yoga also induced significant enhancement in NOx in healthy²⁹ and elderly patients with hypertension,²⁵ but not in women suffering from migraine³⁰ and dysmenorrhea.²⁰ A few studies have demonstrated the beneficial effects of yoga on oxidative stress, inflammation, and its related genes expression.^50

–56 In the studies of Bhasin et al., and Dusek et al., they reported a reduced expression of gene linked to oxidative response, inflammatory response, and stress-related pathways in healthy individuals.^55,56

Thus, the probable mechanism by which yoga improved the endothelial function is by restoring the vasoconstrictor and vasodilator balance (either decreasing ET-1 or increasing bioavailability of NO) by reducing the vascular oxidative stress and inflammation. However, further studies focusing on molecular mechanisms (particularly, expression of genes related to endothelium) are required to understand the precise mechanism of yoga on endothelial function.

Conclusions

Yoga practice improves endothelial function and can restore the endothelial balance toward physiological vasodilator dominance. Yoga could be a safe and potential integrative medicine to improve endothelial function. However, as the statistical heterogeneity, that is, variation in the FMD among the studies was moderate, large clinical trials are necessary for its clinical recommendations.

Footnotes

Acknowledgment

The authors are thankful to Shri Dharmasthala Manjunatheshwara University for the partial support to this project.

Authors' Contributions

S.G.P. and P.D. contributed to the conception or design of the work. V.K., E.C., R.C., A.M.C., H.S.V., R.R., K.A., and S.G.P. contributed to the acquisition, analysis, or interpretation of the work. S.G.P. and R.M.D. drafted the manuscript. K.K.D., A.R., S.K., and P.D. critically revised the manuscript. All authors gave final approval and agree to be accountable for all aspects of the work ensuring the integrity and accuracy.

Author Disclosure Statement

The authors declare that they have no competing interests.

Funding Information

No funding was received for this article.

Supplementary Material

PRISMA Checklist

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