Effect of Yoga on the Autonomic Nervous System: Clinical Implications in the Management of Atrial Fibrillation

Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is seen in approximately 1.5% of the U.S. population [1] and results in substantial morbidity and mortality [2]. One of the largest U.S. epidemiological studies, the Framingham Heart Study, predicted that AF prevalence doubles with each advancing decade of age, from 0.5% at age 50-59 years to almost 9% at age 80-89 years, independent of the increasing prevalence of known predisposing conditions [2]. Although medical treatment involving radiofrequency catheter ablation has become the well-accepted management strategy for AF [3] failure of this therapy is common, with only two-thirds or less of the patients treated remaining free of AF on long-term followup [3]. Early recurrence of atrial tachyarrhythmia, usually defined as arrhythmia recurrence within the first 3 months following ablation, is frequently associated with late recurrence of atrial tachyarrhythmia [4,5]. Acute myocardial injury and the subsequent inflammatory response, as well as modifications of the cardiac autonomic nervous system, provide an early and potentially reversible pro-arrhythmic substrate because of altered atrial myocardial conduction and refractoriness [3]. Research has shown that psychological stressors and imbalance in the autonomic nervous system (ANS) are the most common triggers for paroxysmal AF [6,7]. The mind-body therapy yoga has been shown to reduce stress and maintain autonomic nervous system balance [8]: hence, use of complementary health


Introduction
Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is seen in approximately 1.5% of the U.S. population [1] and results in substantial morbidity and mortality [2]. One of the largest U.S. epidemiological studies, the Framingham Heart Study, predicted that AF prevalence doubles with each advancing decade of age, from 0.5% at age 50-59 years to almost 9% at age 80-89 years, independent of the increasing prevalence of known predisposing conditions [2]. Although medical treatment involving radiofrequency catheter ablation has become the well-accepted management strategy for AF [3] failure of this therapy is common, with only two-thirds or less of the patients treated remaining free of AF on long-term follow-up [3]. Early recurrence of atrial tachyarrhythmia, usually defined as arrhythmia recurrence within the first 3 months following ablation, is frequently associated with late recurrence of atrial tachyarrhythmia [4,5]. Acute myocardial injury and the subsequent inflammatory response, as well as modifications increasing the risk of AF by 40% in men [2]. Likewise, AF is a potent risk factor for ischemic stroke, increasing the risk of stroke 5-fold, thus leading to about 15% of all strokes nationally [10].
The most common AF symptoms include palpitations, shortness of breath, fatigue, dizziness, and anxiety. In a study of 100 randomly selected patients with AF, 88% reported palpitations on exertion, 86% reported palpitations at rest, 70% reported shortness of breath on exertion, 87% reported reduced physical ability, and 59% reported anxiety [6]. Adults with major depression, anxiety, or somatization disorder generally have an associated increase in the severity of their AF symptoms [11].

Quality of life in individuals with AF
AF contributes to increased morbidity in the elderly by adversely affecting their quality of life (QOL) and by deterioration in myocardial function, increasing susceptibility to heart failure, stroke, hospitalization, and mortality [12]. Evaluation of QOL in a group of 264 female patients with AF enrolled in the Canadian Trial of Atrial Fibrillation (N = 403) showed that women had significantly more impaired QOL than men, specifically related to physical rather than emotional functioning [13]. In another study, outpatients with documented AF (N = 152) reported substantially poorer QOL than healthy controls [14]. Three of the four well-known randomized controlled trials (STAF, PIAF, RACE) comparing rate versus rhythm control demonstrated a greater improvement in QOL in patients receiving rate control [15] than those in the rhythm control group. However, the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial revealed a similar improvement in QOL for both rate and rhythm control groups [15].

Health care costs associated with AF
A national survey estimated that direct medical costs were 73% higher in patients with AF compared with matched control subjects, representing a net incremental cost of $8705 per patient per year and a national incremental cost between $6 and $26 billion [16]. Retrospective analyses of three federally funded U.S. databases using 2001 data [17] found that approximately 2,34,000 hospital outpatient department visits, 2,76,000 emergency room visits, 3,50,000 hospitalizations, and 5 million office visits were attributable annually to AF. The total annual medical cost for the treatment of AF in the inpatient, emergency department, and hospital outpatient settings estimated at $6.65 billion is likely an underestimate as costs for long-term anticoagulation, stroke prevention, inpatient drugs, and hospital-based physician services were not included [17].

Patients with AF enrolled in the Fibrillation Registry Assessing
Costs, Therapies, Adverse events, and Lifestyle (FRACTAL) study who were managed with cardioversion and pharmacotherapy incurred AF and other cardiovascular-related health care costs of $4000 to $5000 per year [18]. Among patients with recurrent AF, the frequency of recurrence was strongly associated with higher resource use, with each recurrence increasing annual costs by an average of $1600 [18]. The cost-effectiveness of catheter ablation is difficult to determine because of differences in the experience levels of centers treating these patients, use of technology, and rates of reimbursement, each of which affects cost calculations [19]. Researchers evaluating the costeffectiveness of AF ablation compared with rhythm control or anti arrhythmic agents have shown that ablation treatment results in improved quality-adjusted life expectancy, although at a higher cost [18,19].

Atrial fibrillation and stress
Researchers have shown that psychological stressors and imbalance in the autonomic nervous system are the most common triggers for paroxysmal AF [6,7]. Acute life stressors affect the development and spontaneous conversion of AF and are thought to be mediated by the sympathetic nervous system. This hypothesis is supported by increased circulating catecholamine following an acute life stress and by observation that beta-adrenergic blockade prevents abnormal heart rhythm disturbances triggered by acute life stress [5]. In a study of 100 randomly selected patients with idiopathic paroxysmal atrial fibrillation, 54% reported psychological stress as the most common triggering factor for AF [6]. In another study of 116 patients with AF without an obvious cause, acute life stress significantly affected the development and spontaneous conversion of AF [7].
The autonomic innervations to the heart from the brain, the spinal cord (extrinsic system) and the ganglion plexi of the heart itself comprise the local ANS (intrinsic system) [20]. This intrinsic cardiac ANS of the heart and the pericardium serves as more than a relay station for the intrinsic projections of the vagal-sympathetic system from the brain and spinal cord to the heart. Supporting this theory is the fact that ablation of the major ganglion plexi at the pulmonary vein atrial entrances either eliminates or markedly diminishes AF inducibility. Also, this intrinsic cardiac autonomic system can act independently to modulate numerous cardiac functions, including automaticity, contractility, and conduction [20].
In addition to the sympathetic component of the ANS, the parasympathetic component has been shown to play a role in AF [21]. Amar et al. [22] showed that the onset of AF was preceded by a primary increase in the sympathetic drive followed by marked modulation toward vagal pre-dominance.
The physiologic studies by Patterson et al. [23] further indicate that sympathetic stimulation plays an important modulatory role in the emergence of focal drivers for AF in the presence of an increased vagal tone. The ANS is involved in the genesis of both AF triggers (i.e., ectopic foci that result from interaction between vagal and sympathetic stimulation) and the creation of a more established AF substrate that is needed for the maintenance of AF and is enhanced in the presence of structural heart disease [21].
It has been shown that the abnormal electrical conduction within the pulmonary veins could be sustained only in the presence of isoproterenol or acetylcholine, indicating that sympathomimetic or cholinergic stimulation appears to be necessary to promote the development of sustained focal activity in the pulmonary veins [21].

Relationship between autonomic nervous system and measurement of heart rate variability
Heart rate variability (HRV), the variance between the R-R intervals or complete cardiac cycle on the electrocardiogram, can be used to assess the balance between the sympathetic and parasympathetic branches of the ANS [24]. Efferent sympathetic and parasympathetic activity is integrated in and with the activity occurring in the heart's intrinsic nervous system. Thus, HRV is considered a measure of neurocardiac function that reflects heart-brain interactions and ANS dynamics [25]. HRV is assessed with various analytical approaches, although the most commonly used are frequency domain (power spectral density) analysis and time domain analysis [25]. The European Society of Cardiology and the North American Society of Pacing and Electrophysiology Task Force Report on HRV divided heart rhythm oscillations into 4 primary frequency bands: highfrequency (HF), low-frequency (LF), very-low-frequency (VLF), and ultra-low-frequency (ULF) [24]. It is often assumed that a low LF:HF ratio reflects greater parasympathetic activity relative to sympathetic activity [25]. In contrast, a high LF:HF ratio may indicate higher sympathetic activity relative to parasympathetic activity as can be observed when people engage in meeting a challenge that requires effort and increased sympathetic activation. Alternatively, it can indicate increased parasympathetic activity as it occurs during slow breathing.
Time domain indices quantify the amount of variance in the inter-beat-intervals using statistical measures. The three most important and commonly reported time domain measures are the standard deviation of normal-to-normal (SDNN), the SDNN index, and the root mean square of successive differences (RMSSD) [25]. The modulation of vagal tone helps maintain the dynamic autonomic regulation important for cardiovascular health. Reduced parasympathetic (high frequency) activity has been found in cardiac pathologies and in patients under stress or suffering from panic, anxiety, or worry [24].

Yoga as a complementary health approach in treating atrial fibrillation
Yoga, an ancient discipline from India, is a mind-body exercise in which both physical and mental disciplines are brought together to achieve peacefulness of mind and body, resulting in a relaxed state that is useful in managing stress and anxiety. To date, two studies have assessed the impact of yoga on AF. One, a proof-of-concept study [26], revealed that 60-minute Iyengar yoga sessions at least twice a week for 3 months improved symptoms, arrhythmia burden, heart rate, blood pressure, anxiety and depression scores, and several domains of QOL in adults with paroxysmal AF. A second study [27] using mediyoga as the intervention, showed that this style of yoga might potentially lower blood pressure, lower heart rate in patients with paroxysmal AF, and improve QOL compared to a control group.
Given the potential positive impact of yoga on decreasing AF episodes and symptoms as shown in Table 1   To develop a state-of-the-art review of health impacts of yoga and pranayama

Review of Literature
Yoga and pranayama reduce stress and anxiety, improves autonomic nervous system balance by triggering neuro-hormonal mechanisms by the suppression of sympathetic activity, improves physical health of cancer patients Brown RP et al. [29] To propose a neurophysiologic model to clarify mechanisms by which Sud-harshanKriya yogic breathing can be used to balance the autonomic nervous system and influence psychologic and physiologic parameters Grounded theory A proposed neurophysiologic model that postulates the following: -Strengthening, balancing and stabilizing the autonomic and stress response systems -Decreasing chemoreflex sensitivity -Improved baroreflex response -Shifting to Parasympathetic dominance via vagal stimulation -Balancing of cortical areas (synchronization) by thalamic nuclei -Calming effect on the cortical area involved in executive functions such as anticipation, planning, and worry -Activation of limbic systems leading to stimulation of forebrain reward systems and emotional release. Increased release of prolactin and oxytocin enhancing feelings of calmness and social bonding SudharshanKriya yoga may improve autonomic function, neuroendocrine release, emotional processing, and social binding; The authors' model might be of heuristic value in identifying areas for future clinical research related to yogic breathing

Journal of Yoga and Physiotherapy
Markil N et al. [30] To compare acute sympathovagal changes as measured by HRV responses to yoga nidra relaxation alone compared to yoga nidra relaxation preceded by hatha yoga 15  Following bhastrika pranayamic breathing for 5 min both systolic and diastolic blood pressure decreased significantly, with a slight decrease in heart rate; The group of volunteers whose heart rate and BP were compared before and after breathing exercise following intake of hyoscine-N-butylbromide showed no significant alteration in either of these para-meters

Journal of Yoga and Physiotherapy
Telles S et al. [38] To assess changes in autonomic and respiratory variables in normal healthy volunteers before, during, and after four types of meditation (

Journal of Yoga and Physiotherapy
Wolever RQ et al. [42] To evaluate viability and proofof-concept for two mind-body stress reduction programs (one thera-peutic yoga-based and other mindfulness-based) and to evaluate two delivery venues of a mindfulness-based intervention (online vs in-person) 239 subjects-63 in California and 176 in Con-necticut with 205 com-pleting study; 23.4% male; average age 42.9 yrs; Non-Hispanic = 93.7%, White = 78.2%, Asian = 7.9%, African American = 6.3% Inclusion criteria: Score of ≥16 on 10-item Perceived Stress Scale Exclusion criteria: Arrhythmia requiring medication or pacemaker, pregnancy, tobacco use, medications affecting heart rate; any major medical condition (e.g., COPD, CHF, Angina, traumatic brain injury and type I Diabetes) or psychological disorder (i.e., post-traumatic stress disorder, major depression, bipolar disorder, psychosis, severe anxiety, panic disorders; practicing yoga several times a week currently or participation in an extended meditation or yoga retreat of ≥2 days in past 5 years 239 partici-pants random-ized to either 12-week viniyoga stress reduction program or 1 of 2 mindfulness-based programs or control group assessment (assessment only) Viniyoga taught by trained teachers with instructional handouts provided for home practice; half the participants received a DVD to support home practice; two mindfulness-at-work programs identical except one was provided 'in-person' in a conventional classroom, other one provided through online virtual classroom allowing for real-time bidirectional communication increase in HRV signify-cantly higher during yoga exercise than during pla-cebo and control activity, especially for parameters associated with vagal tone (i.e., SDNNi, rMSSD) Relaxation by yoga training is associated with a significant increase of cardiac vagal modulation; Because this method is easy to apply and leads to a deep mental and physical relaxation, it could be a suitable intervention during cardiac rehabilitation to shift ANS balance to an increase in vagal activity and potentially decrease cardiac mortality

Journal of Yoga and Physiotherapy
Muralikrishnan K et al. [46] To assess effect of Isha yoga, a system of yoga pro-grams offered by Isha Founda-tion, on cardiovas-cular auto-nomic ner-vous system through shortterm HRV

healthy
Isha yoga practitioners (12 men, 2 women; mean age 31.57 ±5.83 yrs) compared with age-and gender-matched non-yoga prac-titioners substance-related or eating disorders and suicidal thoughts or tendencies; any medical illness that would pose a safety concern or limit study participation Yoga interven-tion provided in 3 groups of 12-13 participants for 60-90 mins 3 times/wk/8-weeks (total of 20 sessions per group), with sessions led by 3 highly exper-ienced Iyengar yoga teachers, rotating over the sessions The 20 articles that met the inclusion criteria are shown in Table 2. Seventeen were interventional studies with 14 of these using random sampling; 3 used non-randomized sampling techniques. One of the studies included a discussion of the effect of yoga on the parasympathetic and GABA systems [8] and the other study reviewed the health impacts of yoga and pranayama [28]. The review also identified two relevant articles that provided additional information on the impact of yoga on the ANS. One of the articles, provided a review of the health impacts of yoga and pranayama [28] and the second proposed a neurophysiologic model to clarify the mechanisms by which SudharshanKriya yogic breathing balance the autonomic nervous system activity [29].

Sample characteristics
The participants in all 17 interventional studies were  [33]. Slow breathing exercises can improve sympathetic and parasympathetic reactivity [34]. Slow pace

Journal of Yoga and Physiotherapy
Bhastrikapranayama exercise has shown a strong tendency towards improving function of the ANS through enhanced activation of the parasympathetic system [35]. Yoga practice of cyclic meditation during the day appears to shift sympathovagal balance in favor of parasympathetic dominance during sleep on the following night which promotes improved quality of sleep [36]. Four months of respiratory training in Bhastrika pranayama increased respiratory function and improved cardiac parasympathetic modulation in a group of healthy elderly subjects [37]. The changes during Dhyana (meditation) [38] and guided relaxation [39] resulted in reduced activity of the sympathetic nervous system showing a shift in autonomic balance towards vagal dominance. Laughter yoga therapy for individuals awaiting heart transplant showed improvement in vigor-activity, friendliness, and long-term anxiety. It also improved HRV measures within or close to normal ranges from being low at baseline perhaps related to reduced vagal stimulation [40]. Integrated yoga practice reduced perceived stress and improved adaptive autonomic response to stress in healthy pregnant women [41].
The styles of yoga reported on in the research reviewed include Hatha yoga, viniyoga, Ishayoga, Iyengar yoga, laughter yoga, integrated yoga, yoga nidra relaxation, meditation Only 4 studies mentioned the number of participants who completed the studies, with attrition rates ranging from 3.3% to 54.06%. The primary reasons for participants not completing a study were drop outs, irregular attendance at intervention sessions, and relocation following study enrollment. Higher attrition occurred in 'in-person' mindfulness therapy groups (27.3%) compared to the 'online' mindfulness meditation groups (3.8%) [42], giving rise to the need to consider the format and location of yoga interventions. Also, the studies reviewed did not provide an explicit theoretical or conceptual framework to explain the basis for the yoga interventions used with the study population.

A psychoneuroimmunological framework to explain effects of yoga on AF
To address the deficit in the literature regarding theoretical or conceptual frameworks in the studies reviewed, the authors identified a psychoneuroimmunological framework adapted from McCain et al. Figure 1: Depicts the non-modifiable and modifiable risk factors for development of atrial fibrillation. Psychological stress and the resulting neurological imbalance in the autonomic nervous system trigger inflammation and atrial fibrosis creating the substrate for onset and sustaining persistent atrial fibrillation. The framework indicates that yoga practice can potentially foster the electrical stability of the heart by decreasing stress and reestablishing the autonomic nervous system balance, thereby lessening AF episodes, AF symptoms, stress, depression, and anxiety, thus improving patients' health-related quality of life.
[43] shown in Figure 1 to depict the electrical, mechanical, and structural changes in the heart that lead to a stress-related imbalance in the ANS resulting in AF. Yoga interventions can potentially foster the electrical stability of the heart by maintaining ANS balance and lessening AF episodes, AF symptoms (palpitations, shortness of breath, dizziness, and fatigue), stress, depression, and anxiety, thus improving the participants' health-related QOL. Modulating factors such as stress can cause imbalance in the ANS, which, in turn, can lead to AF. Persistent AF causes inflammation and fibrosis of the atria, resulting in a fixed substrate for re-entry and consequent sustained episodes of AF [21], making treatment options to break this re-entrant cycle challenging. Triggers for atrial fibrosis include the activation of the renin-angiotensinaldosterone system, inflammation, and oxidative stress [44]. The combination of normal and diseased atrial fibers in conjunction with local fibrosis results in spatial dispersion of atrial refractoriness and causes localized conduction abnormalities, including intra-atrial conduction block and slow conduction [44]. Thus, the interplay of stress (psycho), imbalance in the ANS (neuro), activation of the renin-angiotensin-aldosterone system, inflammation and oxidative stress resulting in atrial Journal of Yoga and Physiotherapy fibrosis (immuno) triggers AF and creates a substrate for persistent AF. Mind-body approaches use the concept of body and self-awareness to promote rechanneling of energy within the body thereby maintaining an internal balance. This mindbody balance can further reduce [47] psychological stressors that are important modulating factors in AF and modulate the ANS to parasympathetic dominance in maintaining a stable myocardium, thereby preventing arrhythmias.

Conclusion
Even though the time span of the yoga interventions reported in the studies reviewed ranged from a few minutes to months, all the studies demonstrated some beneficial effect in maintaining nervous system balance and significant impact on selected physiological and psychological factors, thereby improving the participants' overall QOL. Given its impact on modulating autonomic system balance and reducing psychological stress, selected styles of yoga might be considered as cost-effective complementary health approaches in managing AF episodes and symptoms. Further rigorous study is warranted to clarify further the specific mechanisms involved in the use of yoga in patients diagnosed with AF.