The pursuit of health and well-being lies at the core of modern medicine. Beyond merely treating diseases, the medical field seeks to identify risk factors and protective mechanisms that prevent adverse health outcomes and foster a higher quality of life. Equally important is understanding the biological processes that sustain resilience and balance, shifting the focus from managing illness to actively enhancing the elements contributing to overall well-being. Globally, heart disease, cancer, stroke and chronic obstructive pulmonary disease remain the leading causes of mortality, imposing a tremendous burden on individuals and healthcare systems (1). Chronic conditions such as pain, anxiety and depression also significantly contribute to the global burden of disease due to their disabling effects (2). Addressing these challenges requires identifying shared risk factors and implementing cost-effective, evidence-based interventions to improve outcomes, reduce disability, and promote longevity.

The COVID-19 pandemic has underscored the importance of autonomic regulation, as SARS-CoV-2 infection is associated with dysautonomia, inflammatory cytokine storms and long-term autonomic dysfunction (long COVID). Reduced heart rate variability (HRV) has been observed in patients recovering from COVID-19, indicating impaired vagal function (3,4). HRV biofeedback intervention (HRV-B) and the safe and sound protocol (SSP) could potentially serve as non-invasive rehabilitative strategies to restore autonomic balance, mitigate post-viral fatigue and improve cardiovascular function. Preliminary studies suggest that vagus nerve stimulation (VNS) may counteract COVID-19-induced inflammation by modulating the cholinergic anti-inflammatory pathway, reducing excessive cytokine responses. Given the ability of HRV-B and SSP to enhance vagal tone, future research should investigate their role in post-COVID recovery.

Seamless communication between vital systems, orchestrated by the autonomic nervous system (ANS), is fundamental to a healthy organism. The ANS, comprising the sympathetic nervous system and parasympathetic nervous system (PNS), maintains homeostasis by regulating responses to internal and external stimuli (5,6). This dynamic system synchronizes physiological functions and serves as a crucial interface between neurophysiological processes and peripheral markers of disease.

Central to the PNS is the vagus nerve, aptly termed the ‘wandering nerve’ for its expansive reach. Composed of 80% afferent and 20% efferent fibers, it transmits signals from the organs of the body to the brain and regulates organ functions (7,8). Originating from the brainstem, the vagus nerve extends through the neck and thorax, innervating key visceral organs such as the heart, lungs, liver, and colon. Descending fibers from the nucleus ambiguous and dorsal vagal nucleus synapse at cardiac plexuses, influencing cardiac structures, such as the sinoatrial node, atrioventricular node and coronary arteries (9).

The vagus nerve plays a pivotal neuro-immunological role, facilitating communication between the nervous and immune systems. Immune cells express neurotransmitter receptors, while the nervous system innervates lymphoid tissues, enabling the vagus nerve to modulate inflammation via two critical pathways. The hypothalamic-pituitary-adrenal (HPA) axis mediates cortisol release and systemic anti-inflammatory effects. By contrast, the cholinergic anti-inflammatory pathway involves splenic T-cells releasing acetylcholine to suppress inflammatory cytokine production (10-12).

This dual role highlights the potential of the vagus nerve as a therapeutic target. Its ability to regulate inflammation and promote physiological coherence offers profound implications for improving health and reducing global disease burden.

The therapeutic potential of VNS has substantially evolved since its discovery in the late 19th century when James Corning first explored its anti-seizure effects in epileptic patients (64). Over time, various non-pharmacological methods have been developed to harness the therapeutic benefits of the vagus nerve, addressing conditions ranging from chronic headaches (65,66) and inflammation (67) to depression and atrial fibrillation (68).

VNS techniques are categorized into two main approaches: Invasive VNS (iVNS) and non-invasive VNS (nVNS). International consensus recognizes four primary VNS modalities: Cervically implanted (iVNS), transcutaneous cervical VNS (tcVNS), transcutaneous auricular VNS (taVNS) and percutaneous auricular VNS (paVNS) (69). iVNS involves surgically implanting a pulse generator under the skin of the upper chest, and connecting it to the left vagal nerve via electrodes (70-72). Conversely, nVNS stimulates vagal nerve pathways accessible through the skin, typically targeting the external ear (taVNS) or the neck (tcVNS) (73-75).

In 1997, iVNS received FDA approval for the treatment of medically refractory partial epilepsy, followed by its use in severe, recurrent unipolar and bipolar depression in 2005 (76,77). In Europe, iVNS achieved the Conformité Européenne (CE) marking for epilepsy and treatment-resistant depression (77,78). However, the surgical risks and side-effects associated with iVNS prompted the development of non-invasive alternatives.

nVNS provides comparable benefits, while improving safety and accessibility (79,80). Introduced clinically in 1997, nVNS mimics the physiological effects of iVNS, although with improved tolerability and fewer adverse effects (81). The FDA has approved tcVNS for the treatment of migraines (82) and cluster headaches (74). Over the years, VNS has been used in the treatment of hundreds of thousands of patients with various neurological disorders, generating extensive clinical data for exploring new applications.

Stroke rehabilitation represents a promising area for VNS. Randomized controlled trials have indicated that combining VNS, both invasive and non-invasive, with rehabilitation therapy significantly enhances upper limb recovery post-stroke (72,83,84). Additionally, VNS has shown potential in managing chronic pain, tinnitus, epilepsy, and depression (85-90). Notably, the VNS-REHAB study, published in The Lancet, highlighted VNS as an innovative treatment for limb paralysis caused by ischemic stroke, solidifying its role in neurorehabilitation (72).

Non-invasive VNS stands out due to its ease of implementation and favorable safety profile. By eliminating surgical risks, such as infections, peritracheal hematomas, vocal cord damage and dyspnea, nVNS has become a patient-friendly alternative (79). Techniques, such as auricular branch stimulation have proven effective in treating atrial fibrillation, reducing sinus rates, slowing atrioventricular conduction and shortening atrial fibrillation episodes (91,92). Similarly, neck-based nVNS has demonstrated anti-inflammatory properties, broadening its therapeutic utility (93). Furthermore, nVNS is simple, cost-effective, and safe with ECG and HRV monitoring, making it accessible to many patients.

VNS continues to evolve as a versatile therapeutic tool. Its non-invasive modalities enhance accessibility and safety, paving the way for broader clinical applications in managing neurological and systemic conditions. As ongoing research refines these techniques, VNS holds immense promise for advancing patient care and outcomes.

HRV-B is an innovative, non-invasive and evidence-based technique designed to enhance vagal nerve activity by combining slow-paced breathing with real-time HRV feedback. The practice involves regulating breathing to approximately six cycles per minute, significantly lower than the standard respiratory rate of 12 to 20 breaths per minute (94). By synchronizing this controlled breathing pattern with HRV feedback, individuals can effectively boost vagal tone, improving overall autonomic regulation. HRV-B is simple to implement, cost-effective, and carries minimal risk, rendering it an accessible tool for various health interventions. Established protocols further support its practical application (95,96).

This method emphasizes the importance of breathing education, focusing on techniques that lower respiratory rates, relax thoracic muscles, and promote diaphragmatic breathing. Tension in the abdomen, pelvis, or lower back often restricts diaphragmatic movement, leading to reliance on chest and shoulder muscles for respiration. Such inefficient breathing patterns can contribute to hyperventilation, characterized by excessive breathing and reduced end-tidal CO2 levels. Hyperventilation, in turn, is strongly associated with psychological stress and various somatic and behavioral symptoms (97-99). By contrast, slow-paced breathing promotes relaxation and resilience, offering preventive and adjunctive benefits for numerous conditions with minimal adverse effects (100).

HRV-B influences autonomic regulation primarily through baroreflex engagement and the cholinergic anti-inflammatory pathway. At the cellular level, HRV-B enhances the activity of vagal afferents, inhibiting pro-inflammatory cytokines, such as TNF-α, IL-6 and IL-1β through the release of acetylcholine from splenic T-cells. This mechanism directly attenuates systemic inflammation and promotes cardiovascular resilience (15).

HRV-B modulates the activity of the HPA axis, reducing cortisol secretion and enhancing parasympathetic outflow. The resulting physiological state supports neuroplasticity by strengthening prefrontal cortex connectivity with autonomic centers in the brainstem. SSP, although still under investigation, is considered to engage vagal activity through auditory-motor circuits. It likely modulates neuroplasticity within the nucleus ambiguous and dorsal vagal complex, enhancing parasympathetic tone. Preliminary evidence suggests that SSP may influence oxytocin release, contributing to social bonding and stress resilience; however, further studies are required to confirm these cellular-level effects (101-105). HRV-B primarily operates through baroreflex engagement, stabilizing autonomic rhythms and enhancing vagal tone (15).

This results in improved cardiac efficiency, reduced sympathetic overactivation and lower systemic inflammation. On the other hand, SSP engages the ventral vagal complex via auditory-motor pathways, facilitating neuroplasticity and enhancing emotional regulation. Recent research suggests that SSP may function by modulating the influence of the prefrontal cortex on autonomic outflow, promoting a shift toward parasympathetic dominance (101-105).

HRV-B uses audiovisual biofeedback tools to present real-time data on physiological parameters, such as heart rate, muscle activity, brain activity and skin conductance. This feedback empowers individuals to consciously regulate these processes, enhancing psychological and physiological well-being (28). The technique explicitly trains individuals to adopt optimal breathing patterns, significantly increasing vmHRV. By doing so, HRV-B activates autonomic and respiratory regulatory mechanisms, fostering physiological coherence. HRV-B training aims to achieve a steady breathing rate of around six cycles per minute. Reviewing key quantitative metrics across studies to provide a more precise assessment of HRV-B and SSP effectiveness is essential (101-105).

For HRV-B, commonly reported parameters include RMSSD, HF-HRV and SDNN, which indicate vagal activity. SSP studies often measure changes in resting HF-HRV and LF/HF ratios to assess autonomic modulation. The results from major studies are compared in Table II. These results highlight the measurable effects of HRV-B and SSP on autonomic balance.

Although individual variations may exist (106), this synchronization of heart rate oscillations with respiratory patterns leads to a state known as cardiac, respiratory and blood pressure coherence, or HRV coherence (106-108). During this state, frequency-domain metrics often reflect a dominance of the low-frequency (LF) band centered around 0.1 Hz, with decreases in HF and VLF bands and mean heart rate. HRV-B sessions provide visual and auditory representations of heart rate and respiration, helping individuals maintain and amplify LF-HRV power (109).

HRV-B strengthens vagal tone and promotes broader autonomic resilience by fostering physiological coherence, rendering it a powerful tool for managing stress, enhancing mental health and improving overall well-being. Its simplicity, accessibility and efficacy contribute to its value in clinical practice and personal health management. The intervention primarily operates through baroreflex engagement, vagal afferent activation, and modulation of the cholinergic anti-inflammatory pathway, leading to the suppression of pro-inflammatory cytokines, such as TNF-α, IL-6 and IL-1β, which play a crucial role in systemic inflammation and autonomic dysfunction. By contrast, SSP is hypothesized to engage vagal pathways via auditory-motor circuits, potentially enhancing neuroplasticity within autonomic regulatory centers and thereby supporting improved emotional and physiological regulation. The underlying mechanisms, physiological effects, and clinical benefits of HRV-B and SSP are summarized in Table III.

HRV has emerged as a critical indicator of cardiovascular health, particularly in predicting and managing CHD. A reduced HRV is consistently linked with an elevated risk of cardiac events. A prospective study involving 2,501 participants without pre-existing heart disease revealed that a decrease in the SDNN independently predicted a 47% higher risk of future cardiac events (42). Supporting these findings, a meta-analysis of 21 studies revealed that patients with SDNN values <70 msec following a myocardial infarction faced an almost 4-fold greater risk of mortality compared to those with higher SDNN values (43). Further evidence from a review of nine studies demonstrated that patients who experienced ST-elevation myocardial infarction and had low HRV in the time domain or a high LF/HF ratio were at a significantly higher risk of all-cause mortality and major adverse cardiovascular events (123).

The physiological mechanisms linking reduced HRV to cardiovascular diseases involve oxidative stress, heightened sympathetic nervous system activity, and inflammation. Oxidative stress contributes to oxidized low-density lipoprotein (LDL) cholesterol formation, while inflammation attracts macrophages to developing cardiac plaques. These plaques engulf oxidized LDL, worsening coronary blockages (124,125). Excessive sympathetic activity exacerbates the risk of a myocardial infarction by increasing oxygen demand, causing coronary vasoconstriction and aggravating coronary lesions. Conversely, as higher HRV indicates, vagal nerve activity mitigates these risks by reducing oxidative stress, regulating inflammation and curbing sympathetic overactivity (12,51,126).

HRV-B provides promising therapeutic benefits for individuals with myocardial infarction or CHD by directly improving HRV and modulating autonomic responses. In a previous study on 54 with coronary artery disease (CAD), those randomized to HRV-B therapy exhibited significant improvements in HRV and reduced hostility, independent predictors of better outcomes post-MI (127,128). Another randomized controlled trial demonstrated that HRV-B significantly increased LF-HRV and SDNN levels in patients with CHD (129). Similarly, another randomized controlled trial involving 46 patients post-myocardial infarction found that HRV-B enhanced HRV metrics (SDNN and HF-HRV) and improved self-efficacy, while no such benefits were observed in the control group (130).

Further evidence was derived from a year-long study of 210 Chinese patients with CAD, half of whom underwent HRV-B therapy; the HRV-B group exhibited a significantly increased LF-HRV and experienced reduced hospital readmissions at the 1-year follow-up (131). Another randomized controlled trial that combined HRV-B with cognitive-behavioral stress management training demonstrated that improvements in psychological adjustment were closely linked to increases in the HF index of vagal HR modulation, but only in the HRV-B group (132).

These findings establish HRV-B as an effective intervention for enhancing HRV, improving psychological well-being and reducing hospital readmissions in patients with myocardial infarction, CAD, or CHD. By addressing underlying mechanisms, such as inflammation and oxidative stress, HRV-B provides a valuable tool for the management of and recovery from cardiovascular disease.

Several large-scale epidemiological studies have demonstrated that hypertension has also been closely linked to a reduced HRV. For instance, the Atherosclerosis Risk in Communities (ARIC) study followed 7,099 initially normotensive individuals and found that reductions in SDNN and the RMSSD were strong predictors of hypertension development over a period of 9 years (133). These findings underscore the role of diminished HRV as a significant risk factor for elevated blood pressure.

The vagus nerve plays a central role in regulating blood pressure through the baroreflex, a negative feedback mechanism critical for maintaining hemodynamic stability. Mechanoreceptors in large vessels, such as the aorta, detect changes in arterial pressure and activate the vagus nerve, reducing the heart rate via brainstem pathways and lowering cardiac output and blood pressure. Additionally, while vasoconstriction contributes to hypertension, the vagus nerve counteracts this through its vasodilatory effects, further aiding in blood pressure regulation.

The therapeutic potential of HRV-B in managing hypertension is well-supported by randomized controlled trials. In a notable 3-month study of 43 pre-hypertensive participants, those randomized to HRV-B demonstrated significant increases in HRV and reductions in both systolic blood pressure and diastolic blood pressure, unlike participants in the deep breathing or no-intervention groups (134). That study also highlighted the importance of biofeedback in reinforcing and self-monitoring physiological changes, showing its added value over simple-paced breathing (134).

Another randomized controlled trial involving 65 hypertensive patients found that HRV-B significantly reduced systolic blood pressure compared to autogenic relaxation, which was used as a control intervention (132). Similarly, a smaller study on 22 participants explored the effects of R-wave-to-pulse interval biofeedback, a method conceptually similar to HRV-B, over a period of 2 weeks (135). Among the 12 participants with high blood pressure, diastolic levels significantly decreased during the intervention. Notably, participants with low blood pressure experienced increases in diastolic levels, although the absence of a control group in that study complicates the interpretation of these results (135).

These findings provide compelling evidence of the effectiveness of HRV-B in regulating blood pressure. By enhancing vagal tone and improving baroreflex sensitivity, HRV-B serves as a promising non-pharmacological strategy for managing hypertension. Its ability to address the underlying autonomic dysfunction associated with elevated blood pressure highlights its potential to improve cardiovascular health and overall well-being.

The SSP, founded on the principles of the polyvagal theory, represents a groundbreaking, non-invasive approach to vagus nerve stimulation. This protocol capitalizes on the central role of the vagus nerve in maintaining health by focusing on three critical aspects. First, it highlights the connection between the ventral vagal complex and symptom relief, demonstrating how stimulating specific afferent pathways can significantly enhance mental and physical health (101). Second, SSP engages afferent pathways linked to brainstem regions that regulate somatomotor and visceromotor responses, thereby optimizing the autonomic nervous system's regulatory functions (102). Lastly, the protocol acknowledges the profound impact of chronic stress and trauma in disrupting the autonomic balance. These disruptions often hinder the ability of the ventral vagal complex to manage threat responses and maintain the homeostasis essential for growth, recovery and overall health (103).

Advances in understanding the anatomy and physiology of the vagus nerve have driven the evolution of clinical strategies such as neuromodulation. These strategies emphasize exercises to strengthen autonomic function and reduce dependence on long-term interventions (104). SSP employs specially filtered music to stimulate the vagus nerve via the auditory system, fostering a profound sense of physiological safety. This stimulation mitigates defensive responses, such as anxiety and stress, while improving emotional regulation and social engagement. By targeting the middle ear muscles essential for processing human speech, SSP enhances individuals' sensitivity to social cues, improves communication, and fosters a sense of security in social interactions (103). Additionally, the protocol increases parasympathetic activity, stabilizing the autonomic nervous system. Studies have confirmed that SSP significantly enhances HRV, a key marker of autonomic regulation, thus promoting stress resilience and overall well-being (103,105,136).

The SSP is a relatively new intervention based on the principles of the polyvagal theory. SSP aims to influence autonomic function by stimulating auditory pathways linked to vagal regulation. While preliminary studies have reported improvements in autonomic markers and emotional regulation, the existing research is limited to small-scale studies, pilot trials and case reports, often without control groups. The effects of SSP on HRV and vagal tone remain an area of ongoing investigation. Thus, further, randomized controlled trials are warranted to determine its efficacy and applicability in clinical settings. Although some findings suggest that SSP may enhance social engagement and reduce stress responses, these results need to be interpreted with caution until more extensive and rigorous studies confirm its benefits.

In children with ASD, SSP has led to significant improvements in sensory processing, particularly in auditory function, with substantial results observed after only 5 h of exposure to filtered music (105,136). Beyond autism, SSP has gained recognition for its potential in cardiovascular disease rehabilitation. Research consistently associates a low HRV with increased mortality rates in cardiovascular conditions, while chronic stress exacerbates the risk of developing cardiovascular disease by promoting central adiposity, metabolic dysregulation and inflammation (137,138). The stress-buffering hypothesis underscores the critical role of social support in mitigating the physiological impacts of stress, with social engagement identified as a key prognostic factor for cardiovascular health (139,140). By enhancing parasympathetic activity and HRV, SSP is a valuable intervention for counteracting stress-related effects in CVD patients. Its ability to foster social engagement and reduce defensive responses aligns with the stress-buffering hypothesis, suggesting a role of SSP as an integral component of cardiovascular rehabilitation programs. By promoting emotional and physiological regulation, SSP helps patients better manage stress, improving cardiovascular and general health outcomes (138-140).

The intricate association between PTSD and cardiovascular conditions is being increasingly evidence in research, revealing a dual dynamic where PTSD contributes to the onset of heart diseases and exacerbates their progression (141,142). Studies on veteran populations have demonstrated that PTSD significantly increases the risk of heart failure. For example, a previous study found a 47% greater risk of developing heart failure among veterans with PTSD, independent of traditional risk factors, such as diabetes and hypertension (143).

Notably, cardiac conditions themselves can precipitate PTSD, a phenomenon termed cardiac disease-induced PTSD (CDI-PTSD). Acute cardiovascular events such as myocardial infarction or cardiac arrest often function as triggers, given their life-threatening nature. CDI-PTSD differs from conventional PTSD by its distinct focus on an intense fear of recurrence and intrusive, future-oriented thoughts. For example, studies estimate that up to 25% of cardiac arrest survivors develop PTSD (144). Similarly, takotsubo syndrome (TTS), also known as ‘broken heart syndrome’, is frequently linked to emotional trauma. Although TTS typically resolves without causing long-term physical damage, its psychological effects can persist, leading to PTSD-like symptoms in some individuals (145).

HRV-B provides a promising therapeutic approach for managing both PTSD and cardiac conditions. This intervention enhances the vagal tone and restores autonomic nervous system regulation, addressing the dysregulation often seen in PTSD. HRV-B has shown particular efficacy in reducing PTSD symptoms, particularly in military populations (146). Simultaneously, HRV-B improves HRV and lowers the risk of recurrent cardiac events in individuals with cardiovascular disease (147).

The dual effectiveness of vagal neuromodulation techniques such as HRV-B in treating PTSD and cardiac conditions highlights its transformative potential. HRV-B provides an integrated approach that can significantly improve patient outcomes by addressing the psychological and physiological dimensions of managing these interrelated conditions.

The present article discussed two innovative, non-invasive approaches, namely HRV-B and SSP, focusing on their ability to enhance vagal tone and support autonomic regulation. The reviewed body of research underscores the importance of HRV as a prognostic indicator across diverse medical conditions, including myocardial infarction and cancer. While the broad applicability of HRV reduces its specificity for diagnosing particular illnesses, it remains a valuable tool for predicting and improving health outcomes. Employing feasible cardiovascular measurement and stimulation techniques based on HRV presents promising opportunities for advancing physical and mental health. These interventions also lay the groundwork for future research in vagal nerve stimulation and its clinical applications.

The present narrative review consolidates current knowledge and paves the way for future interdisciplinary exploration. By juxtaposing HRV-B and SSP within a cohesive model, it highlights novel avenues for enhancing resilience and autonomic regulation across various health conditions.

HRV-B is a well-established intervention for optimizing autonomic regulation, whereas SSP, although promising, requires further research to confirm its efficacy. Leveraging the crucial regulatory functions of the vagus nerve provides innovative pathways for addressing cardiovascular and mental health conditions. Beyond treatment, they hold immense potential for disease prevention and recovery, reinforcing their role in holistic healthcare approaches. Future research is required refine these techniques, broaden their clinical applications and uncover their full therapeutic potential.