Vagus Nerve Stimulation and Inflammation in Cardiovascular Disease: A State‐of‐the‐Art Review

Abstract

Vagus nerve stimulation (VNS) has been found to exert anti‐inflammatory effects in different clinical settings and has been associated with improvement of clinical outcomes. However, evidence on the mechanistic link between the potential association of inflammatory status with clinical outcomes following VNS is scarce. This review aims to summarize the existing knowledge linking VNS with inflammation and its potential link with major outcomes in cardiovascular diseases, in both preclinical and clinical studies. Existing data show that in the setting of myocardial ischemia and reperfusion, VNS seems to reduce inflammation resulting in reduced infarct size and reduced incidence of ventricular arrhythmias during reperfusion. Furthermore, VNS has a protective role in vascular function following myocardial ischemia and reperfusion. Atrial fibrillation burden has also been reduced by VNS, whereas suppression of inflammation may be a potential mechanism for this effect. In the setting of heart failure, VNS was found to improve systolic function and reverse cardiac remodeling. In summary, existing experimental data show a reduction in inflammatory markers by VNS, which may cause improved clinical outcomes in cardiovascular diseases. However, more data are needed to evaluate the association between the inflammatory status with the clinical outcomes following VNS.

The interaction between the autonomic nervous system and inflammation is well known. Stimulation of adrenergic receptors on immune cells regulates all stages that are important for a coordinated immune response. ¹ The sympathetic nervous system has been found to have a significant impact on the immune system function with regard to the development and exacerbation of chronic immune‐mediated diseases. ¹ On the other hand, the parasympathetic nervous system interacts with innate immunity, by acting as an anti‐inflammatory neural circuit. ²

Recent studies have shown that vagus nerve stimulation (VNS) can reduce the expression of inflammatory proteins. ³ , ⁴ , ⁵ The cardioprotective role of VNS has been attributed to the limitation of myocyte apoptosis and improvement of myocardial metabolism. ⁶ , ⁷ Furthermore, the beneficial role in arrhythmias following VNS has been attributed to the electrical stability by reducing disease‐associated loss of connexin‐43. ⁸ However, the evidence on the mechanistic link between the potential association of inflammatory status with clinical outcomes following VNS is scarce. This review aims to summarize the existing preclinical and clinical data about the association of VNS with inflammation and the potential link of this effect with clinical outcomes in cardiovascular diseases (Table).

Table 1.

Association of VNS With Inflammation in Cardiovascular Diseases

First author	Year of publication	Model	Study design	Outcomes	Biomarkers
Myocardial ischemia and reperfusion
Preclinical studies
Calvillo 30	2011	Rat	VNS group VNS plus atrial pacing VNS plus nicotinic inhibition by mecamylamine	VNS with or without atrial pacing decreased infarct size and inflammatory markers during ischemia/reperfusion.	VNS significantly reduced the number of infiltrated macrophages. VNS decreased the signal intensity for the 2 cytokines involved in the recruitment of neutrophils (LIX) and macrophages (MCP‐1).
Kiss 31	2017	Rat	Sham‐operated Control IR (30‐min ischemia and 2‐h reperfusion) VNS throughout IR The arginase inhibitor nor‐NOHA+IR Nor‐NOHA+VNS+IR Selective α7nAChR blockade by MLA followed by VNS throughout IR MLA+IR	VNS reduced the infarct size.	VNS attenuated the increase in arginase activity compared with control.
Nuntaphum32	2018	Swine	IR no VNS Left midcervical VNS with both vagal trunks intact Left vagus nerve transection, Right vagus nerve transection Atropine pretreatment	VNS led to infarct size reduction and decreased arrhythmia score.	TNF‐α levels in the myocardium were reduced in the group of left midcervical VNS with both vagal trunks intact compared with the ischemia and reperfusion group. The levels of IL‐10 did not differ significantly between groups.
Sheng 34	2016	Canine	IR group IR plus LL‐CBS Sham group	VNS led to reduction of ventricular arrhythmias in the setting of myocardial ischemia and reperfusion injury.	LL‐CBS reduced TNF‐α, IL‐1, IL‐6, and malondialdehyde levels but increased superoxide dismutase level. LL‐CBS modulated the Cx43 expression.
Yi 35	2016	Rat	VNS Anti‐IL‐17A neutralized monoclonal antibodies	VNS was found to have cardioprotective effects (infarct size).	VNS was able to significantly inhibit the increased expression levels of TNF‐α, IL‐6, HMGB‐1, and IL‐17A
Wang 37	2014	Rat	Sham group IR group VNS performed at 15 min of ischemia (VSI15) group VNS performed immediately before reperfusion (VSR0) group VNS performed at 30 min of reperfusion (VSR30) group VNS performed at 60 min of reperfusion (VSR60) group	VNS at 15 min during ischemia significantly decreased the infarct size. Reduction of arrhythmias during reperfusion.	VNS at 15 min significantly decreased serum HMGB‐1 and ICAM‐1 levels at 120 min of reperfusion, myocardial HMGB‐1, IL‐1, and IL‐6 levels in the nonischemic region, and myocardial ICAM‐1 level in the ischemic region. VNS at 15 min increased IL‐10 levels in both ischemic and nonischemic regions.
Zhang 36	2016	Dog	VNS group Sham group	Subthreshold VNS significantly suppressed ventricular arrhythmias.	Reduction of serum inflammatory markers (CRP, IL‐6, TNF‐α, HMGB‐1) and noradrenaline during the ischemia and reperfusion periods.
Clinical studies
Yu 39	2017	N/A	LLTS group Control group (with sham stimulation)	Tragus stimulation reduced the incidence of reperfusion‐related ventricular arrhythmias, the left ventricular ejection fraction, and the wall motion index.	Tragus stimulation reduced CK‐MB and myoglobin, IL‐6, IL‐1β, HMGB‐1, and TNF‐α.
Peripheral artery disease
Preclinical studies
Zhao 42	2013	Rat	Sham group VNS group IR group, in which 60 min of LAD occlusion and 120 min of reperfusion were conducted VNS+IR group, in which stimulation of the vagal nerve was started 15 min before LAD occlusion and continued throughout 60 min of myocardial ischemia and 120 min of reperfusion VNS+IR+MLA, in which the rats received an intraperitoneal injection of selective α7nAChR antagonist (MLA, 10 mg/kg) VNS+IR+MLA	VNS improved ischemia and reperfusion‐induced dysfunctional vasoconstriction and vasodilatation and degradation of endothelial structure in mesenteric arteries.	VNS upregulated expressions of M3AChR and α7nAChR in mesenteric arteries.
Atrial arrhythmias
Preclinical studies
Deng45	2022	Rabbit model of M2 muscarinic acetylcholine receptor‐activating autoantibodies induced POTS	Comparison with preimmune state	Low‐level tragus stimulation suppressed postural tachycardia, improved the sympathovagal balance with increased acetylcholine secretion, and reversed the attenuated heart rate response to a M2 muscarinic agonist.	Reduced TNF‐α, IL‐1β, and IFN‐γ.
Clinical studies
Stavrakis43	2015	N/A	LLTS group Control group	Pacing‐induced AF duration decreased significantly, whereas the AF cycle length increased significantly from baseline in the intervention group, but not in the control group.	Systemic (femoral vein) but not coronary sinus TNF‐α and CRP levels decreased significantly only in the intervention group.
Stavrakis 44	2017	N/A	LLVS Sham group	Following cardiac surgery, VNS reduced postoperative AF.	VNS reduced serum TNF‐α and IL‐6 levels compared with the control group.
Heart failure
Preclinical studies
Zhang 3	2009	Canine tachycardia‐induced, pacing model	VNS group Control group	Chronic VNS led to lower left ventricular end‐diastolic and end‐systolic volumes and improvement in LVEF compared with the control group.	VNS attenuated a rise in plasma norepinephrine, angiotensin II, and CRP levels.
Elkholey4	2022	Rat (HFpEF)	LLTS LLTS with the α7nAchR blocker MLA Sham Olmesartan	Low‐level transcutaneous VNS suppressed cardiac inflammation and fibrosis and improved cardiac function.	The beneficial effect of transcutaneous VNS was attenuated with α7nAchR pharmacological blockade.
Subramanian5	2020	Rat (HFpEF)	LLTS Sham	Low‐level transcutaneous VNS has been found to exert a central anti‐inflammatory and antioxidant role that could mediate the modulation of cardiac vagal tone.	LLTS attenuated inflammation by decreasing IL‐6 levels in the SP5 brainstem site and IL‐1β in the SFO forebrain site.
Clinical studies
Stavrakis 57	2022	N/A	Active (tragus) LLTS Sham (earlobe) LLTS	Global longitudinal strain at 3 months was significantly improved in the active compared with the sham arm.	TNF‐α level reduction in the active LLTS group. The reduction in TNF‐α levels correlated with global longitudinal strain improvement.

α7nAChR indicates α‐7 nicotinic acetylcholine receptor; AF, atrial fibrillation; CK‐MB, creatine kinase‐myocardial band; CRP, C‐reactive protein; Cx43, connexin‐43; HFpEF, heart failure with preserved ejection fraction; HMGB‐1, high mobility group box‐1; ICAM‐1, intercellular adhesion molecule‐1; IFN‐γ, interferon‐gamma; IL, interleukin; IR, ischemia and reperfusion; LAD, left anterior descending artery; LIX, lipopolysaccharide‐induced CXC chemokine; LL‐CBS, low‐level carotid baroreceptor stimulation; LLTS, low‐level tragus stimulation; M3AChR, muscarinic acetylcholine receptor‐3; MCP‐1, monocyte chemoattractant protein‐1; MLA, methyllycaconitine; N/A, not applicable; nor‐NOHA, N‐hydroxy‐nor‐arginine; POTS, postural orthostatic tachycardia syndrome; SFO, subfornical organ; SP5, spinal trigeminal nucleus; TNF‐α, tumor necrosis factor‐a; and VNS, vagus nerve stimulation.

AUTONOMIC NERVOUS SYSTEM AND INFLAMMATION

Given the close interaction between the nervous and immune systems, VNS accelerates the resolution of inflammation. ⁹ Specifically, inflammatory cytokines can trigger the vagal nerve while the afferent neurons transmit these signals to the nucleus tractus solitarius of the medulla oblongata. ⁹ After processing in the higher brain centers, neural signals are transmitted to the dorsal nucleus of the vagus nerve, and the efferent neurons suppress peripheral inflammation, thus completing the inflammatory reflex mechanism. ⁹ , ¹⁰ Acetylcholine is the neurotransmitter of this reflex, and its anti‐inflammatory action is achieved by binding to α7nAchR (α7‐nicotinic acetylcholine receptor) on macrophages and other immune cells (Figure). ⁹ , ¹¹ , ¹²

Figure 1. Vagus nerve stimulation can influence the activity of the splenic nerve, which controls lymphocytes in the spleen.

Lymphocytes can produce acetylcholine, which interacts with a7nAChR (α‐7 nicotinic acetylcholine receptor) expressed on macrophages. The intracellular signaling results in the inhibition of the nuclear factor‐κB leading to the suppression of cytokine production.

The following intracellular signal pathways following α7nAChR activation have been described: (1) regulation of NF‐κB (nuclear factor‐κB), (2) activation of the JAK2/STAT3 (Janus kinase 2/signal transducer and activator of transcription 3) signaling cascade to regulate inflammatory responses, and (3) a calcium (Ca²⁺) dependent mechanism that activates classic PKC (protein kinase C), leading to increased production of reactive oxygen species and the activation of the PI3K/Akt/Nrf‐2 (phosphoinositide 3‐kinase/Akt/nuclear erythroid‐related factor 2) pathway. ⁹

Acetylcholine has been recognized as the neurotransmitter for pre‐ and postganglionic vagal efferent nerves, whereas the primary source of proinflammatory cytokines are the macrophages. ¹³ Strong evidence about the potential impact of VNS on inflammation is provided by Borovikova et al. ¹⁴ The authors have shown that during endotoxemia in a rat model, direct electrical stimulation of the peripheral vagus nerve inhibited TNF (tumor necrosis factor) synthesis in the liver, attenuated peak serum TNF‐α amounts, and prevented the development of shock. ¹⁴ Furthermore, acetylcholine significantly attenuated the release of inflammatory cytokines (TNF, interleukin [IL]‐1β, IL‐6, and IL‐18), but not the anti‐inflammatory cytokine IL‐10, in lipopolysaccharide‐stimulated human macrophage cultures. ¹⁴

Modification of the cholinergic anti‐inflammatory pathway has been proposed as a novel treatment strategy in different clinical settings. ¹⁵

VNS AND NEUROLOGICAL DISORDERS

In the setting of traumatic brain injury, VNS attenuated brain damage by inhibiting oxidative stress, inflammation, and apoptosis, possibly through the NF‐κB/NLRP3 (nucleotide‐binding domain‐like receptor protein 3) signaling pathway. ¹⁶ In the same setting, a previous study showed that ghrelin may play an important role in the anti‐inflammatory effects of VNS following traumatic brain injury. ¹⁷

VNS has been found to be an effective treatment option in patients with epilepsy. Specifically, a 50% to 100% seizure frequency reduction could be achieved in approximately 45% to 65% of the patients. ¹⁸ Barone et al studied the effect of direct left VNS on inflammatory markers and cardiac autonomic function in patients with refractory epilepsy. ¹⁹ Specifically, the authors studied the impact of left VNS in 8 patients who underwent implantation of a VNS device because of refractory epilepsy. Heart rate variability assessed by 24‐hour Holter recording and TNF‐α, IL‐6, and C‐reactive protein (CRP) serum levels measured at baseline and 3 months of follow‐up did not indicate a significant effect of left VNS on cardiac autonomic function and systemic inflammation at short‐term follow‐up. ¹⁹ Another study showed that VNS reduced the inflammatory response and apoptosis of epileptic rats via inhibiting microRNA‐210. ²⁰

VNS AND INFLAMMATORY/AUTOIMMUNE DISEASES

In the setting of autoimmune diseases and specifically in patients with rheumatoid arthritis, VNS significantly inhibited TNF‐α production and improved the disease severity. ²¹ Furthermore, the role of VNS has been also studied in inflammatory bowel disease. In a rat model of indomethacin‐induced small bowel inflammation, VNS significantly reduced small bowel total inflammatory lesion area, intestinal peroxidation and chlorination rates, and intestinal and systemic proinflammatory cytokine levels as compared with sham‐treated animals. ²² Interestingly, the observed reduction of intestinal inflammation following VNS was spleen independent and was mediated by direct innervation of the gut. ²² The association of VNS with the intestinal immune system has also been studied. Specifically, VNS resulted in a significant amelioration of the measured inflammatory markers in an experimental food allergy model. ²³ In regard to the mechanism of this effect, VNS action was independent of α7nAChR and was possibly mediated through the dampening of mast cells and increased phagocytosis of ovalbumin by CX3CR1^hi (chemokine C‐X3‐C motif receptor) macrophages. ²³

In an experimental rat model of lipopolysaccharide‐induced septic shock, vagotomy led to an aggravation of the inflammatory response as measured by elevated cytokine levels in plasma and ventricular tissue. ²⁴ Interestingly, a brief stimulation of the vagus nerve was enough during the initial lipopolysaccharide infusion to reverse both hemodynamic and immunologic effects of diminished vagal tone. ²⁴ VNS has been found to protect against liver injury following renal ischemia and reperfusion, and the proposed mechanism of this action seems to be the reduction of oxidative enzymes, apoptosis, and levels of TNF‐α and IL‐6 in serum and liver following VNS. ²⁵

The role of VNS in the management of patients with autoimmune diseases needs further investigation. A study protocol for a randomized, sham‐controlled trial that aims to investigate the role of VNS in the management of patients with systemic lupus erythematosus has been published. ²⁶

VNS AND MYOCARDIAL ISCHEMIA AND REPERFUSION

In acute coronary syndromes, systemic inflammation has been related to infarct size and adverse clinical outcomes following myocardial infarction. ²⁷ Preclinical data have shown that the inhibition of inflammation can effectively improve cardiac function and depressive behaviors in a postmyocardial infarction mouse model via inhibiting TNF‐α/TNFR1 (tumor necrosis factor receptor 1). ²⁸ , ²⁹ As a result, attenuating the inflammatory response may be a therapeutic target in acute coronary syndromes and improve clinical outcomes.

Calvillo et al studied the effect of VNS on the inflammatory response in the setting of myocardial ischemia. ³⁰ Specifically, 4 groups of male rats underwent myocardial ischemia (30 minutes) and reperfusion (24 hours). One group underwent VNS (40 minutes), 1 VNS plus atrial pacing, and 1 vagal stimulation plus nicotinic inhibition by mecamylamine. VNS, with or without atrial pacing, decreased infarct size and inflammatory markers during ischemia and reperfusion. ³⁰ Interestingly, the infarct size was larger in animals that underwent VNS plus nicotinic inhibition compared with VNS, highlighting the underlying mechanisms of action through the nicotinic pathway. ³⁰ The beneficial impact of VNS was attributed to the action of VNS in the inflammation pathway by significantly reducing the number of infiltrated macrophages. Additionally, VNS decreased the signal intensity of cytokines in the recruitment of neutrophils and macrophages. ³⁰

Further insights about the mechanisms of VNS in the reduction of infarct size were provided by Kiss et al. ³¹ This experimental study aimed to clarify whether VNS downregulates myocardial and vascular arginase via a mechanism that involves the activation of α7nAChR following myocardial ischemia and reperfusion in anesthetized rats. ³¹ The study concluded that VNS reduced the infarct size and reversed the upregulation of arginase, both in the myocardium and aorta. This action was attributed to a mechanism that was dependent on the α7nAChR activation. ³¹

Another topic of interest of investigation has been whether the cardioprotection following VNS was attributed to direct activation through its ipsilateral efferent fibers or to indirect effects mediated by the afferent fibers. Nuntaphum et al showed that selective efferent VNS might potentially be effective in attenuating myocardial ischemia and reperfusion injury. At the same time, full cardioprotection was achieved by stimulating contralateral efferent vagal activities. ³² In the same study, VNS significantly decreased the level of oxidative stress activity in the myocardium compared with the ischemic and reperfusion group. TNF‐α levels in the myocardium were reduced in the group of left midcervical VNS with both vagal trunks intact, compared with the ischemia and reperfusion group, whereas the levels of IL‐10 did not differ significantly between groups. ³²

VNS has been also shown to have a protective role in reperfusion arrhythmias independently of the heart rate changes. ³³ In an experimental canine model, low‐level carotid baroreceptor stimulation showed cardioprotective effects during the ischemia and reperfusion period. Specifically, the stimulation significantly decreased the number of ventricular arrhythmias in the setting of myocardial ischemia and reperfusion injury. ³⁴ Potential mechanisms for this action were proposed to be the inhibition of inflammation, oxidative stress, and apoptosis and the modulation of the Cx43 (connexin‐43) expression. ³⁴ On the other hand, in a rat model of ischemia and reperfusion injury, vagal stimulation was found to have cardioprotective effects that were possibly associated with the inhibition of IL‐17A expression. ³⁵ The role of subthreshold VNS (ie, lower than the threshold for slowing the sinus rate) in attenuating inflammation and ventricular arrhythmias in an ischemia and reperfusion model has also been investigated. ³⁶ In this study, vagal stimulation at 50% below the threshold for slowing the sinus rate significantly suppressed ventricular arrhythmias and decreased serum inflammatory markers (CRP, IL‐6, TNF‐α, HMGB‐1 [high mobility group box 1]) and noradrenaline during the ischemia and reperfusion periods. ³⁶ Thus, CRP, TNF‐α, and IL‐6 may be related to the progression of myocardial ischemia and reperfusion injury. Furthermore, the study's results propose that these inflammatory markers play an essential role in the occurrence of ventricular arrhythmias in this setting. ³⁶ The optimal intervention time of the VNS to attenuate myocardial ischemic and reperfusion injury was studied by Wang et al. ³⁷ The authors found that vagal stimulation performed at 15 minutes during ischemia provided the best protection against myocardial ischemia and reperfusion injury compared with vagal stimulation performed immediately before or during reperfusion. Specifically, compared with the other treatment groups (VNS immediately before reperfusion, at 30 and 60 minutes of reperfusion), VNS at 15 minutes during ischemia significantly decreased the infarct size, serum HMGB‐1, and ICAM‐1 (intercellular adhesion molecule 1) levels at 120 minutes of reperfusion, myocardial HMGB‐1, IL‐ 1, and IL‐6 levels in the nonischemic region, and myocardial ICAM‐1 level in the ischemic region. ³⁷ Furthermore, VNS during ischemia increased IL‐10 levels in both ischemic and nonischemic areas and reduced the incidence of ventricular arrhythmias during initial reperfusion. ³⁷ The study showed that early modulation of inflammatory responses following ischemia and reperfusion injury is probably related to the strongest cardioprotection of VNS performed at 15 minutes after ischemia. This finding suggests that the clinical translation of VNS in myocardial ischemia and reperfusion would require intervention before revascularization rather than during reperfusion. This is akin to the concept of unloading the left ventricle before reperfusion. ³⁸

The impact of low‐level tragus stimulation, a noninvasive method of VNS, on myocardial ischemia and reperfusion injury has been studied in patients with ST‐segment–elevation myocardial infarction. ³⁹ Interestingly, the authors found that tragus stimulation reduced the incidence of reperfusion‐related ventricular arrhythmias during the first 24 hours. In addition, the N‐terminal pro‐B‐type natriuretic peptide, the left ventricular ejection fraction, and the wall motion index were improved by tragus stimulation. At the same time, the area under the curve for CK‐MB (creatine kinase‐myocardial band) and myoglobin over 72 hours was smaller compared with the control group. ³⁹ Given that at 24 hours after reperfusion, IL‐6, IL‐1β, HMGB‐1, and TNF‐α were improved in the tragus stimulation group, it was proposed that the clinical improvement in ST‐segment–elevation myocardial infarction was due to the reduction of inflammation. ³⁹ In addition, Zamotrinsky et al showed that vagal neurostimulation improved left ventricular contractility and angina symptoms in patients with coronary artery disease. ⁴⁰

Rossi et al studied the role of postoperative inferior vena cava‐inferior atrial ganglionated plexus burst stimulation in reducing serum levels of inflammatory cytokines following surgical cardiac revascularization. ⁴¹ The authors found that after 6 hours of stimulation, IL‐6, TNF‐α, vascular endothelial growth factor, and epidermal growth factor were significantly reduced. ⁴¹

In conclusion, preclinical and clinical data show a beneficial role of VNS in reducing the burden of inflammation and in improving outcomes in the setting of myocardial ischemia. However, more studies are needed to elucidate the role of VNS in patients with coronary artery disease.

VNS AND PERIPHERAL ARTERY DISEASE

Beyond the role of vagal stimulation in attenuating myocardial injury in the setting of myocardial ischemia and reperfusion, its role in peripheral arteries has also been studied. ⁴² Specifically, VNS was found to improve myocardial ischemia and reperfusion–induced dysfunctional vasoconstriction and vasodilatation, and degradation of endothelial structure in mesenteric arteries. In regard to the mechanism of this action, VNS upregulated expressions of M3AChR (muscarinic acetylcholine receptor‐3) and α7nAChR in mesenteric arteries. ⁴² Following ischemia and reperfusion, serum levels and vascular expression of TNF‐α and IL‐1β were significantly elevated. This elevation of inflammatory markers could potentially increase reactive oxygen species, causing endothelial dysfunction and vascular damage. Notably, an inverse correlation was found between the maximum acetylcholine‐induced relaxation responses and the inflammatory cytokines TNF‐α and IL‐1β. ⁴² This field is still in its infancy, and human data are lacking, but the promising preclinical data form the basis for translational, proof‐of‐concept studies in humans.

VNS AND ATRIAL ARRHYTHMIAS

The antiarrhythmic and anti‐inflammatory properties of low‐level tragus stimulation have also been studied in patients with paroxysmal atrial fibrillation (AF). ⁴³ Specifically, in patients with paroxysmal AF, after 1 hour of tragus stimulation or sham, pacing‐induced AF duration decreased significantly, whereas the AF cycle length increased significantly from baseline in the intervention group but not in the control group. ⁴³ Furthermore, systemic (femoral vein) but not coronary sinus TNF‐α and CRP levels decreased significantly only in the intervention group. ⁴³ The reduction of inflammatory cytokines in the peripheral vein and not in the coronary sinus shows that the anti‐inflammatory action was achieved through the cholinergic anti‐inflammatory pathway and not just through a local cardiac vagal effect. ⁴³

Low‐level VNS also has a role in attenuating postoperative AF and inflammation following cardiac surgery. ⁴⁴ Specifically, in a randomized study, the incidence of postoperative AF and serum TNF‐α and IL‐6 levels were significantly lower in the intervention group than in the control group. ⁴⁴ According to these findings, the authors concluded that low‐level VNS prevented postoperative AF by inhibiting the activity of the cardiac autonomic nervous system and by suppressing inflammation.

A recent study investigated the effect of low‐level tragus stimulation in postural tachycardia syndrome. In a rabbit model of M2R‐AAb (M2 muscarinic acetylcholine receptor‐activating autoantibodie)‐induced postural orthostatic tachycardia syndrome, low‐level tragus stimulation suppressed postural tachycardia, improved the sympathovagal balance with increased acetylcholine secretion, reduced the levels of inflammatory cytokines, and reversed the attenuated heart rate response to an M2 muscarinic agonist. ⁴⁵ Suppression of inflammation and improvement in the cardiovagal dysfunction may be related to the beneficial clinical effect in this setting.

Existing preclinical and clinical data show that low‐level VNS is an effective treatment for AF. However, further studies are needed to elucidate the mechanism of antiarrhythmic action, the optimal site of stimulation, and the optimal stimulation settings. ⁴⁶

VNS AND HEART FAILURE

VNS has been found to improve the long‐term survival of ischemic chronic heart failure in rats by preventing pumping failure and cardiac remodeling. ⁴⁷ Zhang et al studied the role of chronic VNS in systematic inflammation and heart failure progression in a canine tachycardia‐induced pacing model. ³ The authors found that chronic VNS led to lower left ventricular end‐diastolic and end‐systolic volumes and improvement in left ventricular ejection fraction compared with the control group. ³ Importantly, VNS attenuated a rise in plasma norepinephrine, angiotensin II, and CRP levels. ³ The authors concluded that the anti‐inflammatory effect could be the main mechanism of the beneficial effects of VNS in heart failure settings. Heart failure with preserved ejection fraction (HFpEF) accounts for ~50% of heart failure and is projected to dramatically increase in prevalence in the coming years due to the growing aging population. ⁴⁸ Although there is phenotypic heterogeneity in HFpEF, autonomic imbalances and systemic inflammation play an important role in the disease. ⁴⁹ , ⁵⁰ As such, targeting these 2 processes with VNS appears to be an attractive therapeutic option. In a rat model of HFpEF, low‐level transcutaneous VNS suppressed cardiac inflammation and fibrosis and improved cardiac function. ⁴ , ⁵¹ Importantly, the beneficial effect of transcutaneous VNS was attenuated with an α7nAchR pharmacological blockade. ⁴ In addition to its cardiac anti‐inflammatory and antifibrotic effect, low‐level transcutaneous VNS has been found to exert a central anti‐inflammatory and antioxidant role that could mediate the modulation of cardiac vagal tone in the rat model of HFpEF. ⁵

Despite the promising results from preclinical studies, the results of randomized trials of VNS in heart failure with reduced ejection fraction were rather disappointing. Two studies found neutral effects, ⁵² , ⁵³ and 1 study reported mild benefit. ⁵⁴ Differences in patient characteristics and stimulation parameters may account, in part, for the disparate results of these trials. ⁵⁵ The disappointing results of these trials, despite the clear rationale for decreasing sympathovagal imbalance in heart failure, highlight the notion that optimizing stimulation parameters of VNS therapy is crucial to achieve a beneficial effect. ⁵⁶ Patient selection is equally important to optimize neuromodulation outcomes. Unfortunately, an accurate biomarker of response to VNS therapy is lacking at present. Although heart rate variability is the most commonly used biomarker in autonomic modulation studies, its use is limited by the fact that changes in heart rate variability correspond to the effect of the autonomic nervous system on the sinus node and not necessarily to the clinical outcome of interest.

A recent sham‐controlled, double‐blind clinical trial assessed the role of chronic low‐level transcutaneous VNS in patients with HFpEF. ⁵⁷ It was found that global longitudinal strain and TNF‐α levels at 3 months were significantly improved in the active compared with the sham arm. ⁵⁷ In addition, there was an association between the reduction in TNF‐α levels with global longitudinal strain improvement, suggesting that the 2 may be causally related. ⁵⁷ Furthermore, an open‐label phase II study showed that chronic VNS in chronic heart failure patients with severe systolic dysfunction may improve quality of life and left ventricular function. ⁵⁸

Existing data highlight the need of exploring the reasons behind the mixed results in the clinical studies. Furthermore, the definition of the optimal stimulation parameters before embarking on further clinical studies in patients with heart failure with reduced ejection fraction is of great importance.

CONCLUSIONS

Existing data show the beneficial effect of VNS in reducing inflammatory markers, and this may be the primary mechanism for improving clinical outcomes across many cardiovascular diseases. However, more studies are needed to elucidate the mechanisms linking the improvement of the inflammatory state following VNS with clinical outcomes in patients with heart failure, ⁵⁹ myocardial ischemia, ⁵⁹ and arrhythmias. ⁵⁹ , ⁶⁰

Sources of Funding

A.A.A. is supported by the Institute of Precision Medicine (17UNPG33840017) of the American Heart Association, the RICBAC Foundation, and National Institutes of Health grants 1 R01 HL135335‐01, 1 R01 HL161008‐01, 1 R21 HL137870‐01, 1 R21EB026164‐01, 3R21EB026164‐02S1 and R01 HL161008‐01. S.S. is supported by National Institutes of Health grant R01 HL161008‐01.

Disclosures

None.