Vagus Nerve Stimulation and the Cardiovascular System
Role of Vagus Nerve
The vagus nerve contributes to physiological homeostasis, including reflex pathways regulating cardiac function. It’s linked to the high-frequency component of heart rate variability (HRV), and is connected to vagal tone. Recently, Vagus Nerve Stimulation (VNS) has been explored as a treatment for various diseases like epilepsy, rheumatoid arthritis, Crohn’s disease, and asthma. Given its connection to the heart, VNS may potentially treat cardiovascular disorders like cardiac arrest, myocardial infarction, and stroke.
Cardiac Arrest and VNS
- Cardiac arrest is a cessation of blood flow due to a malignant cardiac arrhythmia such as VF, leading to rapid death if untreated. It requires time-sensitive interventions like CPR, defibrillation, ventilation, and drugs.
- Its treatment follows a three-phase model: electrical phase (first 5 mins), circulatory phase (5-10 mins), and metabolic phase (after 10 mins). Current treatments fail to address the metabolic phase effectively, where most victims die.
- Preclinical studies suggest VNS could be used to improve resuscitation attempts in rats with induced cardiac arrest.
- These studies indicated that VNS increased success rates of Return of Spontaneous Circulation (ROSC), reduced the duration of CPR, and decreased the number of electric shocks required for ROSC.
- The studies suggested that VNS’s protective effects could be linked to α7nAChR and its anti-inflammatory effects.
Heart Failure and VNS
- Heart failure is a condition where the heart muscle fails to maintain adequate blood flow. If the heart’s adaptations fail, symptoms progress and may lead to death despite treatment.
- VNS could be a new therapy for heart failure. Studies suggest an abnormal imbalance exists between the sympathetic and parasympathetic nervous systems during heart failure, which worsens the condition.
- VNS was shown to reduce hyperactivity of the sympathetic nervous system, which leads to tonic and reflex inhibition of cardiac vagal efferent activity.
- VNS showed significant improvement in left ventricular hemodynamics in animals with heart failure, reducing mortality rates. It also showed promising results in canine models of heart failure.
- Chronic application of VNS was found to improve left ventricular systolic function, prevent left ventricular enlargement, and improve heart failure biomarkers.
- VNS influences signaling pathways like the baroreceptor reflex, reduces proinflammatory cytokines, normalizes the NO pathway, and suppresses gap junction remodeling.
Acute Myocardial Infarction (MI)
- MI happens when there’s a lack of perfusion to the heart due to occlusion of coronary arteries, leading to heart damage.
- Coronary artery disease strongly associated with MI.
- Vagus Nerve Stimulation (VNS) is being studied for its impact on blood flow, arrhythmias, inflammatory changes, and progression of heart disease in relation to MI.
- VNS could improve ventricular repolarization and reduce the likelihood of arrhythmia post-MI.
- Low-Level VNS (LL-VNS) could improve ventricular function, reduce ventricular tachycardia episodes, and decrease infarct size.
Atrial Fibrillation (AF)
- AF is a common cardiac arrhythmia with rapid, irregular beating of the atria.
- AF treatment focuses on heart rate control and stroke prevention.
- LL-VNS has been shown to reduce AF risk in preclinical models by modulating the autonomic nervous system.
- LL-VNS can reverse atrial remodeling caused by rapid atrial pacing (RAP) and reduce the likelihood of AF.
- LL-VNS helps in returning the electrical and autonomic systems to their baseline values, thereby reducing AF inducibility.
Stroke
- Stroke is a critical lack of perfusion to the brain leading to death of brain tissue.
- VNS has been shown to promote plasticity in the brain following ischemic stroke, thereby aiding recovery.
- VNS must be paired temporally with rehabilitative training to be effective.
- VNS can also decrease lesion size, attenuate cerebral edema, and improve clinical outcomes in stroke patients.
Coagulopathy and Hemorrhagic Shock
- Coagulopathy in trauma patients significantly impacts survival rates.
- VNS during resuscitation can improve thromboelastomeric parameters and bring cytokine levels closer to baseline.
- VNS could potentially enhance survival in trauma patients by activating the inflammatory reflex.
Hypertension and VNS
- Hypertension is a significant health issue in the US, affecting nearly 75 million people, with approximately 15%-18% of these cases resistant to traditional treatments.
- Vagus Nerve Stimulation (VNS) has been studied as a potential treatment, with early results being promising.
Animal Studies
- A study on salt-sensitive rats showed a significant increase in mean arterial pressure and arrhythmia episodes after 6 weeks of a high-salt diet.
- After 4 weeks of VNS therapy, significant improvements in mean arterial pressure and the number of arrhythmic episodes were observed [Annoni et al. 2015].
- Similar results were found with cardiac-cycle-synchronized selective VNS (ccsVNS) in hypertensive rats. Both static and pulsatile stimulation showed significant, sustained reductions in hypertension [Plachta et al. 2016].
- Pulsatile stimulation had a significantly reduced impact on bradycardia, making it more optimal as a treatment strategy [Plachta et al. 2016].
- Similar effects were seen in pigs, where closed-loop left VNS (CL-LVNS) caused a decrease in blood pressure and heart rate [Sevcencu et al. 2018].
Human Studies
- VNS has been studied in conjunction with medications as part of combination therapy, primarily to assess safety and efficacy [Gierthmuehlen and Plachta 2016; Gierthmuehlen et al. 2016a,b].
- Introduction of a biologic mitigated the effects of selective-afferent VNS (sVNS) on blood pressure, but treatment was still effective without inducing significant bradycardia [Gierthmuehlen and Plachta 2016; Gierthmuehlen et al. 2016a,b].
Side Effects of VNS
- VNS treatment can cause significant side effects, including bradycardia leading to asystole, a potentially fatal condition characterized by a cessation of electrical activity from the heart [Ben-Menachem 2001; Shankar et al. 2013; Pascual 2015].
- Infections are possible from the surgical implantation of VNS devices. Postoperative infections occur in 3% to 6% of patients [Ben-Menachem 2001].
- Other potential side effects include left cord paralysis (with symptoms typically resolving after VNS device removal) and lower facial weakness [Ben-Menachem 2001].
- While deaths have been linked to VNS, evidence suggests that death rates due to sudden unexpected, unexplained deaths in epilepsy tend to be lower in patients receiving VNS [Ben-Menachem 2001].
Conclusion
- VNS has shown promise for treating several cardiovascular conditions, aiding in the resuscitation of animals in cardiac arrest and with severe hemorrhage, improving recovery after myocardial infarction (MI), alleviating symptoms of heart failure and stroke, and modulating arrhythmias.
- However, serious cardiovascular adverse effects like bradycardia and cardiac standstill can occur with improper use or dosage of VNS therapy.
- Therefore, caution must be exercised in future human trials of VNS for cardiovascular conditions.
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