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Vagal nerve stimulation in myocardial ischemia/reperfusion injury: from bench to bedside
Giuseppe Giannino1,2, Lorenzo Nocera1,2, Maria Andolfatto1,2
1Cardiology, Department of Medical Sciences, University of Turin, Torino, Italy.
Abstract:
The identification of acute cardioprotective strategies against myocardial ischemia/reperfusion (I/R) injury that can be applied in the catheterization room is currently an unmet clinical need and several interventions evaluated in the past at the pre-clinical level have failed in translation. Autonomic imbalance, sustained by an abnormal afferent signalling, is a key component of I/R injury. Accordingly, there is a strong rationale for neuromodulation strategies, aimed at reducing sympathetic activity and/or increasing vagal tone, in this setting. In this review we focus on cervical vagal nerve stimulation (cVNS) and on transcutaneous auricular vagus nerve stimulation (taVNS); the latest has the potential to overcome several of the issues of invasive cVNS, including the possibility of being used in an acute setting, while retaining its beneficial effects. First, we discuss the pathophysiology of I/R injury, that is mostly a consequence of the overproduction of reactive oxygen species. Second, we describe the functional anatomy of the parasympathetic branch of the autonomic nervous system and the most relevant principles of bioelectronic medicine applied to electrical vagal modulation, with a particular focus on taVNS. Then, we provide a detailed and comprehensive summary of the most relevant pre-clinical studies of invasive and non-invasive VNS that support its strong cardioprotective effect whenever there is an acute or chronic cardiac injury and specifically in the setting of myocardial I/R injury. The potential benefit in the emerging field of post cardiac arrest syndrome (PCAS) is also mentioned. Indeed, electrical cVNS has a strong anti-adrenergic, anti-inflammatory, antioxidants, anti-apoptotic and pro-angiogenic effect; most of the involved molecular pathways were already directly confirmed to take place at the cardiac level for taVNS. Pre-clinical data clearly show that the sooner VNS is applied, the better the outcome, with the possibility of a marked infarct size reduction and almost complete left ventricular reverse remodelling when VNS is applied immediately before and during reperfusion. Finally, we describe in detail the limited but very promising clinical experience of taVNS in I/R injury available so far.
Insights
Neuromodulation using vagal nerve stimulation (VNS) shows promise for acute cardioprotection against myocardial ischemia/reperfusion (I/R) injury. Transcutaneous auricular VNS (taVNS) offers a non-invasive approach with significant potential for clinical translation.
Area of Science:
- Cardiovascular Medicine
- Neuroscience
- Bioelectronic Medicine
Background:
- Myocardial ischemia/reperfusion (I/R) injury presents an unmet clinical need for acute cardioprotective strategies applicable in catheterization settings.
- Autonomic imbalance, driven by aberrant afferent signaling, significantly contributes to I/R injury pathogenesis.
- Neuromodulation targeting sympathetic activity and vagal tone offers a promising therapeutic rationale.
Purpose of the Study:
- To review the pathophysiology of myocardial I/R injury and the role of the autonomic nervous system.
- To explore the application of cervical vagal nerve stimulation (cVNS) and transcutaneous auricular vagus nerve stimulation (taVNS) for cardioprotection.
- To summarize pre-clinical and clinical evidence supporting VNS, particularly taVNS, in mitigating I/R injury.
Main Methods:
- Review of pre-clinical studies on invasive (cVNS) and non-invasive (taVNS) vagus nerve stimulation.
- Analysis of the functional anatomy of the parasympathetic nervous system and bioelectronic medicine principles.
- Examination of molecular pathways and clinical data related to VNS in cardiac injury and post-cardiac arrest syndrome.
Main Results:
- Vagal nerve stimulation demonstrates potent cardioprotective effects, including anti-adrenergic, anti-inflammatory, antioxidant, anti-apoptotic, and pro-angiogenic actions.
- Pre-clinical data indicate that earlier VNS application correlates with improved outcomes, such as reduced infarct size and improved left ventricular remodeling.
- Transcutaneous auricular VNS (taVNS) shows potential for acute settings, overcoming limitations of invasive cVNS while retaining therapeutic benefits.
Conclusions:
- Vagal nerve stimulation, especially taVNS, is a promising strategy for acute cardioprotection against myocardial I/R injury.
- The non-invasive nature and efficacy shown in pre-clinical models suggest taVNS's potential for clinical translation.
- Further clinical investigation is warranted to establish taVNS as a standard therapeutic option for I/R injury and post-cardiac arrest syndrome.
