Vagal Nerve Stimulation Reduces Ventricular Arrhythmias and Mitigates Adverse Neural Cardiac Remodeling Post–Myocardial Infarction

Hadaya, Joseph; Dajani, Al-Hassan; Cha, Steven; Hanna, Peter; Challita, Ronald; Hoover, Donald B.; Ajijola, Olujimi A.; Shivkumar, Kalyanam; Ardell, Jeffrey L.

doi:10.1016/j.jacbts.2023.03.025

Cited by 13 publications

(7 citation statements)

References 64 publications

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“…By selectively stimulating the cardiac efferents and avoiding majority of the afferent fibers of the vagus nerve, titration could be avoided. As shown in Hadaya et al (2023) 3 , considerable cardioprotection was achieved when VNS was applied at the neural fulcrum. However, titration subsequent to MI was required to reach this optimal point.…”

Section: Discussionmentioning

confidence: 85%

“…By applying electrical stimulation to the nerve, these physiological effects can either be induced or inhibited. At present, vagus nerve stimulation (VNS) is used to treat drug-resistant depression and epilepsy, but a particularly critical application for VNS is in cardiac pathologies such as heart failure (HF), ischemic heart disease, hypertension and arrhythmia [1][2][3] . The autonomic nervous system (ANS), via its vagal and sympathetic limbs, controls cardiac contractile and electrophysiologic function.…”

Section: Introductionmentioning

confidence: 99%

“…MI further leads to downregulation of parasympathetic (vagal) activity, this is associated with lethal ventricular arrhythmias 4 and is intricately involved in the process of maladaptive cardiac remodeling 5 that ultimately leads to cardiac mortality. By performing VNS, regional cardiac electrical and mechanical function is maintained, susceptibility of the myocardium to harmful arrhythmias and the effects of sympathetic system overactivation can be reduced thereby mitigating heart disease progression 3,6 . In preclinical studies, reactive VNS has preserved autonomic control and induced cardioprotection when applied early on post-MI 3 .…”

Section: Introductionmentioning

confidence: 99%

“…By performing VNS, regional cardiac electrical and mechanical function is maintained, susceptibility of the myocardium to harmful arrhythmias and the effects of sympathetic system overactivation can be reduced thereby mitigating heart disease progression 3,6 . In preclinical studies, reactive VNS has preserved autonomic control and induced cardioprotection when applied early on post-MI 3 . VNS has also shown promise for treating HF in recent clinical trials where improvements from baseline were observed in standard deviation in normal-to-normal R-R intervals, left ventricular ejection fraction, Minnesota Living with HF mean score, and an improvement in 6-min walk distance was observed 7,8 .…”

Section: Introductionmentioning

confidence: 99%

“…While this reactive temporal constraint is reasonable for stage 3 HFrEF patients 7,8,24 , the adverse dynamic remodeling that occurs in neural and cardiac tissues post-MI is rapid and, in many cases, irreversible 4,15–17 . As such, refinements in reactive VNS neuromodulation that shorten time to therapeutic efficacy increase the potential for cardioprotection 3,25 .…”

Section: Introductionmentioning

confidence: 99%

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Anatomical and functional organization of cardiac fibers in the porcine cervical vagus nerve allows spatially selective efferent neuromodulation

Thompson,

Ravagli,

Mastitskaya

et al. 2024

Preprint

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Background and Objectives: Spatially-selective vagus nerve stimulation (sVNS) offers a promising solution to mitigate the off-target effects associated with traditional VNS, potentially serving as a precise method for addressing chronic heart failure (HF) by specifically targeting efferent cardiac fibers. This approach holds the potential to enhance therapeutic outcomes by avoiding off-target effects and eliminating the current need for time-consuming titration required for optimal VNS. Recent studies have demonstrated the independent modulation of breathing rate, heart rate, and laryngeal contraction through sVNS. However, the spatial organization of afferent and efferent cardiac-related fibers within the vagus nerve remains unexplored. Methods and Results: By using trial-and-error sVNS in vivo in combination with ex vivo micro-computed tomography fascicle tracing, we show the significant spatial separation of cardiac afferent and efferent fibers (179±55° SD microCT, p<0.05 and 200±137° SD, p<0.05 sVNS - degrees of separation across a cross-section of nerve) at the mid-cervical level. Cardiac afferent fibers are located in proximity to pulmonary fibers consistent with recent findings of cardiopulmonary convergent neurons and circuits. We demonstrate the ability to selectively elicit therapeutic-related effect (heart rate decrease) without stimulating afferent-related reflexes. Conclusions: By investigating the spatial organization of cardiac-related fibers within the vagus nerve, our findings pave the way for more targeted neuromodulation, thereby reducing off-target effects and eliminating the need for titration. This, in turn, will enhance the precision and efficacy of VNS therapy in treating HF, myocardial infarction and other conditions, allowing for therapeutic effect to be achieved much sooner.

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Section: Discussionmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Anatomical and functional organization of cardiac fibers in the porcine cervical vagus nerve allows spatially selective efferent neuromodulation

Thompson,

Ravagli,

Mastitskaya

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

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A Body‐Temperature‐Triggered In Situ Softening Peripheral Nerve Electrode for Chronic Robust Neuromodulation

Ren,

Tang,

Yuan

et al. 2024

Advanced Science

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Implantable peripheral nerve electrodes are crucial for monitoring health and alleviating symptoms of chronic diseases. Advanced compliant electrodes have been developed because of their biomechanical compatibility. However, these mechanically tissue‐like electrodes suffer from unmanageable operating forces, leading to high risks of nerve injury and fragile electrode‐tissue interfaces. Here, a peripheral nerve electrode is developed that simultaneously fulfills the criteria of body temperature softening and tissue‐like modulus (less than 0.8 MPa at 37 °C) after implantation. The central core is altered from the tri‐arm crosslinker to the star‐branched monomer to kill two birds (close the translation temperature to 37 °C and decrease the modulus after implantation) with one stone. Furthermore, the decreased interfacial impedance (325.1 ± 46.9 Ω at 1 kHz) and increased charge storage capacity (111.2 ± 5.8 mC cm−2) are achieved by an in situ electrografted conductive polymer on the strain‐insensitive conductive network of Au nanotubes. The electrodes are readily wrapped around nerves and applied for long‐term stimulation in vivo with minimal inflammation. Neuromodulation experiments demonstrate their potential clinical utility, including vagus nerve stimulation in rats to suppress seizures and alleviation of cardiac remodeling in a canine model of myocardial infarction.

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Outcomes of hypothalamic oxytocin neuron-driven cardioprotection after acute myocardial infarction

Schunke,

Rodriguez,

Dyavanapalli

et al. 2023

Basic Res Cardiol

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Altered autonomic balance is a hallmark of numerous cardiovascular diseases, including myocardial infarction (MI). Although device-based vagal stimulation is cardioprotective during chronic disease, a non-invasive approach to selectively stimulate the cardiac parasympathetic system immediately after an infarction does not exist and is desperately needed. Cardiac vagal neurons (CVNs) in the brainstem receive powerful excitation from a population of neurons in the paraventricular nucleus (PVN) of the hypothalamus that co-release oxytocin (OXT) and glutamate to excite CVNs. We tested if chemogenetic activation of PVN-OXT neurons following MI would be cardioprotective. The PVN of neonatal rats was transfected with vectors to selectively express DREADDs within OXT neurons. At 6 weeks of age, an MI was induced and DREADDs were activated with clozapine-N-oxide. Seven days following MI, patch-clamp electrophysiology confirmed the augmented excitatory neurotransmission from PVN-OXT neurons to downstream nuclei critical for parasympathetic activity with treatment (43.7 ± 10 vs 86.9 ± 9 pA; MI vs. treatment), resulting in stark improvements in survival (85% vs. 95%; MI vs. treatment), inflammation, fibrosis assessed by trichrome blue staining, mitochondrial function assessed by Seahorse assays, and reduced incidence of arrhythmias (50% vs. 10% cumulative incidence of ventricular fibrillation; MI vs. treatment). Myocardial transcriptomic analysis provided molecular insight into potential cardioprotective mechanisms, which revealed the preservation of beneficial signaling pathways, including muscarinic receptor activation, in treated animals. These comprehensive results demonstrate that the PVN-OXT network could be a promising therapeutic target to quickly activate beneficial parasympathetic-mediated cellular pathways within the heart during the early stages of infarction.

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Vagal Nerve Stimulation Reduces Ventricular Arrhythmias and Mitigates Adverse Neural Cardiac Remodeling Post–Myocardial Infarction

Cited by 13 publications

References 64 publications

Anatomical and functional organization of cardiac fibers in the porcine cervical vagus nerve allows spatially selective efferent neuromodulation

Anatomical and functional organization of cardiac fibers in the porcine cervical vagus nerve allows spatially selective efferent neuromodulation

A Body‐Temperature‐Triggered In Situ Softening Peripheral Nerve Electrode for Chronic Robust Neuromodulation

Outcomes of hypothalamic oxytocin neuron-driven cardioprotection after acute myocardial infarction

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