Sudden cardiac death (SCD) as a result of lethal arrhythmias remains a major unsolved clinical problem in which cardiac autonomic control plays a significant role. Sympathetic overactivity in conditions like heart failure is known to be a significant factor in the development of ventricular fibrillation (VF) [1] but the mechanisms are still poorly understood and there is no effective preventative treatment. Our group has been investigating the mechanisms of VF using a unique isolated heart preparation with intact nerve supply which has shown that electrical restitution and myocardial electrical heterogeneity to be important determinants of VF risk. Sympathetic effects on these parameters are proarrhythmic which increases the maximum slope of electrical restitution as well as its heterogeneity leading increased the susceptibility to VF [3-5]. These results have been successfully applied to translational studies in patients with the development of patented ECG markers which have been shown to be strong predictors of ventricular arrhythmias and SCD [6].
The current study builds on the translational expertise to investigate a novel clinical finding that non-invasive neural stimulation could be used to inhibit arrhythmia initiation and proposes to investigate this in the innervated heart preparation. This represents strong clinical translation potential to provide insight into the delivery and refinement of non-invasive neuromodulation in treating life-threatening ventricular arrhythmias. Detailed understanding of the anatomical pathways and electrophysiological effects is required for the progression of clinical interventions.
Current treatments that target the sympathetic nervous system include bilateral or left cardiac sympathetic denervation (CSD), which involves surgical excision of the both or just the left stellate ganglion together with the thoracic ganglia (T1 to T4). Although successful in treating a variety of cardiac arrhythmias, CSD has been found to have serious side effects due to removal of the sympathetic supply to the forelimbs and head, causing palmar and facial anhydrosis, loss of vasomotion, and poorer visual and salivary control [7]. Thus an alternative approach needs to be explored. Interestingly, several studies have found that non-selective stimulation of the dorsal spinal cord can suppress atrial fibrillation [8], reduce symptoms of angina pectoris [9], reduce ventricular arrhythmias [10] and partially restore ventricular function in heart failure [11]. However, the local mechanisms underlying these effects remain unknown.
Implantation of spinal cord stimulation (SCS) devices have been used clinically for 30 years to treat angina and more recent studies are suggesting its effectiveness for treatment of VT and VF in heart failure [12]. However this technique is extremely invasive and it is still puzzling why such a high stimulus is required to produce the desirable effects [13]. Therefore, there exists a need for a less invasive treatment. A recent study in healthy subjects found that non-invasive electrical stimulation using a TENS machine at low frequencies was able to reduce sympathetic nerve response, whereas high frequencies promoted an increased response [14]. TENS at C7 and T4 has also been found to attenuate exaggerated cardiac sympathetic drive in patients with heart failure [15] and blunt the effects of sympathetic stimulation on vasoconstriction and hypertension [16]. Transcutaneous magnetic stimulation of the left stellate ganglion (C7) has been shown to reduce arrhythmic events in patients with ventricular tachycardia storm [17]. This non-invasive potential treatment therefore warrants further investigation as the underlying mechanisms are not understood. With further investigations, refinement of this technique for stimulation of the sympathetic nerves has the potential to treat ventricular arrhythmias whilst having the benefit of being non-invasive.
Using the innervated rabbit heart preparation with intact autonomic nerves [18] and optical mapping, we will investigate the effects of transcutaneous nerve stimulation on cardiac electrophysiological parameters. Unlike in vivo methods, this preparation will allow us to study the effects of SCS without the confounding effects of anaesthesia on the autonomic nervous system and without the effects of hemodynamic reflexes and circulating hormones. We will stimulate using a TENS machine positioned on the back of the preparation between C7 and T4 to engage the sympathetic chain at different spinal segments. With the sympathetic nerves intact, we will measure the effects of transcutaneous nerve stimulation on its ability to interrupt or attenuate the well-documented effects of sympathetic stimulation to increase arrhythmia susceptibility. This research will enable us to better understand the mechanisms underlying transcutaneous nerve stimulation and the potential of this non-invasive method as a treatment for ventricular arrhythmias.
Funding details:
This 3-year The Thomas Herbert Wathes Centenary Scholarship provides:
· UK/EU tuition fee waiver
· Annual stipend at UKRI rates (£15,609 for 2021/22)
*Please note this project is competition funded.
Entry requirements:
Applicants are required to hold/or expect to obtain a UK Bachelor Degree 2:1 or better (or overseas equivalent) in a relevant subject.
The University of Leicester English language requirements apply where applicable.
Application advice:
To apply please refer to the guidance at: https://le.ac.uk/study/research-degrees/funded-opportunities/th-wathes-ng-2021
Project / Funding Enquiries: Prof André Ng: [Email Address Removed]
Application enquiries to [Email Address Removed]
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