Neural control of inflammation for treatment of cardiovascular disease

Background:

Excessive inflammation causes and aggravates atherosclerosis and cardiovascular disease and therapeutic reduction of pro-inflammatory cytokines reduces adverse cardiovascular events in clinical trials. Considering accumulated data over recent decades, several observations suggest that neural signals regulate atherosclerosis development and cardiovascular risk.

However, since atherosclerotic plaques lack direct innervation, neural regulation of inflammation in atherosclerosis was largely disregarded – until now. We recently showed, together with partners in the “Plaquefight consortium”, that not only are atherosclerotic arteries innervated, but neuroimmune cardiovascular interfaces control atherosclerosis.

Clinical translation of discoveries on neural regulation of disease pathogenesis has been hampered by the requirement of neurosurgical implantation of peripheral nerve stimulators. We collaborated to develop technology to enable precision non-invasive activation of peripheral nerves for experimental and clinical purposes. The work resulted in a novel, non-invasive, method for precision stimulation of peripheral nerves (patent pending). This approach is now in the process of approval for clinical trials.

Objectives:

In short, this program aims to detail how neural signals regulate atherosclerosis initiation and progression by studying unique animal models and patient samples, and initiate an clinical interventional study in patients with “inflammatory” microvascular angina. Work plan: A. Map the anatomy of arterial innervation in atherosclerosis by

1) visualizing the anatomy of atherosclerotic disease innervation 2) investigating neuro-immune interactions in adventitia and artery tertiary lymphoid organs B. Map the functional innervation of atherosclerotic arteries by 3) activating and de-activating neural signals in experimental atherosclerosis

C. Investigate the safety and efficacy of non-invasive precision vagus nerve stimulation in microvascular angina by

4) investigating whether non-invasive vagus nerve stimulation in this patient group improves endothelial function and reduces inflammation. Significance:

This research program has the potential to contribute with 1) tools for better understanding of the pathogenesis of atherosclerosis with identification of new therapeutic targets and 2) a novel approach to treatment of arterial inflammation and microvascular angina.