Optogenetic modulation of cardiac vagal function improves prognosis in diabetes

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Project Summary Vagal nerve stimulation (VNS) has emerged as a promising therapy for cardiac arrhythmia by electrical stimulation of vagal nerve at the cervical level. Direct VNS achieves its antiarrhythmic effects through increasing efferent parasympathetic input to the heart. However, patients receiving VNS have reported severe side effects, which are due to off-target stimulation of non-cardiac vagal branches. Cholinergic activation using pharmacological approaches also resulted in serious adverse events due to lack of organ specificity. Increasing vagal efferent input to the heart by targeting cardiac vagal postganglionic (CVP) neurons alone would be ideal to minimize the off-target effects and to achieve precision of parasympathetic activation for anti-arrhythmia. Here, we will introduce a miniaturized bio-optoelectronic implant that avoids limitations of VNS and pharmacological approaches by using optogenetics to treat fatal ventricular arrhythmias in type 2 diabetes mellitus (T2DM). Comparing with electrical and pharmacological approaches, optogenetics provides higher speed and accuracy in regulation of living cell function with less complications. However, a strategy of optogenetic therapy on ventricular arrhythmias in T2DM has not yet been established. Withdrawal of cardiac vagal activity is associated with ventricular arrhythmias-related sudden cardiac death and with high mortality in T2DM patients. Patients with T2DM are two to four times more likely to die from myocardial infarction (MI), compared with non-diabetic patients. Our recent study confirmed that reduction of cell excitability in CVP neurons exacerbates MI-evoked ventricular arrhythmias and mortality in T2DM animals. Considering the advantages of optogenetics including rapid, specific control of neuronal activities by light-sensitive opsins, adeno-associated virus-channelrhodopsin- 2 (AAV-ChAT-ChR2-mcherry) will be transfected into CVP neurons in T2DM animals. Specificity of neuronal expression of ChR2 (an excitatory light-sensitive opsin) in CVP neurons will be achieved by linking the choline acetyltransferase (ChAT, a specific marker of cholinergic neurons) promoter to the ChR2 gene. Continual optogenetic stimulation in CVP neurons will be achieved by illuminating a light-emitting-diodes (LED) probe that is controlled and powered wirelessly in freely moving animals. We hypothesize that optogenetic therapy could restore cell excitability of CVP neurons and acetylcholine (ACh) release from cardiac vagal nerve terminals, further improve vagal control of ventricular function and reduce acute MI-evoked ventricular arrhythmias and high mortality in T2DM. To test this hypothesis, we will determine if optogenetic restoration in CVP neuronal excitability restores ACh release from cardiac vagal nerve terminals, improves vagal control of ventricular function, and reduces MI-evoked fatal ventricular arrhythmias and high mortality in T2DM animals. This proposal will establish the first evidence of the optogenetic therapy on MI-evoked ventricular arrhythmias and mortality in T2DM, and may provide a new therapeutic strategy for improving outcomes and quality of life in T2DM patients.