Abstract
Large clinical trials designed to test the efficacy of vagus nerve stimulation (VNS) in patients with heart failure did not demonstrate benefits with respect to the primary endpoints. The nonselective nature of VNS may account for the failure to translate promising results of preclinical and earlier clinical studies. This study showed that optogenetic stimulation of vagal pre-ganglionic neurons transduced to express light-sensitive channels preserved left ventricular function and exercise capacity in a rat model of myocardial infarction-induced heart failure. These data suggested that stimulation of vagal efferent activity is critically important to deliver the therapeutic benefit of VNS in heart failure.
Highlights
Expression of ChIEFtdTomato by the vagal preganglionic neurons residing in the caudal regions of the left and right DVMN was confirmed in all the animals that received bilateral microinjections of lentiviral vectors (LVV)-PRSx8-ChIEFtdTomato (Figures 1B and 1C)
Stimulation of DVMN neurons expressing ChIEF with 10-ms pulses applied at a frequency of 15 Hz led to a robust increase in vagal efferent activity and was associated with a reduction in heart rate and mean arterial blood pressure (ABP) during the period of stimulation (Figure 1D)
Optogenetic stimulation of the DVMN prevented myocardial infarction (MI)-induced reduction in left ventricular (LV) dP/ dTmax (7,673 Æ 332 mm Hg/s in post-MI rats expressing ChiEFtdTomato vs. 5,656 Æ 495 mmHg/s in postMI rats expressing enhanced green fluorescent protein (eGFP); p < 0.001), in LV endsystolic pressure (LVESP)
Summary
There is no experimental data to suggest that the VNS beneficial effects on the failing heart observed in animal and some human studies are due to the recruitment of afferent (sensory) or efferent (motor) vagal fibers (or both) by the electrical current pulses applied to the nerve at the cervical level. Our research group demonstrated that stimulation of approximately 300 to 400 vagal pre-ganglionic neurons in the dorsal motor nucleus of the vagus nerve (DVMN) markedly reduced the extent of MI in an animal model [11]. These data provided direct evidence of effective cardioprotection by selective stimulation of vagal efferent activity. We genetically targeted the DVMN neurons to express the lightsensitive channel ChiEF and determined the effect of selective stimulation of the DVMN vagal efferent projections using light (optoVNS) on LV function in a rat model of MI-induced heart failure
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