Editors' ChoiceHeart Failure

Shedding light on heart failure

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Science Translational Medicine  02 Sep 2020:
Vol. 12, Issue 559, eabe4436
DOI: 10.1126/scitranslmed.abe4436

Abstract

Optogenetic stimulation of vagal preganglionic neurons preserved left ventricular ejection fraction in an experimental heart failure model.

Therapeutic modalities for treatment of chronic heart failure include medical therapy such as β-blockers and renin-angiotensin system inhibitors. These medications do not preserve heart function over time. Patients with autonomic dysfunction, despite medical therapy, have particularly poor prognosis. Clinical trials for vagal nerve stimulation (VNS) to restore autonomic balance and increase parasympathetic activity in these patients have not demonstrated benefits, and the mechanisms underpinning the potential for VNS to benefit heart failure patients remain unclear. Selective fiber recruitment has been difficult to achieve, and as such there is a paucity of evidence to suggest that VNS benefits are due to recruitment of afferent (sensory) or efferent (motor) fibers or indeed both.

Macchada et al. achieved selective optogenetic stimulation of vagal efferent activity and studied the effect of stimulation in a rat model of heart failure. The researchers transduced dorsal brainstem vagal preganglionic neurons to express light-sensitive channels in rats. Two weeks later, an optrode reaching the dorsal surface of the brainstem was implanted to allow light delivery to the transduced neurons. Study groups included groups with and without myocardial infarction (MI), and with and without optogenetic VNS. A week after the optrode implant, the left anterior descending artery was occluded as a means to induce heart failure in the MI group. Two days after surgery, the rats underwent stimulation of the dorsal vagal motor nucleus with light at 445 nm for 15 min every 48 hours (or a sham VNS for the control groups). Four weeks later, the rats were subjected to exercise testing, echocardiography, and hemodynamic measurements. The results showed that that exercise capacity and cardiac performance were preserved in the animals receiving optogenetic VNS after MI.

Limitations of the study include the fact that stimulation started two days post-MI, which may not be clinically relevant. A more sophisticated approach to VNS may be necessary to minimize the side effects associated with the intensity of stimulation required for the recruitment of cardiac vagal efferent innervation. However, the study elucidates a critically important translational insight; stimulating the vagal efferent innervation of the ventricles may be a key factor to enhancing clinical benefits of VNS therapy for chronic heart failure.

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