Optogenetic Stimulation of Vagal Efferent Activity Preserves Left Ventricular Function in Experimental Heart Failure

Visual Abstract


HIGHLIGHTS
This study was designed to determine the effect of selective optogenetic simulation of vagal efferent activity on left ventricular function in an animal (rat) model of MI-induced heart failure.
Optogenetic stimulation of dorsal brainstem vagal pre-ganglionic neurons transduced to express light-sensitive channels preserved LV function and exercise capacity in animals with MI.
The data suggest that activation of vagal efferents is critically important to deliver the therapeutic benefit of VNS in chronic heart failure.  Autonomic dysfunction characterized by sympathetic activation and parasympathetic (vagal) withdrawal accelerates the development and progression of the disease (2)(3)(4). The current gold standard pharmacological treatment includes drugs that limit the sympathetic effects on the heart and kidneys (e.g., bblockers). However, stimulation of vagal efferent activity to increase parasympathetic tone and redress autonomic balance as a treatment for heart failure has proved to be more difficult to achieve (5,6). Patients with heart failure on optimal medical therapy with persistent autonomic dysfunction have the worst prognosis (7).
Carprofen (5 mg/kg/day subcutaneously) was given for post-operative analgesia for 3 days, and the animals were allowed to recover for 7 days. Rats were 300 to 350 g at the time of the main experiment.  Figures 1B and 1C).

MI/optoVNS group that developed infarcts $30%
were included in the analysis. There was no difference in mean infarct size between the 2 groups (p ¼ 0.14) (Figure 2A).   Table 1). sham-operated animals ( Figure 3). There were no differences in heart rate (measured under urethane anesthesia) between the experimental groups ( Table 1).

DISCUSSION
The data obtained in the present study showed that optogenetic stimulation of vagal pre-ganglionic neu- The intermittent stimulation of the DVMN (which lacks major chronotropic effects) preserved cardiac function in rats with MI (as shown in this study), which was consistent with the results of some previous reports that suggested that the beneficial effects of VNS in heart failure were not entirely dependent on lowering heart rate (13)(14)(15). This was an important conclusion to draw in the context of a strong clinical association between low chronotropic vagal tone and the risk of death after MI or in established heart failure (40,41), and of the effectiveness of pharmacological interventions that lower heart rate (e.g., b-blockers and I f inhibitors) (42)(43)(44). In most clinical trials of VNS in heart failure, the stimulating electrodes were placed on the right cervical vagus nerve, with the aim of lowering the heart rate, but it was not reliably attained (20).  Comparisons are made using 2-way analysis of variance followed by Sidak's correction for multiple comparisons. Abbreviations as in Figures 1 and 2.  (24). GRKs phosphorylate b-adrenoceptors and recruit arrestins to block receptor coupling to G-proteins, which leads to receptor desensitization and internalization (46).
Increased expression and activity of GRKs contribute to the progressive decline of myocardial contractile function in heart failure (47). Therefore, inhibition of GRKs was proposed as a potential therapeutic strategy of heart failure treatment (47 which was defined as the operating point based on the frequency-amplitude-pulse width of VNS, in which the stimulation has no effect on heart rate (51).
The efficacy of VNS applied within the neural fulcrum is currently being tested in the ongoing ANTHEM-HFrEF trial (54). Because recruitment of efferent fibers requires more aggressive stimulation, simultaneous capture of vagal afferents may lead to significant side effects, including dysphonia, neck pain, and cough, as reported by the investigators of the NECTAR-HF trial, in which no beneficial effect of VNS on LV function was observed (20).

CONCLUSIONS
The data obtained in this study suggest that stimulation of vagal efferent innervation of the ventricles might be critically important to deliver the therapeutic benefit of VNS in chronic heart failure.
A revised approach to the electrical VNS may be necessary to minimize the side effects that currently