Reply from Noah J. Marcus, Rodrigo Del Rio and Harold D. Schultz.

Abstract

We appreciate Dr Giannoni and colleagues’ thoughtful commentary on our recent study showing the therapeutic efficacy of carotid body denervation (CBD) on the cardiorespiratory disorders observed during the progression of heart failure (HF). In this study (Marcus et al. 2014) we show that the carotid bodies are a major contributor to autonomic imbalance, oscillatory breathing patterns and enhanced respiratory–sympathetic coupling, which complicate cardiac dysfunction in HF. Using the well-characterized rapid ventricular pacing model of HF (Sun et al. 1999; Liu et al. 2000) we showed that bi-lateral cryoablation of the carotid bodies results in a significant decrease in irregular breathing patterns and apnoea incidence and markedly reduces arrhythmic episodes and sympathetic efferent activity. Furthermore, we found that CBD is an effective strategy to improve both cardiac baroreflex sensitivity and renal sympathetic baroreflex sensitivity. The issue of whether our results will be relevant in a clinical setting as suggested by Dr Giannoni is of significant interest. First, Giannoni and colleagues point out that the rapid ventricular pacing model used for this study may contribute to the increased incidence of arrhythmias independent of the degree of HF. While there is some evidence that ventricular pacing is correlated with increased incidence of arrhythmias in HF patients (Gardiwal et al. 2008), the present results are consistent with our recent findings (Del Rio et al. 2013a) using the coronary infarct model of HF in rats. In this infarct model, similar to the aetiology of HF in most humans, bi-lateral CBD also reduced the incidence of arrhythmias with the development of HF, which was sustained over a 16 week period (Del Rio et al. 2013a). Taken together, our findings indicate that the salutary effect of CBD on arrhythmia incidence in HF is applicable in a chronic as well as a ‘subacute’ model of HF and that this effect is not overestimated by the use of a pacing model. Giannoni et al. point out that our pacing model produces HF over a relatively short time period, and that this time frame (3–4 weeks) may not result in neuro-hormonal activation and global feedback resetting as would be expected in a chronic long-term experimental HF model. We acknowledge that our study design (Marcus et al. 2014) does not replicate all aspects of a long-term chronic study. Nevertheless, it is well established that the rapid ventricular pacing HF model recapitulates many aspects of dilated cardiomyopathy in human HF patients including neurohumoral activation, abnormal oscillatory breathing patterns, reductions in baroreflex sensitivity and cardiac autonomic imbalance (Sun et al. 1999; Liu et al. 2000; Lohmeier et al. 2000; Marcus et al. 2014). Further, our other recent study showing very similar beneficial effects of CBD over a 16 week period in coronary ligated rats (Del Rio et al. 2013a) would argue against these concerns. Finally, it is noted that bi-lateral CBD may be undesirable due to the importance of having a fully operative hypoxic chemoreflex response for the survival of HF patients in acute life-threatening conditions. While bi-lateral CBD has been employed in the past for the treatment of asthma with few reported adverse consequences (Winter, 1973), we agree that bi-lateral CBD may not be desirable in all HF patients. Nevertheless, our current study was not intended to provide a single surgical therapeutic solution for the treatment of HF, but rather to provide definitive evidence of the importance of the carotid body chemoreceptors in mediating the autonomic and respiratory dysregulation observed in HF and contributing to the deterioration of cardiac function. Important in our results is the revelation that sympathetic activity is more tightly coupled to the respiratory cycle in HF with marked sympathetic activation during periods of oscillatory breathing. We agree with Giannoni et al. that unilateral CBD or pharmaceutical therapeutic adjuncts that have the potential to modulate carotid body chemosensitivity should be considered in the development of novel treatments for HF. Indeed, we recently completed two studies in which we employed pharmacological approaches to modulate carotid body function in HF, and observed improvements in autonomic balance, and reductions in arrhythmia incidence and disordered breathing patterns (Del Rio et al. 2013b; Haack et al. 2014). Furthermore, in a recent case study, unilateral CBD reduced the incidence of central apnoeas and plasma noradrenaline (norepinephrine) in a patient with systolic heart failure (Niewinski et al. 2013). In summary, our findings indicate that future studies focusing on the restoration of normal carotid body chemoreflex function will be of great interest in developing treatments to normalize the cardiorespiratory abnormalities observed in the clinical setting of HF.