Heart to breathe: partial ablation of rostral ventrolateral medulla catecholaminergic neurons mediates disordered breathing in volume overload heart failure rats

Heart failure (HF) is a disease characterized by pathophysiological hallmarks which include cardiac autonomic imbalance, patterns of irregular breathing, cardiac dysfunction and enhanced central chemoreflex sensitivity. Previous studies have suggested that hallmarks of HF are interdependent such as the presence of respiratory–sympathetic coupling (Zoccal et al. 2008; Marcus et al. 2014) and increases in chemosensitivity as a result of disordered breathing patterns (Gianonni et al. 2008; Toledo et al. 2017). Recently, rostral ventrolateral medulla catecholaminergic (RVLM-C1) neurons have been shown to play an important role in controlling autonomic function and breathing in healthy rats (Abbott et al. 2013; Burke et al. 2014, 2015). Also, chronic hyperactivation of RVLM-C1 neurons in experimental HF rat models was correlated with cardiac autonomic imbalance (Del Rio et al. 2013; Toledo et al. 2017). No study has yet linked RVLM-C1 neurons to breathing irregularities, respiratory–cardiovascular coupling and enhanced chemoreflex sensitivity in volume overload HF. Ultimately, understanding the role of these neurons in the development and maintenance of HF may provide further insight to treating the disease clinically. In a recent article in The Journal of Physiology, Toledo et al. (2019) induced volume overload HF in rats to measure respiratory and autonomic parameters with or without partial lesions of RVLM-C1 neurons using anti-dopamine-β-hydroxylase–saporin toxin (DβH-SAP). In their model, arteriovenous fistula surgery was used for HF induction followed by bilateral injections of DβH-SAP 4 weeks post-surgery. It was demonstrated that partial lesion of RVLM-C1 neurons reduced breathing irregularities in HF rats by improving breath-to-breath interval variability and reducing tidal volume (VT) oscillations. In addition, selective ablation of RVLM-C1 neurons resulted in a marked reduction in apnoea and hypopnoea incidences compared to non-DβH-SAP HF rats and also attenuated active expiration in HF rats. Regarding autonomic imbalance in HF rats, beat-to-beat analysis of heart rate variability (HRV) showed that partial lesion of RVLM-C1 neurons normalized HRV spectral disturbance (i.e. decreased the sympathetic spectral component and increased the parasympathetic spectral component) to those of sham controlled rats. Thus, the results indicate that selective ablation of RVLM-C1 neurons using DβH-SAP normalized resting breathing patterns and reduced cardiac sympathetic tone in volume overload HF rats. Respiratory–cardiovascular coupling was assessed by calculating the coherence between oscillations in VT and systolic blood pressure. Compared to non-DβH-SAP HF rats, which showed enhanced coupling, DβH-SAP treatment disrupted coupling in HF rats, which resembled the coherence values obtained in sham rats. Additionally, to understand the role of RVLM-C1 neurons on enhanced chemosensitivity, acute hypercapnic stimulation was applied. The results demonstrated that chemoreflex-induced sympathoexcitation and cardiac diastolic dysfunction are RVLM-C1 dependent, although central chemoreflex sensitivity was not reduced by DβH-SAP treatment. This indicates that RVLM-C1 neurons are activated during hypercapnic stimulation and help facilitate these deleterious cardiac effects. Consequently, these results allowed the authors to highlight the role of RVLM-C1 neurons in the development of pathophysiological changes in volume overload HF. The novelty of the study by Toledo et al. is that it is the first to look specifically at the connection between HF and disordered breathing. In previous studies, members of this group looked at the effect of ablating peripheral chemoreceptors in HF rats with reduced ejection fraction. They determined that there is communication between chemoreceptors and RVLM-C1 neurons in rats suffering from chronic HF; these rats show a greater presence of active RVLM-C1 neurons than do sham rats (Del Rio et al. 2013). Continuing their investigation, in another study they determined ablation of the RVLM-C1 neurons can reduce sympathetic tone, progressive cardiac dysfunction and arrhythmogenesis and improve cardiac function (Andrade et al. 2019). Based on these findings, the present study continued their research to determine the influence of RVLM-C1 neurons on disordered breathing in volume overload HF rats, as well as their role in respiratory–cardiovascular coupling and central chemoreflex-mediated cardiac dysfunction. As they were familiar with this model, they applied similar techniques from their previous studies for inducing HF, measuring respiratory variability, using echocardiography, and making telemetric blood pressure recordings and an autonomic assessment. They discovered that a volume-overload HF rat with partial ablation of the RVLM-C1 neurons showed improved breath-to-breath interval variability, normalized cardiac sympathetic tone, removal of any deleterious effects of the end-diastolic pressure–volume relationship caused by hypercapnia, and reduced coherence of respiration and systolic blood pressure. By their comprehensive protocol, they were able to identify not only the beneficial effects of the partial ablation of RVLM-C1 neurons, but also the null effects of ablation to the controls. They discovered that only rats with HF had any substantial effect with the ablation relative to the controls, which illuminates that RVLM-C1 neurons are of greater importance in HF rats. Therefore, identifying the connection between disordered breathing and RVLM-C1 neurons is the next step to a better understanding of HF. The study of Toledo et al. (2019) is not without its limitations, but it is clear the authors have opened the door for future investigations to link disordered breathing and HF. The authors note that the technique they chose to measure active expiration via late expiratory volume was not commonplace, and that abdominal and diaphragmatic electromyography recordings are a much more accurate technique. They also reference another paper which states that breathing regularity is sleep-state dependent (Souza et al. 2018). When measuring ventilation, they measured between 10.00 and 16.00 h, which is during the rat's natural sleep cycle. Using telemetry blood pressure, they made sure the rats were sleeping for a portion of the recording. An interesting addition to this experiment would have been measuring breathing while the rats were active. Adding ventilation measurements during higher levels of activity would have been another useful comparison between each model. Another potential limitation to this protocol is knowing what the long-term effects are of ablating the RVLM-C1 neurons. It is shown in this paper that the control rats showed little effect when their C1 neurons were ablated, but this was done in the short term. It would be necessary to determine the long-term effects of this ablation, especially when considering using such techniques in a clinical setting. When measuring baroreflex sensitivity, they used the sequence method from blood pressure data they collected while the rats were at baseline. This method only gives data on a small window of the baroreflex sensitivity curve; they could have possibly used some sort of intervention (i.e. phenylephrine, sodium nitroprusside) to expand this window and measure the baroreflex sensitivity curve at the extremes. This would determine the extent of the cardiovascular changes seen in these HF models that were due to changes in baroreflex sensitivity. Lastly, when attempting to associate their findings clinically to HF patients, they note that patients with HF typically have co-morbidities such as coronary artery disease, diabetes mellitus, atrial fibrillation and/or hypertension. This suggests that their protocol for disordered breathing in HF must take other potential factors into account before a clinical step can be made. The findings from this paper can potentially be used for a variety of purposes. Cardiovascular disease is one of the leading causes of mortality in North America (Savarese & Lund, 2017), and thus understanding the elements of the disease can serve a multitude of purposes. Though their findings are the quintessential next steps in understanding HF, further investigation into this technique is necessary. RVLM-C1 neurons can synthesize catecholamines, regulate the autonomic nervous system and are activated in hypoglycaemia, acute infection, hypoxia, nociception and hypotension (Guyenet et al. 2013). Therefore, a partial ablation of the RVLM-C1 neurons can benefit rats in HF, but a study must be conducted to determine the long-term effects of ablating these neurons. Along with understanding the consequences of ablating the RVLM-C1 neurons, there may also need to be an investigation into the connection between chemoreceptors and RVLM-C1 neurons. This group has shown that HF is associated with increases in basal sympathetic tone (Andrade et al. 2019). The reason for this increase, also shown by this group, is that chemoreceptor activation caused by hypercapnic stimulation leads to RVLM-C1 neuron activation. Understanding this connection could be of use for applying these findings in a clinical setting. Perhaps limiting the amount of communication between chemoreceptors and RVLM-C1 neurons is of more benefit long-term than ablating the neurons. A potential pharmaceutical drug could be conceived to attenuate the RVLM-C1 neuron response to chemoreceptor activation. It has been shown that at least 50% of patients with HF have sleep apnoea, a disorder which causes a number of deleterious cardiac effects such as daytime and sleep hypertension, accelerated disease progression in HF and myocardial ischaemia (Bradley & Floras, 2003). Considering that a cardinal feature of sleep apnoea is the activation of chemoreceptors as a result of hypoxic and hypercapnic stimulation, it would be interesting to see if the RVLM-C1 neurons are involved in this mechanism. Since the present study indicated that chemoreflex-mediated sympathoexcitation due to hypercapnic stimulation is RVLM-C1 dependent, a link between disordered breathing in sleep apnoea and activation of RVLM-C1 neurons seems plausible. Furthermore, previous studies have shown that the retrotrapezoid nucleus (RTN) is one of the main central chemoreceptor areas in the brain (Toledo et al. 2017) and plays a role in respiratory and cardiorespiratory control (Rosin et al. 2006). Also, it is known that there are synaptic connections between the RTN and RVLM-C1 neurons (Toledo et al. 2017); whether these neurons impact HF is yet to be investigated. Consequently, further understanding the role of these neurons in establishing pathophysiological changes in HF can help revise our current models of how the nervous system influences cardiac disease and help identify pharmacological approaches to attenuating these effects. Lastly, although it is challenging to establish accurate models of human HF, the volume overload HF rat model used in the present study shows comparable levels of disordered breathing and sympathetic activation to those in humans. These results demonstrate that using this model has potential clinical significance and can be useful moving forward in further investigations. In conclusion, Toledo et al. (2019) have shown that investigating RVLM-C1 neurons is relevant in identifying the mechanism by which disordered breathing occurs in volume overload HF. This study demonstrated that partial ablation of the RVLM-C1 neurons improves disordered breathing, autonomic imbalance and cardiac diastolic dysfunction. Therefore, the authors have introduced the significance of studying the RVLM-C1 neurons in association to pathophysiological hallmarks of HF. None declared. Both authors have read and approved the final version of this manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. None.

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