Do C heyne and S tokes have an important message for modern‐day patients with heart failure? Y es, they do

This article refers to ‘Benefit of buspirone on chemoreflex and central apnoeas in heart failure: a randomized controlled crossover trial’ by A. Giannoni et al., published in this issue on pages 312–320. Breathing abnormalities consisting of alternating phases of hyperpnoea and hypopnoea with phases of apnoea were recognized in the 19th century by John Cheyne and William Stokes (Figure 1) .1 However, the original description probably dates back to thousands of years ago, by the father of medicine Hippocrates (460–379 BC) who gave the first account: ‘His respiration was rare and large, like a person who forgot for a time the need of breathing and then suddenly remembered’.2 In 1923, the Italian physiologist Luciani observed that its occurrence is not necessarily a manifestation of illness, as ‘it sometimes occurs during sleep in healthy subjects, especially children and elderly; it is often marked at high altitude (2500–4500 m over sea level), more frequently during sleep, but also during wakefulness’. The same Luciani hypothesized breathing abnormalities as the product of ‘periodic oscillations in the excitability of centres controlling ventilation’.3 Such ‘oscillations in excitability’ could be triggered by an initial variation in respiratory gases, being then sustained by the periodic changes in arterial oxygen and carbon dioxide (CO2) contents. In heart failure, in the search for hidden pathophysiological triggers of its evolution and potential targets of therapy, our group, at that time working together at the Royal Brompton and National Heart Lung Institute, London, UK, pointed out the potential role of this phenomenon. In particular, we contributed to highlighting the occurrence of breathing disorders, and in particular apnoea/hyperpnoea phenomena during both the night and the day, and also during exercise.4 It was observed that the breathing disorder is often overlooked by clinicians, and it can be both a marker of severity and a mediator of risk, possibly as an initial compensatory response, also observed in other cardiovascular conditions.5, 6 The role of overactive peripheral chemoreceptors and muscle receptors was demonstrated in the impairment of exercise tolerance, the increasing ventilatory drive and consequently the induction of periodic breathing. These receptors were triggered by increased blood concentration of metabolites released by the exercising muscles in a setting of catabolism and multiorgan failure. Interventions aiming at reducing the activity of peripheral receptors drives not only a reduction in abnormal ventilation but also an increase in survival in heart failure.7 In our original review paper, we concluded that the observation of these breathing phenomena should oblige the clinician to re-evaluate the physiology of respiration and cardiovascular function and that there is still place for physiology in the decision-making for patients with cardiovascular diseases in the era of imaging, genetics, and molecular biology.4 During the last few decades the underlying derangements of neural control of respiratory centres, its impact on prognosis, and the relevance of the phenomenon as a therapeutic target have been the object of an increase of interest and literature, yet with diverse experimental findings and contradictory opinions. The failure of two large trials testing the effectiveness of non-invasive mechanical ventilation (CANPAP and SERVE-HF)8, 9 in improving the outcome of heart failure patients has confirmed the interest in this field, but also the need for novel and more effective approaches to this disorder. In this setting, the contribution from Giannoni et al.10 in this issue of the Journal is particularly noteworthy, with their novel and original approach to reduce the occurrence of central apnoeas being both proposed and tested. In contrast with the past main interest on peripheral chemoreflex, here a different approach is proposed. The authors focused their attention on the central chemoreceptors as a potential treatment target, and in particular on the serotoninergic (5-hydroxytryptamine, 5-HT) neurons which play an important role in central chemoreception. They used buspirone, a 5-HT1A receptor agonist, to inhibit the central chemoreceptors. Buspirone, long and safely used in general anxiety disorder, does not cause sedation, tolerance or physical dependence. In experimental models of hypoxia-induced apnoeas, it has been shown to decrease CO2 chemosensitivity and central chemoreceptor activity. Here, the safety and efficacy of buspirone on CO2 chemosensitivity and central chemoreceptors in patients with systolic heart failure, on top of optimal medical therapy, in random order for 1 week were reported: significant reductions in CO2 chemosensitivity (41%), apnoea/hypopnoea index, central apnoea index and oxygen desaturation index both during the nighttime and daytime. Importantly, a good safety profile of buspirone was confirmed, without adverse reactions. Of course this is only a proof of concept trial. Considering its monocentric nature, involving only 16 patients, only males, none of whom were very symptomatic (the majority in New York Heart Association heart failure class I or II), this suggests caution when interpreting the findings. However, several important points should be considered. The approach presented here, if confirmed in a larger trial, may be an important step forward with respect to previous attempts to reduce respiratory abnormalities. For example, compared to acetazolamide, which reduces exercise capacity and ventilatory efficiency during cardiopulmonary stress testing, buspirone showed neutral effects on exercise performance. Moreover, buspirone was effective throughout the 24 h period, with positive effects on central apnoea not only at nighttime, but also during daytime. Considering the prevalence/prognostic significance of daytime apnoeas also in the upright position, this may represent a benefit over previous treatments of central apnoea such as gas delivery, non-invasive mechanical ventilation, and phrenic nerve stimulation, which are designed to work only at nighttime, for compliance reasons. Buspirone might be effective also in waking patients in freely moving conditions. Thus, 20 years later, we can still conclude that the autonomic and reflex associations of abnormal breathing, a condition known since ancient times, yet poorly studied in the modern era, may be amenable to therapeutic interventions probably never envisaged by our ancestors. Thus, in the days of molecular biology we should not overlook opportunities that careful physiological observation can reveal. Conflict of interest: none declared.