A review on the treatment of Cheyne Stokes Breathing in patients with congestive heart failure

We read with interest the article by Wang et al. [1] regarding the treatment of Cheyne Stokes Breathing in patients with congestive heart failure (CHF). The findings are of interest and add to a growing body of literature in this patient population. Although there has been concern about potential adverse effects of positive airway pressure (PAP) treatment of patient with CHF, we are not aware of similar issues with phrenic nerve stimulation (PNS). Thus, we challenge the statement of Wang et al. that “past studies have shown a signal of increased mortality in CSA [central sleep apnea] patients treated with PNS.”

Obstructive sleep apnea (OSA) and CSA (CSA or Cheyne Stokes Breathing) are common in patients with CHF. The literature varies but suggests that roughly 1/3 of patients with CHF and reduced ejection fraction (HFrEF) have OSA, whereas 1/3 have CSA and 1/3 are normal. The optimal treatment of these patients is unclear. Nasal CPAP (continuous positive airway pressure) has been shown to improve OSA and to improve left ventricular ejection fraction in patients with HFrEF. However, a mortality benefit for treating OSA in HFrEF has not been demonstrated to date to our knowledge. The treatment of CSA is more controversial. Although some studies suggest that CSA is an independent predictor of mortality in CHF, the data are equivocal in this regard. Treatment of CSA with CPAP was tested in the CANPAP study in NEJM in which no benefit was observed [2]. Furthermore, a possible deleterious effect was observed in a subset of patients. A follow-up report did suggest benefits to PAP in a subset of patients whose apnea was eliminated as compared to those who had persistent respiratory events; however, these findings require prospective corroboration using devices which reliably eliminate sleep disordered breathing. The more recent SERVE-HF study reported deleterious outcomes with ASV (adaptive servo ventilation) in patients with CHF and CSA [3], but the mechanism of the poor outcomes was unclear. While some investigators speculated that there may have been issues with the ASV algorithm, the possibility exists that sleep disturbance or electrolyte imbalances and/or reductions in cardiac output may have occurred in this study. Notably, follow-up reports have suggested no major issues with the ASV algorithm as had been speculated. The ADVENT-HF study was recently reported but has not yet undergone peer review. Early reports suggest no benefit to ASV treatment in CHF, although details about this report remain unclear. The data will be challenging to interpret because the results were affected by the SERVE-HF reports as well as by the global pandemic and a manufacturer’s recall of devices. Regardless, new clinical trial data will be of major interest once published.

The potential mechanisms of benefit of positive airway pressure in CHF may relate to reductions in preload as well as reductions in afterload. In addition, improvement in sleep disordered breathing would be predicted to alleviate hypoxemia, catechola-mine surges, and negative intrathoracic pressures associated with exaggerated respiratory effort. Negative intrathoracic pressure (as occurs with robust respiratory efforts against an occluded airway in obstructive apnea) leads to an increased ventricular transmural pressure which yields a higher ventricular wall stress. Based on the law of Laplace, one would predict a high left ventricular afterload as a result of these respiratory efforts. In addition, hypoxemia and hypercapnia can occur with repetitive apneas: Both stimuli can contribute to pulmonary artery vasoconstriction and thus a load on the right ventricle. Swings in carbon dioxide levels in patients with robust chemosensitivity can contribute to hypocapnia which in the context of alkalosis can contribute to ventricular arrhythmias. Thus, alleviation of disordered breathing in CHF has potential benefits. Although a strong physiological basis exists to support positive airway pressure treatment of CHF, the clinical trial data currently fall short of allowing this recommendation. We have recently observed potential benefits of positive airway pressure in both HFpEF (heart failure preserved ejection fraction) and HFrEF using administrative claims data (as yet unpublished results); however, these data fall short of definitive answers which may emerge from randomized controlled trials. Thus, we are supportive of ongoing efforts in this regard.

Phrenic nerve stimulation (PNS) has been FDA approved for the treatment of central sleep apnea including in patients with congestive heart failure. A paper published in the Lancet [4] showed improvement in the apnea hypopnea index and symptoms with PNS, but a neutral effect on mortality. Some recent data including meta-analyses have suggested beneficial effects of phrenic nerve stimulation on cardiovascular outcomes, although further data are clearly required in this context [5]. Thus, the impact of PNS on hard outcomes is unclear, but we are aware of no credible data that PNS increases mortality in CHF. The possibility exists that alleviation of apnea by PNS has some of the same physiological benefits of PAP in terms of normalizing breathing pattern. For example, the hypoxemia and hypocapnia which can occur with CSA are improved with PNS; thus, the hypocapnic alkalosis which can contribute to arrhythmias may well be alleviated by PNS. In addition, the potential deleterious effects of PAP including embarrassing preload in patients with CHF who are well diuresed may be less of an issue with PNS. Therefore, careful studies of PNS in patients with CHF and CSA will be required to draw definitive conclusions.