High ventricular arrhythmia burden or higher grade ventricular arrhythmias such as frequent premature ventricular complexes (PVCs >30/h) or non-sustained ventricular tachycardia (NSVT) are associated with impaired left ventricular function and increased mortality in patients with heart failure and reduced left ventricular ejection fraction (HFrEF) (1–5). Decreasing the burden of PVCs can prevent the development of PVC-induced cardiomyopathy, which may improve prognosis in patients with HFrEF (4). Furthermore, shortly coupled PVCs may also trigger ventricular arrhythmias contributing to sudden cardiac death.

Sleep-disordered breathing (SDB), either obstructive (OSA) or central (CSA) sleep apnoea, is a common comorbidity in HFrEF, occurring in up to 50% of patients (6). Several studies suggest that SDB-related conditions may contribute to ventricular arrhythmogenesis in HFrEF by various mechanisms (7). In a previous small randomized controlled trial in patients with HFrEF, treatment of co-existing OSA with continuous positive airway pressure (CPAP) reduced the frequency of PVCs during sleep (8). In another randomized controlled pilot trial in patients with HFrEF, treatment of CSA, coexisting CSA-OSA or OSA using flow-triggered adaptive servo-ventilation (ASV) showed a trend toward a reduction of nocturnal PVCs and NSVT (9).

The Treatment of Sleep-Disordered Breathing with Predominant Central Sleep Apnea by Adaptive Servo Ventilation in Patients with Heart Failure (SERVE-HF) trial is the largest randomized trial to investigate the effect of treating CSA with ASV compared with guideline-based medical treatment alone (control) in patients with HFrEF and CSA (10). Unexpectedly, rates of all-cause and cardiovascular mortality were significantly higher in patients randomized to the ASV vs. control group (10). It has been hypothesized that ASV may increase the burden of ventricular arrhythmia triggering sudden death as one potential reason for the observed increased all-cause and cardiovascular mortality in the ASV group (11). Several explanations as to how ASV may trigger ventricular arrhythmias-such as rapid changes in blood gases, pH and potassium levels, in addition to effects on venous return and transmural wall tension by applied positive airway pressure-have been proposed (12).

Therefore, the aim of the present ancillary analysis of the SERVE-HF major substudy (NCT01164592) (13) was to assess the effects of ASV on the burden of nocturnal ventricular arrhythmias (PVCs and NSVT) in ASV-treated patients with HFrEF and CSA.

This study provides unique insights into the observed effects of ASV on nocturnal ventricular arrhythmias in patients with HFrEF and CSA. First, the change in number of nocturnal PVC/h from baseline to 3- and 12-month follow-up was similar in the control and ASV groups. Second, ASV had no significant effect on the proportion of patients with a high burden of nocturnal ventricular arrhythmias (>30 PVC/h) or higher grade nocturnal ventricular arrhythmias (≥1 NSVT/night). Third, all prespecified subgroup analyses did not favour either the control or the ASV group with respect to changes of nocturnal PVC/h over time. This included important subgroups included patients with low LVEF (<30%) (10, 11), low proportion of CSR <20% (10), and high burden of ventricular arrhythmias (1).

In an ancillary analysis of the SERVE-HF major substudy, burden of nocturnal PVC >30/h was observed in 44% of patients with HFrEF and CSA (15). A higher cardiovascular mortality in the ASV group of the SERVE-HF parent study has been proposed to result from sudden cardiac death, presumably due to cardiac arrhythmias (11). To date, randomized controlled trials evaluating the effect of positive airway pressure treatment on ventricular arrhythmias in patients with HFrEF and SDB are scarce and included only a few (or no) patients with CSA. This is important because the pathophysiological impact of obstructive and central apnoeas and PVCs is clearly different (e.g., the timing of PVCs in relation to the apnoea) (7, 23).

In a small randomized pilot trial (n = 20) including HFrEF patients with severe SDB (mean LVEF 32% and AHI 49/h; with CSA, coexisting CSA and OSA, or OSA) ASV also did not impact the PVC burden compared with the control group (9). Another small randomized trial (n = 18) analysed the effect of CPAP on PVC/h in OSA patients (mean AHI 29/h) with HFrEF (mean LVEF 28%) (8). Compared with the control group not receiving CPAP therapy, CPAP was associated with a 58% reduction in the number of PVC/h within 1 month of starting treatment (8). The present study is the first randomized controlled trial to evaluate the effects of ASV on the change in PVC burden over time, and the rates of high PVC burden and higher-grade ventricular arrhythmias in HFrEF patients with CSA and did not find any significant differences between the ASV and control groups. Similar to our results, data from a substudy of the Cardiovascular Improvements With Minute Ventilation-Targeted ASV Therapy in Heart Failure (CAT-HF) trial in hospitalized patients with heart failure with either OSA and/or CSA (AHI >15/h) and with implanted cardioverter-defibrillator (ICD) or cardiac resynchronization therapy with defibrillator (n = 46) reported that the rate of ventricular tachycardia and ventricular fibrillation was similar between groups treated with ASV added to guideline-based medical therapy compared with guideline-based medical therapy only (24).

In addition to the overall analysis, the current study evaluated all endpoints in important patient subgroups. This included patients with a baseline CSR proportion ≥20%, a subgroup in which those in the ASV vs. control group in the parent SERVE-HF study had higher rates of all-cause death or life-saving cardiovascular intervention plus unplanned hospitalization for worsening chronic heart failure (10). Furthermore, CSR ≥20% has been reported to be an independent predictor of PVC/h and the burden of PVC was 86% higher during periods of CSR compared to periods without CSR (15). Another subgroup analysis was based on baseline LVEF because subgroup analysis of the SERVE-HF parent study revealed that ASV was associated with higher cardiovascular mortality in those with baseline LVEF ≤30% (10, 11). In addition, lower LVEF is associated with an increased risk for ventricular arrhythmias in patients without SDB (25), which might also be the case in patients with SDB. Finally, patients were divided into subgroups based on baseline burden of ventricular arrhythmias (PVCs >30 vs. ≤30/h) because PVCs >30/h have been associated with a 2.6-fold higher mortality in the general population (1, 5, 25), but this had not yet been evaluated in patients with HFrEF and CSA. For example, Ryan et al. (8) analysed patients with OSA, the majority of whom had PVCs >30/h, and reported that the rate of this arrhythmia decreased from 170 PVC/h to 70 PVC/h in the group treated with CPAP therapy group compared to an increase from 84/h to 101/h in the control group. The hypothesis was that the effect of treating SDB on ventricular arrhythmias might be more pronounced in those with a high burden of PVCs. However, the present subanalyses did not show any modification of the effect of ASV on PVC burden in these patient subgroups.

The results of our analysis neither further support the hypothesis that CSA contributes to ventricular arrhythmogenesis nor that ASV increases sudden cardiac death by triggering ventricular tachyarrhythmia. In addition, ICD discharge data from the parent SERVE-HF study does not support a tachyarrhythmia mechanism for potentially increased sudden cardiac death (hazard ratio for appropriate shock in the ASV vs. control arm was 0.71 [95% confidence interval 0.48–1.04]; p = 0.08, with rates of 0.024 vs. 0.033 events/year) (10).

This suggests that mechanisms other than tachyarrhythmia (e.g., asystole or electromechanical dissociation that may result from hypoxia and hypercapnia, arousals and sympathetic activation) may be the underlying mechanism for the increase in cardiovascular mortality reported in patients randomized to the ASV vs. control group in the SERVE-HF trial (12). However, in the CANPAP trial suppression of CSA by means of CPAP had no effect on mortality compared to the control group (26). Similarly, in the Bad Oeynhausen prospective ASV registry, ASV therapy was not associated with increased mortality in patients with CSA and HFrEF (27). Therefore, the effect of ASV needs to be investigated in future studies.

The findings of this analysis have to be interpreted in the light of the following limitations. Nocturnal ECG data were obtained in the seven centers participating in SERVE-HF major substudy (13) during one night at baseline, 3 and 12 months only and 24-hour Holter ECG data were not available (13). However, the sampling frequency of the ECG lead during PSG is acceptable for analysis of ventricular and supraventricular arrhythmias (15, 19), and the PVC burden in patients with HFrEF and SDB is similar during the day and at night (28). In addition, cardiovascular deaths in SERVE-HF were distributed throughout the 24-h period. The impact of PVC suppression remains controversial. On the one hand treatment with antiarrhythmic medication have been reported to result in higher mortality (29). On the other hand, in patients with left ventricular systolic dysfunction, ablation of frequent PVCs induces a significant improvement in functional, structural, and neurohormonal status and a sustained reduction in the baseline PVC burden is associated with a lower risk of cardiac mortality, cardiac transplantation, or hospitalization for heart failure (30).

In addition, we cannot rule out the possibility that ASV may have triggered ventricular arrhythmias in some cases during the daytime or in patients who died before the follow-up sleep studies. However, this was not systematically assessed in the SERVE-HF major substudy (13).

In conclusion, addition of ASV to guideline-based medical management had no significant effect on nocturnal ventricular ectopy or tachyarrhythmia over a period of 12 months in alive patients with HFrEF and CSA. Findings do not further support the hypothesis that ASV may lead to sudden cardiac death by triggering ventricular tachyarrhythmia.

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.

The substudy protocol was approved by the Appropriate Local or Regional Ethics Committees [110420d/110420f (Adelaide), 2011-06-303 (Brisbane), HREC-D 153-11 (Melbourne), HPH323 (Perth), HREC/11/WMEAD/124 (Sydney), 27PZT/2012 (Czech Republic), H-D-2008-034 (Denmark), 293/13/03/01/2011 (Finland), 08-RESM-1 (France), 010/1553 (Germany), AA11 (The Netherlands), 2009/2083/REK vest (Norway), dnr M38-08 (Sweden), Rif CE 2581 (Switzerland), 08/H1307/41(UK)]. The trial was conducted according to Good Clinical Practice and the Principles of the Declaration of Helsinki 2002. All participants gave written informed consent. The patients/participants provided their written informed consent to participate in this study.

MA was responsible for conceiving and designing the study and its hypotheses, acquiring study funding, collecting, analysing and interpreting the data, and writing and revising the manuscript prior to submission. CF and MA are the guarantor of the content of the manuscript and were involved in the collection, analysis and interpretation of data, and were responsible for drafting and revising the manuscript prior to submission. LG, JB, VV, JP, SF, DL, HW, RT, HT, and MC were involved in the collection and interpretation of data and critical revision of the manuscript prior to submission. FZ was involved in data analysis and critical revision of the manuscript prior to submission. All authors contributed to the article and approved the submitted version.

The SERVE-HF trial was supported by ResMed and by grants from the National Institute for Health Research (NIHR) Cardiovascular and Respiratory Biomedical Research Units (general award to the hospital; MC). Representatives and scientists from the ResMed participated in the study including design and data collection. This ancillary analysis was supported by ResMed (MA) and by a grant from the German Heart Foundation/German Foundation of Heart Research (F/15/20; CF).

CF reports receiving support from the German Heart Foundation/German Foundation of Heart Research. VV received grant support from the German Society of Sleep Medicine. On behalf of DL, the University of Maastricht has received lecture fees and/or consulting fees and/or research grants from Bayer, LivaNova, ResMed and Respicardia. HW was a former employee of ResMed during the SERVE-HF study. RT has received consulting fees from Agiradom (Healthcare provider) and grant support from ResMed. MC has received consulting fees from ResMed and Respicardia, and grant support through his Institution from ResMed, Bayer and Abbott. HT has received consulting fees, grant support, and hardware and software for the development of devices from ResMed. MA has received consulting fees from ResMed, Philips Respironics, Boehringer-Ingelheim, NRI, Novartis, JAZZ Pharmaceuticals, Bayer, Inspire and Bresotec,and grant support from ResMed Foundation, Philips Respironics and the Else-Kroener Fresenius Foundation (2018_A159) outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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