Europace Advance Access published online on November 12, 2008
Europace, doi:10.1093/europace/eun310
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CLINICAL RESEARCH
Sleep apnoea as a predictor of mid- and long-term outcome in patients undergoing cardiac resynchronization therapy
First Department of Cardiology, Medical University of Silesia, Silesian Center for Heart Diseases, Szpitalna 2 Street, 41-800 Zabrze, Poland
Manuscript submitted 4 July 2008. Accepted after revision 23 October 2008.
* Corresponding author. Tel: +48 322713414, Fax: +48 323733792, Email: bms{at}pro.onet.pl
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Abstract |
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Aims: To assess the impact of baseline apnoea–hypopnoea index (AHI) on mid-term outcome and its change after 6 months of cardiac resynchronization therapy (CRT) on remote outcome.
Methods and results: In 71 patients with CRT devices, Holter-derived AHI was assessed before and 6 months after the procedure. Baseline AHI >20 was considered abnormal. After 6 months of CRT, a 50% decrease of baseline AHI was considered significant and stratified patients into AHI dippers and non-dippers, except those who preserved normal AHI. Prognostic value of baseline AHI and its change were assessed in relation to mortality and major cardiac events (MACE). More patients with an abnormal AHI died during 6 months follow-up (P = 0.02), especially due to sudden cardiac death. MACE-rate was insignificantly higher in abnormal AHI patients. Significantly higher mortality (P = 0.001), especially due to heart failure progression and higher MACE-rate (P < 0.001) during further observation were observed in AHI non-dippers. In multivariate analysis, the absence of AHI reduction was an independent predictor of mortality [hazard ratio (HR) 6.56, P = 0.015)] and MACE (HR 6.05, P = 0.002).
Conclusions: Abnormal baseline AHI identifies patients prone to death during mid-term observation. Lack of AHI reduction after 6 months of CRT is an independent risk factor of death and MACE during further follow-up.
Key Words: Sleep apnoea, Cardiac resynchronization therapy, Sudden cardiac death, Heart failure, Holter monitoring
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Introduction |
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Sleep-disordered breathing (SDB) affects at least 40% of patients with chronic heart failure (HF).1
,2 It has been reported that SDB increases the risk of death in HF patients.3 Numerous clinical trials performed in the last few years have confirmed that cardiac resynchronization therapy (CRT) improves clinical status and survival in patients with advanced, symptomatic HF, lowered left ventricular (LV) ejection fraction (EF) and signs of electrical dyssynchrony.4–7 In the most recent studies, the beneficial effect of CRT on SDB has also been reported.8–10 However, SDB as a marker of clinical outcome in mid- and long-term follow-up in patients treated with CRT has not thus far been investigated. Therefore, the aim of this study was to assess the impact of baseline Holter-derived apnoea–hypopnoea index (AHI) on mid-term outcome and the change of AHI after 6 months of cardiac resynchronization on remote outcome in CRT recipients.
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Methods |
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Study population
The study population consisted of consecutive HF patients who fulfilled the inclusion criteria, who underwent successful implantation of cardiac resynchronization devices and were followed at least 1 year thereafter. All patients granted their written informed consent to undergo diagnostic and therapeutic procedures, including the implantation of a CRT device. Inclusion criteria comprised: symptomatic heart failure in NYHA functional class III–IV despite optimal pharmacotherapy, LVEF
35%, QRS width 
120 ms and the presence of sinus rhythm. Patients were excluded from the analysis if at least one of the following exclusion criteria was present: age under 18, pregnancy, acute coronary syndrome within the last 3 months, any revascularization procedure (percutaneous or surgical), or other cardiac surgical procedure 3 months prior to CRT, haemodynamic instability requiring intravenous inotropic drugs within the last 3 months, pacemaker or automatic defibrillator-cardioverter implanted (ICD), estimated survival <1 year, and chronic atrial fibrillation. Seventy-one consecutive patients implanted with CRT devices were incorporated into the study. Five patients in whom implantation failed were excluded from the analysis. The majority of patients received biventricular pacemakers (InSync III, Medtronic, MN, USA), biventricular automatic ICDs (InSync Protect, Medtronic) were implanted only as secondary prophylaxis of sudden arrhythmic cardiac death in 22 (30.9%) patients.
Follow-up and data acquisition
All the patients underwent a thorough in-hospital evaluation shortly before CRT implementation and 6 months after. Apart from demographic data, comorbidities, HF aetiology, serum creatinine, and haematocrit, the following data were collected at baseline:
- NYHA class;
- QRS width measured as the maximum in leads II, V1, and V6;
- six-minute walking distance (6MWD);
- peak oxygen consumption (VO2max) during the treadmill stress test;
- echocardiographic measurements: LV end-systolic volume, LV end-diastolic volume, and LVEF. The absolute difference between left- and right ventricular pre-ejection periods (measured as time interval between the QRS onset and the beginning of aortic or pulmonary flow, respectively) was considered as the interventricular dyssynchrony. The intraventricular dyssynchrony was defined by two indices measured with colour-coded tissue Doppler imaging: septal-to-lateral and anterior-to-inferior wall motion delays. Time-to-onset systolic myocardial velocities were defined as intervals: QRS, onset of systolic myocardial velocity at basal segments of lateral, septal, anterior, and inferior walls of the LV. Septal-to-lateral wall motion delay was further calculated as the absolute difference between the time-to-onset myocardial velocity of the septum and lateral wall; accordingly anterior-to-inferior wall motion delay was considered as the difference between time-to-onset myocardial velocities of the anterior and inferior wall;
- arrhythmic events recorded in the device memory and collected during interrogation every 6 months;
- 24 h Holter-derived data: presence of supraventricular and ventricular ectopic beats, non-sustained ventricular tachycardia (nsVT) and episodes of atrial fibrillation. During sleeping hours, SDB parameters were assessed and the input data for AHI calculation was formatted.
10% relative increase in EF and 10% relative rise in VO2max and 10% relative increase in 6MWD.
The assessment of sleep-disordered breathing
SDB was assessed using the AHI. It was calculated based on Holter digital recording, using commercial Lifescreen Apnea Software version 2.61 implemented in Pathfinder 700 system (Del Mar Reynolds Medical, Hertford, UK). CRT devices were programmed to DDD mode and the night hysteresis was set to 45/min in every patient to eliminate atrial pacing during night hours. This method enabled the minimizing of atrial pacing burden to the mean 1.8% of the time during AHI determination in the study group, periods of atrial pacing were excluded from the analysis. To detect SDB, the algorithm gathered both RR information and respiratory information from the ECG obtained during sleep hours. It analysed 52 parameters from RR sequences and calculated ECG-derived respiratory signal from 36 parameters, also performing power spectral measurements. AHI was defined as mean apnoeic–hypopnoeic events per hour. Such estimated AHI was further corrected using a constant value determined in the tests to give the best correlation to true AHI values in polysomnogram tests.11,12 The software used in the study was able to detect the following types of SDB: obstructive sleep apnoea (OSA), mixed apnoea, and hypopnoea.13 AHI 5 using software classification was defined for the purpose of this study as normal, AHI >5 and 20 as borderline, and >20 as abnormal.14 Among all apnoeic–hypopnoeic events during the entire sleeping period, the duration of the longest AHI event (max AHI event) was also calculated for every patient. In order to achieve similar conditions of SDB assessment, all the patients were asked to go to sleep around 11 pm and to mark the awakening hour using Holter recorders. The mean sleep duration in our study was 7 h. SDB was assessed shortly before CRT and after 6 months of resynchronization therapy.
The patients' hypopnoeic–apnoeic status was assessed at two different time points based on two different criteria. At baseline, the entire population was divided into two groups: with non-abnormal AHI (AHI 20; this group included patients with both borderline and normal AHI) and with abnormal AHI (AHI >20).
After 6 months of CRT in the patients who survived, a change of baseline AHI was calculated and a 50% reduction of baseline AHI was considered significant. Patients (n=8) who preserved baseline normal AHI (5) after 6 months of CRT were excluded from further analysis. Fifty-nine remaining patients were subsequently divided into another two groups: AHI dippers (50% relative AHI improvement) and non-dippers (<50% AHI improvement or change from baseline normal to borderline abnormal AHI after 6 months of CRT).
Statistical analysis
Continuous parameters were presented as mean ± standard deviation (SD), unless otherwise specified, while categorical variables as numbers and percentages. Intergroup data differences with normal distribution were analysed using the unpaired Student's t-test; for non-normally distributed values, the Mann–Whitney U test was used. Paired Student's t-test was used to analyse the changes in AHI within the study population following 6 months of CRT. The 
2 test or Fisher's exact test were used when appropriate for categorical variables. Long-term mortality rate was plotted as Kaplan–Meier curves and compared with log-rank test. Independent predictors of death and MACE events were identified with multivariate Cox regression model and expressed as hazard ratios (HR) with 95% confidence intervals (CI). Regression models were developed after the inclusion of the following parameters: age, serum creatinine, presence of AHI reduction, increase of VO2max, and reduction of interventricular dyssynchrony after 6 months of CRT. All the tests were double-sided. P-value <0.05 was considered statistically significant. All analyses were performed using the software package Statistica (version 6.1, StatSoft Inc., Tulsa, OK, USA).
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Results |
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Characteristics of sleep-disordered breathing in the entire study population
Mean value of AHI in the entire study population before CRT was 18.5 ± 14.4. Abnormal AHI was observed in 31 patients (44%) and non-abnormal AHI in 40 subjects (56%). After 6 months of CRT, a significant (P < 0.001) decrease of AHI was observed in the study population, reaching the value of 6.9 ± 6.9.
Comparative characteristics of patients with abnormal and non-abnormal baseline apnoea–hypopnoea index
The comparison of patients with abnormal and non-abnormal AHI did not reveal significant differences with regard to demographic and clinical data, concomitant diseases and echocardiographic parameters at baseline. The mean value of baseline AHI was significantly higher (P < 0.001) in patients with abnormal AHI than in patients with non-abnormal AHI (31.7 vs. 8.2). Ventricular arrhythmias in Holter monitoring were common in both groups, with slightly, but insignificantly higher prevalence to nsVT (32% vs. 18%, P = 0.17) and atrial fibrillation episodes (6.5% vs. 5%, respectively; P = 0.79) among patients with abnormal AHI. Comparative analysis of both the groups is shown in Table 1. The example of SDB assessment in a patient with high AHI value and an episode of nsVT during apnoeic event is shown in Figure 1.
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Mid-term and remote outcomes in patients with abnormal and non-abnormal baseline apnoea–hypopnoea index
During 6 months of follow-up period, four patients (12.9%) in abnormal AHI group and none in non-abnormal group died (P = 0.02). Of the patients in whom fatal event occurred, three died due to SCD (9.7% vs. 0%, P = 0.04). One patient (3.2%) from abnormal AHI group and none from non-abnormal died in the course of progressive, intractable HF (P = 0.26). All patients who died suddenly had a biventricular pacemaker without ICD function implanted. Two patients in the abnormal AHI and two in the non-abnormal group underwent hospitalization due to HF progression (6.4% vs. 5%, P = 0.80), no patient underwent heart transplantation during 6 months after CRT. The MACE rate during mid-term follow-up was slightly higher in the abnormal group when compared with the non-abnormal AHI group (19.3% vs. 5%, respectively, P = 0.06).
Over the median follow-up of 674 days, 20 patients died. No significant differences were observed between groups with regard to all-cause mortality rate (29% vs. 27.5%, P = 0.89), MACE rate (32.3% vs. 35%, P = 0.81), death due to HF progression (12.9% vs. 15%, P = 0.80), hospitalization due to HF (12.9% vs. 20%, P = 0.43), and heart transplantation (0% vs. 2.5%, P = 0.38). However, SCD rate was significantly higher in patients with baseline abnormal AHI when compared with non-apnoeic patients (16.1% vs. 2.5%, P = 0.04). Out of 49 patients without ICD, six died due to SCD (three during the first 6 months after implantation). No significant differences with regard to baseline characteristics were found between patients without ICD who died and those who did not die due to SCD. However, 83.3% of those who did and 32.6% of those who did not die suddenly had an abnormal baseline AHI (P = 0.016).
During the entire follow-up period, out of 22 subjects with an ICD, adequate ICD interventions were recorded in seven patients (31.8%) owing to malignant ventricular arrhythmias. A trend (P = 0.06) towards more frequent adequate ICD interventions was observed in the abnormal when compared with the non-abnormal group (16.1% vs. 5%, respectively).
Among survivors of the first 6 months, groups with abnormal and non-abnormal baseline AHI did not differ with regard to remote mortality rate (18.5% vs. 27.5%, P = 0.40) or MACE rate (22.2% vs. 35%, P = 0.27).
Apnoea–hypopnoea dippers vs. non-dippers after 6 months
After exclusion of eight patients in whom baseline normal AHI remained within a normal range following CRT, out of 59 patients who survived the first 6 months in 39 (66%), a significant improvement of AHI occurred, whereas the remaining 20 (34%) met the criteria of non-dippers (19 patients did not reach the demanded level of 50% reduction and in one patient AHI worsened after 6 months from normal to borderline). A significantly greater shortening of maximum AHI event and the tendency to its shorter duration was observed in AHI dippers, compared with patients in whom AHI did not improve. The AHI dippers showed significantly lower NYHA class (1.7 vs. 2.0, P = 0.02), higher EF (35.6% vs. 28.3%, P = 0.002), and shorter septal-to-lateral wall motion delay (14.3 ms vs. 38.2 ms, P = 0.01) after 6 months of resynchronization. A significantly more marked increase in EF, VO2max, reduction of septal-to-lateral wall motion delay, and larger proportion of responders to CRT (89.7% vs. 55%, respectively; P = 0.002) was also present in AHI dippers.
The comparative characteristics of both groups are shown in Table 2.
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Long-term outcome in relation to apnoea–hypopnoea index improvement
Out of 59 patients who survived 6 months post-operatively and were evaluated with regard to AHI improvement, four AHI dippers (10.3%), and 11 non-dippers (55%, P < 0.001) died during further median follow-up of 503 days. The predominant cause of death within that period was progressive HF and the resulting mortality-rate was significantly (P = 0.002) more frequent in AHI non-dippers than dippers (35% vs. 5.1%, respectively). On the other hand, dippers and non-dippers did not differ significantly with regard to rates of SCD (2.6% vs. 10%) and non-cardiac death (2.6% vs. 10%, both P = 0.22).
The occurrence of MACE during long-term observation was higher in the non-dippers than in the group in which AHI improved (60% vs. 15.4%, P < 0.001). This was due to the higher mortality in non-dippers, as rates of hospitalizations due to HF progression (30% vs. 10.3%, P = 0.057) and heart transplantations (5% vs. 0%, P = 0.16) were similar in both groups.
Multivariate Cox regression analysis identified the absence of AHI reduction after 6 months of CRT as an independent risk factor of all-cause death during further observation (covariate-adjusted HR 6.56, P = 0.015). Similar analysis performed for the MACE indicated that the absence of significant AHI reduction during the first 6 months after CRT was an independent predictor of future MACE events (covariate-adjusted HR 6.05, P = 0.002).
The results of Cox regression models for mortality and MACE events are presented in Table 3. Kaplan–Meier curves of cumulative mortality and MACE are shown in Figures 2 and 3.
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Discussion |
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The beneficial effects of CRT on the functional indices and quality-of-life in HF patients in short- and long-term observations are well documented.4
,5,15 The recently published results of CARE-HF trial also revealed that CRT diminished any-cause mortality in patients with advanced HF by 36%.7 Meta-analysis of five CRT randomized trials performed by Rivero et al.16 confirmed this observation. Moreover, the last meta-analysis showed that CRT reduced mortality predominantly in cases of worsening HF, but not by affecting the rates of SCD.
In the last several years great efforts have been made to identify factors that influence the outcome in patients undergoing cardiac resynchronization. Although some clinical data have been considered as markers of future response to CRT and a more favourable outcome after resynchronization therapy, the independent predictors of death and adverse cardiac events in CRT recipients still remain unknown.16,17
The main finding of our study is that high AHI values prior to CRT identify patients who are at a higher risk of death, especially SCD, during the first 6 months of pacing. The second important finding is that the absence of 50% decrease of the baseline AHI after 6 months of CRT is an independent predictor of mortality, mainly due to the progressive HF, during further follow-up.
Our results are in-line with the data published by other authors demonstrating the reduction of central sleep apnoea8,9,18 and OSA following CRT.10
The AHI index has recently been shown to be an important marker of adverse cardiovascular events in patients with OSA as well as in patients with OSA concomitant to coronary artery disease.19,20 Marin et al. reported that severe OSA increased independently the risk of fatal cardiovascular events by 2.9-fold and the risk of non-fatal events by 3.2-fold.19 Milleron et al.20 reported similar results in a group of patients with coronary artery disease during 86 months follow-up.
In our study performed on a population of patients with advanced HF, we found AHI to be crucial in risk stratification. Our methodology allowed to investigate mainly OSA and mixed apnoeas–hypopnoeas. As has been previously demonstrated, OSA often coexist with HF, being present in as many as 11–38% of HF patients. It has also been postulated that OSA can lead to a progression of HF and refractoriness to therapy.2,21,22 Moreover, Sleep Heart Health Study revealed that OSA increases the risk of HF morbidity by 2.2-fold.23 Various consequences of apnoeas have been investigated; many of them could explain the unfavourable effects of apnoea in HF but the exact mechanisms remain poorly understood. OSA was shown to negatively influence LV filling, reducing stroke volume in HF patients.22 Apnoeic patients demonstrate an elevated sympathetic activity; the postulated mechanism of this phenomenon is the intermittent episodes of hypoxia during night-time. Furthermore, apnoeas often coexist with obesity and other comorbidities that are also known to elevate the sympathetic tone.21,24 Increased afterload caused by elevated sympathetic activity, with the following alteration in cardiac output has been postulated as one of the potential adverse effects of apnoea.25 Some authors found higher levels of serum noradrenaline and impaired vagal tone in patients with severe apnoea.26,27 Such autonomic imbalance, persisting during day-time, has been shown to predispose to tachyarrhythmias.21,27 In addition, negative influence of OSA on endothelial function and promoting systemic inflammation has been postulated by some authors.28 It has also been reported that OSA, being associated with the elevated levels of plasma angiotensin II and aldosterone, can influence the renin–angiotensin system and can participate in cardiac remodelling and fibrosis.29
All these mechanisms can potentially explain the results obtained in our HF population treated with CRT. The persistent heightened sympathetic activity can be responsible for SCD events during the first 6 months of observation. It is noteworthy that the group with abnormal baseline AHI in our study included a high percentage of patients with nsVT, which can confirm the greater susceptibility to malignant ventricular tachyarrhythmias in this subpopulation. This hypothesis can also be supported by the trend towards a higher incidence of ICD interventions owing to life-threatening ventricular arrhythmias in patients with abnormal AHI. High values of baseline AHI in our study identified patients prone to death during the first 6 months after CRT implementation and to SCD during mid- and long-term observation.
The other above-mentioned mechanisms, which are thought to contribute to the progression of HF, may have been responsible for the higher occurrence of adverse cardiac events during further observation in our study. They can also explain the fact that the absence of significant reduction of AHI following CRT was a strong and independent risk factor for death owing to the HF progression and for MACE during long-term follow-up. However, mechanisms responsible for the effects of hypopnoea on HF progression warrant a further evaluation.
The process of AHI improvement during CRT seems to be time-dependent. To our knowledge, only one study failed to demonstrate a decrease of SDB parameters after the implementation of cardiac resynchronization. The authors assessed SDB at baseline the night before CRT, a second measurement was performed the night after pacemaker implantation. The authors did not find any acute beneficial effects of CRT on SDB indices.30 In our study significant changes in SDB were found after 6 months of pacing. After that time, the AHI dippers were shown to gain more from CRT, demonstrating lower NYHA class, higher EF, and less pronounced ventricular dyssynchrony than patients in whom AHI did not decrease after 6 months of CRT. It can be suspected that SDB improvement is strongly related to, or even caused by, the regression of HF. However, it should be stressed, that in our study the absence of AHI reduction following CRT remained a significant and independent predictor of poor outcome even after adjustment for other indices of HF, increasing by six-fold the risk of death and of fatal cardiac events during long-term follow-up. These findings suggest that apnoeas may act via mechanisms, which are independent of other conventional parameters of cardiac capacity. Further studies on larger groups of patients are needed to clarify the mechanisms responsible for the effects of SDB on the outcome in HF patients.
Clinical implications
Our data indicate that HF patients with unfavourable SDB profile, especially those in whom AHI did not decrease after CRT, constitute a group with particularly poor outcome. Certain measures are desirable to protect this high-risk group against future adverse events. Recent studies documented that the treatment of patients with HF and OSA with nocturnal continuous positive airway pressure (CPAP), besides reducing blood pressure and lowering heart rate, improves cardiac function increasing EF and reducing LV end-diastolic dimension.31 Such an approach is also supported by the results of Usui et al.,14 who documented additional therapeutic effect of CPAP in patients with HF and optimal medical treatment. Our observations indicate that CPAP can be considered in subsets in whom AHI did not improve after 6 months of CRT. However, despite the optimistic preliminary data, the significance of CPAP in HF population needs further evaluation.
Limitations of the study
Holter-based assessment of SDB is limited to OSA evaluation. Polysomnography, in which all types of SDB, including central sleep apnoea and Cheney-Stokes respiration can be assessed, remains a gold standard in SDB assessment. Therefore, we could not evaluate the role of central sleep apnoea, which is present in 33–40% of HF patients.32 Polysomnography is indicated for detailed SDB diagnostics in highly symptomatic apnoeic patients.33 Nevertheless, this method requires sophisticated sleep laboratories, which are accessible to a very limited number of patients, and all-night monitoring of many sleep parameters. Conversely, Holter monitoring is easily accessible and comfortable for the patient. Nevertheless, until its role in risk stratification is confirmed by greater studies, it can be considered a screening method. Therefore, we suggest that the absence of AHI response documented in Holter recordings after 6 months of CRT should be confirmed by polysomnography.
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Conclusions |
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Abnormal baseline AHI identifies patients prone to death during mid-term observation after CRT implementation. Lack of AHI reduction after 6 months of pacing is an independent risk factor of death and MACE during long-term follow-up.
Conflict of interest: none declared.
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References |
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