Severe Central Sleep Apnea Is Associated with Atrial Fibrillation in Patients with Left Ventricular Systolic Dysfunction WOLFRAM GRIMM, M.D.,* JULIA SASS, M.D.,* EMAD SIBAI, M.D.,† WERNER CASSEL, M.SC.,† OLAF HILDEBRANDT, M.SC.,† SANDRA APELT, PH.D.,† CHRISTOPH NELL, M.SC,† and ULRICH KOEHLER, M.D.† From the *Department of Cardiology, University Hospital of Marburg and Gießen, Marburg, Germany; and †Sleep Disorder Center, University Hospital of Marburg and Gießen, Marburg, Germany
Background: The results of previous studies investigating the association between atrial fibrillation (AF) and central sleep apnea (CSA) in patients with left ventricular (LV) systolic dysfunction are contradictory. Methods: We prospectively enrolled 267 patients in this cross-sectional study with LV ejection fractions ࣘ50%, who were screened for sleep disordered breathing using cardiorespiratory polysomnography after patients with predominantly obstructive sleep apnea or insufficient sleep studies had been excluded. Results: AF at study entry was found in 70 of 267 patients (26%). CSA with an apnea/hypopnea index (AHI) ࣙ15/hour was present in 116 patients (43%) and 67 patients (25%) had severe CSA with an AHI > 30/hour. Univariate analysis revealed a significant association between AF and severe CSA, age, male gender, arterial hypertension, left atrial diameter, brain natriuretic peptide, chronic kidney disease, New York Heart Association class, digitalis, and the lack of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Multivariate analysis revealed a significant association between AF and severe CSA (odds ratio [OR]: 5.21; 95% confidence interval [CI]: 1.67–16.27, P = 0.01), age (OR: 1.22 per 5-year increase; 95% CI: 1.05–1.40, P = 0.01), left atrial diameter (OR 1.61 per 5-mm increase; 95% CI: 1.22–2.01, P < 0.01), and digitalis (OR: 2.7; 95% CI: 1.26–5.79, P = 0.01). Conclusions: AF is associated with severe CSA but not with moderate CSA in addition to age, use of digitalis, and left atrial size in patients with LV systolic dysfunction. Future studies evaluating the potential benefit of adaptive servo-ventilation therapy to prevent AF or to decrease the AF burden in heart failure patients should therefore focus on patients with severe central sleep apnea. (PACE 2014; 00:1–7) central sleep apnea, atrial fibrillation, heart failure
Introduction Central sleep apnea (CSA) and atrial fibrillation (AF) are both highly prevalent findings in patients with heart failure due to left ventricular (LV) systolic dysfunction.1–18 In contrast to obstructive sleep apnea (OSA), which has been shown to be an independent risk factor for AF in patients with and without LV dysfunction,19–23 the relationship Funding: The work was supported by a research grant from Resmed GmbH&Co.KG, Martinsried, Germany. Conflicts of Interest: Dr. Koehler received grant support from Resmed, AstraZeneca, GlaxoSmithKline, Berlin-Chemie, IFM, Heinen and Loewenstein, Respironics, and UCB Biosciences. The remaining authors have no conflicts of interest. Address for reprints: Wolfram Grimm, M.D., Department of Cardiology, Philipps-University Marburg, Baldingerstraße, 35033 Marburg, Germany. Fax: 49–6421–586–8954; e-mail: [email protected] Received May 16, 2014; revised July 15, 2014; accepted July 19, 2014. doi: 10.1111/pace.12495
between AF and CSA remains controversial. Therefore, we prospectively performed a crosssectional study to determine the association between AF and CSA in patients with systolic LV dysfunction. Methods Patients From August 2007 to June 2011, 300 adult patients with systolic heart failure New York Heart Association (NYHA) class I to III with LV ejection fractions ࣘ 50% by echocardiography due to ischemic or nonischemic cardiomyopathy were prospectively screened for sleep disordered breathing using cardiorespiratory polysomnography in a single-center study at the University Hospital of Marburg. Patients were excluded from study participation if they had one or more of the following conditions: history of sleep disordered breathing, advanced kidney disease with an estimated glomerular filtration rate (eGFR) 30 seconds with spontaneous conversion within 7 days, whereas an AF duration >7 days defined persistent AF according to the European Society of Cardiology guidelines for diagnosis, classification, and management of AF.24 The study protocol was reviewed and approved by the ethics committee of the University of Marburg. Written informed consent had been obtained from all study patients. Unattended overnight cardiorespiratory polysomnography was performed during one night using Somnocheck R&KTM instruments (Weinmann, Hamburg, Germany) and analyzed according to the recommendations of the American Academy of Sleep Medicine.25 Standard definitions were used for sleep-related disordered breathing.25 An apnea was defined as cessation of inspiratory airflow >10 seconds. The number of apneas and hypopneas per hour of sleep is referred to as apnea/hypopnea index (AHI). An AHI ࣙ 15/hour defined the presence of sleep apnea. Severe sleep apnea was diagnosed in the presence of an AHI cutoff point >30/hour as recommended by the task force of the American Society of Sleep Medicine.25 Central apnea was defined as the absence of rib cage and abdominal excursions with absence of airflow. Obstructive apnea was defined as the absence of airflow in the presence of rib cage and abdominal excursions. CSA was diagnosed when the number of central apneas exceeded the number of obstructive apneas in the presence of an AHI ࣙ 15 hours. OSA was diagnosed in the presence of a predominantly obstructive rather than central apnea pattern. All polysomnographic recordings were scored by a sleep technician who was unaware of the patients’ clinical characteristics. Two-dimensional echocardiographic examinations were performed in all patients using a Vingmed Vivid SevenTM machine (General Elec-
2
tronics Medical Systems, Solingen, Germany) to determine left atrial diameter, LV ejection fraction, and LV size. LV ejection fraction was measured in the apical four-chamber view and orthogonal two-chamber view using the disc summation method (modified Simpson’s rule algorithm). Echocardiographic studies were performed by cardiologists unaware of the sleep study results. Kidney function was assessed at study entry by the eGFR using the Modification of Diet in Renal Disease (MDRD) formula.26 Chronic kidney disease of at least stage 3 was diagnosed in patients with two eGFR values below 60 mL/min per 1.73 m2 with an interval of at least 3 months.27 Statistical Analysis Clinical characteristics and results of polysomnography were stratified for patients with and without AF at study enrollment. For comparison of continuous variables, the unpaired Student’s t-test and the Mann-Whitney rank sum test were used when data were normally and nonnormally distributed. Fisher’s exact test was used for comparison of nominal variables. Univariate logistic regression and multivariate stepwise logistic regression analysis with likelihood-ratio test and backward selection with a cutoff level of 0.2 was used to assess the association between AF at study enrollment and clinical characteristics including CSA and severe CSA as defined above. Odds ratio (OR) and corresponding 95% confidence intervals (CIs) are reported for multivariate analyses. Results are expressed as mean ± standard deviation unless specified otherwise. All probability values reported are two-sided, and a probability value of P < 0.05 was considered to indicate statistical significance. SPSS-software version 21 (IBM Corp., Armonk, NY, USA) was used for all statistical analyses. Results Of the 267 study patients, 201 patients (75%) were men and 66 (25%) were women (Table I). Mean age was 60 ± 14 years, and mean LV ejection fraction was 34 ± 14%. The majority of patients were in NYHA heart failure class II (37%) or in NYHA class III (48%). Ischemic cardiomyopathy was present in 124 patients (46%) and nonischemic cardiomyopathy in 143 patients (54%). AF at study entry was present in 70 patients (26%). Sixteen of 70 patients with AF (23%) had paroxysmal AF, and 54 patients (77%) had persistent AF.
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59 ± 14 143 (73) 27 ± 5 128 (65) 116 (60) 50 (25) 52 (26) 41 (21) 657 ± 896 85 (43) 112 (57) 44 ± 8 62 ± 8 34 ± 10 111 (56) 86 (44) 66 (34) 22 (11) 30 (15) 139 (71) 140 (71) 83 (42) 159 (81) 113 (57) 84 (43) 157 (80) 40 (20)
60 ± 14 201 (75) 28 ± 5 183 (69) 152 (57) 75 (28) 84 (32) 50 (19) 685 ± 852 124 (46) 143 (54) 46 ± 8 61 ± 9 34 ± 10 138 (52) 129 (48) 86 (32) 34 (13) 55 (21) 177 (66) 194 (73) 105 (39) 211 (79) 151 (57) 116 (43) 200 (75) 67 (25)
43 (61) 27 (39)
38 (54) 32 (46)
25 (33) 38 (54) 54 (77) 22 (31) 52 (74)
20 (29) 12 (17)
27 (39) 43 (61)
49 ± 7 60 ± 10 34 ± 10
39 (56) 31 (44)
66 ± 12 58 (83) 28 ± 5 55 (79) 36 (51) 25 (33) 32 (46) 9 (13) 762 ± 713
Atrial Fibrillation (n = 70)
0.002
0.66
0.001 0.04 0.33 0.12 0.26
0.21
0.04
0.001 0.34 0.88
0.07
0.001 0.09 0.63 0.04 0.29 0.10 0.003 0.26 0.002
P Univariate
0.01
0.01 0.06
0.07
5.21 (1.67–16.27)
2.70 (1.26–5.79) 0.51 (0.25–1.03)
1.92 (0.96–3.87)
1.61 (122–2.01)§
1.0 (0.99–1.0)
0.06
30/hour), n (%) No severe CSA Severe CSA
Sinus Rhythm (n = 197)
All Patients (n = 267)
Presenting Characteristics of 267 Study Patients with and Without Atrial Fibrillation
Table I.
ATRIAL FIBRILLATION AND CENTRAL SLEEP APNEA
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Table II. Polysomnography Results
Baseline Characteristics No sleep apnea (AHI < 15/hour) Central sleep apnea (AHI ࣙ 15/hour) Severe central sleep apnea (AHI > 30/hour) Epworth sleepiness scale Epworth sleepiness scale >10, n (%) AHI (n/hour) Central apnea index (n/hour) Obstructive apnea index (n/hour) Mixed apnea index (n/hour) Hypopnea index (n/hour) Total in bed time (minutes) Total sleep time (minutes) Mean O2 -saturation (%) O2 -saturation 10 was present in 13% of patients. No sleep apnea was found in 151 patients (57%), and 116 patients (43%) had CSA using an AHI cutoff of 15. Sixtyseven patients (25%) had severe CSA with an AHI > 30/hour. Univariate analysis revealed a significant association between AF and age, male gender, arterial hypertension, chronic kidney disease, brain natriuretic peptide, left atrial diameter, NYHA heart failure class, the use of digitalis, the lack of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), and the presence of severe CSA (Table I). Multivariate logistic regression analysis revealed a significant association between AF and severe CSA (OR: 5.21; 95% CI: 1.67–16.27, P = 0.01), age (OR: 1.22 per 5-year increase in age; 95% CI: 1.05–1.40, P = 0.01), left atrial diameter (OR 1.61 per 5 mm left atrial diameter increase; 95% CI: 1.22–2.01, P < 0.01), and the use of digitalis (OR: 2.7; 95% CI: 1.26–5.79, P = 0.01).
4
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1999 2005 2006 2006 2007 2007 2007 2007 2007 2007 2008 2009 2009 2010 2011 2011 2012 2013 2014
Sin1 Staniforth2 Mehra3 Rao4 Shigemitsu5 Oldenburg6 Schulz7 Vazir8 Christ9 Javaheri10 Oldenburg11 Bitter12 Paulino13 Konecny14 Jilek15 Bitter16 Grimm17 Kreuz18 Present study
450 101 566† 84 93 700 203 55 102 88 105 244‡ 316 91§ 296 255 204 133 267
Patients (n) PSG Yes No Yes No No No No Yes No Yes No No No Yes Yes No No No Yes
EF (%) 23 ± 16 33 n.a. n.a. 55 30 ± 11 68 ± 8 ࣘ50 10 ࣙ22.5 ࣙ15 >5 ࣙ10 >30
AHI cutoff/hour
† Subgroup sample from the Sleep Heart Health Study including patients ‡ Patients with heart failure and normal left ventricular ejection fraction.
Year
First author
Atrial Fibrillation and CSA in Patients with LV Dysfunction
Table III.
ATRIAL FIBRILLATION AND CENTRAL SLEEP APNEA
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of variables, including patient selection, heart failure severity and etiology, age, gender, heart failure medication, and various AHI cutoff values used to define CSA. Although most previous studies found a similar prevalence of AF in patients with versus without CSA,2,4,5,8–11,15–18 several investigators reported a significantly higher prevalence of AF in patients with CSA compared to patients without CSA.1,3,6,7,12–14 The discrepancy between these studies may, in part, be explained by differences in methodology to detect and define CSA as well as differences in patient selection and, most importantly, study size. Eight of nine smaller studies with less than 200 patients were unable to distinguish whether AF was a risk factor for CSA,2,4,5,8–11,18 whereas six of nine larger studies enrolling more than 200 patients found a significantly higher prevalence of AF in patients with versus without CSA using univariate analysis1,3,6,7,12,13 (Table III). Although most previous studies used polygraphy4–7,9,11–13,16–18 or simple overnight oxymetry2,14 to detect CSA, polysomnography as gold standard to diagnose CSA was used only in less than one-third of previous studies.1,3,8,10,15 Finally, several previous studies3,14,15,18 did not differentiate between patients with OSA and CSA, which makes it difficult to interpret the results, because these two breathing disorders have different underlying pathophysiology and probably different prognostic and therapeutic consequences. To date, only one previous study1 reported the relation between AF and CSA in 450 patients with congestive heart failure using multivariate analysis. As a result, Sin et al.1 found AF, male gender, and age > 60 years to be independent risk factors for CSA using an AHI cutoff >10/hour to diagnose sleep apnea (Table III). Our study differs from the study by Sin et al. in several important aspects. First, Sin et al.1 performed a retrospective analysis of consecutive heart failure patients referred to the sleep laboratory by cardiologists, whereas unselected patients with LV dysfunction and heart failure NYHA I to III were prospectively enrolled in our cross-sectional study with no patient being referred to our sleep laboratory for a reason other than participation in this study. Second, since patients were enrolled more than 15 years ago in the study by Sin et al.,1 they did not routinely receive modern heart failure therapy including β-blockers or aldosterone antagonists in addition to ACE inhibitors or ARBs as in our study. Furthermore, 13% of heart failure patients in our study received cardiac resynchronization
6
therapy, which was also not available in study of Sin et al.1 A meta-analysis by Lamba et al.23 found that the substantial improvement of systolic LV function by cardiac resynchronization therapy was accompanied by a significant decrease in sleep apnea severity in CSA patients with a mean AHI reduction of 13/hour. In contrast, cardiac resynchronization therapy did not result in a significant AHI decrease in OSA patients, which may be explained by the different pathophysiology of OSA versus CSA. Mehra et al.3 analyzed the association of nocturnal arrhythmias in two samples of the Sleep Heart Health Study consisting of a sample of 228 subjects with severe sleep-disordered breathing with an AHI ࣙ 30/hour compared to an age-, sex-, ethnicity-matched sample of 338 subjects without sleep apnea with an AHI < 5/hour. Similar to our study, Mehra et al.3 found a significantly higher prevalence of AF in patients with versus without sleep-disordered breathing (4.8 vs 0.9%). In contrast to the study by Sin et al.1 and our study, Mehra et al.3 did not differentiate between CSA and OSA. In addition, only 3% of patients in the study by Mehra et al.3 had heart failure due to the design of the Sleep Heart Health Study as a community-based epidemiologic study in participants aged ࣙ40. This explains the much lower prevalence of AF in the study by Mehra et al.,3 which almost equals the AF prevalence in an age-matched normal population rather than the AF prevalence in a heart failure population. In conclusion, our study confirms a significant association between AF and severe CSA but not with mild or moderate CSA in patients with LV dysfunction in addition to age and left atrial size. In contrast to patients with severe OSA, CPAP therapy failed to improve the outcome of heart failure (HF) patients with CSA in the prospective randomized CANPAP trial.28 More recently, several small studies have shown improvements of HF symptoms and improvements of cardiac function with adaptive servo-ventilation for severe CSA, which has the greater ability to normalize the breathing pattern in HF patients with CSA compared to CPAP.29,30 Future studies need to clarify whether adaptive servo-ventilation for severe CSA is helpful to prevent AF or to decrease the AF burden in patients with LV dysfunction. The results of our study strongly suggest that an AHI cutoff of 30 rather than 15 should be considered when designing future studies to determine whether ventilation therapy might be helpful to prevent the development of AF or facilitates rhythm management in patients with CSA.
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References 17. Grimm W, Apelt S, Timmesfeld N, Koehler U. Sleep-disordered breathing in patients with implantable cardioverter-defibrillator. Europace 2013; 15:515–522. 18. Kreuz J, Skowasch D, Horlbeck F, Atzinger C, Schrickel JW, Lorenzen H, Nickenig G, et al. Usefulness of sleep-disordered breathing to predict occurrence of appropriate and inappropriate implantable-cardioverter defibrillator therapy in patients with implantable cardioverter-defibrillator for primary prevention of sudden cardiac death. Am J Cardiol 2013; 111:1319–1323. 19. Gami AS, Pressman G, Caples SM, Kanagala R, Gard JJ, Davison DE, Malouf JF, et al. Association of atrial fibrillation and obstructive sleep apnea. Circulation 2004; 110:364–367. 20. Gami AS, Somers VK. Implications of obstructive sleep apnea for atrial fibrillation and sudden cardiac death. J Cardiovasc Electrophysiol 2008; 19:997–1003. 21. Somers VK, White DP, Amin R, Abraham WT, Costa F, Culebras A, Daniels S, et al. Sleep apnea and cardiovascular disease: An American Heart Association/American College of Cardiology Foundation Scientific Statement from the American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology, Stroke Council, and Council on Cardiovascular Nursing. J Am Coll Cardiol 2008; 52:686– 717. 22. Kanagala R, Murali NS, Friedman PA, Ammash NM, Gersh BJ, Ballman KV, Shamsuzzaman AS, Somers VK, et al. Obstructive sleep apnea and the recurrence of atrial fibrillation. Circulation 2003; 107:2589–2594. 23. Lamba J, Simpson CS, Redfearn DP, Michael KA, Fitzpatrick M, Baranchuk A. Cardiac resynchronization therapy for the treatment of sleep apnoea: A meta-analysis. Europace 2011; 13:1174– 1179. 24. Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, Van Gelder IC, et al.; ESC Committee for Practice Guidelines. Guidelines for the management of atrial fibrillation: The Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Europace 2010; 12:1360–1420. 25. The Report of an American Academy of Sleep Medicine Task Force.Sleep-related breathing disorders in adults: Recommendations for syndrome definition and measurement techniques in clinical research. Sleep 1999; 22:667–689. 26. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. Modification of Diet in Renal Disease Study Group: A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Ann Intern Med 1999; 130:461– 470. 27. Levey AS, Coresh J, Balk E, Kausz AT, Levin A, Steffes MW, Hogg RJ, et al.; National Kidney Foundation. National Kidney Foundation practice guidelines for chronic kidney disease: Evaluation, classification, and stratification. Ann Intern Med 2003; 139:137–147. 28. Bradley TD, Logan AG, Kimoff RJ, S´eri`es F, Morrison D, Ferguson K, Belenkie I, et al. CANPAP Investigators. Continuous positive airway pressure for central sleep apnea and heart failure. N Engl J Med 2005; 353:2025–2033. 29. Sharma BK, Bakker JP, McSharry DG, Desai AS, Javaheri S, Malhotra A. Adaptive servoventilation for treatment of sleep-disordered breathing in heart failure: A systematic review and meta-analysis. Chest 2012; 142:1211–1221. 30. Cowie MR, Woehrle H, Wegscheider K, Angermann C, d’Ortho MP, Erdmann E, Levy P, et al. Rationale and design of the SERVE-HF study: Treatment of sleep-disordered breathing with predominant central sleep apnoea with adaptive servo-ventilation in patients with chronic heart failure. Eur J Heart Fail 2013; 15:937– 943.
1. Sin DD, Fitzgerald F, Parker JD, Newton G, Floras JS, Bradley TD. Risk factors for central and obstructive sleep apnea in 450 men and women with congestive heart failure. Am J Respir Crit Care Med 1999; 160:1101–1106. 2. Staniforth AD, Sporton SC, Early MJ, Wedzicha JA, Nathan AW, Schilling RJ. Ventricular arrhythmia, Cheyne-Stokes respiration, and death: Observations from patients with defibrillators. Heart 2005; 91:1418–1422. 3. Mehra R, Benjamin EJ, Shahar E, Gottlieb DJ, Nawabit R, Kirchner HL, Sahadevan J, et al. Association of nocturnal arrhythmias with sleep-disordered breathing: The Sleep Heart Health Study. Am J Respir Crit Care Med 2006; 173:910–916. 4. Rao A, Georgiadou P, Francis DP, Johnson A, Kremastinos DT, Simonds AK, Coats AJ, et al. Sleep-disordered breathing in a general heart failure population: Relationships to neurohumoral activation and subjective symptoms. J Sleep Res 2006; 15:81–88. 5. Shigemitsu M, Nishio K, Kusuyama T, Itoh S, Konno N, Katagiri T. Nocturnal oxygen therapy prevents progress of congestive heart failure with central sleep apnea. Int J Cardiol 2007; 115:354–360. 6. Oldenburg O, Lamp B, Faber L, Teschler H, Horstkotte D, Topfer ¨ V. Sleep-disordered breathing in patients with symptomatic heart failure: A contemporary study of prevalence in and characteristics of 700 patients. Eur J Heart Fail 2007; 9:251–257. 7. Schulz R, Blau A, Borgel J, Duchna HW, Fietze I, Koper I, Prenzel ¨ R, et al. Working group Kreislauf und Schlaf of the German Sleep Society (DGSM). Sleep apnoea in heart failure. Eur Respir J 2007; 29:1201–1205. 8. Vazir A, Hastings PC, Dayer M, McIntyre HF, Henein MY, PooleWilson PA, Cowie MR, et al. A high prevalence of sleep disordered breathing in men with mild symptomatic chronic heart failure due to left ventricular systolic dysfunction. Eur J Heart Fail 2007; 9:243– 250. 9. Christ M, Sharkova Y, Fenske H, Rostig S, Herzum I, Becker HF, Mueller C, et al. Brain natriuretic peptide for prediction of CheyneStokes respiration in heart failure patients. Int J Cardiol 2007; 116:62–69. 10. Javaheri S, Shukla R, Zeigler H, Wexler L. Central sleep apnea, right ventricular dysfunction, and low diastolic blood pressure are predictors of mortality in systolic heart failure. J Am Coll Cardiol 2007; 49:2028–2034. 11. Oldenburg O, Bitter T, Wiemer M, Langer C, Horstkotte D, Piper C. Pulmonary capillary wedge pressure and pulmonary arterial pressure in heart failure patients with sleep-disordered breathing. Sleep Med 2009; 10:726–730. 12. Bitter T, Faber L, Hering D, Langer C, Horstkotte D, Oldenburg O. Sleep-disordered breathing in heart failure with normal left ventricular ejection fraction. Eur J Heart Fail 2009; 11:602–608. 13. Paulino A, Damy T, Margarit L, Sto¨ıca M, Deswarte G, Khouri L, Vermes E, et al. Prevalence of sleep-disordered breathing in a 316-patient French cohort of stable congestive heart failure. Arch Cardiovasc Dis 2009; 102:169–175. 14. Konecny T, Brady PA, Orban M, Lin G, Pressman GS, Lehar F, Tomas K, et al. Interactions between sleep disordered breathing and atrial fibrillation in patients with hypertrophic cardiomyopathy. Am J Cardiol 2010; 105:1597–1602. 15. Jilek C, Krenn M, Sebah D, Obermeier R, Braune A, Kehl V, Schroll S, et al. Prognostic impact of sleep disordered breathing and its treatment in heart failure: An observational study. Eur J Heart Fail 2011; 13:68–75. 16. Bitter T, Westerheide N, Prinz C, Hossain MS, Vogt J, Langer C, Horstkotte D, et al. Cheyne-Stokes respiration and obstructive sleep apnoea are independent risk factors for malignant ventricular arrhythmias requiring appropriate cardioverter-defibrillator therapies in patients with congestive heart failure. Eur Heart J 2011; 32:61–74.
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Background: The results of previous studies investigating the association between atrial fibrillation (AF) and central sleep apnea (CSA) in patients with left ventricular (LV) systolic dysfunction are contradictory. Methods: We prospectively enrolled 267 patients in this cross-sectional study with LV ejection fractions ࣘ50%, who were screened for sleep disordered breathing using cardiorespiratory polysomnography after patients with predominantly obstructive sleep apnea or insufficient sleep studies had been excluded. Results: AF at study entry was found in 70 of 267 patients (26%). CSA with an apnea/hypopnea index (AHI) ࣙ15/hour was present in 116 patients (43%) and 67 patients (25%) had severe CSA with an AHI > 30/hour. Univariate analysis revealed a significant association between AF and severe CSA, age, male gender, arterial hypertension, left atrial diameter, brain natriuretic peptide, chronic kidney disease, New York Heart Association class, digitalis, and the lack of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Multivariate analysis revealed a significant association between AF and severe CSA (odds ratio [OR]: 5.21; 95% confidence interval [CI]: 1.67–16.27, P = 0.01), age (OR: 1.22 per 5-year increase; 95% CI: 1.05–1.40, P = 0.01), left atrial diameter (OR 1.61 per 5-mm increase; 95% CI: 1.22–2.01, P < 0.01), and digitalis (OR: 2.7; 95% CI: 1.26–5.79, P = 0.01). Conclusions: AF is associated with severe CSA but not with moderate CSA in addition to age, use of digitalis, and left atrial size in patients with LV systolic dysfunction. Future studies evaluating the potential benefit of adaptive servo-ventilation therapy to prevent AF or to decrease the AF burden in heart failure patients should therefore focus on patients with severe central sleep apnea. (PACE 2014; 00:1–7) central sleep apnea, atrial fibrillation, heart failure
Introduction Central sleep apnea (CSA) and atrial fibrillation (AF) are both highly prevalent findings in patients with heart failure due to left ventricular (LV) systolic dysfunction.1–18 In contrast to obstructive sleep apnea (OSA), which has been shown to be an independent risk factor for AF in patients with and without LV dysfunction,19–23 the relationship Funding: The work was supported by a research grant from Resmed GmbH&Co.KG, Martinsried, Germany. Conflicts of Interest: Dr. Koehler received grant support from Resmed, AstraZeneca, GlaxoSmithKline, Berlin-Chemie, IFM, Heinen and Loewenstein, Respironics, and UCB Biosciences. The remaining authors have no conflicts of interest. Address for reprints: Wolfram Grimm, M.D., Department of Cardiology, Philipps-University Marburg, Baldingerstraße, 35033 Marburg, Germany. Fax: 49–6421–586–8954; e-mail: [email protected] Received May 16, 2014; revised July 15, 2014; accepted July 19, 2014. doi: 10.1111/pace.12495
between AF and CSA remains controversial. Therefore, we prospectively performed a crosssectional study to determine the association between AF and CSA in patients with systolic LV dysfunction. Methods Patients From August 2007 to June 2011, 300 adult patients with systolic heart failure New York Heart Association (NYHA) class I to III with LV ejection fractions ࣘ 50% by echocardiography due to ischemic or nonischemic cardiomyopathy were prospectively screened for sleep disordered breathing using cardiorespiratory polysomnography in a single-center study at the University Hospital of Marburg. Patients were excluded from study participation if they had one or more of the following conditions: history of sleep disordered breathing, advanced kidney disease with an estimated glomerular filtration rate (eGFR) 30 seconds with spontaneous conversion within 7 days, whereas an AF duration >7 days defined persistent AF according to the European Society of Cardiology guidelines for diagnosis, classification, and management of AF.24 The study protocol was reviewed and approved by the ethics committee of the University of Marburg. Written informed consent had been obtained from all study patients. Unattended overnight cardiorespiratory polysomnography was performed during one night using Somnocheck R&KTM instruments (Weinmann, Hamburg, Germany) and analyzed according to the recommendations of the American Academy of Sleep Medicine.25 Standard definitions were used for sleep-related disordered breathing.25 An apnea was defined as cessation of inspiratory airflow >10 seconds. The number of apneas and hypopneas per hour of sleep is referred to as apnea/hypopnea index (AHI). An AHI ࣙ 15/hour defined the presence of sleep apnea. Severe sleep apnea was diagnosed in the presence of an AHI cutoff point >30/hour as recommended by the task force of the American Society of Sleep Medicine.25 Central apnea was defined as the absence of rib cage and abdominal excursions with absence of airflow. Obstructive apnea was defined as the absence of airflow in the presence of rib cage and abdominal excursions. CSA was diagnosed when the number of central apneas exceeded the number of obstructive apneas in the presence of an AHI ࣙ 15 hours. OSA was diagnosed in the presence of a predominantly obstructive rather than central apnea pattern. All polysomnographic recordings were scored by a sleep technician who was unaware of the patients’ clinical characteristics. Two-dimensional echocardiographic examinations were performed in all patients using a Vingmed Vivid SevenTM machine (General Elec-
2
tronics Medical Systems, Solingen, Germany) to determine left atrial diameter, LV ejection fraction, and LV size. LV ejection fraction was measured in the apical four-chamber view and orthogonal two-chamber view using the disc summation method (modified Simpson’s rule algorithm). Echocardiographic studies were performed by cardiologists unaware of the sleep study results. Kidney function was assessed at study entry by the eGFR using the Modification of Diet in Renal Disease (MDRD) formula.26 Chronic kidney disease of at least stage 3 was diagnosed in patients with two eGFR values below 60 mL/min per 1.73 m2 with an interval of at least 3 months.27 Statistical Analysis Clinical characteristics and results of polysomnography were stratified for patients with and without AF at study enrollment. For comparison of continuous variables, the unpaired Student’s t-test and the Mann-Whitney rank sum test were used when data were normally and nonnormally distributed. Fisher’s exact test was used for comparison of nominal variables. Univariate logistic regression and multivariate stepwise logistic regression analysis with likelihood-ratio test and backward selection with a cutoff level of 0.2 was used to assess the association between AF at study enrollment and clinical characteristics including CSA and severe CSA as defined above. Odds ratio (OR) and corresponding 95% confidence intervals (CIs) are reported for multivariate analyses. Results are expressed as mean ± standard deviation unless specified otherwise. All probability values reported are two-sided, and a probability value of P < 0.05 was considered to indicate statistical significance. SPSS-software version 21 (IBM Corp., Armonk, NY, USA) was used for all statistical analyses. Results Of the 267 study patients, 201 patients (75%) were men and 66 (25%) were women (Table I). Mean age was 60 ± 14 years, and mean LV ejection fraction was 34 ± 14%. The majority of patients were in NYHA heart failure class II (37%) or in NYHA class III (48%). Ischemic cardiomyopathy was present in 124 patients (46%) and nonischemic cardiomyopathy in 143 patients (54%). AF at study entry was present in 70 patients (26%). Sixteen of 70 patients with AF (23%) had paroxysmal AF, and 54 patients (77%) had persistent AF.
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59 ± 14 143 (73) 27 ± 5 128 (65) 116 (60) 50 (25) 52 (26) 41 (21) 657 ± 896 85 (43) 112 (57) 44 ± 8 62 ± 8 34 ± 10 111 (56) 86 (44) 66 (34) 22 (11) 30 (15) 139 (71) 140 (71) 83 (42) 159 (81) 113 (57) 84 (43) 157 (80) 40 (20)
60 ± 14 201 (75) 28 ± 5 183 (69) 152 (57) 75 (28) 84 (32) 50 (19) 685 ± 852 124 (46) 143 (54) 46 ± 8 61 ± 9 34 ± 10 138 (52) 129 (48) 86 (32) 34 (13) 55 (21) 177 (66) 194 (73) 105 (39) 211 (79) 151 (57) 116 (43) 200 (75) 67 (25)
43 (61) 27 (39)
38 (54) 32 (46)
25 (33) 38 (54) 54 (77) 22 (31) 52 (74)
20 (29) 12 (17)
27 (39) 43 (61)
49 ± 7 60 ± 10 34 ± 10
39 (56) 31 (44)
66 ± 12 58 (83) 28 ± 5 55 (79) 36 (51) 25 (33) 32 (46) 9 (13) 762 ± 713
Atrial Fibrillation (n = 70)
0.002
0.66
0.001 0.04 0.33 0.12 0.26
0.21
0.04
0.001 0.34 0.88
0.07
0.001 0.09 0.63 0.04 0.29 0.10 0.003 0.26 0.002
P Univariate
0.01
0.01 0.06
0.07
5.21 (1.67–16.27)
2.70 (1.26–5.79) 0.51 (0.25–1.03)
1.92 (0.96–3.87)
1.61 (122–2.01)§
1.0 (0.99–1.0)
0.06
30/hour), n (%) No severe CSA Severe CSA
Sinus Rhythm (n = 197)
All Patients (n = 267)
Presenting Characteristics of 267 Study Patients with and Without Atrial Fibrillation
Table I.
ATRIAL FIBRILLATION AND CENTRAL SLEEP APNEA
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Table II. Polysomnography Results
Baseline Characteristics No sleep apnea (AHI < 15/hour) Central sleep apnea (AHI ࣙ 15/hour) Severe central sleep apnea (AHI > 30/hour) Epworth sleepiness scale Epworth sleepiness scale >10, n (%) AHI (n/hour) Central apnea index (n/hour) Obstructive apnea index (n/hour) Mixed apnea index (n/hour) Hypopnea index (n/hour) Total in bed time (minutes) Total sleep time (minutes) Mean O2 -saturation (%) O2 -saturation 10 was present in 13% of patients. No sleep apnea was found in 151 patients (57%), and 116 patients (43%) had CSA using an AHI cutoff of 15. Sixtyseven patients (25%) had severe CSA with an AHI > 30/hour. Univariate analysis revealed a significant association between AF and age, male gender, arterial hypertension, chronic kidney disease, brain natriuretic peptide, left atrial diameter, NYHA heart failure class, the use of digitalis, the lack of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), and the presence of severe CSA (Table I). Multivariate logistic regression analysis revealed a significant association between AF and severe CSA (OR: 5.21; 95% CI: 1.67–16.27, P = 0.01), age (OR: 1.22 per 5-year increase in age; 95% CI: 1.05–1.40, P = 0.01), left atrial diameter (OR 1.61 per 5 mm left atrial diameter increase; 95% CI: 1.22–2.01, P < 0.01), and the use of digitalis (OR: 2.7; 95% CI: 1.26–5.79, P = 0.01).
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1999 2005 2006 2006 2007 2007 2007 2007 2007 2007 2008 2009 2009 2010 2011 2011 2012 2013 2014
Sin1 Staniforth2 Mehra3 Rao4 Shigemitsu5 Oldenburg6 Schulz7 Vazir8 Christ9 Javaheri10 Oldenburg11 Bitter12 Paulino13 Konecny14 Jilek15 Bitter16 Grimm17 Kreuz18 Present study
450 101 566† 84 93 700 203 55 102 88 105 244‡ 316 91§ 296 255 204 133 267
Patients (n) PSG Yes No Yes No No No No Yes No Yes No No No Yes Yes No No No Yes
EF (%) 23 ± 16 33 n.a. n.a. 55 30 ± 11 68 ± 8 ࣘ50 10 ࣙ22.5 ࣙ15 >5 ࣙ10 >30
AHI cutoff/hour
† Subgroup sample from the Sleep Heart Health Study including patients ‡ Patients with heart failure and normal left ventricular ejection fraction.
Year
First author
Atrial Fibrillation and CSA in Patients with LV Dysfunction
Table III.
ATRIAL FIBRILLATION AND CENTRAL SLEEP APNEA
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of variables, including patient selection, heart failure severity and etiology, age, gender, heart failure medication, and various AHI cutoff values used to define CSA. Although most previous studies found a similar prevalence of AF in patients with versus without CSA,2,4,5,8–11,15–18 several investigators reported a significantly higher prevalence of AF in patients with CSA compared to patients without CSA.1,3,6,7,12–14 The discrepancy between these studies may, in part, be explained by differences in methodology to detect and define CSA as well as differences in patient selection and, most importantly, study size. Eight of nine smaller studies with less than 200 patients were unable to distinguish whether AF was a risk factor for CSA,2,4,5,8–11,18 whereas six of nine larger studies enrolling more than 200 patients found a significantly higher prevalence of AF in patients with versus without CSA using univariate analysis1,3,6,7,12,13 (Table III). Although most previous studies used polygraphy4–7,9,11–13,16–18 or simple overnight oxymetry2,14 to detect CSA, polysomnography as gold standard to diagnose CSA was used only in less than one-third of previous studies.1,3,8,10,15 Finally, several previous studies3,14,15,18 did not differentiate between patients with OSA and CSA, which makes it difficult to interpret the results, because these two breathing disorders have different underlying pathophysiology and probably different prognostic and therapeutic consequences. To date, only one previous study1 reported the relation between AF and CSA in 450 patients with congestive heart failure using multivariate analysis. As a result, Sin et al.1 found AF, male gender, and age > 60 years to be independent risk factors for CSA using an AHI cutoff >10/hour to diagnose sleep apnea (Table III). Our study differs from the study by Sin et al. in several important aspects. First, Sin et al.1 performed a retrospective analysis of consecutive heart failure patients referred to the sleep laboratory by cardiologists, whereas unselected patients with LV dysfunction and heart failure NYHA I to III were prospectively enrolled in our cross-sectional study with no patient being referred to our sleep laboratory for a reason other than participation in this study. Second, since patients were enrolled more than 15 years ago in the study by Sin et al.,1 they did not routinely receive modern heart failure therapy including β-blockers or aldosterone antagonists in addition to ACE inhibitors or ARBs as in our study. Furthermore, 13% of heart failure patients in our study received cardiac resynchronization
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therapy, which was also not available in study of Sin et al.1 A meta-analysis by Lamba et al.23 found that the substantial improvement of systolic LV function by cardiac resynchronization therapy was accompanied by a significant decrease in sleep apnea severity in CSA patients with a mean AHI reduction of 13/hour. In contrast, cardiac resynchronization therapy did not result in a significant AHI decrease in OSA patients, which may be explained by the different pathophysiology of OSA versus CSA. Mehra et al.3 analyzed the association of nocturnal arrhythmias in two samples of the Sleep Heart Health Study consisting of a sample of 228 subjects with severe sleep-disordered breathing with an AHI ࣙ 30/hour compared to an age-, sex-, ethnicity-matched sample of 338 subjects without sleep apnea with an AHI < 5/hour. Similar to our study, Mehra et al.3 found a significantly higher prevalence of AF in patients with versus without sleep-disordered breathing (4.8 vs 0.9%). In contrast to the study by Sin et al.1 and our study, Mehra et al.3 did not differentiate between CSA and OSA. In addition, only 3% of patients in the study by Mehra et al.3 had heart failure due to the design of the Sleep Heart Health Study as a community-based epidemiologic study in participants aged ࣙ40. This explains the much lower prevalence of AF in the study by Mehra et al.,3 which almost equals the AF prevalence in an age-matched normal population rather than the AF prevalence in a heart failure population. In conclusion, our study confirms a significant association between AF and severe CSA but not with mild or moderate CSA in patients with LV dysfunction in addition to age and left atrial size. In contrast to patients with severe OSA, CPAP therapy failed to improve the outcome of heart failure (HF) patients with CSA in the prospective randomized CANPAP trial.28 More recently, several small studies have shown improvements of HF symptoms and improvements of cardiac function with adaptive servo-ventilation for severe CSA, which has the greater ability to normalize the breathing pattern in HF patients with CSA compared to CPAP.29,30 Future studies need to clarify whether adaptive servo-ventilation for severe CSA is helpful to prevent AF or to decrease the AF burden in patients with LV dysfunction. The results of our study strongly suggest that an AHI cutoff of 30 rather than 15 should be considered when designing future studies to determine whether ventilation therapy might be helpful to prevent the development of AF or facilitates rhythm management in patients with CSA.
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