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• W3090607777 abstract "The role of central sleep apnea (CSA) in pacing-induced cardiomyopathy (PICM) remains speculative. In a prospective trial entitled UPGRADE, the presence of CSA was assessed by single-night polysomnography (PSG) in 54 PICM patients within 1 month after left ventricular lead implantation (with biventricular stimulation still not activated). CSA was diagnosed in half of patients (n = 27). Patients with moderate or severe CSA were randomized to cardiac resynchronization therapy (CRT) versus right ventricular pacing (RVP) in a double-blinded cross-over design and re-scheduled for a follow-up PSG within 3 to 5 months. After crossing-over of stimulation mode another PSG was conducted 3 to 5 months later. CRT led to a significant increase in left ventricular ejection fraction and significant reduction in left ventricular end systolic volumes and N-terminal pro brain natriuretic peptide plasma levels, whereas no significant effects were observed with ongoing RVP. CSA was significantly improved after 3.9 (3.2 to 4.4) months of CRT: apnea-hypopnea index decreased from 39.1 (32.1 to 54.0) events per hour at baseline to 22.2/h (10.9 to 36.7) by CRT (p <0.001). Central apnea index decreased from 27.1/h (17.7 to 36.1) at baseline to 6.8/h (1.1 to 14.4) after CRT activation (p <0.001). Ongoing RVP yielded only a minor improvement in apnea-hypopnea index and central apnea index. Pre-existent CSA did not affect structural response rate and had no impact on mid-term follow-up (median 2.8 years). In conclusion, CSA is highly prevalent in patients with PICM. CRT upgrading significantly improves CSA leading to a similar outcome in PICM patients without pre-existent CSA. The role of central sleep apnea (CSA) in pacing-induced cardiomyopathy (PICM) remains speculative. In a prospective trial entitled UPGRADE, the presence of CSA was assessed by single-night polysomnography (PSG) in 54 PICM patients within 1 month after left ventricular lead implantation (with biventricular stimulation still not activated). CSA was diagnosed in half of patients (n = 27). Patients with moderate or severe CSA were randomized to cardiac resynchronization therapy (CRT) versus right ventricular pacing (RVP) in a double-blinded cross-over design and re-scheduled for a follow-up PSG within 3 to 5 months. After crossing-over of stimulation mode another PSG was conducted 3 to 5 months later. CRT led to a significant increase in left ventricular ejection fraction and significant reduction in left ventricular end systolic volumes and N-terminal pro brain natriuretic peptide plasma levels, whereas no significant effects were observed with ongoing RVP. CSA was significantly improved after 3.9 (3.2 to 4.4) months of CRT: apnea-hypopnea index decreased from 39.1 (32.1 to 54.0) events per hour at baseline to 22.2/h (10.9 to 36.7) by CRT (p <0.001). Central apnea index decreased from 27.1/h (17.7 to 36.1) at baseline to 6.8/h (1.1 to 14.4) after CRT activation (p <0.001). Ongoing RVP yielded only a minor improvement in apnea-hypopnea index and central apnea index. Pre-existent CSA did not affect structural response rate and had no impact on mid-term follow-up (median 2.8 years). In conclusion, CSA is highly prevalent in patients with PICM. CRT upgrading significantly improves CSA leading to a similar outcome in PICM patients without pre-existent CSA. Right ventricular pacing (RVP) results in iatrogenic electrical and mechanical left ventricular dyssynchrony similar to what is seen in patients with a left bundle branch block. This may induce LV dysfunction and consequently heart failure in around 10% to 20% of pacemaker patients, an entity termed pacing-induced cardiomyopathy (PICM).1Cho SW Gwag HB Hwang JK Chun KJ Park KM On YK Kim JS Park SJ Clinical features, predictors, and long-term prognosis of pacing-induced cardiomyopathy.Eur J Heart Fail. 2019; 21: 643-651Crossref PubMed Scopus (29) Google Scholar,2Dor O Haim M Barrett O Novack V Konstantino Y Incidence and clinical outcomes of pacing induced cardiomyopathy in patients with normal left ventricular systolic function and atrioventricular block.Am J Cardiol. 2020; 128: 174-180Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar Although a RVP burden of 40% or more is traditionally seen as the critical amount which can harm the left ventricle,3Khurshid S Epstein AE Verdino RJ Lin D Goldberg LR Marchlinski FE Frankel DS Incidence and predictors of right ventricular pacing-induced cardiomyopathy.Heart Rhythm. 2014; 9: 1619-1625Abstract Full Text Full Text PDF Scopus (155) Google Scholar even a smaller percentage of RVP can lead to PICM.4Sweeney MO Hellkamp AS Ellenbogen KA Greenspon AJ Freedman RA Lee KL Lamas GA Adverse effect of ventricular pacing on heart failure and atrial fibrillation among patients with normal QRS duration in a clinical trial of pacemaker therapy for sinus node dysfunction.Circulation. 2003; 107: 2932-2937Crossref PubMed Scopus (1223) Google Scholar Furthermore, the occurrence of PICM can vary between very early (within weeks) to very late (years to decades) after pacemaker implantation.5Dreger H Maethner H Bondke H Baumann G Melzer C Pacing-induced cardiomyopathy in patients with right ventricular stimulation for >15 years.Europace. 2012; 14: 238-242Crossref PubMed Scopus (68) Google Scholar The pathophysiology of PICM is poorly understood, thus there is an urgent need for research in this area. In clinical routine, PICM is often treated by additional implantation of a left ventricular lead, which results in biventricular instead of right ventricular electrical activation of the heart. This procedure is being referred to as upgrading to cardiac resynchronization therapy (CRT).6Fröhlich G Steffel J Hürlimann D Enseleit F Lüscher TF Ruschitzka F Abraham WT Holzmeister J Upgrading to resynchronization therapy after chronic right ventricular pacing improves left ventricular remodelling.Eur Heart J. 2010; 31: 1477-1485Crossref PubMed Scopus (66) Google Scholar Although there are still no data from randomized controlled studies on this treatment approach, it accounts for almost a quarter of all CRT implantations as recently shown in a survey throughout Europe involving 11,088 patients.7Linde CM Normand C Bogale N Auricchio A Sterlinski M Marinskis G Stichering C Bulava A Cano OP Maas A Witte KK Rekvava R Abdelali S Dickstein K Upgrades from a previous device compared to de novo cardiac resynchronization therapy in the European Society of Cardiology CRT Survey II.Eur J Heart Fail. 2018; 20: 1457-1468Crossref PubMed Scopus (20) Google Scholar Sleep disordered breathing, in particular central sleep apnea (CSA) is common in heart failure patients,8Pearse SG Cowie MR. Sleep-disordered breathing in heart failure.Eur J Heart Fail. 2016; 18: 353-361Crossref PubMed Scopus (60) Google Scholar but its role in PICM has not been studied yet. CRT improves CSA when applied de-novo in established indications,9Lamba 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: 1174-1179Crossref PubMed Scopus (57) Google Scholar,10Oldenburg O Faber L Vogt J Dorszewski A Szabados F Horstkotte D Lamp B Influence of cardiac resynchronisation therapy on different types of sleep disordered breathing.Eur J Heart Fail. 2007; 9: 820-826Crossref PubMed Scopus (90) Google Scholar but whether this effect is found in CRT upgrades is unknown. In this study entitled UPGRADE, we set out to evaluate the effect on sleep architecture and sleep disordered breathing in PICM patients receiving biventricular pacing using single-night polysomnography (PSG). Moreover, this is the first reported randomized controlled trial on CRT upgrading in PICM. We sought to examine, whether CSA is an aggravating factor or just a symptom of PICM, and if CRT response in PICM is influenced by CSA. The UPGRADE study (ClinicalTrials.gov Identifier: NCT01970423) is an investigator-driven prospective assessment of CRT upgrading in patients with CSA. Inclusion and exclusion criteria are displayed in the supplementary.11Barbieri F, Adukauskaite A, Heidbreder A, Brandauer E, Bergmann M, Stefani A, Holzknecht E, Senoner T, Rubatscher A, Schgör W, Stühlinger M, Pfeifer B, Bauer A, Hintringer F, Högl B, Dichtl W. Supplemental dataset on the influence of cardiac resynchronisation therapy in pacing-induced cardiomyopathy and concomitant central sleep apnea. Data Brief 2020, in press.Google Scholar Following enrolment patients underwent upgrading to CRT. Within 1 month after left ventricular lead implantation (with stimulation still not activated), presence of sleep apnea (SA) was assessed in all participants by single-night PSG. Consequently, CRT was activated in patients without SA, in patients suffering from obstructive sleep apnea (OSA) or patients with mild CSA. However, in case of moderate or severe CSA (n = 22), patients were randomly assigned to either receive CRT or continued RVP. Seven patients were not randomized as heart failure progression did not allow any further withholding of CRT. Patients were then re-scheduled for a follow-up PSG 3 to 5 months later. Subsequently, patients underwent a cross-over and scheduled for another follow-up PSG 3 to 5 months later. Two patients died before their first re-examination after randomization and were consequently not considered for analysis. Upper and lower rate limits and settings for atrioventricular delay were programmed at the discretion of the treating physician, but were not changed throughout the trial. Major adverse cardiovascular events (MACE) and survival rate were assessed during study visits, the hospital information system, and phone calls. MACE was defined as heart failure hospitalization necessitating intravenous application of diuretics, occurrence of a sustained ventricular tachyarrhythmia with hemodynamic compromise (or adequate implantable cardioverter-defibrillator therapy in case of an implanted CRT defibrillator [CRT-D] device), myocardial infarction, stroke or death. Patients and personnel, who were assigned to perform diagnostic procedures (echocardiography, PSG) were blinded to the randomization. Programming of the device was conducted by a single unblinded investigator. Transthoracic echocardiography was performed by WD and clips (lasting for 5 cardiac cycles) were analyzed at the end of the study in a blinded fashion off-line by AA (both being class III observers). CRT response was defined by a decrease of >15% of left ventricular end systolic volume (LVESV). Twelve-lead ECG was recorded before and after the start of CRT. Besides evaluating the effect of CRT on CSA, the validation of the AP scan by using PSG was also part of this trial and has been published recently.12Barbieri F Dichtl W Heidbreder A Brandauer E Stefani A Adukauskaite A Senoner T Schgör W Hintringer F Högl B Sleep apnea detection by a cardiac resynchronization device integrated thoracic impedance sensor: a validation study against the gold standard polysomnography.PLoS One. 2018; 13e0195573Crossref PubMed Scopus (10) Google Scholar PSG was performed and analyzed according to standard procedures of the American Academy of Sleep Medicine13American Academy of Sleep MedicineThe AASM manual for the scoring of sleep and associated events: rules, terminology and technical specification. Version 2.6.Am Acad Sleep Med. 2020; Google Scholar and included 6 electroencephalography derivations, horizontal and vertical electrooculography, mental and submental electromyography, oronasal pressure cannula, thermistor, thoracic and abdominal respiratory movements (piezo), and transcutaneous oxygen saturation. In accordance with recommendations of the SINBAR group,14Frauscher B Iranzo A Gaig C Gschliesser V Guaita M Raffelseder V Ehrmann L Sola N Salamero M Tolosa E Poewe W Santamaria J Högl B SINBAR (Sleep Innsbruck Barcelona) GroupNormative EMG values during REM sleep for the diagnosis of REM sleep behavior disorder.Sleep. 2012; 35: 835-847Crossref PubMed Scopus (241) Google Scholar all PSG included surface electromyography of both upper (flexor digitorum superficialis) and lower (tibialis anterior muscles) extremities.15Mitterling T Högl B Schönwald SV Hackner H Gabelia D Biermayr M Frauscher B Sleep and respiration in 100 healthy caucasian sleepers – a polysomnographic study according to American Academy of Sleep Medicine standards.Sleep. 2015; 38: 867-875PubMed Google Scholar An apnea event was scored when there was (1) a drop in the peak signal excursion by ≤90% of pre-event baseline by using an oronasal thermal sensor, and (2) a ≥10 seconds duration of the ≤90% drop. It was scored as obstructive, when it was associated with continued or increased inspiratory effort throughout the entire period of absent airflow. A central apnea was scored, when it was associated with an absent inspiratory effort, and mixed apnea with absence of inspiratory effort in the initial portion of the event, followed by resumption of inspiratory effort in the second portion of the event. A hypopnea was scored when (1) the peak signal excursions dropped by ≥30% of pre-event baseline using nasal pressure, (2) the duration of the ≥30% drop in signal excursion was ≥10 seconds, and (3) there is a ≥3% oxygen desaturation from pre-event baseline or the event is associated with an arousal. Following formulas were used to calculate apnea-hypopnea index (AHI) [(number of apneas + number of hypopneas) x 60/total sleep time (in minutes)] and central apnea index [number of central apneas x 60/total sleep time (in minutes)].13American Academy of Sleep MedicineThe AASM manual for the scoring of sleep and associated events: rules, terminology and technical specification. Version 2.6.Am Acad Sleep Med. 2020; Google Scholar PSG criteria for CSA syndrome were met when 5 or more central apneas/or central hypopneas per hour of sleep were present and the total number of central apneas was >50% of the total number of apneas and hypopneas. OSA syndrome was diagnosed when PSG showed 5 or more predominantly obstructive respiratory events. Sleep apnea syndromes were grouped as mild (AHI ≥5/h), moderate (≥15/h), or severe (AHI ≥30/h).16American Academy of Sleep MedicineInternational Classification of Sleep Disorders.3rd ed. American Academy of Sleep Medicine, Darien, IL2014Google Scholar The study protocol was approved by the ethics committee of the Medical University Innsbruck. The study was conducted in accordance with the “Declaration of Helsinki” and written informed consent was obtained from each patient included in the study. Continuous variables are expressed as median and interquartile range, categorical variables are reported as number and percentage. Distribution of continuous variables was assessed by using the Kolmogorov-Smirnov test and inspection of histograms. Differences in repeated measurements were analyzed either with the paired t test or the Wilcoxon test, according to their distribution. Comparisons of categorical variables were performed by using the chi-square test. Analysis of MACE and survival were estimated with the Kaplan-Meier method, differences were assessed with the log-rank test. Whiskers in the boxplot demonstrate the 95% percentile (2.5 to 97.5). N-terminal pro brain natriuretic peptide (NT-proBNP) was logarithmized only for demonstrational purposes, calculations were conducted by using true values. Statistical analysis was conducted using IBM SPSS, version 24 (IBM Corporation, Armonk, NY), graphics were designed using GraphPad PRISM, version 5 (GraphPad Software, Inc., La Jolla, CA). p values ≤0.05 were considered statistically significant. Between January 2014 and August 2019, 54 patients were recruited at the Medical University Innsbruck, Austria and underwent PSG. Baseline characteristics of the study cohort and PSG findings are shown in Table 1. CRT-D devices (Boston Scientific INCEPTA or AUTOGEN) were used in 21 (38.9%) patients; CRT pacemaker (CRT-P) devices (Boston Scientific INLIVEN or VISIONIST) were used in 33 (61.1%) patients. As expected, PICM was clearly associated with a paced QRS of >140 milliseconds,17Kim JH Kang KW Chin JY Kim TS Park JH Choi YJ Major determinant of the occurrence of pacing-induced cardiomyopathy in complete atrioventricular block: a multicentre, retrospective analysis over a 15-year period in South Korea.BMJ Open. 2018; 8e019048Crossref PubMed Scopus (36) Google Scholar,18Kiel EL Makki T Kumar R Gumber D Kwon DH Rickard JW Kanj M Wazni OM Saliba WI Varma N Wilkoff BL Cantillon DJ Incidence and predictors of right ventricular pacing-induced cardiomyopathy in patients with complete atrioventricular block and preserved left ventricular systolic function.Heart Rhythm. 2016; 13: 2272-2278Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar,19Khurshid S Obeng-Gyimah E Supple GE Schaller R Lin D Owens AT Epstein AE Dixit S Marchlinski FE Frankel DS Reversal of pacing-induced cardiomyopathy following cardiac resynchronization therapy.JACC Clin Electrophysiol. 2018; 4: 168-177Crossref PubMed Scopus (32) Google Scholar and CRT significantly decreased QRS duration from 195 (176 to 209) milliseconds to 148 (134 to 166) milliseconds (p <0.001).Table 1Baseline characteristicsVariableAll patients (n = 54)No SA (n = 11)OSA (n = 16)CSA (n = 27)Men43 (79.6%)6 (54.5%)13 (81.3%)24 (88.9%)Age (years)75.0 (71.5–78.0)74.0 (64.0–77.0)74.5 (71.0–77.5)75.0 (73.0–78.0)Body mass index26.2 (24.0–28.5)24.1 (22.9–25.4)27.1 (25.0–31.2)26.3 (23.7–29.0)Cardiac resynchronization therapy defibrillator21 (38.9%)3 (27.3%)7 (43.8%)11 (40.7%)Coronary artery bypass grafting14 (25.9%)1 (9.1%)6 (37.5%)7 (25.9%)Percutaneous coronary intervention12 (22.2%)4 (36.4%)3 (18.8%)5 (18.5%)Mitral valve repair5 (9.3%)1 (9.1%)1 (6.3%)3 (11.1%)Tricuspid valve repair5 (9.3%)2 (18.2%)1 (6.3%)2 (7.4%)Aortic valve replacement6 (11.1%)04 (25.0%)2 (7.4%)Atrioventricular node ablation5 (9.3%)03 (18.8%)2 (7.4%)N-terminal pro natriuretic peptide (ng/L)2354 (1236–4690)3400 (1100–15458)1486 (827–3176)2509 (1402–5042)Creatinin (mg/dl)1.37 (1.07–1.61)1.60 (1.07–1.73)1.34 (1.08–1.54)1.34 (1.05–1.60)Arterial hypertension48 (88.9%)9 (81.8%)15 (93.8%)24 (88.9%)Diabetes mellitus type II22 (40.7%)7 (63.6%)5 (31.3%)10 (37.0%)Hyperlipidemia34 (63.0%)5 (45.5%)11 (68.8%)18 (66.7%)Atrial fibrillation31 (57.5%)7 (63.6%)10 (62.5%)14 (51.9%)Medication Betablocker43 (79.6%)10 (90.9%)12 (75.0%)21 (77.8%) Mineralocorticoid antagonist29 (53.7%)5 (45.5%)9 (56.3%)15 (55.6%) Angiotensin-converting enzyme inhibitor /Angiotensin receptor blocker /Angiotensin receptor neprilysin inhibitor46 (85.2%)8 (72.7%)14 (87.5%)24 (88.9%) Clopidgrel4 (7.4%)01 (6.3%)3 (11.1%) Acetylsalicylat16 (29.6%)3 (27.3%)5 (31.3%)8 (29.6%) Vitamin K antagonist19 (35.2%)5 (45.5%)3 (18.8%)11 (40.7%) Nonvitamin K oral anticoagulant16 (29.6%)3 (27.3%)6 (37.5%)7 (25.9%) Loop diuretic47 (87.0%)9 (81.8%)15 (93.8%)23 (85.2%) Hydrochlorothiazide6 (11.1%)1 (9.1%)3 (18.8%)2 (7.4%) Xipamid5 (9.3%)2 (18.2%)03 (11.1%) Statin36 (66.7%)6 (54.5%)13 (81.3%)17 (63.0%) Calcium channel blocker2 (3.7%)1 (9.1%)0 (0.0%)1 (3.7%) Amiodaron6 (11.1%)3 (27.3%)2 (12.5%)1 (3.7%) Metformin7 (13.0%)1 (9.1%)3 (18.8%)3 (11.1%) Sulfonyl4 (7.4%)01 (6.3%)3 (11.1%) Dipeptidyl peptidase-4 inhibitor11 (20.4%)3 (27.3%)1 (6.3%)7 (25.9%) Insulin4 (7.4%)004 (14.8%) Proton pump inhibitor34 (63.0%)8 (72.7%)10 (62.5%)16 (59.3%) Antidepressant8 (14.8%)1 (9.1%)2 (12.5%)5 (18.5%)Echocardiography Left ventricular ejection fraction (%)28.0 (21.9–35.9)34.0 (23.0–36.0)27.0 (21.0–39.0)30.0 (21.7–35.0) Left ventricular end diastolic volume (ml)182 (139–223)139 (113–167)194 (140–222)195 (158–238) Left ventricular end systolic volume (ml)132 (97–160)90 (75–122)131 (105–164)146 (103–169) Left ventricular end diastolic diameter (mm)66 (56–71)58 (54–68)60 (55–73)68 (62–72) Left ventricular end systolic diameter (mm)54 (47–60)48 (35–58)52 (47–62)55 (50–60)Electrocardiogram QRS during right ventricular pacing (ms)195 (176–209)194 (172–216)197 (176–209)193 (180–208)Polysomnography Sleep efficiency (% sleep period time)74.3 (61.1–84.8)73.9 (39.7–81.8)66.3 (57.7–80.5)76.2 (63.7–88.5) Time in bed (min)480.0 (460.8–522.3)476.0 (466.0–522.0)473.5 (453.3 -529.0)500.0 (466.0–523.0) Total sleep time (min)356.5 (297.3–415.0)377.0 (186.0–427.0)337.0 (278.5–396.3)358.0 (318.0–432.0) Total wake time (min)98.3 (52.0–161.3)126.0 (53.5–181.0)128.8 (78.3–165.0)81.0 (47.5–155.0) Sleep onset latency (min)13.2 (4.5–39.8)16.0 (7.3–52.2)27.4 (2.8–50.7)12.9 (5.5–22.5) Rapid eye movement sleep latency (min)146.5 (67.5–268.1)90.0 (64.5–266.5)157.8 (87.9–272.6)155.0 (59.5–273.0) Sleep period time (min)457.5 (428.8–509.3)461.0 (429.0–516.0)447.5 (423.5–495.5)459.0 (432.0–510.0) Stage N1 (% sleep period time)21.0 (15.1–29.8)11.3 (8.8–19.8)24.3 (14.4–30.5)23.8 (19.5–31.8) Stage N2 (% sleep period time)37.3 (28.8–48.1)38.5 (28.6–53.7)31.2 (18.9–40.2)38.7 (30.9–49.0) Stage N3 (% sleep period time)1.9 (0.0–7.2)3.1 (0.0–9.9)2.3 (0.0–11.7)0.0 (0.0–4.8) Rapid eye movement (% sleep period time)8.6 (5.4–15.7)16.4 (1.9–18.3)8.4 (4.2 -13.7)8.0 (5.5–12.4) Wake after sleep onset (% sleep period time)21.6 (12.3–35.3)24.7 (12.5–50.6)27.0 (15.7–36.3)18.8 (9.3–34.4) Apnea-hypopnea index21.6 (6.7–35.6)1.9 (0.7–3.9)19.3 (8.7–29.5)32.3 (22.5–51.6) Oxygen desaturation index > 4%16.4 (5.8–35.9)1.3 (0.2–2.7)15.0 (8.3–29.5)33.1 (19.4–48.5) Oxygen saturation baseline95.0 (93.1–96.5)95.0 (94.0–96.9)95.3 (93.0–97.1)94.9 (92.9–96.3) Amount waking phasis30.5 (19.0–51.3)19.0 (18.0–48.0)43.0 (26.8–54.8)29.0 (17.0–51.0) Total duration central apnea (min)2.6 (0.5–53.3)0.0 (0.0–0.4)0.7 (0.4–1.9)52.0 (16.7–80.3) Average duration central apnea (sec)17.6 (14.5–22.2)0.0 (0.0–12.1)16.5 (14.2–18.2)22.2 (17.6–29.6) Total duration obstructive apnea (min)0.5 (0.0 –2.4)0.0 (0.0–0.0)2.7 (0.7–8.1)0.5 (0.0–1.9) Average duration obstructive apnea (sec)16.1 (0.0–24.3)0.0 (0.0–0.0)21.8 (16.3–27.4)16.2 (0.0–25.2) Periodic leg movement syndrome38 (70.4%)9 (81.8%)9 (56.3%)20 (76.9%)Numbers are presented as median (interquartile range) or number of patients (percentage). Open table in a new tab Numbers are presented as median (interquartile range) or number of patients (percentage). As shown in Table 1, 27 of 54 patients (50.0%) suffered from CSA (mild: n = 5, moderate: n = 6, severe: n = 16), 16 (29.6%) were diagnosed having OSA (mild: n = 7, moderate: n = 5, severe: n = 4), and 11 (20.4%) had no sleep disordered breathing. CRT led to a significant increase in LVEF, as shown in Figure 1: whereas baseline LVEF (31%, 23 to 36) improved significantly under CRT (45%, 33 to 55; p <0.001), no effect was detected under RVP (35%, 24 to 40; p = 0.187). Similar results were observed in LVESV measurements as baseline LVESV 144 ml (109 to 158) decreased significantly under CRT (108 ml, 65 to 140; p <0.001). In contrast, no effect was detected under RVP (150 ml, 131 to 164; p = 0.824). Further, there was also a significant decrease in NT-proBNP (2,343 ng/l, 1,290 to 4,890) due to biventricular pacing (1,282 ng/L, 624 to 2,054; p <0.001), whereas the decrease under RVP (1,446 ng/L, 1,255 to 1,939) was not statistically significant (p = 0.052). Other parameters displaying the effect of CRT on cardiac remodeling as well as functional parameters are presented in the supplementary.11Barbieri F, Adukauskaite A, Heidbreder A, Brandauer E, Bergmann M, Stefani A, Holzknecht E, Senoner T, Rubatscher A, Schgör W, Stühlinger M, Pfeifer B, Bauer A, Hintringer F, Högl B, Dichtl W. Supplemental dataset on the influence of cardiac resynchronisation therapy in pacing-induced cardiomyopathy and concomitant central sleep apnea. Data Brief 2020, in press.Google Scholar As shown in Figure 2, there was significant improvement of AHI from baseline (39.1/h, 32.1 to 54.0) to the measurement taken after 3.9 (3.2 to 4.4) months of CRT (22.2/h, 10.9 to 36.7; p <0.001). There was also an improvement in AHI due to RVP (33.6/h, 18.4 to 46.6; p = 0.016) but to a much lesser degree (CRT vs RVP: p = 0.046). Further, there was also a clear reduction in central apnea index (27.1/h, 17.7 to 36.1) under CRT (6.8/h, 1.1 to 14.4; p <0.001), whereas the mean duration of CSA events (21.5 seconds, 17.7 to 30.8) remained unchanged (19.1 seconds, 16.2 to 24.8; p = 0.144). In-depth analysis of several other sleep parameters including the hypopnea and OSA index as well as differences in oxygen saturation during PSG due to CRT are displayed in the supplementary.11Barbieri F, Adukauskaite A, Heidbreder A, Brandauer E, Bergmann M, Stefani A, Holzknecht E, Senoner T, Rubatscher A, Schgör W, Stühlinger M, Pfeifer B, Bauer A, Hintringer F, Högl B, Dichtl W. Supplemental dataset on the influence of cardiac resynchronisation therapy in pacing-induced cardiomyopathy and concomitant central sleep apnea. Data Brief 2020, in press.Google Scholar CRT responder rate was independent from pre-existing sleep apnea (51.9% in patients with CSA, 62.5% of patients with OSA, and 54.5% in patients without SA, p = 0.916). During a median follow-up of 2.8 years (1.9 to 4.3), MACE occurred in 24 patients (44.4%) whereas death was observed in 16 patients (29.6%). As shown in Figure 3, MACE and overall mortality rates were not influenced by pre-existent CSA (p = 0.970 and 0.986, respectively). Severity of sleep apnea and its influence on MACE and overall mortality are displayed in the supplemental dataset (Figure 4).11Barbieri F, Adukauskaite A, Heidbreder A, Brandauer E, Bergmann M, Stefani A, Holzknecht E, Senoner T, Rubatscher A, Schgör W, Stühlinger M, Pfeifer B, Bauer A, Hintringer F, Högl B, Dichtl W. Supplemental dataset on the influence of cardiac resynchronisation therapy in pacing-induced cardiomyopathy and concomitant central sleep apnea. Data Brief 2020, in press.Google ScholarFigure 4Representative case showing x-ray images and cartoons from PSG examinations before and after CRT upgrading. CRT = cardiac resynchronization therapy; PSG = polysomnography.View Large Image Figure ViewerDownload Hi-res image Download (PPT) In this study, we report four new observations: (1) CSA is very common in PICM, affecting almost half of these patients. (2) Structural improvement by CRT upgrading is shown in a prospective randomized trial. (3) CRT responder rate is independent from pre-existent SA and CSA is improved in PICM patients by CRT upgrading. (4) Mid-term prognosis in PICM patients is not different in patients with pre-existent CSA after upgrading to CRT as compared with patients without pre-existent CSA. Despite a responder rate similar or even better than when applied in heart failure patients with left bundle branch block, CRT upgrading in PICM patients is still not supported by randomized clinical trials. Therefore, it is still underused. In a recent study, only 29% with PICM received an upgrade to CRT despite an 84% responder rate, showing an increase in LVEF of almost 19% and a decrease in LVESV of 45% in responders.19Khurshid S Obeng-Gyimah E Supple GE Schaller R Lin D Owens AT Epstein AE Dixit S Marchlinski FE Frankel DS Reversal of pacing-induced cardiomyopathy following cardiac resynchronization therapy.JACC Clin Electrophysiol. 2018; 4: 168-177Crossref PubMed Scopus (32) Google Scholar Multicenter randomized clinical trials such as the BUDAPEST-CRT upgrade study are ongoing to better define the impact of this treatment strategy.20Merkely B Kosztin A Roka A Geller L Zima E Kovacs A Boros AM Wranicz JK Hindricks G Clemens M Duray GZ Moss AJ Goldenberg I Kutyifa V Rationale and design of the BUDAPEST-CRT upgrade study: a prospective, randomized, multicenter clinical trial.Europace. 2017; 19: 1549-1555PubMed Google Scholar UPGRADE supports the concept that CRT upgrading in PICM patients leads to a significant structural improvement (as defined by a decrease of LVESV). Paced QRS duration clearly predicts development of PICM, with hardly any risk if its duration is less than 140 milliseconds and a substantial risk if its duration exceeds 176 milliseconds.17Kim JH Kang KW Chin JY Kim TS Park JH Choi YJ Major determinant of the occurrence of pacing-induced cardiomyopathy in complete atrioventricular block: a multicentre, retrospective analysis over a 15-year period in South Korea.BMJ Open. 2018; 8e019048Crossref PubMed Scopus (36) Google Scholar This was confirmed by our study: median paced QRS duration was 195 milliseconds before CRT implantation and decreased significantly by CRT upgrading to a median of 148 milliseconds. The main study hypothesis—improvement of CSA in PICM patients by CRT—could be confirmed in the UPGRADE study. CRT led to a median reduction of AHI by 16.9 events per hour which is higher than the effects reported in a meta-analysis in patients with de-novo CRT (mean reduction in AHI of 13.1/h).9Lamba 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: 1174-1179Crossref PubMed Scopus (57) Google Scholar,10Oldenburg O Faber L Vogt J Dorszewski A Szabados F Horstkotte D Lamp B Influence of cardiac resynchronisation therapy on different types of sleep disordered breathing.Eur J Heart Fail. 2007; 9: 820-826Crossref PubMed Scopus (90) Google Scholar This pronounced effect of new-onset CRT in PICM on the reduction of AHI may be partly because baseline PSG had been performed shortly after the implantation of the left ventricular lead (which then still had not been activated). In the early postoperative phase AHI might have been somewhat higher than during a state in stable heart failure. This shortcoming of the study design is probably also responsible for the decrease in AHI after RVP (median reduction in AHI of 5.5/h), along with a hangover effect often encountered in cross-over designed trials. Similar results were observed regarding the central apnea index (median reduction of 20.3/h) supporting strongly our hypothesis that biventricular pacing improves CSA. On the contrary the OSA and mixed apnea index were not affected after onset of CRT.11Barbieri F, Adukauskaite A, Heidbreder A, Brandauer E, Bergmann M, Stefani A, Holzknecht E, Senoner T, Rubatscher A, Schgör W, Stühlinger M, Pfeifer B, Bauer A, Hintringer F, Högl B, Dichtl W. Supplemental dataset on the influence of cardiac resynchronisation therapy in pacing-induced cardiomyopathy and concomitant central sleep apnea. Data Brief 2020, in press.Google Scholar The structural CRT responder rate was not hampered by pre-existent CSA, being around 60% in patients with CSA, OSA and without SA. This correlates well with the effects reported in recent randomized CRT trials such as RESPOND CRT.21Brugada J Delnoy PP Brachmann J Reynolds D Padeletti L Noelker G Kantipudi C Rubin Lopez JM Dichtl W Borri-Brunetto A Verhees L Ritter P Singh JP RESPOND CRT InvestigatorsContractility sensor-guided optimization of cardiac resynchronization therapy: results from the RESPOND-CRT trial.Eur Heart J. 2017; 38: 730-738PubMed Google Scholar It remains speculative whether CSA is a symptom due to central dysregulation in the context of heart failure or whether it may itself lead to increased risk or progression of PICM. Whereas CPAP therapy improves symptoms and concomitant risk factors such as arterial hypertension or atrial fibrillation in OSA patients, therapeutic options in CSA are still not established. Although effective to reduce CSA, adaptive servoventilation (ASV) failed to decrease mortality in patients with reduced LVEF in the randomized SERVE-HF study.22Cowie MR Woehrle H Wegscheider K Angermann C d´Ortho MP Erdmann E Levy P Simonds AK Somers VK Zannad F Teschler H Adaptive servo-ventilation for central sleep apnea in systolic heart failure.N Engl J Med. 2015; 373: 1095-1105Crossref PubMed Scopus (616) Google Scholar More than a decade ago the CANPAP trial could not prove a mortality benefit by CPAP in heart failure patients with CSA. However, in those patients in whom CPAP therapy reduced the AHI below 15, there was a positive effect on mortality.23Arzt M Floras JS Logan AG Kimoff RJ Series F Morrison D Ferguson K Belenkie I Pfeifer M Fleetham J Hanly P Smilovitch M Ryan C Tomlinson G Bradley TD Suppression of central sleep apnea by continuous positive airway pressure and transplant-free survival in heart failure: a post hoc analysis of the Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure Trial.Circulation. 2007; 115: 3173-3180Crossref PubMed Scopus (534) Google Scholar If this is due to the reduction of vegetative stress caused by recurrent respiratory events remains an unresolved issue. In our UPGRADE study pre-existing (and later ameliorated) CSA had no impact on mid-term outcome after CRT upgrading, but it remains to be proven whether the decrease of CSA by CRT upgrading is prognostically relevant. One of the main limitations of the study is the small sample size. Further, a single PSG may represent sleep apnea insufficiently, as a certain night-to-night variability cannot be excluded. It is worth mentioning that 7 patients were not randomized, but received CRT directly after successful execution of the index PSG, as symptoms progressed and further withholding of therapy would have been unethical. In conclusion, UPGRADE is the first study analyzing CSA in PICM. CSA is highly prevalent in patients with PICM and is significantly improved by upgrading to CRT. CRT upgrading significantly increases LVEF, decreases NT-proBNP plasma levels and enhances cardiac remodeling. Structural response by new-onset CRT is not affected by pre-existing CSA yielding a similar postoperative mid-term outcome in patients with and without pre-existing CSA. Fabian Barbieri: Conceptualization, Investigation, Resources, Formal analysis, Writing–Original draft preparation; Agne Adukauskaite: Writing–Original draft preparation, Investigation, Methodology; Anna Heidbreder: Investigation, Formal analysis, Writing–Reviewing–Editing; Elisabeth Brandauer: Investigation, Formal analysis, Methodology; Melanie Bergmann: Investigation, Formal analysis, Methodology; Ambra Stefani: Investigation, Formal analysis, Methodology, Writing–Reviewing–Editing; Evi Holzknecht: Investigation, Formal analysis, Methodology; Thomas Senoner: Investigation, Formal analysis, Data curation; Methodology; Andrea Rubatscher: Investigation, Data curation; Wilfried Schgör: Investigation; Markus Stühlinger: Investigation, Writing–Reviewing–Editing; Bernhard Erich Pfeifer: Software, Validation; Axel Bauer: Resources, Supervision; Florian Hintringer: Conceptualization, Resources, Supervision, Writing–Reviewing–Editing; Birgit Högl: Conceptualization, Resources, Supervision, Writing–Reviewing–Editing, Supervision; Wolfgang Dichtl: Conceptualization, Writing–Reviewing–Editing, Project administration, Funding acquisition. The authors declare that they have no known competing financial interests or personal relations that could have appeared to influence the work reported in this study. The authors gratefully recognize the assistance of Heinz Hackner for exceptional technical quality of polysomnographies." @default.
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• W3090607777 title "Central Sleep Apnea and Pacing-Induced Cardiomyopathy" @default.
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