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Cardiac Resynchronization Therapy and Obstructive Sleep-Related Breathing Disorder in Patients with Congestive Heart Failure

ALAA SHALABY, M.D.,*, CHARLES W. ATWOOD, M.D.,*, FAITH SELZER, PH.D., MATTHEW SUFFOLETTO, M.D., JOHN GORCSAN III, M.D., and PATRICK STROLLO, M.D.
From the *Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania; Divisions of Cardiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; Pulmonary, Allergy and Critical Care Medicine, Pittsburgh, Pennsylvania; and Epidemiology Data Center, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania

Objectives: To assess the impact of cardiac resynchronization therapy (CRT) with or without atrial overdrive pacing, on sleep-related breathing disorder (SRBD). Introduction: CRT may have a positive inuence on SRBD in patients who qualify for the therapy. Data are inconclusive in patients with obstructive SRBD. Methods: Consenting patients eligible for CRT underwent a baseline polysomnography (PSG) 2 weeks after implantation during which pacing was withheld. Patients with an apnea hypopnea index (AHI) 15 but <50 were enrolled and randomized to atrial overdrive pacing (DDD) versus atrial synchronous pacing (VDD) with biventricular pacing in both arms. Patients underwent two further PSGs 12 weeks apart. Results: Nineteen men with New York Heart Association class III congestive heart failure participated in the study (age 67.2 7.5, Caucasian 78.9%, ischemic 73.7%). The score on Epworth Sleepiness Score was 7.3 4.0, Pittsburgh Sleep Quality Index 7.4 3.1, and Minnesota Living with Heart Failure Questionnaire 36.9 21.9. There were no differences between the groups. At baseline, patients exhibited poor sleep efciency (65.3 16.6%) with nadir oxygen saturation of 83.5 5.3% and moderate to severe SRBD (AHI 21.5 15.3) that was mainly obstructive (central apnea index 3.3 6.7/hour). On both followup assessments, there was no improvement in indices of SRBD (sleep efciency [68.3 17.9%], nadir oxygen saturation of 82.8 4.6%, and AHI 24.9 21.9). Conclusion: In a cohort of elderly male CHF patients receiving CRT, CRT had no impact on obstructive SRBD burden with or without atrial overdrive pacing. (PACE 2011; 34:593603) congestive heart failure, CRT , pacing Introduction Cardiac resynchronization therapy (CRT) has emerged as a benecial nonpharmacologic therapy in congestive heart failure (CHF). In addition to improving survival and morbidity, CRT has been demonstrated to have a positive effect on maladaptive neurohormonal patterns.15 Patients with CHF are frequently affected by concomitant sleep-related breathing disorders (SRBD).69 Both disorders may have synergistic adverse effects in
ClinicalTrials.gov Identier: NCT00521534. Conicts of Interest: This study was supported by Boston Scientic, Inc. Cardiac Rhythm Management Division. Alaa Shalaby: Research support from Boston Scientic. No other authors received support. Address for reprints: Alaa Shalaby, M.D., F.A.C.C., Director of Cardiac Electrophysiology, 111C University Drive, Pittsburgh, PA 15240. Fax: 412-360-6904; e-mail: Alaa.Shalaby@va.gov Received August 11, 2010; revised November 4, 2010; accepted November 17, 2010. doi: 10.1111/j.1540-8159.2010.03015.x 2011, The Authors. Journal compilation

regard to adverse neurohormonal activation911 as well as adverse implications for quality of life and survival outcomes.913 SRBD may be a suitable target for therapy. Continuous positive airway pressure (CPAP) in CHF patients with obstructive SRBD reduced heart rate and left ventricular (LV) dimension and improved ejection fraction (EF).14 In patients with CHF and central SRBD, CPAP improved EF and effort tolerance15 and in a subset of patients decreased mortality.16 Interestingly, preliminary results have indicated a salutary effect for CRT on SRBD of both central and obstructive types.1724 Nevertheless, questions remain as to the reproducibility across centers, the potential confounding effect of atrial pacing, as well as the sustainability of the reported ndings. We conducted this study to assess the potential impact of CRT on coexistent SRBD in patients with CHF. Furthermore, in an attempt to delineate mechanistic relationships between these disease states, we sought to establish the timeline of an effect on SRBD.

2011 Wiley Periodicals, Inc.

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Methods The study was designed by the investigators and sponsored by Boston Scientic (Natick, MA, USA). The conduct of the study was monitored by the Epidemiology Data Center of the Graduate School of Public Health, University of Pittsburgh, who were also responsible for both the integrity and analysis of the data. All patients submitted a written informed consent and the institutional review boards of both Veterans Affairs Pittsburgh Healthcare System and the University of Pittsburgh approved the study. Patient Enrollment All patients were recruited at the Veterans Affairs Pittsburgh Healthcare System. All candidates for CRT debrillator were eligible for enrollment while randomization occurred only after the screening polysomnogram (PSG) as detailed below. Patients were considered CRT debrillator candidates if they had a life expectancy of at least 1 year, cardiomyopathy with an EF of less than 36%, were in CHF New York Heart Association (NYHA) functional class III, and had a QRS duration >120 ms. All patients were on optimized stable medical therapy for CHF. Patients were excluded by any of the following: unstable angina or decompensated heart failure, atrial brillation, prior indication for CPAP, severe renal insufciency, medication with narcotics or benzodiazepines that could not be discontinued for ve half lives prior to any PSG, current alcohol or drug abuse, or if on baseline screening PSG the mean sleep heart rate (MSHR) was found to be greater than 80 beats per minute (bpm) or the apnea hypopnea index (AHI) exceeded 50/hour on any (baseline or subsequent) PSG during the study. Severe symptomatic sinus bradycardia with persistent heart rates below 40 bpm was also an exclusion. Study Procedure Implant and Randomization Enrolled patients were implanted with a transvenous CRT debrillator device according to established techniques. Subsequently, patients were discharged for a run-in period of 2 weeks where only backup demand ventricular pacing was programmed (VVI 40 bpm) and pacing from the LV lead was disabled. Two to 4 weeks after implant, the patients underwent a baseline screening PSG. Patients with an AHI between 14 and 50 events/hour with a mean atrial rate <80 bpm were randomized. To control for the potential interaction of atrial pacing, patients were randomized to an atrial overdrive pacing arm (DDD) with the lower rate limit set to 15 beats

above the MSHR, not to exceed 85 bpm or an atrial synchronous pacing mode (VDD) with a lower rate limit of 40 bpm. Our intent was to exclude patients with SRBD severe enough that standard therapy could not be ethically delayed as well as those in whom atrial overdrive pacing could not be implemented. Regardless of randomization arm, maximization of ventricular pacing was attempted by adjusting the atrioventricular delay (AVD) at randomization and on subsequent follow-up visits as necessary. Polysomnography The initial screening PSG and all subsequent studies recorded electroencephalogram, electrocardiogram, electromyogram, oral-nasal airow, thoraco-abdominal respiratory effort, and arterial oxyhemoglobin saturation estimated by pulse oximetry. A posture sensor capable of differentiating supine versus lateral positions was used, as was continuous video recording. All signals were recorded on a multichannel PSG (SensorMedics SomnoStar, Yorba Linda, CA, USA). MSHR was calculated by averaging heart rate during periods of normal sleep (i.e., absence of apnea, hypopnea, or arousal events). Interpretation of the sleep studies was performed by the participating sleep specialist investigators blinded to the programmed pacing mode. Sleep time was calculated from the length of time the patient showed Stage 1 4 or Rapid Eye Movement (REM) sleep based on the electroencephalogram. Time in bed was calculated as the number of hours between when the patient went to bed and arose from sleep. Airow patterns of apnea and hypopnea were qualitatively measured. Apnea was dened as cessation of inspiratory airow lasting 10 seconds or longer. Obstructive apnea was dened as the absence of airow in the presence of rib cage and/or abdominal excursions. Central apnea was dened as the cessation of airow with absence of rib cage and abdominal excursion. Hypopnea was dened as a reduction of airow of 50% or more of baseline tidal volume, lasting 10 seconds or more, associated with a desaturation of 4%. In keeping with the most recent recommendations of the American Academy of Sleep Medicine, hypopneas were not classied.25 The diagnosis of SDB and its severity were assessed by the AHI as; the average number of apneas and hypopneas per hour of sleep. Biochemical Markers The following biomarkers of inammation and neurohormonal activation were collected: Creactive protein, interleukin 6, beta-natriuretic

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peptide (BNP), overnight urine norepinephrine, and plasma norepinephrine. Echocardiographic Assessment of Dyssynchrony Blinded study echocardiograms were obtained at the University of Pittsburgh Research Echocardiography Laboratory at enrollment, and after CRT at the time of each follow-up PSG, to assess for LV function and the presence of dyssynchrony, as previously described. This echocardiogram for research purposes was obtained only after the patient was enrolled. In summary, for tissue Doppler longitudinal dyssynchrony analysis, digital tissue Doppler cine-loops from three consecutive beats were obtained from the three standard apical views. For speckletracking radial strain dyssynchrony analysis, cineloops from three consecutive beats were obtained from mid-LV short-axis. Off-line analysis of tissue Doppler longitudinal velocity and speckletracking radial strain were then performed.26 LVEF and volume by biplane Simpsons rule were measured in each case.27 The standard deviation of 12-site time to peak systolic velocity (Yu index) was also calculated.28,29 The opposing wall delay was determined as the maximal difference in time to peak systolic velocity across opposing myocardial walls in any standard apical view, with 65 ms dened as signicant dyssynchrony.26,28,30 Signicant radial dyssynchrony was dened as the difference between the anteroseptal and posterior wall peak strain 130 ms.26 A tissue Doppler measure of right ventricular dyssynchrony was included in this study. Regions of interest were placed in the basal and mid segments of the RV free wall and interventricular septum in the fourchamber view.31 Patient Follow-Up Patients underwent two follow-up PSGs at 12-week intervals. At each visit, including the baseline visit, the patients received a brief history and physical, a 12-lead electrocardiogram, a 6minute walk test, and an echocardiogram. At each visit including baseline, patients completed the following standard questionnaires: Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, and the Minnesotal Living with Heart Failure Questionnaire (MLWHFQ), in addition to a selfassessment global score whereby on a scale of 13 patients reported their perception of worsening, no change, or improvement in health status. Endpoints The primary endpoint was reduction in AHI from baseline to subsequent visits. Secondary endpoints included change in arterial oxygen

saturation, sleep efciency, sleep architecture, and cardiac and neurohormonal markers. Response to CRT Response to CRT was assessed based on change in EF, 6-minute walk test, and selfassessment global score. Patients were considered responders if the last echocardiogram demonstrated an absolute improvement of 5% or 15% relative to the baseline in addition to any improvement in 6-minute walk test and global score. Statistical Analysis Baseline demographic and clinical characteristics, sleep assessment measures, and quality of life scores were compared on an intention-to-treat basis according to the randomized study group assignment. The 2 test or Fishers exact test were used to assess categorical data and the Wilcoxon rank sum test or Students t-test for continuous data. Paired t-tests were used to evaluate the treatment effect within each arm as well as in the entire cohort from baseline to rst follow-up and then again from baseline to last follow-up. A twosided P-value 0.05 was considered statistically signicant. Results Between February 2006 and March 2008, 128 patients received a de novo CRT-debrillator implant at Veterans Affairs Pittsburgh Healthcare System and were approached for enrollment in this study. Of those, 50 patients declined participation. Of those who agreed to initial screening, 15 were in atrial brillation, 13 were already receiving CPAP for SRBD, and 11 were on narcotics or benzodiazepines that could not be withheld for the study. Of the 39 patients who met clinical criteria for this trial, three patients withdrew consent, while 36 underwent the screening PSG. Of those, 17 patients were excluded based on AHI or nocturnal heart rate criteria (nine had AHI >50/hour, four had AHI <15/hour, and seven had MSHR >80 bpm). Of the 19 patients who were randomized, 10 were randomized to DDD and nine to VDD. Figure 1 recaps the above. On follow-up interrogations, all patients had >90% LV pacing and those in DDD arm had >92% atrial pacing. None of the randomized patients experienced heart failure hospitalizations or received device shocks for the duration of the study. Echocardiographic optimization of the AVD was not performed on any of the patients during the study period as

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Figure 1. Flow chart depicting conduct of the study. Abbreviations as in text.

our practice was to reserve that for nonresponders assessed at 6 months after implant. Table I shows the baseline characteristics of the patients who were all male and mostly Caucasian and elderly. There were no signicant differences between groups in etiology of cardiomyopathy, functional class, QRS duration, or medication utilization. Other than mild-tomoderate renal insufciency (DDD 66% vs VDD 0%, P = 0.003), there was no difference in cardiovascular or pulmonary comorbid conditions.

Physical signs of heart failure were not different between the groups. Similarly, there were no differences in EF, LV dimensions, measures of dyssynchrony, or in biomarker levels between both groups. Patients in both groups had equivalent scores on the sleep quality questionnaires as well as the Minnesota Living with Heart Failure Questionnaire. Performance on the 6minute walk was also similar in both groups. Table II shows the results of the baseline PSG. All patients had at least moderate SRBD with

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Table I. Baseline Variables of the Cohort and According to Group Assignment Total (n = 19) 67.2 7.5 100.0 78.9 28.1 3.5 149.5 33.7 84.2 84.2 63.2 26.3 68.4 21.0 89.5 15.8 10.5 78.9 31.6 63.1 1010.4 346.7 33.3 9.8 60.9 6.2 51.3 8.3 43.8 6.1 2.2 0.81 39.0 8.0 85.5 30.7 32.0 13.8 110.9 79.1 4.1 10.6 0.64 0.22 6.0 4.4 350.1 329.0 613.0 248.8 32.2 20.9 7.3 4.0 7.4 3.1 36.9 21.9 DDD (n = 9) 68.6 8.4 100.0 77.8 27.1 4.3 155.4 42.2 77.8 88.9 55.6 44.4 77.8 11.1 77.8 22.2 11.1 77.8 37.5 62.5 1188.2 218.5 30.2 7.3 61.2 4.7 51.0 8.0 43.1 6.6 2.4 0.73 36.6 9.1 86.2 32.0 32.0 14.0 138.2 77.6 5.0 15.1 0.64 0.24 5.6 5.1 390.6 317.8 559.5 202.0 23.1 12.7 6.2 2.9 7.1 2.9 26.6 15.4 VDD (n = 10) 66.0 6.8 100.0 80.0 29.0 2.4 144.2 24.8 90.0 80.0 70.0 10.0 60.0 30.0 100.0 10.0 10.0 80.0 30 60.0 852.3 372.8 35.7 11.2 60.6 7.5 51.6 8.9 44.3 5.9 1.9 0.87 41.1 7.0 85.0 31.4 32.0 14.4 89.1 77.2 3.3 5.0 0.65 0.20 6.4 4.0 317.6 351.1 661.2 286.5 41.2 24.2 8.5 4.9 7.6 3.5 47.3 23.2

Variable Demographic characteristics Age (mean, years) Male % White % BMI QRS duration History of hypertension % Smoking (ever) % Diabetes % Peripheral vascular disease% Current Medication Use % Angiotensin-converting enzyme inhibitor Angiotensin receptor blocker -blocker Antihypertensive Antiarrhythmic class III Loop diuretic Aldosterone antagonist Digoxin 6-minute walk (feet) Echocardiogram Left ventricular ejection fraction (%) Left ventricular end-diastolic diameter (mm) Left ventricular end-systolic diameter (mm) Left atrial dimension (mm) Peak tricuspid regurgitation velocity (m/s) Right ventricular (RV) fractional area change (%) Dyssynchrony Opposing wall delay (all sites mean ms) 12-site standard deviation (mean ms) Radial strain opposing wall delay (mean ms) RV septalfree wall dyssynchrony (mean ms) Inammatory/Neurohormonal Biomarkers C-reactive protein (mg/dL) IL-6 (pg/mL) Brain natriuretic peptide (pg/mL) Plasma norepinephrine (pg/dL) Urine norepinephrine (g) Sleep Quality Epworth sleepiness score Pittsburgh sleep quality index Quality of Life Minnesota heart failure

P-Value

0.66 1.0 0.24 0.40 0.58 1.0 0.65 0.14 0.63 0.58 0.21 0.58 1.0 1.0 0.88 0.85 0.13 0.30 0.60 0.86 0.54 0.29 0.20 0.93 1.0 0.19 0.66 0.81 0.62 0.83 0.69 0.05 0.45 1.0 0.11

poor sleep efciency and signicant desaturation. SRBD was mainly obstructive in nature with a low central apnea index. Table III demonstrates the change from baseline over the two follow-up times in clinical parameters. While the improvement in 6-minute walk distance and mean MLWHFQ

scores at both follow-up points was signicant, improvements in EF, LV dimensions, and BNP were not. Of the various dyssynchrony measures obtained, only the radial strain opposing wall delay decreased, albeit not signicantly. There was no appreciable difference in scores on

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Table II. Baseline Sleep Study Results for the Cohort and both Groups Total (n = 19) 406.9 75.5 267.3 87.9 65.3 16.6 237.8 75.7 29.7 28.5 21.5 15.3 8.7 13.5 10.8 10.5 3.3 6.7 93.8 2.2 92.3 3.1 83.5 5.3 DDD (n = 10) 419.0 40.0 252.1 68.7 60.2 15.6 222.6 61.8 29.8 15.9 20.3 17.2 6.7 11.9 10.0 5.1 1.3 2.1 93.1 1.9 91.2 2.9 82.7 4.5 VDD (n = 9) 394.8 100.9 282.4 105.8 70.3 16.8 253.1 88.6 29.6 38.5 22.9 13.9 10.8 15.3 11.5 14.4 5.2 9.0 94.5 2.3 93.4 3.0 84.4 6.1

Sleep Study Time in bed (minutes) Total sleep time (minutes) Sleep efciency (%) NREM time (minutes) REM (minutes) AHI (number/hour) Obstructive apnea index (number/hour) Hypopnea index (number/hour) Central apnea index (number/hour) Baseline SpO 2 (%) Average SpO 2 (%) Lowest SpO 2 (%)

P-Value 0.86 0.34 0.25 0.30 0.52 0.45 0.38 0.79 0.24 0.21 0.17 0.52

sleep quality questionnaires at any follow-up time. In Table IV, sleep data from all participants are compared between baseline and over both follow-up points after CRT utilization. There was no change at either of the follow-up points. Specically, patients continued to exhibit at least moderate SRBD, predominantly obstructive in nature with signicant sleep time desaturation. There was no change in sleep architecture or distribution of apneic/hypopneic episodes among sleep stages with pacing for the cohort. Analysis by randomization group also revealed no difference. Figure 2 demonstrates the primary endpoint for the cohort as a whole and within both groups. Response to CRT Based on the criteria listed above, eight of the 19 patients were classied as responders (four VDD and four DDD), while seven additional patients (three DDD and four VDD) demonstrated improvement in 6-minute walk and global score but not in EF. In those patients who responded to all three measures, EF and global score improved signicantly (29.75 7.05 to 40.63 9.81, P = 0.003 and 2.0 0.0 to 1.37 0.5, P = 0.01, respectively), whereas there was a trend to improvement in 6-minute walk distance in feet (1019.75 346.47 to 1194.375 276.8233, P = 0.08). Similar to the cohort at large, these patients also did not demonstrate improvement in SRBD. AHI changed from 18.9 16.3 on the baseline study after implant but before CRT to 31.6 24.7 (P = 0.11) on the last follow-up after CRT.

Discussion Main Findings In this study, we demonstrate that in a cohort of optimally medically treated CHF patients who otherwise qualify for CRT based on EF, functional class, and QRS prolongation with or without echocardiographic evidence of dyssynchrony, CRT application resulted in no improvement in their SRBD of moderate or severe degree. Furthermore, the utilization of atrial overdrive pacing in addition to CRT had no appreciable impact on SRBD. This nding held true even when strict criteria for CRT response were used. SRBD among CRT Recipients Among the patients we screened, SRBD was highly prevalent, when according to our inclusion criteria the disorder had not been previously diagnosed. Moreover, the severity of SRBD was more likely to be high when found. Thus, of the 36 patients screened, 32 (89%) were found to have AHI >15 and nine (25%) had AHI >50. Moreover, the responses to the sleep quality surveys we utilized underestimated the SRBD burden subsequently identied by PSG. This is not unusual, as daytime sleepiness in heart failure patients has been found to underestimate the amount of SRBD, perhaps reecting the degree of sympathetic activation.32 It may be advantageous to advance screening tools that can be incorporated into cardiac rhythm management devices to identify SRBD in these patients.33 It is interesting that all our patients demonstrated obstructive SRBD. This comes at odds with other reports of predominantly central SRBD in CHF patients. Temporal and geographic trends in

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Table III. Mean Echocardiographic, Biomarker, and Self-Assessment Values at Baseline and Follow-Up Visits. P-Values Shown Reect Change from Baseline for the Cohort and within Each Group All Participants Variable Mean SD P-Value DDD Mean SD P-Value VDD Mean SD P-Value

Echocardiogram Ejection Fraction (%) Baseline 33.3 9.8 First follow-up 34.8 10.8 Last follow-up 36.1 9.3 LV End-Diastolic Volume Baseline 167.2 43.5 First follow-up 157.4 35.1 Last follow-up 147.2 47.9 LV End-Systolic Volume Baseline 114.0 42.3 First follow-up 106.5 37.0 Last follow-up 96.9 41.8 Radial Strain Opposing Wall Delay Baseline 110.9 79.1 First follow-up 90.4 66.7 Last follow-up 80.4 70.6 RV Fractional Area Change Baseline 39.0 8.0 First follow-up 38.5 6.6 Last follow-up 37.4 7.0 Biomarkers: C-Reactive Protein Baseline 0.65 0.22 First follow-up 0.58 0.22 Last follow-up 0.55 0.13 IL-6 Baseline 6.0 4.4 First follow-up 5.7 4.9 Last follow-up 4.6 3.5 Brain Natriuretic Peptide Baseline 350.1 329.0 First follow-up 282.1 266.1 Last follow-up 309.1 333.4 Norepinephrine Baseline 613.0 248.8 First follow-up 584.6 279.3 Last follow-up 513.7 174.0 Self-Assessments Minnesota Heart Failure Baseline 36.9 21.9 First follow-up 29.2 22.4 Last follow-up 25.5 15.4 Epworth Sleepiness Score Baseline 7.3 4.0 First follow-up 6.9 4.0 Last follow-up 6.6 2.6

0.43 0.14

30.2 7.3 31.6 8.2 33.5 6.9 168.1 36.1 156.1 21.5 149.0 44.8 118.7 38.4 112.6 24.6 101.9 41.6 138.2 77.6 101.1 54.2 61.9 39.2 36.6 9.1 40.2 9.1 37.5 5.2 0.64 0.24 0.50 0.0 0.52 0.07 5.6 5.1 3.6 1.9 4.3 3.9 390.6 317.8 253.0 273.5 205.9 157.1 559.6 202.0 596.9 233.2 425.2 181.2 26.6 15.4 26.6 18.8 17.1 11.0 6.2 2.9 6.7 2.3 6.4 1.4

0.64 0.36

35.7 11.2 37.5 12.4 38.6 11.1 166.5 50.7 158.3 44.3 145.5 53.8 110.2 46.9 101.8 45.3 92.0 44.2 89.1 77.2 82.0 77.2 99.0 91.4 41.1 7.0 37.5 5.1 37.2 8.4 0.65 0.20 0.64 0.29 0.58 0.16 6.4 4.0 7.7 6.2 4.8 3.3 317.6 351.1 311.2 273.9 400.9 425.0 661.2 286.5 573.8 328.9 592.3 130.5 47.3 23.2 31.2 25.8 32.7 15.4 8.5 4.9 7.1 5.2 6.8 3.5

0.56 0.29

0.31 0.13

0.24 0.37

0.84 0.23

0.31 0.13

0.46 0.40

0.54 0.20

0.60 0.22

0.38 0.06

0.67 0.52

0.96 0.42

0.67 0.84

0.42 0.15

0.47 0.12

0.17 0.23

0.86 0.28

0.83 0.38

0.36 0.71

0.69 0.33

0.06 0.68

0.14 0.05

0.29 0.69

0.64 0.06

0.92 0.01

0.51 0.41

0.02 0.004

0.81 0.08

0.002 0.03

0.57 0.22

0.88 0.80

0.44 0.21
Continued.

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Table III. Continued All Participants Variable Mean SD P-Value DDD Mean SD 7.1 2.9 6.5 1.7 7.2 1.5 1188.2 218.5 1295.7 135.7 1300.6 178.2 P-Value VDD Mean SD 7.5 3.5 5.8 3.1 6.2 1.9 852.3 372.8 1206.4 240.5 1144.8 386.1 P-Value

Pittsburgh Sleep Quality Index Baseline 7.4 3.1 First follow-up 6.1 2.5 Last follow-up 6.7 1.8 6-Minute Walk Baseline 1010.4 346.7 First follow-up 1245.5 200.7 Last follow-up 1212.9 314.0

0.04 0.39

0.45 1.0

0.03 0.32

0.008 0.04

0.33 0.42

0.01 0.06

Table IV. Sleep Study Results at Baseline and Follow-Up. P-Values Shown Reect Change from Baseline for the Cohort and within Each Group All Participants Mean SD Time in Bed Baseline 406.9 75.5 First follow-up 409.2 57.7 Last follow-up 429.3 30.3 Total Sleep Time Baseline 267.3 87.9 First follow-up 287.4 83.0 Last follow-up 291.5 72.5 Sleep Efciency Baseline 65.3 16.6 First follow-up 70.2 17.4 Last follow-up 68.3 17.9 NREM Time Baseline 237.8 75.7 First follow-up 251.5 67.0 Last follow-up 257.4 56.9 REM Time Baseline 29.7 28.5 First follow-up 36.1 24.5 Last follow-up 34.2 28.3 Overnight Urinary Norepinephrine Baseline 32.2 20.9 10 weeks 28.1 18.4 Last follow-up 26.7 12.7 AHI Baseline 21.5 15.3 First follow-up 18.9 16.3 Last follow-up 24.9 21.9 P-Value DDD Mean SD 394.8 100.9 396.0 75.4 413.7 22.2 282.4 105.8 291.6 111.1 301.1 65.5 70.3 16.8 72.9 21.3 73.2 18.0 253.1 88.6 250.1 91.8 264.2 57.2 29.6 38.5 41.7 28.5 37.1 22.0 23.1 12.7 21.1 15.5 21.0 13.5 22.9 13.9 15.5 12.6 17.5 28.8 P-Value VDD Mean SD 419.0 40.0 420.9 36.9 443.1 30.7 252.1 68.7 283.7 54.3 283.0 81.1 60.2 15.6 67.8 14.0 63.9 17.7 222.6 61.8 252.8 40.1 251.3 59.4 29.8 15.9 31.1 20.7 31.7 34.1 41.2 24.2 34.1 19.5 32.4 9.6 20.3 17.2 21.9 19.3 31.4 28.1 P-Value

0.15 0.58

0.27 0.03

0.35 0.21

0.99 0.59

0.64 0.74

0.52 0.38

0.42 0.69

0.91 0.86

0.38 0.73

0.80 0.77

0.42 0.55

0.52 0.46

0.52 0.49

0.56 0.72

0.83 0.56

0.80 0.20

0.60 0.66

0.59 0.25

0.56 0.34

0.56 0.42

0.97 0.17
Continued.

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Table IV. Continued All Participants Mean SD Obstructive Apnea Index Baseline First follow-up Last follow-up Hypopnea Index Baseline First follow-up Last follow-up Central Apnea Index Baseline First follow-up Last follow-up Baseline SpO 2 Baseline First follow-up Last follow-up Average SpO 2 Baseline First follow-up Last follow-up Lowest SpO 2 Baseline First follow-up Last follow-up 8.7 13.5 6.1 6.2 9.8 15.6 10.8 10.5 11.5 10.3 10.4 9.8 3.3 6.7 1.4 3.7 4.8 9.1 93.8 2.2 93.5 2.3 93.3 1.7 92.3 3.1 91.5 2.4 91.5 2.4 83.6 5.3 83.0 5.0 82.8 4.6 P-Value DDD Mean SD 10.8 15.3 5.4 5.8 5.5 6.7 11.5 14.4 9.6 11.1 8.6 5.7 5.2 9.0 0.62 1.2 3.6 5.6 94.6 2.3 94.0 1.8 93.5 1.1 93.4 3.0 93.0 1.8 92.4 1.5 84.4 6.1 85.2 5.7 83.4 3.7 P-Value VDD Mean SD 6.7 11.9 6.7 6.9 13.7 20.3 10.0 5.1 13.1 9.9 12.0 12.5 1.3 2.1 2.1 4.9 5.9 11.7 93.1 1.9 93.1 2.8 93.1 2.1 91.2 2.9 90.2 2.2 90.7 2.9 82.7 4.5 81.0 3.4 82.2 5.4 P-Value

0.35 0.77

0.48 0.40

0.54 0.27

0.66 0.46

0.59 0.50

0.73 0.84

0.03 0.31

0.07 0.47

0.29 0.47

0.58 0.43

1.0 0.38

0.42 0.76

0.43 0.33

0.87 0.47

0.24 0.57

0.70 1.0

0.27 0.87

0.54 0.78

Figure 2. Change in AHI (mean standard deviation) for the cohort and according to pacing group (P = NS for all).

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demographics and pharmacological therapy may have impacted the nature of SRBD in our patients. We note that among the published trials of CRT for SRBD in CHF patients the only other reported cohort with obstructive SRBD was also from the United States.20 Relation to Previous Studies Several groups have explored the potential impact of CRT in reducing SRBD burden in qualifying CHF patients.1724 The cumulative experience endorses a benet in reducing central SRBD. The reduction is tied to improvement in various parameters of LV dysfunction, neurohormonal balance, and CHF functional status in response to CRT application. The impact of CRT on central SRBD is evident both acutely and after longer periods of follow-up and is lost upon withdrawal of CRT. The reduction in SRBD burden is reected in improvement in sleepspecic symptoms as well as other general quality of life indicators. Data on obstructive SRBD are conicting, however. Contrary to our ndings, Stanchina et al., who studied a group of patients eligible for CRT with at least mild obstructive SRBD (AHI >5/hour) on a screening PSG, reported that the mean AHI had improved signicantly concomitant with improvement in EF and signicantly correlated to lung to nger circulation time, a measure of cardiac output.20 In a subsequent night, atrial overdrive pacing added no further improvement to the AHI. On the other hand, Oldenburg et al. screened 77 CHF patients eligible for CRT and found central SRBD in 36 and obstructive in 26.21 The investigators determined response to CRT as good, moderate, or not relevant. On followup PSG, signicant improvement was noted in SDB parameters in patients with central but not in those with obstructive SRBD notwithstanding their equivalent response to CRT. Our ndings corroborate those of Oldenburg et al. where we found no signicant improvement in our cohort who exhibited primarily obstructive SRBD with no signicant central component.21 The lack of improvement with atrial overdrive pacing noted in our trial echoes the ndings of Stanchina et al.20 and Luthje et al.,24 keeping References
1. Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, Carson P, et al. Cardiac-resynchronization therapy with or without an implantable debrillator in advanced chronic heart failure. N Engl J Med 2004; 350:21402150. 2. Linde C, Abraham WT, Gold MR, St John Sutton M, Ghio S, Daubert C; REVERSE (REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction) Study Group. Randomized trial of cardiac resynchronization in mildly symptomatic heart

in mind the latter studied a cohort with central SRBD. In fact, the utility of atrial pacing for SRBD of any type regardless of underlying cardiac pathology is highly doubtful.3436 Limitations Our study involved a relatively small number of patients. We attribute this to the difculty of recruiting to studies involving nighttime PSG tests. Our cohort is representative of patients receiving CRT, based on NYHA, EF, QRS duration, and optimal pharmacological therapy. While there was improvement in quality of life and 6minute walk distance, improvements in EF and cardiac reverse remodeling parameters were not signicant. It is possible that adverse neurohormonal activation, heightened sympathetic tone, and increased levels of circulating inammatory molecules and byproducts attendant with the degree of obstructive SRBD had signicant impact on CRT response.37 Diminished response to CRT has been observed in conditions similarly characterized by maladaptive neurohormonal activation.3841 Finally, the decision to implant was based on clinical echocardiograms with EF <36%. However, the baseline EF obtained after implant but prior to CRT as reported by the core lab was greater than 35% in some cases. We utilized a blinded core lab to ensure uniformity of analysis, but this was only after patients were enrolled and implanted. Specically, three patients had baseline EF >35 with one outlier signicantly affecting the cohorts mean. The results hold true when these cases are excluded from the analysis, as they did with those who demonstrated unequivocal response to CRT. Our patients were all male, reecting the makeup of the clinical population at a tertiary Veterans Affairs Medical Center. Since our patients represent a self-selected cohort, extrapolations as to the prevalence of SRBD among CRT recipients should be taken with caution. In conclusion, in patients with advanced CHF on optimal medical therapy and who are appropriate CRT candidates, obstructive SRBD of moderate to severe degree was frequently encountered. Despite improvement in neurohormonal activation and functional capacity, CRT with or without atrial overdrive pacing was not effective in improving SRBD.

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