CLINICAL RESEARCH: HEART FAILURE
Cardiac resynchronization therapy improves central sleep apnea and Cheyne-Stokes respiration in patients with chronic heart failure
Anil-Martin Sinha, MD, DPhil*,
Erik C. Skobel, MD*,
Ole-Alexander Breithardt, MD*,
Christine Norra, MD ,
Kai U. Markus, MD*,
Christian Breuer, MD*,
Peter Hanrath, MD, FESC, FACC* and
Christoph Stellbrink, MD, FESC*,*
* Department of Cardiology, University Hospital, RWTH, Aachen, Germany
Clinic for Psychiatry and Psychotherapy, University Hospital, RWTH, Aachen, Germany
Manuscript received September 16, 2003;
revised manuscript received March 11, 2004,
accepted March 16, 2004.
* Reprint requests and correspondence: Dr. Christoph Stellbrink, Medizinische Klinik I, University Hospital, RWTH Aachen, Pauwelsstrasse 30, D-52074 Aachen, Germany.
cstellbrink{at}ukaachen.de
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Abstract
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OBJECTIVES: We studied the effects of cardiac resynchronization therapy (CRT) on heart failure (HF) patients with central sleep apnea (CSA).
BACKGROUND: Patients with advanced HF often suffer from CSA with Cheyne-Stokes respiration. Cardiac resynchronization therapy improves myocardial function and exercise capacity in HF patients with conduction disturbances. The relationship between CRT and CSA is currently unknown.
METHODS: Twenty-four patients (7 females; 62 ± 11 years) with HF, a reduced left ventricular ejection fraction (24 ± 6%), and left bundle branch block (QRS duration 173 ± 22 ms) received a CRT device. The number of apneas and hypopneas per hour (apnea-hypopnea index [AHI]) and minimal oxygen saturation (SaO2min) were quantified by cardiorespiratory polygraphy. Fourteen patients showed CSA (AHI >5/h), and 10 patients had an AHI <5/h without CSA. Subjective sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI). Data were evaluated before and after 17 ± 7 weeks of CRT.
RESULTS: In patients with CSA, CRT led to a significant decrease in AHI (19.2 ± 10.3 to 4.6 ± 4.4, p < 0.001) and PSQI (10.4 ± 1.6 to 3.9 ± 2.4, p < 0.001) without Cheyne-Stokes respiration and to a significant increase in SaO2min (84 ± 5% to 89 ± 2%, p < 0.001). There was no significant change in AHI (1.7 ± 0.7 to 1.5 ± 1.6), PSQI (2.4 ± 0.5 to 2.6 ± 0.9), and SaO2min (90 ± 2% to 91 ± 1%) in patients without CSA.
CONCLUSIONS: Cardiac resynchronization therapy leads to a reduction of CSA and to increased sleep quality in patients with HF and sleep-related breathing disorders. This may have prognostic implications in patients receiving CRT.
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Abbreviations and Acronyms
| | AHI | = apnea hypopnea index | | CRT | = cardiac resynchronization therapy | | CSA | = central sleep apnea | | HF | = heart failure | | LV | = left ventricular | | NYHA | = New York Heart Association | | PSQI | = Pittsburgh Sleep Quality Index | | SaO2min | = minimal oxygen saturation | | VE/VCO2 | = slope of increase in ventilation relative to carbon dioxide production | | VO2 | = oxygen consumption |
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Patients with heart failure (HF) often present with central sleep apnea syndrome (CSA) and Cheyne-Stokes respiration, which is associated with increased mortality (1,2).
Treatment with continuous positive airway pressure ventilation may improve sleep disorders (3) and cardiac function (4), whereas pharmacologic therapy alone has only minor effects (5). Atrial overdrive pacing reduces the number of sleep apnea episodes in pacemaker patients without HF (6). Cardiac resynchronization therapy (CRT) improves the hemodynamic and functional status of HF patients with ventricular conduction delay (7,8) and may reduce cardiac mortality (9).
We conducted a prospective trial to study the effects of CRT on CSA with Cheyne-Stokes respiration in HF patients.
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Methods
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Patients.
Twenty-four consecutive patients were included in the study. Of these, 14 showed evidence of CSA and Cheyne-Stokes respiration. All patients presented with heart failure of New York Heart Association (NYHA) functional class III, were in a clinically stable condition for two months or more, and took optimized heart failure medication, including beta-blockers (n = 22), angiotensin-converting enzyme inhibitors (n = 23), diuretics (n = 23), spironolactone (n = 21), and digitalis (n = 17).
Cardiac resynchronization therapy was applied using left or biventricular pacing in an atrially triggered mode. No patient had a conventional indication for pacemaker therapy. Table 1 shows patient characteristics and pacemaker device configurations. Data were evaluated before and after 17 ± 7 weeks of CRT.
The study was conducted in accordance with institutional guidelines, and all patients gave written, informed consent.
Sleep evaluation.
Sleep-related breathing disorders were established by an ambulatory overnight cardiorespiratory polygraph (Somnocheck, Weinmann, Germany), which records nasal/oral airflow, chest and abdominal wall movements, oxygen saturation, and heart rate. Central sleep apnea was defined by absent chest and abdominal wall motion and airflow for  10 s, Cheyne-Stokes respiration by periodic occurrence of apnea and hyperventilation, and hypopnea by a reduction in respiratory airflow of >50% for 10 s, associated with desaturation >3%. The average number of episodes of apnea and hypopnea per hour (apnea-hypopnea index [AHI]) was determined. A "sleep-related breathing disorder" was diagnosed if the AHI was >5/h (10).
The Pittsburgh Sleep Quality Index (PSQI), a retrospective self-rating questionnaire, measures the sum score of sleep quality of the last month (11). "Good" sleepers show a global PSQI sum score <5.
Exercise capacity, ventilatory response, and echocardiography.
Cardiopulmonary exercise testing was performed on a bicycle ergometer using a ramp increment of 10 W/min. Oxygen consumption (VO2) was determined by breath gas analysis (Jaeger Oxycon Alpha, Germany) at peak VO2 in the terminal phase of exercise and at the anaerobic threshold. To analyze the ventilatory response to exercise, we calculated the slope of ventilation increase relative to carbon dioxide production (VE/VCO2 slope) during exercise.
The 6-min walk test was performed between two points of 45-m distance on a plane floor.
Biplane left ventricular (LV) end-diastolic and end-systolic volumes and ejection fraction were quantified according to the modified Simpson's rule by two-dimensional echocardiography.
Statistics.
Continuous data are expressed as the mean value ± SD. Statistical analyses were performed with SPSS software (SPSS Inc., Chicago, Illinois).
The Wilcoxon signed-rank test was applied for paired comparisons before and during CRT. Unpaired data were compared by the Mann-Whitney U test. The chi-square test was used for nominal variables. Correlation between measures was calculated using the Spearman rank correlation. For statistical analysis, only complete data sets of single parameters were included. A value of p < 0.05 was considered significant for all comparisons.
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Results
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Clinical response to CRT.
During CRT, NYHA functional class improved from III to II in 8 patients with and in 5 patients without CSA, whereas it was unchanged in the remaining 11 patients.
Table 2 shows the results of cardiopulmonary exercise testing, 6-min walk test, and echocardiographic data.
The anaerobic threshold was indeterminable in two patients with and two without CSA. One patient of each group was unable to perform cardiopulmonary exercise testing due to noncardiac reasons. There was no correlation of AHI with parameters of exercise testing or echocardiography.
Sleep evaluation.
The effects of CRT on AHI are shown in Figure 1 and on minimal oxygen saturation (SaO2min) and PSQI in Table 3. Although the PSQI was reduced in all CSA patients, it was still >5 in two patients during CRT. There was a significant correlation between the improvement of AHI and PSQI (r = 0.831, p < 0.05) in patients with, but not in patients without CSA (r = –0.13, p = NS) during CRT.
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Figure 1 Effects of cardiac resynchronization therapy (CRT) on apnea hypopnea index (AHI) in patients with and without central sleep apnea (CSA). The area under the dotted line represents a normal AHI (<5). Squares = mean ± SD of all patients; triangles = mean ± SD of patients with CSA; octagons = mean ± SD of patients without CSA. Stars = p < 0.005 vs. baseline.
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Table 3 Effects of Cardiac Resynchronization Therapy on Cardiorespiratory Polygraph and Pittsburgh Sleep Quality Index (PSQI)
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There was no change in body mass index or medication and no weight loss or exercise training that could have influenced AHI in any patient during the study. No patient received supplemental oxygen or continuous positive airway pressure therapy.
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Discussion
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In HF patients, increased LV filling pressures can lead to pulmonary congestion and activation of pulmonary vagal irritant receptors, provoking hyperventilation and hypocapnia. Central sleep apnea occurs when arterial carbon dioxide partial pressures fall below the apneic threshold. The cycle length of alternating periods of hypocapnia-induced apnea and reflex hyperventilation (i.e., Cheyne-Stokes respiration [1]) is inversely proportional to cardiac output (12) and thus directly related to the severity of HF. A reduced LV function delays the circulation time between the lungs and the chemoreceptors (13) and increases the sensitivity of chemoreceptors, especially to carbon dioxide (14). The degree of carbon dioxide hypersensitivity is a major determinant of Cheyne-Stokes respiration (15). An increase in chemoreflex sensitivity is mirrored by an elevated ventilatory response to exercise in HF patients (16).
Our study is the first to show that CRT improves cardiac function and reduces the severity of CSA with Cheyne-Stokes respiration in HF patients with a ventricular conduction delay. A significant decrease in AHI and a significant increase in SaO2min was observed during CRT without the application of noninvasive ventilatory support.
These beneficial effects could be explained by the CRT-related improvement in cardiac function. It has been shown that CRT leads to a more efficient LV contraction (17), accompanied by a reduction in functional mitral regurgitation (18). This may, in turn, result in reduced pulmonary congestion as a triggering factor of the reflex mechanisms responsible for Cheyne-Stokes respiration.
We also found a significant decrease in ventilatory response to exercise measured by the VE/VCO2 slope in CSA patients. This points to a reduction in circulation time between lungs and peripheral chemoreceptors, as well as a decrease in chemoreflex sensitivity to carbon dioxide. Therefore, our findings suggest that impaired LV function may be the primary cause of the reflex cascade, leading to Cheyne-Stokes respiration, and not vice versa.
Elevated VE/VCO2 slopes (19) and Cheyne-Stokes respiration (2) are associated with increased mortality in HF patients. Thus, the interruption of this vicious cycle of Cheyne-Stokes respiration may have a positive effect on prognosis.
Although the AHI is the result of a single-night evaluation, we could demonstrate positive long-term effects of CRT on sleep quality. The PSQI was significantly reduced and directly related to AHI improvement during CRT. These sleep-related effects might contribute to the significant improvement of patients' quality of life, as found in other CRT studies (7,8). Based on our findings, the improvement of CSA with Cheyne-Stokes respiration could be used as a helpful tool to evaluate the efficacy of CRT.
Breathing patterns, like respiration rate and minute ventilation, can be determined by implanted pacemaker sensors measuring the transthoracic impedance minute ventilation. Several studies have shown a high correlation between transthoracic impedance minute ventilation and actual minute ventilation measured by standard methods (20,21). Different breathing patterns and daily activities, including exercise testing, affect the transthoracic impedance minute ventilation (21) and allow one to draw conclusions about the patient's condition.
Therefore, analysis of breathing patterns may be used to determine the choice of CRT devices in the future. Patients with CSA may benefit from devices with a minute ventilation sensor capable of analyzing specific breathing patterns. This would allow continuous and noninvasive monitoring of CRT efficacy.
Study limitations.
We applied a single-night cardiorespiratory polygraphy, which is used for the initial ambulatory diagnosis of sleep apnea syndromes (22). Although polysomnography is regarded as the "gold standard," previous studies have shown a high diagnostic accuracy of the portable recording device (22).
Conclusions.
In patients receiving CRT, the improvement of cardiac function and exercise capacity is associated with a significant improvement of CSA with Cheyne-Stokes respiration and sleep quality. Therefore, the analysis of breathing patterns could be used for device-based monitoring of CRT efficacy in the future. Further studies are necessary to evaluate the prognostic implications of breathing pattern analysis in HF patients receiving CRT.
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M. Arzt and T. D. Bradley
Treatment of Sleep Apnea in Heart Failure
Am. J. Respir. Crit. Care Med.,
June 15, 2006;
173(12):
1300 - 1308.
[Abstract]
[Full Text]
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A.-M. Sinha, E. C. Skobel, O.-A. Breithardt, H. Zheng, H. Zhan, I. Wilcox, V. Booth, J. Lattimore, P. N. Chhajed, M. Tamm, et al.
Sleep apnea and heart disease.
N. Engl. J. Med.,
March 9, 2006;
354(10):
1086 - 1089.
[Full Text]
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E. N. Simantirakis, S. E. Schiza, S. I. Chrysostomakis, G. I. Chlouverakis, N. C. Klapsinos, N. M. Siafakas, and P. E. Vardas
Atrial Overdrive Pacing for the Obstructive Sleep Apnea-Hypopnea Syndrome
N. Engl. J. Med.,
December 15, 2005;
353(24):
2568 - 2577.
[Abstract]
[Full Text]
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S. M. Caples, R. Wolk, and V. K. Somers
Influence of cardiac function and failure on sleep-disordered breathing: evidence for a causative role
J Appl Physiol,
December 1, 2005;
99(6):
2433 - 2439.
[Abstract]
[Full Text]
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C. Unterberg, L. Luthje, J. Szych, D. Vollmann, G. Hasenfuss, and S. Andreas
Atrial overdrive pacing compared to CPAP in patients with obstructive sleep apnoea syndrome
Eur. Heart J.,
December 1, 2005;
26(23):
2568 - 2575.
[Abstract]
[Full Text]
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J. Y. Gabor, D. A. Newman, V. Barnard-Roberts, V. Korley, I. Mangat, P. Dorian, and P. J. Hanly
Improvement in Cheyne-Stokes respiration following cardiac resynchronisation therapy
Eur. Respir. J.,
July 1, 2005;
26(1):
95 - 100.
[Abstract]
[Full Text]
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J. S. Floras and T. D. Bradley
Atrial Overdrive Pacing for Sleep Apnea: A Door Now Closed?
Am. J. Respir. Crit. Care Med.,
July 1, 2005;
172(1):
1 - 3.
[Full Text]
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A.-M. Sinha, C. Stellbrink, E. C. Skobel, C. Scharf, K. E. Bloch, C. Brunckhorst, F. Duru, R. Candinas, Y. K. Cho, K. Balaban, et al.
Letter Regarding Article by Scharf et al, "Diagnosis of Sleep-Related Breathing Disorders by Visual Analysis of Transthoracic Impedance Signals in Pacemakers" * Response
Circulation,
May 17, 2005;
111(19):
e301 - e302.
[Full Text]
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C. Scharf, A. Turk, T. Brack, and K. Bloch
Cardiac resynchronization therapy, central sleep apnea, and Cheyne-Stokes respiration in chronic heart failure patients
J. Am. Coll. Cardiol.,
February 15, 2005;
45(4):
633 - 633.
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C. Stellbrink, E. Skobel, and A.-M. Sinha
Cardiac resynchronization therapy, central sleep apnea, and Cheyne-Stokes respiration in chronic heart failure patients: Reply
J. Am. Coll. Cardiol.,
February 15, 2005;
45(4):
633 - 634.
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H J Nesser, O-A Breithardt, and B K Khandheria
Established and evolving indications for cardiac resynchronisation
Heart,
December 1, 2004;
90(suppl_6):
vi5 - vi9.
[Abstract]
[Full Text]
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G. Grassi, A. Vincenti, R. Brambilla, F. Q. Trevano, R. Dell'Oro, A. Ciro, G. Trocino, A. Vincenzi, and G. Mancia
Sustained Sympathoinhibitory Effects of Cardiac Resynchronization Therapy in Severe Heart Failure
Hypertension,
November 1, 2004;
44(5):
727 - 731.
[Abstract]
[Full Text]
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