Abstract
Purpose
Cheyne–Stokes respiration during sleep is associated with increased mortality in heart failure. The magnitude of oxidative stress is a marker of disease severity and a valuable predictor of mortality in heart failure. Increased oxidative stress associated with periodic breathing during Cheyne–Stokes respiration may mediate increased mortality in these patients. We hypothesized that the presence of Cheyne–Stokes respiration is associated with oxidative stress by increasing the formation of reactive oxygen species in patients with heart failure.
Methods and results
Twenty-three patients with heart failure [left ventricular ejection fraction 30.2±9% (mean±standard deviation)] and 11 healthy controls underwent nocturnal polysomnography. Subjects with obstructive sleep apnea were excluded. The majority (88%) of patients with heart failure had Cheyne–Stokes respiration during sleep. The intensity of oxidative stress in neutrophils was greater in patients with heart failure (4,218±1,706 mean fluorescence intensity/cell vs. 1,003±348 for controls, p<0.001) and correlated with the duration of Cheyne–Stokes respiration. Oxidative stress was negatively correlated with SaO2 nadir during sleep (r=−0.43, p=0.039). The duration of Cheyne–Stokes respiration predicted severity of oxidative stress in patients with heart failure (beta=483 mean fluorescence intensity/cell, p<0.02).
Conclusions
Levels of oxidative stress are increased in patients with heart failure and Cheyne–Stokes respiration during sleep compared with healthy controls. The duration of Cheyne–Stokes respiration predicts the magnitude of oxidative stress in heart failure. Increased oxidative stress may mediate increased mortality associated with Cheyne–Stokes respiration in patients with heart failure.
Keywords: Oxidative stress, Heart failure, Cheyne-stokes respiration, Periodic breathing, Hypoxemia, Sleep apnea
Cheyne–Stokes respiration, the predominant form of sleep-related respiratory disturbance in patients with heart failure, is characterized by alternating periods of crescendo and decrescendo respiration followed by central apneas [1–5]. Unlike obstructive sleep apnea, which occurs due to airway obstruction, Cheyne–Stokes respiration is caused by oscillations in central respiratory control. Little is known about the effects of altered central respiratory control on cellular oxidative stress. Cheyne–Stokes respiration during sleep is associated with increased mortality among patients with heart failure when compared to heart failure patients without Cheyne–Stokes respiration, independent of left ventricular function [6–11]. However, the mechanisms linking Cheyne–Stokes respiration during sleep to increased mortality in heart failure are unknown. We hypothesized that intermittent hypoxemia periods associated with transient cessation of breathing during Cheyne–Stokes respiration increase cellular oxidative stress resulting in progression of myocardial failure and, ultimately, cell death. We compared the levels of oxidative stress in neutrophils of heart failure patients with Cheyne–Stokes respiration during sleep and healthy controls.
Materials and methods
Study sample
Adult male patients with stable heart failure and New York Heart Association (NYHA) class ≥2 were recruited from the Cardiology Clinic at the VA New York Harbor Healthcare System. All participants signed an informed consent approved by the Institutional Review Board. The inclusion criteria for the heart failure subjects were as follows: left ventricular ejection fraction <40% by radionuclide angiography, stable clinical symptoms without changes in medication or hospitalizations within 30 days of study inclusion, and optimized standard pharmacological therapy. Subjects with inability to walk on a treadmill, history of unstable angina or myocardial infarction within 3 months of study inclusion, history of snoring, stroke, oxygen use at home, or previously diagnosed with sleep apnea were excluded. Healthy male controls with no history of cardiovascular disease, dyslipidemia, diabetes, or renal insufficiency were recruited by advertisement in subspecialty clinics. Enrolled subjects with heart failure underwent measurement of maximum oxygen consumption (VO2 max) by multistage treadmill exercise test using a modified Bruce protocol and a 6-min walk under the supervision of a trained nurse [12–15]. All subjects underwent baseline vital signs, height and weight measurements followed by an overnight sleep study and a morning blood draw within 2 weeks of study enrolment. Clinical information collected for all subjects included a complete medical history and medication list, including the use of vitamin supplementation, physical activity, and NYHA classification.
Polysomnography
Nocturnal polysomnography recording consisted of four-channel electroencephalogram, bilateral electrooculogram, submental and anterior tibilais electro- myogram, two lead electrocardiograms, rib cage and abdominal movement by inductive plethysmography, body position, pulse oximetry, and nasal pressure monitoring. Sleep and respiration were scored by a single sleep research technician according to the American Academy of Sleep Medicine guidelines. Exclusion due to obstructive sleep apnea was based on having ≥10% of all respiratory events obstructive in nature. The oxygen desaturation index was calculated based on the hourly index of oxygen saturation (SaO2) decrease of ≥4% during sleep using a beat-to-beat oximetry recording. Cheyne–Stokes respiration was defined as a crescendo–decrescendo pattern of the respiratory airflow signal associated with simultaneous alteration in chest and abdominal wall motion, which were not paradoxical or obstructive in nature. Quantification of Cheyne–Stokes respiration was performed by determining the hourly index of crescendo–decrescendo respiratory cycles (Cheyne–Stokes respiration index) and by adding the duration of all Cheyne–Stokes respiration periods during sleep (Cheyne–Stokes respiration duration) [16].
Quantification of oxidative stress
In the morning following the sleep study, phlebotomy was performed after 30 min of recumbent rest. The formation of reactive oxygen species in neutrophils was measured by flow cytometry. Blood samples were processed within 1 h of collection. Leukocytes from ammonium chloride lysed whole blood were loaded at 4°C with dichlorofluorescin diacetate (Sigma, St. Louis, MO, USA), a non-polar compound that is converted into a non-fluorescent, polar derivative by cellular esterases, then oxidized to fluorescent carboxydichloroflourescein in the presence of intracellular H2O2 and peroxidases following incubation for 30 min at 37°C [17, 18]. Cells were analyzed on a FACSCalibur (BD Biosciences, San Jose, CA, USA). Neutrophils were differentiated from lymphocytes and monocytes by forward- and side-scattered laser light. At least 10,000 neutrophils were analyzed for each subject. The magnitude of reactive oxygen species formation was detected in the fluorescein channel above autofluorescence. Plasma cathecolamine levels, brain natriureic peptide (BNP) and C-reactive protein (CRP) were measured in the heart failure group using commercially available radioimmunoassay kits.
Statistical analysis
Data were analyzed using unpaired, two-tailed t test for continuous variables and ANOVA with post hoc comparisons by Fisher's exact test for testing multiple factors. All correlation analyses were performed using linear regression.
Results
Twenty-six male patients with heart failure met the inclusion criteria for this study. Three subjects were excluded after undergoing polysomnography due to obstructive sleep apnea. Twenty-three patients with heart failure and 11 healthy controls were available for final analyses. Participants' baseline characteristics and medical history are shown in Table 1. All heart failure subjects were receiving beta-blockers, angiotensin-converting enzyme inhibitors (or angiotensin-receptor blockers), and at least one diuretic. Patients with heart failure were older than controls. The individual values for physiological parameters in the heart failure group are shown in Table 2. Their mean left ventricular ejection fraction was 30.2%.
Table 1. Baseline demographic and clinical characteristics of all subjects.
| Heart failure patients (n=23) | Healthy controls (n=11) | |
|---|---|---|
| Mean±SD | Mean±SD | |
| Age (years)* | 66.2±10.1 | 38.7±8.8 |
| Body mass index (kg/m2) | 27.7±3.5 | 25.6±3.3 |
| n (%) | n (%) | |
| Ethnicity | ||
| White | 4 (17.4%) | 4 (36.4%) |
| Black | 9 (39.1%) | 3 (27.3%) |
| Hispanic | 10 (43.5%) | 4 (36.4%) |
| Medical history | ||
| Coronary artery disease | 11 (47.8%) | 0 |
| Prior myocardial infarction | 7 (30.4%) | 0 |
| Hypertension | 10 (43.5%) | 0 |
| Dyslipidemia | 7 (30.4%) | 0 |
| Renal insufficiency | 7 (30.4%) | 0 |
| Diabetes | 9 (39.1%) | 0 |
| Medications | ||
| Aspirin | 18 (78.3%) | 0 |
| ACEI/ARB | 23 (100%) | 0 |
| Beta blocker | 23 (100%) | 0 |
| Digoxin | 13 (56.5%) | 0 |
| Furosemide | 19 (82.6%) | 0 |
| Hydralazine | 4 (17.4%) | 0 |
| Spironolactone | 15 (65.2%) | 0 |
| Statins | 16 (69.6%) | 0 |
SD standard deviation, ACEI angiotensin-converting enzyme inhibitor, ARB angiotensin-receptor blocker
p<0.05
Table 2. Measures of cardiac function and sympathetic activity in the heart failure group.
| Subject | EF (%) | VO2 (kg/m) | 6mw (ft) | CRP (mg/L) | BNP (pg/mL) | NE (pg/mL) | EPI (pg/mL) | DA (pg/mL) |
|---|---|---|---|---|---|---|---|---|
| 1 | 39 | 33.0 | 1,300 | 8.2 | 422 | 480 | 32 | 11 |
| 2 | 40 | 9.3 | 1,200 | 4.1 | 520 | 376 | 20 | 13 |
| 3 | 25 | 25.7 | 1,200 | 3.7 | 66 | 291 | 36 | 12 |
| 4 | 13 | 13.1 | 450 | 13.1 | 3,250 | 832 | 79 | 27 |
| 5 | 40 | 12.9 | 800 | 4.5 | 67 | 323 | 14 | 11 |
| 6 | 37 | 25.9 | 1,125 | 0.4 | 621 | 302 | 64 | 16 |
| 7 | 40 | 3.5 | 675 | 18.3 | 253 | 486 | 22 | 5 |
| 8 | 27 | 2.3 | 375 | 6.7 | 566 | 528 | 5 | 6 |
| 9 | 26 | 12.3 | 775 | 3.5 | 272 | 244 | 15 | 11 |
| 10 | 37 | 9.6 | 1,200 | 3.5 | 151 | 562 | 44 | 15 |
| 11 | 33 | 11.0 | 690 | 2.7 | 67 | 234 | 5 | 5 |
| 12 | 23 | 14.7 | 1,100 | 3.9 | 266 | 278 | 13 | 5 |
| 13 | 37 | 16.3 | 1,125 | 8.0 | 355 | 660 | 21 | 43 |
| 14 | 24 | 1.5 | 500 | 2.6 | 135 | 488 | 19 | 11 |
| 15 | 38 | 18.6 | 1,125 | 1.2 | 116 | 460 | 36 | 23 |
| 16 | 31 | 12.8 | 900 | 0.3 | 419 | 390 | 11 | 5 |
| 17 | 13 | 17.9 | 1,200 | 8.1 | 2,270 | 620 | 14 | 13 |
| 18 | 20 | 1.6 | 1,010 | 24.4 | 168 | 396 | 10 | 10 |
| 19 | 15 | 5.3 | 890 | 11.2 | 198 | 157 | 5 | 21 |
| 20 | 35 | 7.0 | 450 | 0.9 | 213 | 693 | 62 | 21 |
| 21 | 38 | 14.0 | 800 | 22.9 | 3,272 | 354 | 24 | 13 |
| 22 | 35 | 16.9 | 1,000 | 2.7 | 68 | 183 | 17 | 5 |
| 23 | 28 | 7.0 | 725 | 1.5 | 226 | 539 | 5 | 13 |
| Mean | 30.17 | 12.70 | 896.30 | 6.80 | 607.00 | 429.39 | 24.91 | 13.70 |
| SD | 9.06 | 8.09 | 280.86 | 6.90 | 949.84 | 173.05 | 20.36 | 8.84 |
Normal range for supine values: norepinephrine=70–750 pg/mL, epinephrine=0–110 pg/mL and dopamine=0–30 pg/mL
EF ejection fraction, VO2 maximum oxygen consumption, 6mw 6-min walk distance, CRP C-reactive protein, BNP brain natriuretic peptide, NE plasma norepinephrine, EPI plasma epinephrine, DA plasma dopamine, SD standard deviation
All patients with heart failure had Cheyne–Stokes respiration during sleep. The baseline characteristics, blood pressure, and sleep parameters for all subjects are shown in Table 3. The mean Cheyne–Stokes respiration index was 43.2±19.3 events/hour (median of 45.4 events/hour) in the heart failure group. Their average sleep time in Cheyne–Stokes respiration was 3.49±1.6 h vs. 0.46±0.38 in the controls (median, 3.58 vs. 0.29). Patients with heart failure had a significantly lower mean SaO2 during sleep (94.5% vs. 97.8%) and lower SaO2 nadir (79.2% vs. 88.4%), as compared to healthy controls.
Table 3. Physiological and sleep related parameters in all subjects.
| Heart failure subjects Mean±SD (n=23) | Controls Mean±SD (n =11) | p value (two-tailed) | |
|---|---|---|---|
| Heart rate (bpm)* | 75.1±14.4 | 60.0±9.2 | 0.005 |
| Systolic BP (mmHg)* | 129.7±26.9 | 108.0±10.1 | 0.020 |
| Diastolic BP (mmHg)* | 69.3±11.7 | 59.8±4.3 | 0.019 |
| Total sleep time (min) | 314±88 | 361 ±46 | 0.106 |
| Arousal index (events/hour)* | 30.9±13.9 | 9.3±3.4 | <0.001 |
| CSR index (events/hour)* | 43.2±19.3 | 0.56±0.67 | <0.001 |
| CSR duration (h)* | 3.49±1.6 | 0.46±0.38 | <0.001 |
| Mean SaO2 sleep (%)* | 94.5±2.8 | 97.8±1.4 | 0.001 |
| Lowest SaO2 sleep (%)* | 79.2±9.9 | 88.4±6.3 | 0.008 |
| ODI (events/h)* | 25.7±21.0 | 0.4±0.4 | <0.001 |
| ROS (MFI/cell)* | 4,218±1,706 | 1,003±348 | <0.001 |
SD standard deviation, BP blood pressure, CSR Cheyne–Stokes respiration, SaO2 oxygen saturation, ODI oxygen desaturation index, ROS reactive oxygen species, MFI mean fluorescence index
p<0.05
The oxygen desaturation index during sleep was greater in patients with heart failure (25.7±21 events/hour vs. 0.4±0.4 for the controls, p<0.001). It strongly correlated with the hourly index of Cheyne–Stokes respiration cycles (r=0.84, p<0.001) and the duration of Cheyne–Stokes respiration during sleep (r=0.74, p<0.005) in all subjects, as well as within heart failure subjects (r=0.77, p<0.001 and r=0.69, p<0.001, respectively), as displayed in Fig. 1. Oxidative stress was greater in heart failure patients than in controls (4,218±1,706 vs. 1,003±348 mean fluorescence intensity/cell, p<0.001).
Fig. 1. Relationship between measures of Cheyne–Stokes respiration during sleep and oxygen desaturation during sleep in heart failure (n=23).
The mean value of reactive oxygen species formation was not statistically different after dichotomizing the heart failure group according to multiple characteristics, as follows: history of coronary artery disease, hypertension, dyslipidemia, renal insufficiency, or diabetes; the use of individual cardiac medications or statins except for angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker and beta blockers (as all heart failure subjects were taking these medications), the use of vitamins; NYHA class (≥3); and body mass index (BMI), analyzed by dividing the groups according to BMI categories using two different cutoffs (25 or 30 kg/m2). All subjects had a BMI<35 kg/m2. The vast majority of patients were sedentary, which prevented an accurate analysis of the exercise effect. None of these analyses demonstrated a significant difference in mean values of oxidative stress.
In a second analysis, when dividing heart failure subjects in two groups based on the severity of the Cheyne–Stokes respiration index in relation to the median (45.4 events/hour), there was a significant difference in the arousal index (p=0.001), mean SaO2 (p=0.007), lowest SaO2 during sleep (p<0.001), and oxygen desaturation index (p<0.001) between groups. The Cheyne–Stokes duration was longer, and the magnitude of oxidative stress was significantly elevated in the group with a higher Cheyne–Stokes respiration index during sleep (p<0.001 and p=0.028, respectively), as compared to the remaining heart failure subjects. No statistically significant differences in cardiac functional status or sympathetic activation levels were detected between groups, as shown in Table 4. The higher mean value of VO2 max seen in heart failure patients with lower indices of Cheyne–Stokes respiration may reflect a better functional state; however, this difference was not statistically significant.
Table 4. Physiological and respiratory related parameters in the heart failure subjects.
| CSR index <45 events/hour Mean±SD (n=11) | CSR index ≥45 events/hour Mean±SD (n=12) | p value (two-tailed) | |
|---|---|---|---|
| Age (years) | 66.5±11.3 | 65.9±9.2 | 0.901 |
| Body mass index (kg/m2) | 27.1 ±3.3 | 29.3±3.1 | 0.206 |
| Heart rate (bpm) | 74.1 ±14.6 | 76.0±14.8 | 0.759 |
| Systolic BP (mmHg) | 128.6±28.9 | 130.8±26.3 | 0.856 |
| Diastolic BP (mmHg) | 68.7±11.4 | 69.8±12.4 | 0.839 |
| Ejection fraction (%) | 31.0±8.9 | 29.4±9.6 | 0.686 |
| VO2 max (kg/m) | 15.4±10.6 | 10.7±6.2 | 0.216 |
| 6-min walk distance (ft) | 881 ±320 | 910±253 | 0.808 |
| CRP (mg/L) | 6.0±5.5 | 7.6±8.7 | 0.626 |
| BNP (pg/mL) | 558±966 | 676±1,064 | 0.793 |
| NE plasma (pg/mL) | 408±192 | 449±177 | 0.616 |
| Epi plasma (pg/mL) | 29.7±25.5 | 20.4±16.5 | 0.327 |
| DA plasma (pg/mL) | 10.6±7.7 | 16.1 ± 10.7 | 0.237 |
| Total sleep time (min) | 299±104 | 332±73 | 0.322 |
| Arousal index (events/hour)* | 22.1±7.2 | 39±12.9 | 0.001 |
| CSR duration (hours)* | 2.14±0.6 | 4.74±1.02 | <0.001 |
| Mean SaO2 sleep (%)* | 96.1 ±1.6 | 93.1 ±2.9 | 0.007 |
| Lowest SaO2 sleep (%)* | 86.5±5.3 | 72.5±8.2 | <0.001 |
| ODI (events/hour)* | 9.2±10.4 | 42.3±14.6 | <0.001 |
| ROS (MFI/cell)* | 3,421 ±1,944 | 4,949±1,083 | 0.028 |
CSR Cheyne–Stokes respiration, SD standard deviation, BP blood pressure, VO2 max maximum oxygen consumption, CRP C-reactive protein, BNP brain natriuretic peptide, NE norepinephrine, Epi epinephrine, DA dopamine, SaO2 oxygen saturation, ODI oxygen desaturation index, ROS reactive oxygen species, MFI mean fluorescence intensity
p<0.05
Severity of Cheyne–Stokes respiration, as measured by the Cheyne–Stokes respiration index and duration Cheyne–Stokes respiration during sleep, correlated with mean fluorescence intensity of carboxydichloroflourescein in neutrophils of patients with heart failure (r=0.38, p=0.06 and r=0.44, p=0.034, respectively), as demonstrated in Fig. 2. Multivariate linear regression analyses showed that the total duration of Cheyne–Stokes respiration during sleep was the best independent predictor of oxidative stress in the heart failure group [beta=652 mean fluorescence intensity/cell per hour of Cheyne–Stokes respiration duration (95%CI 312, 992), p<0.001]. This relationship was maintained after adjusting for age and BMI, signifying that for each additional hour of Cheyne–Stokes Respiration, the expected increase in reactive oxygen species formation would fall within the confidence interval in 95% of the cases.
Fig. 2. Relationship between measures of Cheyne–Stokes respiration during sleep and the intensity of reactive oxygen species formation in neutrophils in subjects with heart failure (n=23).
The oxygen saturation nadir during sleep correlated inversely with the magnitude of reactive oxygen species formation in patients with heart failure (p=0.039) using univariate analysis (Fig. 3). However, this relationship was not maintained after multivariate analyses. No other variable, including measurements of cardiac function, was a significant predictor of oxidative stress in patients with heart failure.
Fig. 3. Relationship between oxygen saturation nadir during sleep and oxidative stress in heart failure subjects (n=23).
Dopamine levels correlated with the overnight oxygen desaturation index (r=0.48, p=0.03) and arousal index from sleep (r=0.51, p=0.03, data not shown). Neither serum catecholamines nor functional measures of heart failure, such as ejection fraction, VO2 max, total distance in a 6-min walk test, BNP, or CRP levels were significantly correlated with either measures of Cheyne–Stokes respiration or oxidative stress in patients with heart failure.
After a mean follow-up of 4.3 years, 11 of 23 (48%) of the heart failure subjects had died. The mortality rate during this period was greater in the patients with Cheyne–Stokes indices ≥45 when compared to heart failure patients with indices <45 events/hour (58.3% vs.33.3%). When comparing the mean values of physiological and sleep-related parameters according to survival in heart failure, the arousal index was higher, and the nadir SaO2 was lower in the deceased group. There was a trend toward higher oxygen desaturation index and increased oxidative stress in this group (p=0.09). This is demonstrated in Table 5. One patient underwent successful heart transplant and was excluded from this analysis.
Table 5. Physiological and respiratory-related parameters in the heart failure subjects according to survival.
| Alive N=11 | Deceased N=11 | p value | |
|---|---|---|---|
| Age (years) | 65.5±10.8 | 66.9±10.3 | 0.749 |
| Body mass index (kg/m2) | 26.5±3.7 | 28.7±3.1 | 0.149 |
| Heart rate (bpm) | 78.2±10.5 | 74.7±15.7 | 0.551 |
| Systolic BP (mmHg) | 129.7±27.9 | 132.3±27.0 | 0.830 |
| Diastolic BP (mmHg) | 67.3±10.8 | 72.1±12.7 | 0.349 |
| Ejection fraction (%) | 32.7±7.5 | 26.7±9.7 | 0.121 |
| VO2 max (kg/m) | 13.4±10.5 | 12.0±5.7 | 0.698 |
| 6-min walk distance (ft) | 952.3±272.6 | 849.1±304.0 | 0.412 |
| CRP (mg/L) | 8.6±8.8 | 5.2±4.4 | 0.277 |
| BNP (pg/mL) | 540.6±924.2 | 722.5±1,040.2 | 0.669 |
| NE serum (pg/mL) | 383.0±109.9 | 485.5±216.5 | 0.177 |
| Epi serum (pg/mL) | 26.5±16.8 | 24.4±24.8 | 0.819 |
| DA serum (pg/mL) | 11.1 ±3.5 | 16.5± 11.9 | 0.162 |
| Total sleep time (min) | 322.8±92.3 | 308.5±91.5 | 0.718 |
| Arousal index (events/hour)* | 25.2±8.6 | 36.9±16.0 | 0.046 |
| CSR duration (hours) | 3.1±1.3 | 4.1 ± 1.7 | 0.141 |
| CSR index (cycles/h) | 39.0±21.9 | 48.6±16.3 | 0.253 |
| Mean SaO2 sleep (%) | 94.9±2.4 | 94.1±3.3 | 0.578 |
| SaO2 nadir (%)a | 83.0±7.5 | 74.6±10.6 | 0.045 |
| ODI (events/hour) | 18.7±18.9 | 34.2±20.7 | 0.090 |
| Oxidative stress (MFI/cell) | 3,601.0±1,871.4 | 4,853.0±1,427.1 | 0.093 |
BP blood pressure, VO2 max maximum oxygen consumption, CRP C-reactive protein, BNP brain natriuretic peptide, NE norepinephrine, Epi epinephrine, DA dopamine, SaO2 oxygen saturation, ODI oxygen desaturation index, ROS reactive oxygen species, MFI mean fluorescence intensity
p<0.05
Discussion
The present data indicate that the duration of Cheyne–Stokes respiration during sleep is an independent predictor of oxidative stress in patients with heart failure. Furthermore, our data confirm that Cheyne–Stokes respiration during sleep is highly prevalent among heart failure patients with decreased left ventricular systolic function who are receiving standard medical therapy [19].
Periodic breathing in heart failure patients is associated with increased mortality regardless of cardiac function [20, 21]. However, the mechanism linking Cheyne–Stokes respiration to mortality in heart failure remains unknown. Oxidative stress is a marker of disease severity and a valuable predictor of mortality in heart failure [22–26]. Our data suggest that increased cellular oxidative stress is a potential link between Cheyne–Stokes respiration and increased mortality.
Traditionally, Cheyne–Stokes respiration has been quantified using an hourly index, having a cutoff for determining presence or absence of disease in heart failure, without establishing levels of disease severity. Given that Cheyne–Stokes is not an all or none phenomena in heart failure, we measured both the hourly index and the total duration of Cheyne–Stokes respiration during the overnight polysomnography, and observed a strong relationship between Cheyne–Stokes respiration and SaO2 nadir during sleep and increased cellular oxidative stress, independently of echocardiographic indices of heart function and functional status. Our findings suggest that the severity of Cheyne–Stokes respiration is a critical factor associated with the development of oxidative stress, and the duration of Cheyne–Stokes respiration during sleep may be an additional and useful indicator of disease severity in heart failure, being closely correlated with levels of oxidative stress.
The repetitive hypoxia/reoxygenation associated with Cheyne–Stokes breathing in heart failure likely contributes to endothelial and other tissue injury owing to decreased oxygen availability. Under physiological conditions, reactive oxygen species are generated as by-products of oxygen metabolism. When exposed to intermittent hypoxemia, cellular and mitochondrial control of the oxidative pathways is disturbed. Intermittent hypoxia resembles ischemia–reperfusion injury, leading to generation of reactive oxygen species during the reoxygenation period [27]. La Rocca et al. [28] recently demonstrated that the endothelium plays a critical role in the generation of oxidative stress. Endothelial dysfunction may then be further exacerbated by the presence of reactive oxygen species, which could lead to deterioration of cardiac function [29, 30]. Therefore, Cheyne–Stokes respiration during sleep may promote oxidative stress and progressive deterioration of clinical status in patients with heart failure.
Nadir and mean levels of oxygen saturation during sleep, while closely correlated with oxidative stress levels, were not independent predictors of intracellular reactive oxygen species formation in patients with heart failure. This finding highlights the need for using more accurate measures of oxygen availability to the tissue given the intermittent nature of the hypoxia in Cheyne–Stokes respiration [31, 32]. Intermittent hypoxemia has been linked to diurnal increases in blood pressure [33, 34]. The cyclic nature of Cheyne–Stokes respiration may also invoke other mechanisms, such as increased sympathetic activation and sleep fragmentation, which could increase cellular oxidative stress. While elevated sympathetic activation is an established risk factor for mortality in heart failure [35], our study did not find an association between the magnitude of oxidative stress and plasma levels of catecholamines, or measures of sleep fragmentation in patients with heart failure. Nonetheless, a higher arousal index, indicating fragmented sleep, was seen among the deceased patients with heart failure. Plasma dopamine levels were significantly associated with sleep fragmentation and oxygen desaturation index during sleep. It is important to note that more specific and refined methods for measuring sympathetic activation were not used in this study, bringing forth an important limitation of this negative finding in our sample. Additional limitations of our study include the small sample size, the fact that only men participated in this study, and differences in age between groups, determining our use of adjusted regression models in the analyses concerning heart failure and healthy controls. The prevalence of Cheyne–Stokes respiration in our sample may have been affected by a selection bias. Additionally, the results are only applicable to sleep-related conditions, as Cheyne–Stokes respiration during wakefulness was not assessed by this study.
Several methods have been developed for the measurement of oxidative stress and reactive oxygen species. When comparing results, careful attention should be given to the methodology used as data may not be readily comparable unless strict methodological standardization was applied. The detection of reactive oxygen species using hydrogen peroxide formation in neutrophils used in this study has been shown to correlate with other measurements of oxidative stress [36].
More recently developed techniques to control the respiratory oscillation associated with Cheyne–Stokes respiration, such as adaptive servo ventilation, may have a role in modulating oxidative stress in heart failure, possibly reducing cell damage and impacting mortality by overcoming the respiratory abnormalities during sleep [37, 38]. The potential effects of alternative treatments proposed for Cheyne–Stokes respiration, including cardiac resynchronization, increased carbon dioxide concentration in the inhaled air, use of supplemental oxygen, and positional changes, also deserve further investigation [39–48]. It remains to be seen if the use of antioxidants could counteract some of the effects seen in this study.
During clinical assessment of heart failure patients with Cheyne–Stokes respiration, special consideration should be given to using the currently available techniques for overcoming this respiratory abnormality while awaiting more clinical and research data on outcome.
In conclusion, the present data implicate the generation of cellular oxidative stress as a potential link to cell injury in heart failure patients with Cheyne–Stokes respiration. This pathway could lead to progression of myocardial failure and increased mortality. Further studies are needed to ascertain whether treatment of Cheyne–Stokes respiration would lead to decreased oxidative stress and improved patient outcome [25, 49].
Acknowledgments
We would like to thank Ming Chen and Vanessa Coradin at the NYU Sleep Disorder Center for assistance in the performance and scoring of the sleep studies, Daniel Meyer and Michael Gregory at the Flow Cytometry Core for their contribution in performing the flow cytometry analyses, and Dr. Robert Kaner for his valuable comments in reviewing the manuscript.
Grant support: American Heart Association National Center, Scientist Development Award and National Institutes of Health.
Footnotes
Conflict of interest: None of the authors has a conflict of interest to disclose.
Contributor Information
Ana C. Krieger, Weill Cornell Medical College of Cornell University, 425 East 61th Street – 5th floor, New York, NY 10065, USA
Daniel Green, North Shore University Hospital, Manhasset, NY, USA.
Muriel T. Cruz, VA New York Harbor Health Care System, New York, NY, USA
Frank Modersitzki, New York University School of Medicine, New York, NY, USA.
Gita Yitta, University of Pennsylvania School of Dental Medicine, Philadelphia, PA, USA.
Sanja Jelic, Columbia University College of Physicians and Surgeons, New York, NY, USA.
Doris S. Tse, New York University School of Medicine, New York, NY, USA
Steven P. Sedlis, VA New York Harbor Health Care System, New York, NY, USA; New York University School of Medicine, New York, NY, USA
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