Bioprofiles and mechanistic pathways associated with Cheyne-Stokes respiration: insights from the SERVE-HF trial.

INTRODUCTION: The SERVE-HF trial included patients with heart failure and reduced ejection fraction (HFrEF) with sleep-disordered breathing, randomly assigned to treatment with Adaptive-Servo Ventilation (ASV) or control. The primary outcome was the first event of death from any cause, lifesaving cardiovascular intervention, or unplanned hospitalization for worsening heart failure. A subgroup analysis of the SERVE-HF trial suggested that patients with Cheyne-Stokes respiration (CSR) < 20% (low CSR) experienced a beneficial effect from ASV, whereas in patients with CSR ≥ 20% ASV might have been harmful. Identifying the proteomic signatures and the underlying mechanistic pathways expressed in patients with CSR could help generating hypothesis for future research. METHODS: Using a large set of circulating protein-biomarkers (n = 276, available in 749 patients; 57% of the SERVE-HF population) we sought to investigate the proteins associated with CSR and to study the underlying mechanisms that these circulating proteins might represent. RESULTS: The mean age was 69 ± 10 years and > 90% were male. Patients with CSR < 20% (n = 139) had less apnoea-hypopnea index (AHI) events per hour and less oxygen desaturation. Patients with CSR < 20% might have experienced a beneficial effect of ASV treatment (primary outcome HR [95% CI] = 0.55 [0.34-0.88]; p = 0.012), whereas those with CSR ≥ 20% might have experienced a detrimental effect of ASV treatment (primary outcome HR [95% CI] = 1.39 [1.09-1.76]; p = 0.008); p for interaction = 0.001. Of the 276 studied biomarkers, 8 were associated with CSR (after adjustment and with a FDR1%-corrected p value). For example, higher PAR-1 and ITGB2 levels were associated with higher odds of having CSR < 20%, whereas higher LOX-1 levels were associated with higher odds of CSR ≥ 20%. Signalling, metabolic, haemostatic and immunologic pathways underlie the expression of these biomarkers. CONCLUSION: We identified proteomic signatures that may represent underlying mechanistic pathways associated with patterns of CSR in HFrEF. These hypothesis-generating findings require further investigation towards better understanding of CSR in HFrEF. SUMMARY OF THE FINDINGS: PAR-1 proteinase-activated receptor 1, ADM adrenomedullin, HSP-27 heat shock protein-27, ITGB2 integrin beta 2, GLO1 glyoxalase 1, ENRAGE/S100A12 S100 calcium-binding protein A12, LOX-1 lectin-like LDL receptor 1, ADAM-TS13 disintegrin and metalloproteinase with a thrombospondin type 1 motif, member13 also known as von Willebrand factor-cleaving protease.

Arterial oxygen saturation during Cheyne-Stokes respiration in heart failure patients: does measurement site matter?

OBJECTIVE: Despite the fact that the ear is the site to monitor arterial oxygen saturation by pulse oximetry (SpO2) closest to carotid chemoreceptors, sleep studies almost invariably use finger probes. This study aimed to assess the timing and morphological differences between SpO2 signals at the ear and finger during Cheyne-Stokes respiration (CSR) in heart failure (HF) patients. METHODS: We studied 21 HF patients with CSR during a 40-min in-laboratory resting recording. SpO2 was recorded by: (1) two identical bedside pulse-oximeters with an ear (SpO2_Ear) and a finger probe (SpO2_Finger), and (2) a standard polysomnograph with a finger probe (SpO2_PSG). We estimated the delays between signals and, for each signal, computed the mean and minimum SpO2, the magnitude of cyclic desaturations and the overall time spent with SpO2<90% (T90%). RESULTS: The SpO2_Finger signal was significantly delayed [bias: 12.7 s (95% limits of agreement: 2.2, 23.0 s)] and slightly but not significantly downward-shifted with respect to SpO2_Ear. SpO2_PSG was almost synchronous with SpO2_Finger; however, a further significant downward shift was observed relative to the latter. In particular, minimum SpO2_PSG was significantly lower [-2.1% (- 4.8, 0.6%)], and desaturations and T90% were significantly higher than SpO2_Finger [1.2% (-1.3, 3.7%), and 13.9% (-12.3, 40.0%), respectively]. CONCLUSION: During CSR in HF patients, the marked delay between SpO2_Ear and SpO2_Finger makes the interpretation of the timing relationship between peripheral chemoreceptor stimulation and ventilatory events rather difficult. The observed discrepancies between SpO2_PSG and SpO2_Finger, which may be due to differences in the processing of raw SpO2 signals, call for a standardization of processing algorithms.

Effect of oxygen versus adaptive pressure support servo-ventilation in patients with central sleep apnoea-Cheyne Stokes respiration and congestive heart failure.

BACKGROUND AND AIMS: Central sleep apnoea with Cheyne-Stokes respiration (CSA-CSR) is a common, serious consequence of congestive heart failure. Optimal treatment is yet to be established. We compared two common treatments for CSA-CSR. METHODS: Subjects with CSA-CSR and stable congestive heart failure were randomised to 8 weeks treatment: oxygen 2 L/min through nasal prongs and concentrator or 8 weeks adaptive servo-ventilation (ASV) using a crossover design separated by a 3-week washout. Polysomnography, indices of sleep and breathing, shuttle walk distance, symptoms, urinary catecholamines, plasma brain natriuretic peptide (NT-BNP) and echocardiography were collected at baseline and completion of each arm. RESULTS: Ten subjects (age 64 ± 10 years, left ventricular ejection fraction (LVEF) 28 ± 10.5%, apnoea-hypopnoea index (AHI) 63 ± 30/h) were recruited. Seven completed the protocol (one died, one refused ASV, one was withdrawn after hospital admission). On therapy, an AHI of < 10/h was achieved in two out of seven using oxygen (29%), six of seven using ASV (86%) and six of seven with either (86%). Compliance with ASV: 5.2 ± 2 h/night (range 1.45-7.1 h/night). Median AHI on oxygen therapy: 13.4 /h (range 2.6-42.9/h), ASV, 1.4 /h (range 0.6-17.8/h, P = 0.03). LVEF was not changed by either therapy (oxygen 30.9% vs 30.9% P = 0.97, ASV 32.5% vs 35.0% P = 0.24). NT-BNP, urinary catecholamines, shuttle walk distance and symptoms were not significantly changed by either therapy. CONCLUSION: CSA-CSR is reduced to a greater extent by ASV than oxygen therapy over 8 weeks but was not accepted long term. Neither treatment improved prognostic indices of heart failure or symptoms in the short term.

Hypocapnia increases the prevalence of hypoxia-induced augmented breaths.

Augmented breaths promote respiratory instability and have been implicated in triggering periods of sleep-disordered breathing. Since respiratory instability is well known to be exacerbated by hypocapnia, we asked whether one of the destabilizing effects of hypocapnia might be related to an increased prevalence of augmented breaths. With this question in mind, we first sought to determine whether hypoxia-induced augmented breaths are more prevalent when hypocapnia is also present. To do this, we studied the breath-by-breath ventilatory responses of a group of freely behaving adult rats in a variety of different respiratory background conditions. We found that the prevalence of augmented breaths was dramatically increased during hypocapnic-hypoxia compared with room air conditions. When hypocapnia was prevented during exposure to hypoxia by adding 5% CO2 to the inspired air, the rate of occurrence of augmented breaths was no greater than that observed in room air. The addition of CO2 alone to room air had no effect on the prevalence of augmented breaths. We conclude that in spontaneously breathing rats, hypoxia promotes the generation of augmented breaths, but only in poikilocapnic conditions, where hypocapnia develops. Our results, therefore, reveal a means by which CO2 exerts a stabilizing influence on breathing, which may be of particular relevance during sleep in conditions commonly associated with respiratory instability.

Models of Cheyne-Stokes respiration with cardiovascular pathologies.

Cheyne-Stokes respiration (CSR) is a periodic breathing pattern, characterized by short intervals of very little or no breathing (apnea), each followed by an interval of very heavy breathing (hyperpnea). This work presents a new compartmental model of the human cardio-respiratory system, simulating the factors that determine the concentrations of carbon dioxide in the compartments of the cardiovascular system and the lungs. The parameter set on which a Hopf bifurcation gives birth to stable CSR oscillations has been determined. The model predicts that the onset of CSR oscillations may result from an increase in any of: ventilation-perfusion ratio, feedback control gain, transport delay, left heart volume, lung congestion, or cardiovascular efficiency. The model is employed to investigate the relationship between CSR and serious cardiovascular pathologies, such as congestive heart failure and encephalitis, as well as the effects of acclimatization to higher altitudes. In all cases, the model is consistent with medical observations.

Impaired pulmonary diffusing capacity and hypoxia in heart failure correlates with central sleep apnea severity.

BACKGROUND: Heart failure (HF) is often associated with interstitial pulmonary edema and structural changes, resulting in thickening of the alveolar-capillary membrane and reductions in diffusing capacity of the lung for carbon monoxide (Dlco). Reduced Dlco reflects an impaired efficiency of gas exchange, which may increase plant gain, influence ventilatory control stability, and result in central sleep apnea (CSA). In this study, we test the hypothesis that reductions in Dlco would be associated with increased apnea-hypopnea index (AHI) in patients with CSA. METHODS: Overnight polysomnography, pulmonary function tests, and arterial blood gas analyses were performed in 45 patients with chronic, stable HF. Univariate and multivariate regression analyses were performed in those patients with predominant CSA to test which variables were associated with AHI. RESULTS: Patients had a mean (+/-SD) age of 52.7+/-8.9 years, a mean left ventricular ejection fraction of 26.5+/-9.9%, and a mean AHI of 22.0+/-17.4 events per hour. In CSA patients, Dlco and Pao2 both correlated with total AHI (r=-0.43, p=0.046 and r=-0.53, p=0.011, respectively) and with supine AHI (r=-0.56, p=0.009 and r=-0.60, p=0.004, respectively). In a forward stepwise estimation model, Dlco, Pao2, and body mass index were independent predictors of total AHI, explaining 51% of variability, as was supine AHI, explaining 64% of variability. Dlco and Pao2 accounted for 37% of the variability in total AHI and 49% of the variability in supine AHI. CONCLUSIONS: In patients with HF and CSA, reductions in Dlco and Pao2 are independently associated with respiratory disturbance during sleep. The increase in ventilatory instability may be due to plant gain effects.

Effect of inspired oxygen on periodic breathing in methy-CpG-binding protein 2 (Mecp2) deficient mice.

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the X-linked gene methyl-CpG-binding protein 2 (Mecp2) that encodes a DNA binding protein involved in gene silencing. Periodic breathing (Cheyne-Stokes respiration) is commonly seen in RTT. Freely moving mice were studied with continuous recording of pleural pressure by telemetry. Episodes of periodic breathing in heterozygous Mecp2 deficient (Mecp2(+/-)) female mice (9.4 +/- 2.2 h(-1)) exceeded those in wild-type (Mecp2(+/+)) animals (2.5 +/- 0.4 h(-1)) (P = 0.010). Exposing Mecp2(+/-) animals to 40% oxygen increased the amount of periodic breathing from 118 +/- 25 s/30 min in air to 242 +/- 57 s/30 min (P = 0.001), and 12% oxygen tended to decrease it (67 +/- 29 s/30 min, P = 0.14). Relative hyperoxia and hypoxia did not affect the incidence of periodic breathing in Mecp2(+/+) animals. The ventilation/apnea ratio (V/A) was less at all levels of oxygen in heterozygous Mecp2(+/-) females compare with wild type (P = 0.003 to P < 0.001), indicating that their loop gain is larger. V/A in Mecp2(+/-) fell from 2.42 +/- 0.18 in normoxia to 1.82 +/- 0.17 in hyperoxia (P = 0.05) indicating an increase in loop gain with increased oxygen. Hyperoxia did not affect V/A in Mecp2(+/+) mice (3.73 +/- 0.28 vs. 3.5 +/- 0.28). These results show that periodic breathing in this mouse model of RTT is not dependent on enhanced peripheral chemoreceptor oxygen sensitivity. Rather, the breathing instability is of central origin.

Effects of nasal continuous positive airway pressure on oxygen body stores in patients with Cheyne-Stokes respiration and congestive heart failure.

STUDY OBJECTIVES: The mechanism(s) by which nasal continuous positive airway pressure (CPAP) is effective in the treatment of Cheyne-Stokes respiration (CSR) in patients with congestive heart failure (CHF) remains uncertain, and may involve an increase in total oxygen body stores (dampening), changes in central and peripheral controller gain, and/or improvement in cardiac function. The purpose of this study was to evaluate the effects of nasal CPAP on total oxygen stores, as measured by the rate of fall of arterial oxyhemoglobin saturation (dSaO(2)/dt), to determine if dampening may play a role in the attenuation of CSR in patients with CHF. DESIGN: Prospective controlled trial. SETTING: University hospital. PATIENTS: Nine male patients (mean +/- SD age, 59 +/- 8 years) with CHF and a mean left ventricular ejection fraction (LVEF) of 16 +/- 4%. INTERVENTIONS AND MEASUREMENTS: All patients had known CSR, as identified on a baseline polysomnographic study. Patients then underwent repeat polysomnography while receiving nasal CPAP (9 +/- 0.3 cm H(2)O). The polysomnography consisted of recording of breathing pattern, pulse oximetry, and EEG. dSaO(2)/dt was measured as the slope of a line drawn adjacent to the falling linear portion of the arterial oxygen saturation (SaO(2)) curve associated with a central apnea. All patients underwent echocardiography and right-heart catheterization within 1 month of the study to measure LVEF and cardiac hemodynamics, respectively. RESULTS: There was a significant decrease in the apnea-hypopnea index (AHI) with nasal CPAP, from 44 +/- 27 events per hour at baseline to 15 +/- 24 events per hour with nasal CPAP (p = 0.004). When compared to baseline, dSaO(2)/dt significantly decreased with nasal CPAP from 0.42 +/- 0.15% to 0.20 +/- 0.07%/s (p < 0.001). The postapneic SaO(2), when compared to baseline, significantly increased with nasal CPAP, from 87 +/- 5% to 91 +/- 4% (p < 0.05). The preapneic SaO(2) did not significantly change, from a baseline of 96 +/- 2% to 96 +/- 3% with nasal CPAP (p = 0.8). When compared to baseline, the apnea duration and heart rate did not change with nasal CPAP. While there was a significant correlation noted between baseline postapneic SaO(2) and dSaO(2)/dt (r = 0.8, p = 0.02), no correlation was seen between baseline preapneic SaO(2) and dSaO(2)/dt (r = 0.1, p = 0.7). A significant correlation was noted between baseline dSaO(2)/dt and the AHI (r = 0.7, p = 0.02). With CPAP, there was a significant correlation noted between dSaO(2)/dt and the AHI (R = 0.7, p = 0.04), but no correlation was noted between dSaO(2)/dt and postapneic SaO(2) (R = 0.1, p = 0.8). CONCLUSION: Nasal CPAP significantly decreases dSaO(2)/dt and thus increases total body oxygen stores in patients with CSR and CHF. By increasing oxygen body stores, dampening may be one of the mechanisms responsible for the attenuation of CSR seen with nasal CPAP.

Adaptive pressure support servo-ventilation: a novel treatment for Cheyne-Stokes respiration in heart failure.

Adaptive servo-ventilation (ASV) is a novel method of ventilatory support designed for Cheyne-Stokes respiration (CSR) in heart failure. The aim of our study was to compare the effect of one night of ASV on sleep and breathing with the effect of other treatments. Fourteen subjects with stable cardiac failure and receiving optimal medical treatment were tested untreated and on four treatment nights in random order: nasal oxygen (2 L/min), continuous positive airway pressure (CPAP) (mean 9.25 cm H(2)O), bilevel (mean 13.5/5.2 cm H(2)O), or ASV largely at the default settings (mean pressure 7 to 9 cm H(2)O) during polysomnography. Thermistor apnea + hypopnea index (AHI) declined from 44.5 +/- 3.4/h (SEM) untreated to 28.2 +/- 3.4/h oxygen and 26.8 +/- 4.6/h CPAP (both p < 0.001 versus control), 14.8 +/- 2.3/h bilevel, and 6.3 +/- 0.9/h ASV (p < 0.001 versus bilevel). Effort band AHI behaved similarly. Arousal index decreased from 65.1 +/- 3.9/h untreated to 29.8 +/- 2.8/h oxygen and 29.9 +/- 3.2/h CPAP, to 16.0 +/- 1.3/h bilevel and 14.7 +/- 1.8/h ASV (p < 0.01 versus all except bilevel). There were large increases in slow-wave and rapid eye movement (REM) sleep with ASV but not with oxygen or CPAP. All subjects preferred ASV to CPAP. One night ASV suppresses central sleep apnea and/or CSR (CSA/CSR) in heart failure and improves sleep quality better than CPAP or 2 L/min oxygen.

Effects of nasal CPAP on sympathetic activity in patients with heart failure and central sleep apnea.

We hypothesized that (1) patients with congestive heart failure (CHF) and Cheyne-Stokes respiration with central sleep apnea (CSR-CSA) would have greater nocturnal urinary and daytime plasma norepinephrine concentrations (UNE and PNE, respectively) than those without CSR-CSA because of apneas, hypoxia and arousals from sleep and (2) attenuation of CSR-CSA by nasal continuous positive airway pressure (NCPAP) would reduce UNE and PNE concentrations. Eighteen patients with and 17 without CSR-CSA (Non-CSR-CSA group) were studied. Left ventricular ejection fraction was similar in the two groups, but overnight UNE and awake PNE concentrations were greater in the CSR-CSA group (30.2 +/- 2.5 nmol/mmol creatinine and 3.32 +/- 0.29 nmol/L) than in the Non-CSR-CSA group (15.8 +/- 2.1 nmol/mmol creatinine, p < 0.005, and 2.06 +/- 0.56 nmol/L, p < 0.05, respectively). Patients with CSR-CSA were randomized to a control group or to nightly NCPAP for 1 mo. CSR-CSA was attenuated in the NCPAP but not in the control group. The NCPAP group experienced greater reductions in UNE and PNE concentrations (-12.5 +/- 3.3 nmol/mmol creatinine and -0.74 +/- 0.40 nmol/L) than did the control group (-1.3 +/- 2.8 nmol/mmol creatinine, p < 0.025 and 1.16 +/- 0.66 nmol/L, p < 0.025, respectively). In conclusion, in patients with CHF, CSR-CSA is associated with elevated sympathoneural activity, which can be reduced by NCPAP.