Daytime cardiac repolarization in patients with obstructive sleep apnea.

PURPOSE: Obstructive sleep apnea (OSA) has been implicated in complications of cardiovascular disease, including arrhythmias and sudden cardiac death (SCD). Prolonged QT interval is associated with arrhythmias and SCD in patients with cardiovascular disease and apparently healthy humans. Apneic episodes during sleep in OSA patients are associated with QT prolongation due to increased vagal activity, but it is not understood whether chronic QT prolongation persists during normoxic daytime wakefulness. METHODS: To determine whether daytime QT intervals in OSA patients are prolonged compared to control subjects, we recruited 97 (76 male, 21 female) newly diagnosed patients with OSA [apnea-hypopnea index (AHI) ≥5 events/h] and 168 (100 male, 68 female) healthy volunteers (AHI <5 events/h) and measured daytime resting QT and RR intervals from the electrocardiograms to determine QT prolongation corrected for heart rate (QTc). RESULTS: All subjects with OSA were older and heavier, with increased heart rate, significantly increased AHI and arousal index, and reduced oxygen saturation (SpO2) during sleep, and spent less time in sleep with >90 % SpO2 compared to respective controls. QTc in patients with OSA (410 ± 3.3 for male and 433 ± 5.6 for female) was significantly increased compared to respective control groups (399 ± 2.9 for male and 417 ± 2.9 for female), after adjustment for age and body mass index. CONCLUSIONS: Our data show that OSA in either men or women is associated with a significant increase in resting daytime QTc. The propensity for ventricular arrhythmias in patients with OSA may be a result of abnormalities in resting cardiac repolarization.

Standardization criteria for an ischemic surgical model of acute hepatic failure in pigs.

The establishment of a reliable large animal model of acute hepatic failure (AHF) is critical for the evaluation of supportive therapies such as bioartificial liver support systems (BALSS). Large animal surgical models bear some resemblance to the clinical syndrome of AHF in humans. However, these are inherently complex and are predisposed to inter-individual variation. The development of considerable skill is required and no precise standardization criteria for such models have been defined as yet. This study investigates a surgically induced ischemic model of AHF in 15 female Landrace pigs. A large set of systemic and biochemical variables were measured. The absolute values of systemic variables during the surgery and the rates of change of the biochemical variables following the surgery were correlated with the duration of survival of each animal. A multivariate prognosis was revealed, with several variables simultaneously determining survival. Those of importance in the surgical period included the duration of portal occlusion, the pulse rate during this time, the total blood lost, the mean arterial pressure and the body temperature after the procedure. In the post-surgical period the rates of change of blood ammonia, branch chain amino acids, haemoglobin, hematocrit, body temperature, total urinary excretion and mean blood pH all demonstrated some importance to survival. Based on the above and clinical experience, standardization criteria specific for this model were defined. Additional variables that posses value in AHF but demonstrate lower correlations with survival were also included, e.g. the prothrombin time, clotting factors, liver enzymes, potassium, bilirubin, creatinine and lactate. Valuable procedural information was generated, which stabilized the model, limited unnecessary blood sampling and cut laboratory costs. The criteria allow the early exclusion of compromized animals and the identification of those demonstrating characteristics predictive of longer survival prior to BALSS connection. This is likely to allow more accurate comparisons between small treatment and control groups. In effect, the above are the converse of the King's college criteria (for humans) as they are designed to exclude animals with prognoses that are insufficiently bleak or due to factors other than AHF. The statistical analysis employed also identified the variables that in future may allow the evaluation of prognosis in real-time.

Leptin deficiency promotes central sleep apnea in patients with heart failure.

BACKGROUND: Leptin-deficient animals hyperventilate. Leptin expression by adipocytes is attenuated by atrial natriuretic peptide (ANP). Increased circulating natriuretic peptides (NPs) are associated with an increased risk of central sleep apnea (CSA). This study tested whether serum leptin concentration is inversely correlated to NP concentration and decreased in patients with heart failure (HF) and CSA. METHODS: Subjects with HF (N = 29) were studied by measuring leptin, NPs, CO2 chemosensitivity (Δminute ventilation [V.e]/Δpartial pressure of end-tidal CO2 [Petco2]), and ventilatory efficiency (V.e/CO2 output [V.co2]) and were classified as CSA or no sleep-disordered breathing by polysomnography. CSA was defined as a central apnea-hypopnea index ≥ 15. The Student t test, Mann-Whitney U test, and logistic regression were used for analysis, and data were summarized as mean ± SD; P < .05 was considered significant. RESULTS: Subjects with CSA had higher ANP and brain natriuretic peptide (BNP) concentrations (P < .05), ΔV.e/ΔPetco2 (2.39 ± 1.03 L/min/mm Hg vs 1.54 ± 0.35 L/min/mm Hg, P = .01), and V.e/V.co2 (43 ± 9 vs 34 ± 7, P < .01) and lower leptin concentrations (8 ± 10.7 ng/mL vs 17.1 ± 8.8 ng/mL, P < .01). Logistic regression analysis (adjusted for age, sex, and BMI) demonstrated leptin (OR = 0.07; 95% CI, 0.01-0.71; P = .04) and BNP (OR = 4.45; 95% CI, 1.1-17.9; P = .05) to be independently associated with CSA. CONCLUSIONS: In patients with HF and CSA, leptin concentration is low and is inversely related to NP concentration. Counterregulatory interactions of leptin and NP may be important in ventilatory control in HF.

Effects of experimental sleep restriction on caloric intake and activity energy expenditure.

BACKGROUND: Epidemiologic studies link short sleep duration to obesity and weight gain. Insufficient sleep appears to alter circulating levels of the hormones leptin and ghrelin, which may promote appetite, although the effects of sleep restriction on caloric intake and energy expenditure are unclear. We sought to determine the effect of 8 days/8 nights of sleep restriction on caloric intake, activity energy expenditure, and circulating levels of leptin and ghrelin. METHODS: We conducted a randomized study of usual sleep vs a sleep restriction of two-thirds of normal sleep time for 8 days/8 nights in a hospital-based clinical research unit. The main outcomes were caloric intake, activity energy expenditure, and circulating levels of leptin and ghrelin. RESULTS: Caloric intake in the sleep-restricted group increased by +559 kcal/d (SD, 706 kcal/d, P=.006) and decreased in the control group by -118 kcal/d (SD, 386 kcal/d, P=.51) for a net change of +677 kcal/d (95% CI, 148-1,206 kcal/d; P=.014). Sleep restriction was not associated with changes in activity energy expenditure (P=.62). No change was seen in levels of leptin (P=.27) or ghrelin (P=.21). CONCLUSIONS: Sleep restriction was associated with an increase in caloric consumption with no change in activity energy expenditure or leptin and ghrelin concentrations. Increased caloric intake without any accompanying increase in energy expenditure may contribute to obesity in people who are exposed to long-term sleep restriction. TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT01334788; URL: www.clinicaltrials.gov.

Relation of natriuretic peptide concentrations to central sleep apnea in patients with heart failure.

BACKGROUND: Central sleep apnea (CSA) is frequent among patients with heart failure (HF) and associated with increased morbidity and mortality. Elevated cardiac filling pressures promote CSA and atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) secretion. We hypothesized that circulating natriuretic peptide concentrations predict CSA. METHODS: Consecutive patients with HF (n = 44) with left ventricular ejection fraction (LVEF) ≤ 35% underwent polysomnography for detection of CSA. CSA was defined as an apnea-hypopnea index ≥ 15 with ≥ 50% central apneic events. The relation of natriuretic peptide concentrations to CSA was evaluated by estimation of ORs and receiver operator characteristics (ROCs). RESULTS: Twenty-seven subjects (61%) had CSA, with men more frequently affected than women (73% vs 27%; OR, 7.1; P = .01); given that only three women had CSA, further analysis was restricted to men. Subjects with CSA had higher mean ANP (4,336 pg/mL vs 2,510 pg/mL, P = .03) and BNP concentrations (746 pg/mL vs 379 pg/mL, P = .05). ANP and BNP concentrations were significantly related to CSA (OR, 3.7 per 3,000 pg/mL, P = .03 and OR, 1.5 per 200 pg/mL, P = .04, respectively), whereas age, LVEF, and New York Heart Association functional class were not. Concentrations of ANP and BNP were predictive of CSA as ROC demonstrated areas under the curve of 0.75 and 0.73, respectively. CONCLUSIONS: Risk of CSA is related to severity of HF. ANP and BNP concentrations performed similarly for detection of CSA; low concentrations appear associated with low risk for CSA in men.

Sleep-disordered breathing in patients with the Brugada syndrome.

We investigated breathing patterns and the occurrence of arrhythmias and ST-segment changes during sleep in patients with Brugada syndrome. Patients with Brugada syndrome are more likely to die from ventricular arrhythmias during sleep. ST-segment changes have been correlated with risk of sudden cardiac death. Whether sleep disturbances may contribute to arrhythmogenesis is unknown. Patients with Brugada syndrome underwent overnight polysomnography with simultaneous 12-lead electrocardiographic recording. A control group matched by age, gender, and body mass index (BMI) also underwent polysomnography. Twenty patients were included (50 ± 15 years old, 75% men). Despite their normal BMI (24.7 ± 2.7 kg/m(2)), 45% had sleep-disordered breathing (SDB), with a mean apnea-hypopnea index of 17.2 ± 14 events/hour. In patients with a high risk of arrhythmias, 5 (63%) had SDB. In the control group, 27% had SDB. Atrial or ventricular arrhythmias were not observed. Spontaneous ST-segment changes occurred in 2 patients over 45 different time points. Most ST-segment changes were observed during rapid eye movement sleep (31%) or within 1 minute of arousals (44%). Regarding respiratory events, 25 (56%) of ST-segment changes were related to occurrence of apnea or hypopnea. In conclusion, patients with Brugada syndrome have a high prevalence of SDB even in the setting of normal BMI. The higher incidence of nocturnal death in patients with Brugada syndrome may be conceivably related to co-morbid SDB. Moreover, autonomic instability encountered in rapid eye movement sleep and arousals could potentiate the risk of arrhythmias.

Patients with obstructive sleep apnea exhibit impaired endothelial function after myocardial infarction.

BACKGROUND: Impaired brachial flow-mediated dilation (FMD) is associated with risk for subsequent cardiovascular events in patients after myocardial infarction (MI). These patients often have obstructive sleep apnea (OSA). We tested the hypothesis that patients with OSA post MI will exhibit more severe impairment in FMD. METHODS: We studied 64 patients with MI admitted to our hospital. OSA was determined using polysomnography. FMD was measured using high-resolution ultrasonography, with researchers blind to the OSA diagnosis. RESULTS: The mean age was 60 ± 11 years, and the mean BMI was 29 (26, 32 kg/m(2)), 84% of patients were men, 39% had moderate to severe OSA (apnea-hypopnea index [AHI] > 15), and 31% of the patients had mild OSA (5 ≤ AHI < 15). FMD was severely impaired in patients with moderate to severe OSA (0.8% ± 0.7%) as compared with patients without OSA (4.7% ± 0.8%, P = .001) and with mild OSA (3.9% ± 0.8%, P = .015). Linear regression showed that FMD was associated with log nocturnal nadir oxygen saturation (minSaO(2)) (ß = 31.17, P = .0001), age (ß = -0.11, P = .006). MinSaO(2) was an independent predictor of FMD after adjustment for possible confounders (ß = 26.15, P = .001). CONCLUSIONS: FMD is severely impaired in patients with moderate to severe OSA post MI, which may be partially related to nocturnal hypoxemia. Patients with OSA may, therefore, be at higher risk for subsequent cardiovascular events after an MI. Identifying and treating OSA may have important implications in the long-term prognosis of patients post MI. Further studies are necessary to determine if the presence of OSA would affect the long-term occurrence of cardiovascular events after an MI.

Effect of weight gain on cardiac autonomic control during wakefulness and sleep.

Obesity has been associated with increased cardiac sympathetic activation during wakefulness, but the effect on sleep-related sympathetic modulation is not known. The aim of this study was to investigate the effect of fat gain on cardiac autonomic control during wakefulness and sleep in humans. We performed a randomized, controlled study to assess the effects of fat gain on heart rate variability. We recruited 36 healthy volunteers, who were randomized to either a standardized diet to gain ≈4 kg over 8 weeks followed by an 8-week weight loss period (n=20) or to serve as a weight-maintainer control (n=16). An overnight polysomnogram with power spectral analysis of heart rate variability was performed at baseline, after weight gain, and after weight loss to determine the ratio of low-frequency to high-frequency power and to examine the relationship between changes in heart rate variability and changes in insulin, leptin, and adiponectin levels. Mean weight gain was 3.9 kg in the fat gain group versus 0.1 kg in the maintainer group. Low frequency/high frequency increased both during wakefulness and sleep after fat gain and returned to baseline after fat loss in the fat gain group and did not change in the control group. Insulin, leptin, and adiponectin also increased after fat gain and fell after fat loss, but no clear pattern of changes was seen that correlated consistently with changes in heart rate variability. Short-term fat gain in healthy subjects is associated with increased cardiac sympathetic activation during wakefulness and sleep, but the mechanisms remain unclear.

Diagnostic accuracy of the Berlin Questionnaire in detecting sleep-disordered breathing in patients with a recent myocardial infarction.

BACKGROUND: The Berlin Questionnaire (BQ) has been used to identify patients at high risk for sleep-disordered breathing (SDB) in a variety of populations. However, there are no data regarding the validity of the BQ in detecting the presence of SDB in patients after myocardial infarction (MI). The aim of this study was to determine the performance of the BQ in patients after MI. METHODS: We conducted a cross-sectional study of 99 patients who had an MI 1 to 3 months previously. The BQ was administered, scored using the published methods, and followed by completed overnight polysomnography as the "gold standard." SDB was defined as an apnea-hypopnea index of ≥ 5 events/h. The sensitivity, specificity, and positive and negative predictive values of the BQ were calculated. RESULTS: Of the 99 patients, the BQ identified 64 (65%) as being at high-risk for having SDB. Overnight polysomnography showed that 73 (73%) had SDB. The BQ sensitivity and specificity was 0.68 and 0.34, respectively, with a positive predictive value of 0.68 and a negative predictive value of 0.50. Positive and negative likelihood ratios were 1.27 and 0.68, respectively, and the BQ overall diagnostic accuracy was 63%. Using different apnea-hypopnea index cutoff values did not meaningfully alter these results. CONCLUSION: The BQ performed with modest sensitivity, but the specificity was poor, suggesting that the BQ is not ideal in identifying SDB in patients with a recent MI.

Diagnostic accuracy of split-night polysomnograms.

STUDY OBJECTIVES: American Academy of Sleep Medicine (AASM) practice parameters indicate that split-night polysomnograms (SN-PSG) may be performed when the apnea hypopnea index (AHI) is > or = 20 to 40, depending on clinical factors. The aim of this study was to determine the diagnostic accuracy of SN-PSG, including at the lower range of AHIs. METHODS: We reviewed 114 consecutive full-night PSGs (FN-PSG) performed at our center between August 2006 and November 2008 on subjects enrolled in studies in which obstructive sleep apnea (OSA) was the sleep disorder of interest. We compared the AHI from the first 2 hours (2 hr-AHI) and 3 hours (3 hr-AHI) of sleep with the "gold standard" AHI from FN-PSG (FN-AHI), considering OSA present if FN-AHI > or = 5. RESULTS: The 2 hr-AHI and 3 hr-AHI correlated strongly with the FN-AHI (concordance correlation coefficient [CCC] = 0.93 and 0.97, respectively). After adjusting for percentage of sleep in stage REM sleep and in supine position, the correlation of 2 hr- and 3 hr-AHI with FN-AHI remained strong (0.92 and 0.96, respectively). The area under the receiver operating curves (AUC) for 2 hr-AHI and 3 hr-AHI using FN-AHI > or = 5 were 0.93 and 0.95, respectively. CONCLUSIONS: The AHI derived from the first 2 or 3 hours of sleep is of sufficient diagnostic accuracy to rule-in OSA at an AHI threshold of 5 in patients suspected of having OSA. This study suggests that the current recommended threshold for split-night studies (AHI > or = 20 to 40) may be revised to a lower number, allowing for more efficient use of resources.

Advanced heart failure and nocturnal hypoxaemia due to central sleep apnoea are associated with increased serum erythropoietin.

AIMS: Central sleep apnoea (CSA) and increased serum erythropoietin (EPO) concentration have each been associated with adverse prognosis in heart failure (HF) patients. The aim of this study was to examine the relationship between nocturnal hypoxaemia due to CSA and the serum EPO concentration in patients with HF. METHODS AND RESULTS: Heart failure subjects (n = 33) and healthy controls (n = 18) underwent polysomnography (PSG) for diagnosis of CSA and identification and quantification of hypoxaemia. Blood collection for measurement of EPO was performed immediately post-PSG. For the analysis, HF subjects were dichotomized into subgroups defined by the presence or absence of CSA and by HF severity. Multivariate analyses were performed to evaluate the relationships of hypoxaemia and advanced HF to EPO concentration. Mean EPO concentration was 62% higher for HF subjects with CSA than for healthy controls (P = 0.004). The magnitude of nocturnal hypoxaemia was significantly and positively related to EPO concentration (r = 0.45, P = 0.02). Advanced HF was also significantly and positively related to EPO concentration (r = 0.43, P = 0.02). On multivariate analysis, the presence of combined nocturnal hypoxaemia and advanced HF yielded greater correlation to EPO concentration than either factor alone (r = 0.57, P = 0.04 and P = 0.05, respectively). Linear regression demonstrated that the combination of New York Heart Association Class and CSA was strongly associated with EPO concentration (P < 0.0001). CONCLUSION: In non-anaemic HF patients, advanced HF and hypoxaemia due to CSA may each be independently associated with increased serum EPO concentration.

Day-night variation of acute myocardial infarction in obstructive sleep apnea.

OBJECTIVES: This study sought to evaluate the day-night variation of acute myocardial infarction (MI) in patients with obstructive sleep apnea (OSA). BACKGROUND: Obstructive sleep apnea has a high prevalence and is characterized by acute nocturnal hemodynamic and neurohormonal abnormalities that may increase the risk of MI during the night. METHODS: We prospectively studied 92 patients with MI for which the time of onset of chest pain was clearly identified. The presence of OSA was determined by overnight polysomnography. RESULTS: For patients with and without OSA, we compared the frequency of MI during different intervals of the day based on the onset time of chest pain. The groups had similar prevalence of comorbidities. Myocardial infarction occurred between 12 am and 6 am in 32% of OSA patients and 7% of non-OSA patients (p = 0.01). The odds of having OSA in those patients whose MI occurred between 12 am and 6 am was 6-fold higher than in the remaining 18 h of the day (95% confidence interval: 1.3 to 27.3, p = 0.01). Of all patients having an MI between 12 am and 6 am, 91% had OSA. CONCLUSIONS: The diurnal variation in the onset of MI in OSA patients is strikingly different from the diurnal variation in non-OSA patients. Patients with nocturnal onset of MI have a high likelihood of having OSA. These findings suggest that OSA may be a trigger for MI. Patients having nocturnal onset of MI should be evaluated for OSA, and future research should address the effects of OSA therapy for prevention of nocturnal cardiac events.