Takatoshi Kasai

Obstructive sleep apnea and heart failure: pathophysiologic and therapeutic implications.

Obstructive sleep apnea (OSA) exposes the cardiovascular system to intermittent hypoxia, oxidative stress, systemic inflammation, exaggerated negative intrathoracic pressure, sympathetic overactivation, and elevated blood pressure (BP). These can impair myocardial contractility and cause development and progression of heart failure (HF). Epidemiological studies have shown significant independent associations between OSA and HF. On the other hand, recent prospective observational studies reported a significant association between the presence of moderate to severe OSA and increased risk of mortality in patients with HF. In randomized trials, treating OSA with continuous positive airway pressure suppressed sympathetic activity, lowered BP, and improved myocardial systolic function in patients with HF. These data suggest the potential for treatment of OSA to improve clinical outcomes for patients with HF. However, large-scale randomized trials with sufficient statistical power will be needed to ascertain whether treatment of OSA will prevent development of, or reduce morbidity and mortality from HF.

Prognosis of Patients With Heart Failure and Obstructive Sleep Apnea Treated With Continuous Positive Airway Pressure

BACKGROUND Therapy with continuous positive airway pressure (CPAP) provides several benefits for patients with heart failure (HF) complicated by obstructive sleep apnea (OSA). However, the effect on the prognosis of such patients remains unknown. AIMS To determine whether CPAP therapy and compliance affects the prognosis of HF patients with OSA. METHODS We classified 88 patients with HF and moderate-to-severe OSA into a CPAP-treated group (n = 65) and an untreated group (n = 23), and then those treated with CPAP were further subclassified according to CPAP therapy compliance. The frequency of death and hospitalization was analyzed using multivariate analysis. RESULTS During a mean (+/- SD) period of 25.3 +/- 15.3 months, 44.3% of the patients died or were hospitalized. Multivariate analysis showed that the risk for death and hospitalization was increased in the untreated group (hazard ratio [HR], 2.03; 95% confidence interval [CI], 1.07 to 3.68; p = 0.030) and in less compliant CPAP-treated patients (HR, 4.02; 95% CI, 1.33 to 12.2; p = 0.014). CONCLUSION Therapy with CPAP significantly reduced the risk of death and hospitalization among patients with HF and OSA. However, reduced compliance with CPAP therapy was significantly associated with an increased risk of death and hospitalization.

Sleep Apnea and Cardiovascular Disease A Bidirectional Relationship

Sleep apnea occurs in ≈5% to 10% of the general population, regardless of race and ethnicity.1 By contrast, in patients with cardiovascular diseases (CVDs), its prevalence, depending on the specific disorder surveyed, can range between 47% and 83%.2–4 One form, central sleep apnea (CSA), is rare in the general population, but is detected often in conditions characterized by sodium and water retention, such as heart failure (HF).2 Such epidemiological observations raise several important and as yet unresolved questions: What accounts for this remarkable concentration of sleep apnea among patients with CVD and its association with fluid retaining states? Does obstructive sleep apnea (OSA) predispose at-risk individuals to develop, over time, hypertension, coronary artery disease, stroke, or HF? Conversely, could mechanisms engaged by CVD, such as activation of the sympathetic nervous and renin-angiotensin-aldosterone systems, with consequences including renal sodium retention, contribute over time to the development or exacerbation of sleep apnea? From the clinical perspective, is sleep apnea, when present in patients with CVD an epiphenomenon, perhaps related to ageing, or a causal contributor to worse prognosis? And if so, are there now sufficient data to recommend randomized controlled trials to determine whether specific treatment of sleep apnea can reduce mortality or cardiovascular event rates? Our objectives, in this review, are to provide novel insight into each of these specific questions by integrating into our contemporary understanding of relationships between sleep apnea and CVD5 newer epidemiological, observational, mechanistic, and trial data; to introduce a hypothetical model of bidirectional causality; and to consider directions for future research. In healthy subjects, during non–rapid eye movement sleep (which constitutes ≈85% of total sleep time), efferent sympathetic nerve activity (SNA) diminishes and vagal tone increases, resulting in reductions in metabolic rate, blood pressure (BP), and heart rate (HR).6 …

Effect of Flow-Triggered Adaptive Servo-Ventilation Compared With Continuous Positive Airway Pressure in Patients With Chronic Heart Failure With Coexisting Obstructive Sleep Apnea and Cheyne-Stokes Respiration

Background—In patients with chronic heart failure (CHF), the presence of sleep-disordered breathing, including either obstructive sleep apnea or Cheyne-Stokes respiration-central sleep apnea, is associated with a poor prognosis. A large-scale clinical trial showed that continuous positive airway pressure (CPAP) did not improve the prognosis of such patients with CHF, probably because of insufficient sleep-disordered breathing suppression. Recently, it was reported that adaptive servo-ventilation (ASV) can effectively treat sleep-disordered breathing. However, there are no specific data about the efficacy of flow-triggered ASV for cardiac function in patients with CHF with sleep-disordered breathing. The aim of this study was to compare the efficacy of flow-triggered ASV to CPAP in patients with CHF with coexisting obstructive sleep apnea and Cheyne-Stokes respiration-central sleep apnea. Methods and Results—Thirty-one patients with CHF, defined as left ventricular ejection fraction <50% and New York Heart Association class ≥II, with coexisting obstructive sleep apnea and Cheyne-Stokes respiration-central sleep apnea, were randomly assigned to either CPAP or flow-triggered ASV. The suppression of respiratory events, changes in cardiac function, and compliance with the devices during the 3-month study period were compared. Although both devices decreased respiratory events, ASV more effectively suppressed respiratory events (&Dgr;AHI [apnea-hypopnea index], −35.4±19.5 with ASV; −23.2±12.0 with CPAP, P<0.05). Compliance was significantly greater with ASV than with CPAP (5.2±0.9 versus 4.4±1.1 h/night, P<0.05). The improvements in quality-of-life and left ventricular ejection fraction were greater in the ASV group (&Dgr;LVEF [left ventricular ejection fraction], +9.1±4.7% versus +1.9±10.9%). Conclusions—These results suggest that patients with coexisting obstructive sleep apnea and Cheyne-Stokes respiration-central sleep apnea may receive greater benefit from treatment with ASV than with CPAP.

Effect of Flow-triggered Adaptive Servo-ventilation Compared with Continuous Positive Airway Pressure in Chronic Heart Failure Patients with Coexisting Obstructive Sleep Apnea and Cheyne-Stokes Respiration

Background—In patients with chronic heart failure (CHF), the presence of sleep-disordered breathing, including either obstructive sleep apnea or Cheyne-Stokes respiration-central sleep apnea, is associated with a poor prognosis. A large-scale clinical trial showed that continuous positive airway pressure (CPAP) did not improve the prognosis of such patients with CHF, probably because of insufficient sleep-disordered breathing suppression. Recently, it was reported that adaptive servo-ventilation (ASV) can effectively treat sleep-disordered breathing. However, there are no specific data about the efficacy of flow-triggered ASV for cardiac function in patients with CHF with sleep-disordered breathing. The aim of this study was to compare the efficacy of flow-triggered ASV to CPAP in patients with CHF with coexisting obstructive sleep apnea and Cheyne-Stokes respiration-central sleep apnea. Methods and Results—Thirty-one patients with CHF, defined as left ventricular ejection fraction <50% and New York Heart Association class ≥II, with coexisting obstructive sleep apnea and Cheyne-Stokes respiration-central sleep apnea, were randomly assigned to either CPAP or flow-triggered ASV. The suppression of respiratory events, changes in cardiac function, and compliance with the devices during the 3-month study period were compared. Although both devices decreased respiratory events, ASV more effectively suppressed respiratory events (&Dgr;AHI [apnea-hypopnea index], −35.4±19.5 with ASV; −23.2±12.0 with CPAP, P<0.05). Compliance was significantly greater with ASV than with CPAP (5.2±0.9 versus 4.4±1.1 h/night, P<0.05). The improvements in quality-of-life and left ventricular ejection fraction were greater in the ASV group (&Dgr;LVEF [left ventricular ejection fraction], +9.1±4.7% versus +1.9±10.9%). Conclusions—These results suggest that patients with coexisting obstructive sleep apnea and Cheyne-Stokes respiration-central sleep apnea may receive greater benefit from treatment with ASV than with CPAP.

Rostral overnight fluid shift in end-stage renal disease: relationship with obstructive sleep apnea

BACKGROUND In both healthy male subjects and men with heart failure, the severity of obstructive sleep apnea (OSA) is related to the amount of fluid displaced from their legs into the neck overnight. Whether overnight rostral fluid shift contributes to the pathogenesis of OSA in patients with end-stage renal disease (ESRD) is unknown. We hypothesized that the change in neck circumference (NC) and severity of OSA are related to the extent of overnight change in leg fluid volume (LFV) in patients with ESRD. METHODS We studied 26 patients with ESRD (14 men) on conventional hemodialysis. All subjects underwent polysomnography. LFV was measured by bioelectric impedance at bedtime and repeated in the next morning on awakening. RESULTS Our cohorts overall apnea-hypopnea index was 22.8±26.8 episodes/h of sleep. Their overnight change in LFV was -243±278 mL. The change in LFV correlated with apnea-hypopnea time (AHT) (P=0.001) and NC (P=0.0016). Other independent factors associated with AHT included age (P=0.005), baseline neck (P=0.0002), sitting time (P=0.008) and male gender. Stepwise multiple regression analysis revealed that age, change in LFV and male gender remained independent related to AHT. CONCLUSIONS Nocturnal rostral fluid shift is associated with the severity of OSA in ESRD. Prospective evaluation of the effect of reducing fluid overload and severity of OSA in ESRD patients warrants further examination.

Determination of physiological plasma pentraxin 3 (PTX3) levels in healthy populations

Abstract Background: The aim of this study was to evaluate the distribution of pentraxin 3 (PTX3) values in healthy subjects and to characterize its relationship with gender, age, body mass index (BMI), lipid profile, and blood sugar levels. Methods: A Japanese population of 1749 healthy subjects (818 men and 931 women) with a mean (SD) age of 59.6 (11.4) years (range 37–87 years) were examined. Results: Plasma PTX3 levels (PTX3 data are expressed as the geometric mean and confidence intervals) were i) significantly lower in men than in women (1.87 [1.81, 1.94] ng/mL vs. 2.12 [2.05, 2.19] ng/mL, p<0.0001), ii) significantly higher in the high age group (men, lowest quartile 1.62 [1.50, 1.74] ng/mL vs. highest quartile 2.14 [2.02, 2.27] ng/mL, p<0.001; women, lowest quartile 2.05 [1.92, 2.18] ng/mL vs. highest quartile 2.23 [2.02, 2.46] ng/mL, p<0.05), iii) inversely correlated with triglycerides (r=−0.19 in men and r=−0.18 in women, p<0.00001), and BMI (r=−0.16 in men and r=−0.24 in women, p<0.00001), and iv) lower in subjects with metabolic syndrome (MetS) than in the absence of MetS (1.82 [1.70, 1.95] ng/mL vs. 2.11 [2.06, 2.16] ng/mL, p=0.021). Conclusions: We defined the normal range of plasma PTX3 in healthy Japanese subjects, and also showed the relationship between plasma PTX3 levels and established coronary risk factors, including MetS. PTX3 could be an ideal biomarker because it is a marker relatively independent from established coronary risk factors. Clin Chem Lab Med 2009;47:471–7.

Relationship of pharyngeal water content and jugular volume with severity of obstructive sleep apnea in renal failure

BACKGROUND In patients with end-stage renal disease (ESRD), fluid overload may contribute to their high prevalence of obstructive sleep apnea (OSA) by increasing the amount of fluid displaced from the legs into the neck overnight, and possibly compressing the upper airway (UA). Indeed, in ESRD patients, the amount of overnight rostral fluid displacement from the legs is related to the frequency of apneas and hypopneas per hour of sleep (apnea-hypopnea index, AHI). We, therefore, hypothesized that in ESRD patients, the greater the UA-mucosal water content (UA-MWC) and internal jugular vein volume (IJVVol), the higher the AHI. METHODS We studied 20 patients with ESRD on thrice weekly hemodialysis who had undergone diagnostic polysomnography (age 41.0 ± 12.3 years, with a body mass index (BMI) of 25.8 ± 6.3 kg/m(2) and an AHI of 20.2 ± 26.8). The leg fluid volume (LFV) was measured by bioelectric impedance. The IJVVol and MWC were measured by UA magnetic resonance imaging (MRI). RESULTS The only significant independent correlates of the AHI were IJVVol (r = 0.801, P < 0.0001) and UA-MWC (r = 0.720, P = 0.0005) which together explained 72% of its variability. CONCLUSIONS These data suggest that fluid overload via increased IJVVol, and UA-MWC, contributes to the pathogenesis of OSA in patients with ESRD. These findings help us to explain the high prevalence of OSA in ESRD patients, and attenuation of OSA in association with nocturnal dialysis. They also suggest the need for randomized trials to determine whether more aggressive fluid removal in ESRD patients will alleviate OSA.

Effect of intensified diuretic therapy on overnight rostral fluid shift and obstructive sleep apnoea in patients with uncontrolled hypertension.

Objectives: Fluid displacement from the lower extremities to the upper body during sleep is strongly associated with obstructive sleep apnoea in hypertensive patients. The present pathophysiological study tests the hypothesis that intensified diuretic therapy will reduce the apnoea-hypopnoea index and blood pressure of uncontrolled hypertensive patients with obstructive sleep apnoea in proportion to the reduction in overnight change in leg fluid volume. Methods: Uncontrolled treated hypertensive patients underwent overnight polysomnography and measurement of overnight changes in leg fluid volume and neck circumference. Those with an apnoea-hypopnoea index at least 20 events per hour (n = 16) received metolazone 2.5 mg and spironolactone 25 mg daily for 7 days after which the daily dose was doubled for 7 additional days. Baseline testing was again repeated. Results: Intensified diuretic therapy reduced the apnoea-hypopnoea index from 57.7 ± 33.0 to 48.5 ± 28.2 events per hour (P = 0.005), overnight change in leg fluid volume from –418.1 ± 177.5 to –307.5 ± 161.9 ml (P < 0.001) and overnight change in neck circumference from 1.2 ± 0.6 to 0.7 ± 0.4 cm (P < 0.001). There was an inverse correlation between the reduction in overnight change in leg fluid volume and decrease in apnoea-hypopnoea index (r = –0.734, P = 0.001). The reduction in overnight change in leg fluid volume was also significantly correlated with the change in morning blood pressure (r = 0.708, P = 0.002 for SBP; r = 0.512, P = 0.043 for DBP). Conclusion: The findings provide further evidence that fluid redistribution from the legs to the neck during sleep contributes to the severity of obstructive sleep apnoea in hypertension and may be an important link between these two conditions.

Differing Effects of Obstructive and Central Sleep Apneas on Stroke Volume in Patients with Heart Failure

RATIONALE Obstructive sleep apnea and central sleep apnea increase risk of mortality in patients with heart failure (HF), possibly because of hemodynamic compromise during sleep. However, beat-to-beat stroke volume (SV) has not been assessed in response to obstructive and central events during sleep in patients with HF. Because obstructive events generate negative intrathoracic pressure that reduces left ventricular (LV) preload and increases afterload, but central events do not, obstructive events should lead to greater hemodynamic compromise than central events. OBJECTIVES To determine the effects of obstructive and central apneas and hypopneas during sleep on SV in patients with HF. METHODS Patients with systolic HF (LV ejection fraction ≤ 45%) and sleep apnea underwent beat-to-beat measurement of SV by digital photoplethysmography during polysomnography. Change in SV from before to the end of obstructive and central respiratory events was calculated and compared between these types of events. MEASUREMENTS AND MAIN RESULTS Changes in SV were assessed during 252 obstructive and 148 central respiratory events in 40 patients with HF. Whereas SV decreased by 6.8 (±8.7)% during obstructive events, it increased by 2.6 (±5.4)% during central events (P < 0.001 for difference). For obstructive events, reduction in SV was associated independently with LV ejection fraction, duration of respiratory events, and degree of oxygen desaturation. CONCLUSIONS In patients with HF, obstructive and central respiratory events have opposite hemodynamic effects: whereas obstructive sleep apnea appears to have an adverse effect on SV, central sleep apnea appears to have little or slightly positive effects on SV. These observations may have implications for therapeutic approaches to these two breathing disturbances.