PURPOSE:Central sleep apnoea (CSA) and Cheyne-Stokes respiration (CSR) are prevalent in patients with heart failure with reduced ejection fraction (HFrEF) and are associated with increased mortality. Previous trials evaluating adaptive servo-ventilation (ASV) for CSA/CSR in HFrEF have yielded conflicting safety outcomes. This analysis aims to determine the sample size and number of events required to reliably detect safety signals, specifically all-cause mortality, in future trials assessing new treatments for CSA/CSR in HFrEF patients. METHODS:Utilizing data from the SERVE-HF trial, we conducted event-driven, non-inferiority sample size calculations focusing on all-cause mortality as the primary endpoint. The analysis employed a one-sided alpha of 0.025 and 80% power, considering hazard ratios (HRs) ranging from 1.15 to 1.35, in line with FDA guidelines for cardiovascular safety assessments. Calculations assumed a control group event rate of 0.093 events/year, a 5-year accrual period, and a minimum follow-up of 3 years. RESULTS:To detect a non-inferiority margin with an HR of 1.35, a trial would require at least 851 patients and 349 events. More stringent margins necessitate larger sample sizes; for an HR of 1.15, 3,924 patients and 1,607 events are needed. These findings underscore the importance of adequately powered studies to detect potential safety concerns in this patient population. CONCLUSION:Future clinical trials investigating treatments for CSA/CSR in HFrEF patients must incorporate sufficient sample sizes and event counts to ensure reliable detection of safety signals, particularly concerning all-cause mortality. This approach is critical for accurately assessing the risk-benefit profile of new therapeutic interventions.

BACKGROUND: In people with OSA, excessive daytime sleepiness is a prominent symptom and can persist despite adherence to CPAP, the first -line therapy for OSA. Pitolisant was effective in reducing daytime sleepiness in two 12-week randomized controlled trials (RCTs), one in patients adherent to CPAP (BF2.649 in Patients With OSA and Treated by CPAP But Still Complaining of EDS [HAROSA 1]) and the other in patients refusing or not tolerating CPAP (BF2.649 in Patients With OSA, Still Complaining of EDS and Refusing to be Treated by CPAP [HAROSA 2]). RESEARCH QUESTION: Does the efficacy and safety of pitolisant persist when these patients take it long -term? STUDY DESIGN AND METHODS: All adults included in the HAROSA 1 and HAROSA 2 RCTs (both pitolisant and placebo arms) were offered pitolisant (up to 20 mg/d) after completion of the short -term double-anonymized phase (ie, from week 13) in an open -label cohort study. The primary efficacy outcome was the change in Epworth Sleepiness Scale score between baseline and week 52. Safety outcomes were treatment-emergent adverse event(s) (TEAE[s]), serious TEAEs, and special interest TEAEs. RESULTS: Out of 512 adults included in the two RCTs, 376 completed the 1 -year follow-up. The pooled mean difference in Epworth Sleepiness Scale score from baseline to 1 year for the intention-to-treat sample was -8.0 (95% CI, -8.3 to -7.5). The overall proportions of TEAEs, serious TEAEs, and TEAEs of special interest were 35.1%, 2.0%, and 11.1%, respectively, without any significant difference between patients in the initial pitolisant and placebo arms. No cardiovascular safety issues were reported. INTERPRETATION: Pitolisant is effective in reducing daytime sleepiness over 1 year in adults with OSA, with or without CPAP treatment. Taken for 1 year, it has a good safety profile (including cardiovascular). TRIAL REGISTRATION: ClinicalTrials.gov; Nos.: NCT01071876 and NCT01072968; URL: www.clinicaltrials.gov

SummaryThis SERVE‐HF (Treatment of Predominant Central Sleep Apnea by Adaptive Servo Ventilation in Patients With Heart Failure) sub study analysis evaluated polysomnography (PSG) data in patients with heart failure with reduced ejection fraction (HFrEF) and predominant central sleep apnea (CSA) randomised to guideline‐based medical therapy, with or without adaptive servo ventilation (ASV). Patients underwent full overnight PSG at baseline and at 12 months. All PSG recordings were analysed by a core laboratory. Only data for patients with baseline and 3‐ or 12‐month values were included. The sub study included 312 patients; the number with available PSG data differed for each variable (94–103 in the control group, 77–99 in the ASV group). After 12 months, baseline‐adjusted respiratory measures were significantly better in the ASV group versus control. Although some between‐group differences in sleep measures were seen at 12 months (e.g., better sleep efficiency in the ASV group), these were unlikely to be clinically significant. The number of periodic leg movements during sleep (PLMS) increased in the ASV group (p = 0.039). At 12 months, the respiratory arousal index was significantly lower in the ASV versus control group (p < 0.001), whilst the PLMS‐related arousal index was significantly higher in the ASV group (p = 0.04 versus control). ASV attenuated the respiratory variables characterising sleep apnea in patients with HFrEF and predominant CSA in SERVE‐HF. Sleep quality improvements during ASV therapy were small and unlikely to be clinically significant. The increase in PLMS and PLMS‐related arousals during ASV warrants further investigation, particularly relating to their potential association with increased cardiovascular risk.

Summary Sympathetic overactivity caused by chronic intermittent hypoxia is a hallmark of obstructive sleep apnea. A high sympathetic tone elicits increases in plasma free fatty acid and insulin. Our objective was to assess the impact of 14 nights of chronic intermittent hypoxia exposure on sympathetic activity, glucose control, lipid profile and subcutaneous fat tissue remodelling in non‐obese healthy humans. In this prospective, double‐blinded crossover study, 12 healthy subjects were randomized, among them only nine underwent the two phases of exposures of 14 nights chronic intermittent hypoxia versus air. Sympathetic activity was measured by peroneal microneurography (muscle sympathetic nerve activity) before and after each exposure. Fasting glucose, insulin, C‐peptide and free fatty acid were assessed at rest and during a multisampling oral glucose tolerance test. We assessed histological remodelling, adrenergic receptors, lipolysis and lipogenesis genes expression and functional changes of the adipose tissue. Two weeks of exposure of chronic intermittent hypoxia versus ambient air significantly increased sympathetic activity ( p = 0.04). Muscle sympathetic nerve activity increased from 24.5 [18.9; 26.8] before to 21.7 [13.8; 25.7] after ambient air exposure, and from 20.6 [17.4; 23.9] before to 28.0 [24.4; 31.5] bursts per min after exposure to chronic intermittent hypoxia. After chronic intermittent hypoxia, post‐oral glucose tolerance test circulating free fatty acid area under the curve increased ( p = 0.05) and free fatty acid sensitivity to insulin decreased ( p = 0.028). In adipocyte tissue, intermittent hypoxia increased expression of lipolysis genes (adipocyte triglyceride lipase and hormone‐sensitive lipase) and lipogenesis genes (fatty acid synthase; p < 0.05). In this unique experimental setting in healthy humans, chronic intermittent hypoxia induced high sympathetic tone, lipolysis and decreased free fatty acid sensitivity to insulin. This might participate in the trajectory to systemic insulin resistance and diabetes for patients with obstructive sleep apnea.

The high prevalence of undiagnosed sleep disordered breathing (SDB), and its health consequences, require improved routine screening, assessment and diagnosis. The sleep study is the most important investigation in the process of making the diagnosis of SDB [1]. Typically, there are three major types of sleep studies: full polysomnography, respiratory polygraphy and overnight oximetry. These three types of nocturnal recording have been classified as type I (attended full polysomnography), type II (unattended full polysomnography), type III (respiratory polygraphy or equivalent), and type IV (devices that measure only one or two parameters, typically oxygen saturation and heart rate or, in some cases, just airflow) [2]. Polysomnography is still regarded as the diagnostic gold standard and usually includes assessment of oximetry, snoring, body and leg movements, nasal pressure as a surrogate for nasal airflow, mouth breathing via a thermistor, and excursion of the chest and abdomen, as well as an electrocardiogram, electroencephalogram, electrooculogram and electromyogram to identify sleep stages. Respiratory polygraphy usually includes all these assessments but without an electroencephalogram, electrooculogram or electromyogram. To diagnose sleep apnoea, novel devices and emerging technologies are being increasingly used. Portable monitoring (PM) also benefits from telemedicine and artificial intelligence. PM should be further validated in terms of clinical outcomes in OSA. https://bit.ly/3ge1hEy

La présence d’un SAOS chez des patients avec une cardiopathie ischémique est un facteur de mauvais pronostic. Au cours des apnées, les patients présentent des épisodes de désaturation–resaturation en dioxygène, aussi appelés hypoxie intermittente (HI). L’HI est une des conséquences du SAOS la plus délétère sur le système cardiovasculaire. Le traitement de référence des apnées du sommeil consiste en l’application d’une pression positive continue (PPC) pendant le sommeil mais l’efficacité en regard de la morbi-mortalité cardiovasculaire est discutée. Les modèles animaux permettent d’étudier les mécanismes expliquant la réponse cardiovasculaire à l’HI et ce, dans différents contextes physiopathologiques. Les objectifs de cette revue sont donc de souligner le rôle délétère de l’HI chronique et des mécanismes associés dans un contexte de cardiopathie ischémique. Nous nous intéresserons particulièrement au stress oxydatif, à l’activation de l’Hypoxia Inducible Factor-1 et au stress du réticulum endoplasmique, ainsi qu’à l’activation du système nerveux sympathique. Ces mécanismes pourraient représenter de nouveaux biomarqueurs de mauvais pronostic chez les patients souffrant de SAOS et de cardiopathie ischémique, et/ou de nouvelles cibles thérapeutiques, complémentaires ou alternatives à la PPC.Obstructive sleep apnea syndrome (OSAS) is a factor of poor prognosis in patients suffering from ischemic cardiomyopathy. During sleep, apneic patients exhibit repetitive apneas causing chronic blood dioxygen desaturation-resaturation, currently named intermittent hypoxia (IH). IH is one the most detrimental feature of OSAS for the cardiovascular system. Whereas positive airway pressure (PAP) remains the gold standard treatment, the efficacy in regard of the cardiovascular mortality is not clear. Animal models make it possible to study the mechanisms explaining the cardiovascular response to IH in different pathophysiological contexts. The objectives of this review are to highlight the deleterious role of chronic IH and associated mechanisms in the context of ischemic heart disease. We will be particularly interested in oxidative stress, activation of HIF-1 and ER stress, as well as activation of the sympathetic nervous system. These mechanisms could represent new biomarkers of poor prognosis in patients with OSAS and ischemic heart disease, and/or new therapeutic targets, complementary or alternative to PAP.

Purpose: With the development of neoadjuvant treatment (NAT), DP-CAR for DLA-PDAC is more frequently performed. In this study we describe the selection strategy and the outcome of DP-CAR for DLA-PDAC Methods: Retrospective single-center analysis (2008-2021) of candidates for DP-CAR after presentation in a tumor board meeting. All patients received NAT (Chemotherapy: mainly by FOLFIRINOX; Radiotherapy: 54Gy plus Xeloda), DP-CAR was indicated in patients with DLA-PDAC responding to NAT but with persisting celiac axis (CA) invasion. Surgical strategy included laparoscopic exploration (LE), preoperative radiological CA embolization followed 2 weeks later by surgery. The Ethics Committee of the center approved the study. Results: Of 24 patients, 7(29%) demonstrated tumor progression (including 5 at LE), and 17(71%) underwent DP-CAR (13/17 received FOLFIRINOX). Preoperative embolization (100%) was efficient except in one patient who had an aorto-hepatic shunt. DP-CAR included adjacent organ resection (77%), venous resection (59%), and spleen preservation (29%). There was one (6%) postoperative mortality, Clavien-Dindo≥III complications in 7(42%) patients, no ischemic complications, and a 21 (IQR 17-28) days median hospital stay. Pathological data showed R0 resection in 14 (82%) patients, N+ in 5 (29%), perineural invasion in 14 (82%) and CA microscopic invasion in 7 (41%); 12(71%) patients received adjuvant chemotherapy within a median delay of 70 days (IQR 50-95). After a median follow-up of 34 (IQR 27-45) months, DFS was 12 (IQR 5-18) months. Median OS was 21(IQR 9-34) months after DP-CAR versus 10 (IQR 8– 29) months in non-operated patients, respectively Conclusion: For DLA-PDAC, a strategy including NAT, LE and CA embolization is efficient as demonstrated by the prevalence of positive LE and the absence of ischemic complications. Frequent need for extended resection and mitigated oncological results argue for a stricter selection including a reinforced perioperative therapy.

Obstructive sleep apnoea (OSA) is the main cause of secondary hypertension. The main trigger mechanism for the causality is increase in sympathetic tone. Randomized controlled trials have suggested that blood pressure (BP) reduction is higher with fixed CPAP versus APAP but mechanisms are poorly established. We hypothesized a different impact of the two PAP modalities on sympathetic tone. This double blind randomized controlled trial compared sympathetic activity after 4-week of APAP versus fixed CPAP in treatment-naive OSA patients. We included 56 adults OSA. 43 were compliant during a run-in one-week period and were randomized to APAP, (23 (53.5%)) or fixed CPAP (20 (46.51%)) arms. Muscle sympathetic nerve activity (MSNA), urinal catecholamines and 24-hour BP were obtained at baseline and intervention. Median age, BMI, and percentage of prevalent hypertension were 57 [49;64] years, 30.5 [28.6;34.6] kg/m², 37.2%. Patients exhibited severe OSA with a median Epworth sleep Scale, AHI and ODI of 11 [9;16], 35.7/h [28.6;44.2], and 30.2/h [24.6;43.5], respectively. MSNA bursts/min reductions after APAP and CPAP were 32.7 [29.2;37] to 29.9 [22.6;37.3] and 37 [30.4;52.1] to 31.3 [18.5;39], respectively. There was a significant larger reduction of sympathetic tone in the CPAP group consistent across the different methods of assessment (i.e.: MSNA burst/min and burst/100hb, urinal epinephrin and norepinephrine, p<0.01, p<0.01, p=0.02 and p=0.02, respectively). Improvement in BP was similar between the two arms. Higher reduction in sympathetic tone was achieved by CPAP compared to APAP, that may impact hypertension managemen in OSA.

Purpose of work: The main complication of distal pancreatectomy with resection of the splenic vessels and splenic preservation (Warshaw) is splenic ischemia (SI), which was not frequently studied on imaging studies. SI is at risk of secondary splenectomy for infection. This work evaluates the incidence, evolution and risk factors of SI using imaging studies. Method: Monocentric retrospective study (2008-2020) including all patients operated on for laparoscopic Warshaw. An early CT was performed in all patients and a late one (>12 months) in 113 patients. The imaging was reviewed by a radiologist without knowledge of the postoperative course of the patients. Results: One hundred and fifty-four patients were included (mean age=57 years; women=70%) including 26 (17%) for pancreatic adenocarcinoma. Early evaluation showed SI (67%) associated with splenomegaly (mean splenic volume: +41% compared to preoperative volume). There was no secondary splenectomy. Two patients required percutaneous drainage for infected SI (1.3%) and only one remained asplenic. Late evaluation showed no SI in 94 (83%) patients, asymptomatic venous collateral circulation in 111 (98%) and a larger spleen (+14% compared to preoperative volume). The late mean platelet count was normal (253,000/mm3). Predictive factors of SI were a short tail-splenic hilum distance (mean: 16 vs 23mm; p<0.001), male gender (p=0.005) and pancreatic adenocarcinoma (p=0.002). Conclusion: Splenic ischemia after laparoscopic Warshaw surgery are frequent, but the risk of infection is low (<1%) and splenic function remains preserved. A short distance between the tail of the pancreas and the splenic hilum might require technical adaptation to reduce the risk of SI.

The debate of central apnoea and its treatment in heart failure is very much alive, and measures comprising the effects on sympathetic measures of therapeutic options should be evaluated, albeit with careful considerationhttps://bit.ly/3EVpXKv

Purpose: After initial pancreatic resection, recurrence or evolution of preexisting pancreatic lesions may occur in the remnant pancreas and redo pancreatectomy (RP) can be indicated, and the open approach was the standard. However, the there is a widespread of laparoscopy and the feasibility of laparoscopic-redo-pancreatetcomy (LRP) was rarely studied. Herein we aimed to evaluate the feasibility of LRPs in a single study series. Method: In the study high volume center, laparoscopic pancreatic surgery was introduced in 2008. Since 2013, LRP was considered in any candidate patient regardless of the approach (open or laparoscopic) of the first pancreatic resection. Perioperative parameters and outcomes were retrospectively evaluated. Results: Between March 2013 and July 2021, 22 patients (14-females and 8-men) with a mean age of 61 (35-83)years and a mean BMI at 24.1kg/m2 underwent 23LRPs. The first pancreatic resection was done by open (n=12; 52%) and laparoscopic (n=11; 48%) approaches and consisted of 8 pancreatoduodenectomies (PD), 9 distal pancreatectomy with (7) or without (2) spleen preservation, 3 central pancreatectomies (CP), 1 enucleation (EN) and in 2 cases a previous CP was already completed with PD and an enlarged pancreatic resection respectively. The mean interval, between first pancreatic resection and LRP was 43 (4-146)months. The most common indications for surgery were: intraductal-papillary-mucinous-neoplasms (15), pancreatic ductal adenocarcinoma recurrence (4), neuroendocrine tumor (2), pancreatic intraepithelial neoplasm (1) and mucinous cystadenoma (1). Completion pancreatectomies (n=16) were performed after a previous open procedures (63%) and included PDs after DP (n=8) and DP after previous PD (n=8). Redo partial pancreatectomies (n=7) included two DP after a CP, 2 parenchymal-sparing resections after CP and DP , 1 PD after CP, 1 CP after EN, 1 EN after PD. Conversion was observed in 2 patients. Mean operative-time was 212 (90-360)min with a median blood loss of 100 (range 0 – 2500)mL and transfusion in 2 patients (9%). There was no perioperative mortality and overall morbidity was 39%. The median postoperative-hospital-stay was 9 (3-30)days. Conclusion: The application of a minimally-invasive approach to perform RP has proven to be safe and feasible. The mature expertise of referral HPB-centers may expand the indication of minimally-invasive surgery to treat recurrence and new primary in the remnant pancreas.

Sleep Breathing Disorders in their various forms represent a major public health problem, owing to their prevalence and their associated consequences, in particular Excessive Daytime Sleepiness (EDS), impairment of vigilance, cardiovascular and metabolic morbidities. Although the large scale use of Positive Airway Pressure and Non-Invasive Ventilation dates back to the eighties, the scientific evidence has been built progressively. Since 2000, randomi-zed controlled trials (RCTs) have been designed in order to evaluate the treatment effects in Obstructive Sleep Apnea (OSA), then Sleep Apnea and Heart Failure and Obesity-Hypoventilation Syndrome. However, the effects on cardiovascular morbidity and mortality remain limited, in primary as well as secondary prevention. It remains a conflicting issue and there are pending questions on study designs and specific sub-groups responsiveness to apneas and Intermittent Hypoxia. There is some evidence that OSA patients presenting with severe EDS may also exhibit greater cardiovascular consequences. Thus, they could represent one of the target groups that should be specifically tested. Also, large RCTs including repeated diurnal and nocturnal tests remain difficult to implement. An alternative could be using "real life" comparative cohort studies.(c) 2023 l'Academie nationale de medecine. Published by Elsevier Masson SAS. All rights reserved.

Background Adaptive servo-ventilation (ASV) effectively suppresses central sleep apnoea (CSA) but has been associated with increased all-cause and cardiovascular mortality in chronic heart failure patients with reduced ventricular ejection fraction (HFrEF). All-cause and, especially, cardiovascular mortality in chronic heart failure is highly correlated with sympathetic tone. This analysis of SERVE-HF data investigated the effect of ASV on sympathetic tone in patients with HFrEF and CSA.Methods HFrEF patients in the SERVE-HF trial (left ventricular ejection fraction (LVEF) <= 45%, apnoea- hypopnoea index (AHI) > 15 events center dot h-1with predominant CSA) were randomly assigned to receive guideline-based heart failure treatment alone (controls) or plus ASV. For this analysis, the primary outcome was change in muscle sympathetic nerve activity (MSNA) at 3-month follow-up. The effects of baseline MSNA and change in MSNA over time on mortality in the main study were also assessed.Results 40 patients with HFrEF were included in this analysis (age 71.3 +/- 11.7 years, LVEF 34.2 +/- 7.7%, 57.5% in New York Heart Association (NYHA) Functional Class II, 42.5% in NYHA Functional Class III, AHI 35.2 +/- 11 events center dot h-1). Sympathetic tone evolution during follow-up did not differ between groups (controls: 47.6 +/- 8.3 bursts center dot min-1 at baseline to 44.6 +/- 11.2 bursts center dot min-1; ASV group: 43.0 +/- 9.0 bursts center dot min-1 at baseline to 42.74 +/- 9.45 bursts center dot min-1). The reduction in sympathetic tone was associated with significantly increased cardiovascular mortality in the ASV group, whereas in the control group reduced sympathetic tone appeared to be protective. Conclusions Suppression of CSA with ASV did not seem to have a significant effect on chronic heart failure-related sympathetic activation. Simultaneous suppression of CSA and reduction in MSNA was associated with increased cardiovascular mortality.