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[EN] Objetivos: En una estrategia de manejo de la enfermedad pulmonar obstructiva crónica (EPOC) basada en fenotipos clínicos sería deseable que todos los pacientes pudieran adscribirse al menos a un fenotipo sin adscribirse a otro. El objetivo de este trabajo fue evaluar si todos los pacientes tienen un fenotipo y sólo uno asignado según la actual guía española de la EPOC (GesEPOC 2017) y evaluar los criterios que los definen. Método: El estudio Time-based Register and Analysis of COPD Endpoints (TRACE; clinicaltrials.gov NCT03485690) es una cohorte prospectiva de pacientes con EPOC en visitas anuales desde 2012 que recoge los fenotipos GesEPOC. A pesar de que GesEPOC recomienda no fenotipar a los pacientes considerados de bajo riesgo, se realizó un análisis de los criterios de identifican los fenotipos en alto y bajo riesgo, comparando la distribución de los fenotipos y sus criterios en estos dos grupos. Resultados: La cohorte incluye 970 pacientes con diagnóstico confirmado de EPOC, divididos en 427 (44,02%) pacientes de bajo riesgo y 543 (55,9%) de alto riesgo. El fenotipo más frecuente fue el no agudizador (44,9% de los pacientes de alto riesgo). Un 20,6% de los pacientes de bajo riesgo cumplían criterios de solapamiento entre EPOC y asma. Un 9,2% de la cohorte no cumplía los criterios diagnósticos de ningún fenotipo y el 19,1% cumplía los criterios de dos fenotipos, sin diferencias entre grupos de riesgo. Conclusiones: Nuestros datos ponen de manifiesto algunas de las debilidades de la actual estrategia basada en fenotipos clínicos, existiendo solapamiento en algunos casos y pacientes sin fenotipos., [EN] Objectives: In a clinical phenotype-based management strategy for COPD, it would be preferable to at least assign all patients to a phenotype, but to a single phenotype only. The aim of this study was to evaluate whether all patients are assigned to one and only one phenotype using the Spanish COPD guidelines (GesEPOC) and to evaluate the criteria that define these categories. Method: The Time-based Register and Analysis of COPD Endpoints study (TRACE; clinicaltrials.gov NCT03485690) is a prospective cohort of COPD patients attending annual visits since 2012, which collects GesEPOC phenotypes. Although the GesEPOC recommends that patients considered to be at low risk are not phenotyped, an analysis of the criteria for identifying high- and low-risk phenotypes was performed, comparing the distribution of phenotypes and the criteria applied between these 2 groups. Results: The cohort included 970 patients with a confirmed diagnosis of COPD, divided into 427 (44.02%) low-risk and 543 (55.9%) high-risk patients. The most frequent phenotype was the non-exacerbator (44.9% of high-risk patients). Overall, 20.6% of low-risk patients met criteria for asthma-COPD overlap syndrome, while 9.2% of the cohort did not meet the diagnostic criteria for any phenotype, and 19.1% met the criteria for 2 phenotypes, with no differences between risk groups. Conclusions: Our data highlight some of the weaknesses of the current clinical phenotype strategy, revealing overlapping categories in some cases, and patients to whom no phenotype was assigned., El proyecto TRACE (clinicaltrials.gov NCT03485690) ha sido financiado con una beca no condicionada de Laboratorios Gebro Phama (Barcelona, España).

Debido a la pandemia por COVID-19 declarada por la OMS en marzo del 2020, la gran mayoría de los hospitales españoles han debido transformarse para adaptarse a este nuevo escenario, resultando en cambios en su infraestructura y organización, generando estrategias de colaboración y coordinación entre diferentes especialidades..., El presente trabajo ha sido realizado gracias a la financiación por parte de Philips de la empresa externa IPSOS.

Background Noninvasive ventilation (NIV) is an effective form of treatment in obesity hypoventilation syndrome (OHS) with severe OSA. However, there is paucity of evidence in patients with OHS without severe OSA phenotype. Research Question Is NIV effective in OHS without severe OSA phenotype? Study Design and Methods In this multicenter, open-label parallel group clinical trial performed at 16 sites in Spain, we randomly assigned 98 stable ambulatory patients with untreated OHS and apnea-hypopnea index Results Forty-nine patients in the NIV group and 49 in the control group were randomized, and 48 patients in each group were analyzed. During a median follow-up of 4.98 years (interquartile range, 2.98-6.62), the mean hospitalization days per year ± SD was 2.60 ± 5.31 in the control group and 2.71 ± 4.52 in the NIV group (adjusted rate ratio, 1.07; 95% CI, 0.44-2.59; P = .882). NIV therapy, in contrast with the control group, produced significant longitudinal improvement in Paco2, pH, bicarbonate, quality of life (Medical Outcome Survey Short Form 36 physical component), and daytime sleepiness. Moreover, per-protocol analysis showed a statistically significant difference for the time until the first ED visit favoring NIV. In the subgroup with high NIV adherence, the time until the first event of hospital admission, ED visit, and mortality was longer than in the low adherence subgroup. Adverse events were similar between arms. Interpretation In stable ambulatory patients with OHS without severe OSA, NIV and lifestyle modification had similar long-term hospitalization days per year. A more intensive program aimed at improving NIV adherence may lead to better outcomes. Larger studies are necessary to better determine the long-term benefit of NIV in this subgroup of OHS. Trial Registry ClinicalTrials.gov; No.: NCT01405976; URL: www.clinicaltrials.gov

Spanish Sleep Network., [Rationale] Obesity hypoventilation syndrome (OHS) has been associated with cardiac dysfunction. However, randomized trials assessing the impact of long-term noninvasive ventilation (NIV) or continuous positive airway pressure (CPAP) on cardiac structure and function assessed by echocardiography are lacking. Rationale: Obesity hypoventilation syndrome (OHS) has been associated with cardiac dysfunction. However, randomized trials assessing the impact of long-term noninvasive ventilation (NIV) or continuous positive airway pressure (CPAP) on cardiac structure and function assessed by echocardiography are lacking., [Objectives] In a prespecified secondary analysis of the largest multicenter randomized controlled trial of OHS (Pickwick Project; N = 221 patients with OHS and coexistent severe obstructive sleep apnea), we compared the effectiveness of three years of NIV and CPAP on structural and functional echocardiographic changes., [Methods] At baseline and annually during three sequential years, patients underwent transthoracic two-dimensional and Doppler echocardiography. Echocardiographers at each site were blinded to the treatment allocation. Statistical analysis was performed using a linear mixed-effects model with a treatment group and repeated measures interaction to determine the differential effect between CPAP and NIV. Measurements and Main Results: A total of 196 patients were analyzed: 102 were treated with CPAP and 94 were treated with NIV. Systolic pulmonary artery pressure decreased from 40.5 ± 1.47 mm Hg at baseline to 35.3 ± 1.33 mm Hg at three years with CPAP, and from 41.5 ± 1.56 mm Hg to 35.5 ± 1.42 with NIV (P, [Conclusions] In patients with OHS who have concomitant severe obstructive sleep apnea, long-term treatment with NIV and CPAP led to similar degrees of improvement in pulmonary hypertension and left ventricular diastolic dysfunction.

Pulmonary hypertension (PH) is prevalent in obesity hypoventilation syndrome (OHS). However, there is a paucity of data assessing pathogenic factors associated with PH. Our objective is to assess risk factors that may be involved in the pathogenesis of PH in untreated OHS.

Chronic obstructive pulmonary disease (COPD) patients constitute a heterogeneous population in terms of treatment response. Our objective was to identify possible predictive factors of response to treatment with single bronchodilation monotherapy in patients diagnosed with COPD. The Time-based Register and Analysis of COPD Endpoints (TRACE, clinicaltrials.gov NCT03485690) is a prospective cohort of COPD patients who have been attending annual visits since 2012. Patients who were kept on a single bronchodilator during the first year of follow-up were selected. The responders were defined according to all of the following variables: any improvement in morning post-dose forced expiratory volume in 1 s or deterioration &lt, 100 mL, no change or improvement in dyspnea score, and no occurrence of exacerbations. Significant and plausible variables were analyzed using a proportional hazard Cox regression for single bronchodilator responders. We analyzed 764 cases, of whom 128 (16.8%) were receiving monotherapy with one bronchodilator. Of these, 85 patients (66.4%) were responders. Factors affecting responder status were: female gender (hazard ratio (HR) 0.276, 95% confidence interval (CI) 0.089–0.858), dyslipidemia (HR 0.436, 95%CI 0.202–0.939), not performing regular exercise (HR 0.523, 95%CI 0.254–1.076), active smoking (HR 0.413, 95%CI 0.186–0.920), and treatment adherence (HR 2.527, 95%CI 1.271–5.027). The factors associated with a single bronchodilation response are mainly non-pharmacological interventions and comorbidities.

[Rationale] Obesity hypoventilation syndrome (OHS) with concomitant severe obstructive sleep apnea (OSA) is treated with CPAP or noninvasive ventilation (NIV) during sleep. NIV is costlier, but may be advantageous because it provides ventilatory support. However, there are no long-term trials comparing these treatment modalities based on OHS severity., [Objective] To determine if CPAP have similar effectiveness when compared to NIV according to OHS severity subgroups., [Methods] Post hoc analysis of the Pickwick randomized clinical trial in which 215 ambulatory patients with untreated OHS and concomitant severe OSA, defined as apnoea-hypopnea index (AHI) ≥ 30 events/h, were allocated to NIV or CPAP. In the present analysis, the Pickwick cohort was divided in severity subgroups based on the degree of baseline daytime hypercapnia (PaCO2 of 45–49.9 or ≥50 mmHg). Repeated measures of PaCO2 and PaO2 during the subsequent 3 years were compared between CPAP and NIV in the two severity subgroups. Statistical analysis was performed using linear mixed-effects model., [Results] 204 patients, 97 in the NIV group and 107 in the CPAP group were analyzed. The longitudinal improvements of PaCO2 and PaO2 were similar between CPAP and NIV based on the PaCO2 severity subgroups., [Conclusion] In ambulatory patients with OHS and concomitant severe OSA who were treated with NIV or CPAP, long-term NIV therapy was similar to CPAP in improving awake hypercapnia, regardless of the severity of baseline hypercapnia. Therefore, in this patient population, the decision to prescribe CPAP or NIV cannot be solely based on the presenting level of PaCO2., [Introducción] El síndrome de hipoventilación-obesidad (SHO) con apnea obstructiva del sueño (AOS) grave concomitante se trata con CPAPo ventilación no invasiva (VNI) durante el sueño. La VNI es más costosa, pero puede ser beneficiosa porque proporciona soporte ventilatorio; sin embargo, no existen estudios a largo plazo que comparen estas modalidades de tratamiento basándose en la gravedad del SHO., [Objetivo] Determinar si la CPAP tiene una eficacia similar a la VNI según los subgrupos de gravedad del SHO., [Métodos] Análisis a posteriori del ensayo clínico aleatorizado Pickwick en el que 215 pacientes ambulatorios con SHO sin tratar y con AOS grave concomitante (definida como un índice de apnea-hipopnea [IAH] ≥ 30 episodios/hora) recibieron tratamiento con VNI o CPAP. En el presente análisis, la cohorte Pickwick se dividió en subgrupos según la gravedad basándose en el grado de hipercapnia diurna al inicio del estudio (PaCO2 de 45-49.9 mm Hg o ≥ 50 mm Hg). Se compararon las mediciones periódicas de PaCO2 y PaO2 durante los 3 años siguientes entre la CPAP y la VNI entre los dos subgrupos de gravedad. Se realizó un análisis estadístico utilizando un modelo lineal mixto., [Resultados] Se analizaron 204 pacientes, 97 en el grupo de VNI y 107 en el grupo de CPAP. Las mejoras lineales de PaCO2 y PaO2 fueron similares entre la CPAP y la NIV según los subgrupos de gravedad en función de la PaCO2., [Conclusión] En los pacientes ambulatorios con SHO y AOS grave concomitante a los que se trató con VNI o CPAP, el tratamiento a largo plazo con VNI resultó similar a la CPAP, en cuanto a la mejora de la hipercapnia en vigilia, independientemente de la gravedad de la hipercapnia de inicio. Por lo tanto, en esta población de pacientes la decisión de prescribir CPAP o VNI no puede basarse exclusivamente en el nivel de partida de PaCO2., Instituto de Salud Carlos III (Fondo de Investigaciones Sanitarias, Ministerio de Sanidad y Consumo, Madrid, Spain) PI050402, Spanish Respiratory Foundation 2005 (FEPAR) and Air Liquide Spain.

Rationale: Noninvasive ventilation (NIV) is an effective treatment in obesity hypoventilation syndrome (OHS) with severe obstructive sleep apnoea (OSA) but there is paucity of evidence in OHS patients without severe OSA phenotype. Methods: In this multicentre (16 sites in Spain), open-label parallel group clinical trial, we randomly assigned 98 stable ambulatory patients with untreated OHS and apnoea-hypopnoea index Results:49 patients were randomised in each group and 48 patients were analysed in each one of them. During a median [IQR] follow-up of 4.98 [2.98; 6.62] years, mean (SD) hospitalization days/year was 2.60 (5.31) in the control group and 2.71 (4.52) in the NIV group [adjusted rate ratio (95% CI) 1.07 (0.44; 2.59) (p = 0.882)]. Cardiovascular events occurred in 11 (23%) participants in the control group and 10 (21%) in the NIV group (hazard ratio (95% CI) 0.96 (0.40;2.30), p=0.927). Similar results were observed in the per-protocol analysis [rate ratio (95% CI) 1.21 (0.43;3.41) (p=0.717)]. Death occurred in 9 (19%) participants in both arms (adjusted hazard ratio (95% CI) 1.07 (0.41;2.82), p=0.893). Similar results were found in the per-protocol analysis [rate ratio (95% CI) 1.38 (0.50;3.79) (p=0.529)]. Conclusion: In stable ambulatory patients with OHS without severe OSA, NIV and lifestyle modification had similar long-term hospitalization days-year. Larger studies are necessary to better determine the long-term benefit of NIV in this subgroup of OHS.

Rationale: Obesity hypoventilation syndrome (OHS) has been associated with cardiac dysfunction. However, randomized trials have assessing the impact of long-term noninvasive ventilation (NIV) or CPAP on cardiac structure and function assessed by echocardiography are lacking. Methods: In a pre-specified secondary analysis of the largest multicenter randomized controlled trial of OHS〔Pickwick project, n=221 patient with OHS and coexistent severe obstructive sleep apnea (OSA)〕, we compared the effectiveness of 3 years of NIV and CPAP on structural and functional echocardiographic changes. At baseline and annually during 3 sequential years patients underwent transthoracic two-dimensional and doppler echocardiography. Echocardiographers were blinded to the treatment allocation. Statistical analysis was performed using a linear mixed-effects model with a treatment group/repeated measures interaction to determine the differential effect between CPAP and NIV. Results:196 patients were analyzed, 102 treated with CPAP and 94 treated with NIV. Systolic pulmonary artery pressure decreased from 40.5±1.47 mmHg at baseline to 35.3±1.33 mmHg at 3 years with CPAP and from 41.5±1.56 mmHg to 35.5±1.42 with NIV (p Conclusion: In patients with OHS and concomitant severe OSA, long-term treatment with NIV and CPAP led to similar degrees of improvement in pulmonary hypertension and LVDF.

Obstructive sleep apnea (OSA) is an independent cause of resistant hypertension (RH) but its association with refractory hypertension (RfH), a recently described form of severe hypertension, has not yet been investigated. This study seeks to analyze the association between the presence and severity of OSA/OSA syndrome with RfH and to compare it with a group of patients with OSA/OSA syndrome and RH. We conducted a multicenter, cross-sectional study of consecutive patients diagnosed with RH by means of 24-hour ambulatory blood pressure monitoring. Those patients with blood pressure levels ≥130/80 mm Hg, despite taking at least 5 antihypertensive drugs, were considered to have true RfH. All patients underwent a sleep study and completed a detailed clinical history related to OSA, current medication, and cardiovascular diseases. Overall, 229 patients were included (mean age, 58.3 years; 63% male), of whom 42 (18.3%) satisfied the criteria for RfH. Compared with those with RH, patients with RfH had a higher cardiovascular risk profile, higher blood pressure measurements, and a 2-fold greater risk of having both severe OSA (odds ratio, 2.1, with a prevalence of apnea-hypopnea index ≥15, 95.2% and apnea-hypopnea index ≥30, 64.3%) and OSA syndrome (apnea-hypopnea index ≥5+Epworth Sleepiness Scale >10; odds ratio, 1.9; 52.4% versus 37.3%; P =0.023), as well as higher OSA severity (apnea-hypopnea index, 41.8 versus 33.8 events/h; P =0.026). Patients with RfH had an even greater prevalence and severity of OSA and OSA syndrome than RH patients, highlighting the need to identify these patients to refer them to sleep units on a preferential basis.

Rationale: Obesity hypoventilation syndrome (OHS) is commonly treated with noninvasive ventilation (NIV) or CPAP. NIV is more complex and costly but provides ventilatory support. To date there have been no long-term or cost trials comparing these treatment modalities. Methods: We performed a large, randomized, multicenter, open-label controlled trial in Spain to compare the long-term effectiveness of NIV and CPAP using hospitalization days/year-patient as the primary end point. We carried out a simple cost analysis including effectiveness cost during 3 year of follow-up. We included the following cost groups: visits, adjustment of NIV, tests, medication, therapies and hospital resources utilization. A sensitivity analysis was conducted according to 3 different scenarios guided by the International Gross Domestic Product. Results: In total, 215 patients with untreated OHS and severe obstructive sleep apnea (OSA) were randomized to NIV or CPAP therapy and followed at least 3 years. The effectiveness was close between arms (mean difference NIV-CPAP: -0.19, 95% CI -1.13 to 0.75). The cost per patient/year was lower in the CPAP arm (1,898.2€; SD 1939.5) than the cost in the NIV arm (2,809.3€; SD 2901.6), mean difference -911.1€ (p Conclusions: In stable patients with OHS and severe OSA, despite NIV having a slight advantage in effectiveness, CPAP could be considered the first line of treatment due to its lower cost but, a case-by-case assessment is recommended to detect patients who would benefit from a switch to NIV.

Rationale: Obesity hypoventilation syndrome (OHS) is commonly treated with CPAP or noninvasive ventilation (NIV). NIV is more complex and costly but it provides ventilatory support. To date there have been no long-term trials comparing these treatment modalities. Methods: We performed a large, multicenter, open-label controlled trial in Spain to compare the long-term effectiveness of NIV and CPAP: respiratory function, Epworth sleepness scale (ESS), other clinical symptoms, blood pressure (BP) and health related quality of life (HRQL). The analysis was performed according to the intention-to-treat principle. Results: In total, 215 patients with untreated OHS and severe obstructive sleep apnea (OSH) were randomized to NIV or CPAP therapy and followed at least 3 years. PaCO2, bicarbonate and pH improved significantly with both treatments without group differences. FEV1 and FVC improved with positive airway pressure (PAP) but without significant group differences. The 6-MWD test did not improve with either PAP modality and there were no significant group differences. ESS and other clinical symptoms like dyspnea or unrefreshing sleep improved similarly with CPAP and NIV therapy. Both systolic and diastolic BP improved significantly with PAP but without group differences. HRQL tests (SF-36 physical and mental, FOSQ and VAWS) improved with PAP without any significant group differences. Conclusions: In stable patients with OHS and severe OSA, NIV and CPAP have similar long-term effectiveness improving respiratory function, symptoms, BP and HRQL. Given that CPAP has lower complexity and cost, CPAP may be the preferred treatment modality until more studies become available.

Spanish Sleep Network., [Rationale] Continuous positive airway pressure (CPAP) can significantly reduce blood pressure (BP) levels in patients with resistant hypertension and sleep apnea (OSA); however, the effect on patients with refractory hypertension (RfH) is not known. This study seeks to evaluate the effect of CPAP treatment on BP levels in patients with OSA and RfH, compared with those with OSA and resistant hypertension., [Methods] Post-hoc analysis of the HIPARCO randomized clinical trial on the effect of CPAP treatment on BP levels in patients with resistant hypertension. Those patients with uncontrolled 24-h ambulatory BP monitoring readings (>130 and/or >80 mmHg) in SBP or DBP were considered to have resistant hypertension (if they were taking three or four antihypertensive drugs) or RfH (if they were taking at least five drugs). OSA patients were randomized to receive CPAP or usual care for 3 months. They underwent a second 24-h ambulatory BP monitoring study to establish the effect of CPAP treatment on BP levels in both groups., [Results] A total of 98 patients were randomized to CPAP (19 RfH/79 resistant hypertension) and 96 to usual care (21 RfH/75 resistant hypertension). BP readings dropped more marked in patients with RfH than resistant hypertension, in both 24-h SBP (−9 vs. −1.6 mmHg, P = 0.021) and 24-h DBP (−7.3 vs. −2.3 mmHg, P = 0.074), especially at night (−11.3 vs. −3.8, P = 0.121 and −8.8 vs. −2.2, P = 0.054) respectively. Adjusted difference between groups was statistically significant in 24-h SBP levels (−7.4 mmHg, P = 0.021)., [Conclusion] CPAP lowers BP levels in both resistant hypertension and RfH patients although the degree of this reduction is higher in those with RfH especially during the night.

Refractory hypertension (RfH) is defined as a lack of blood pressure control despite the administration of at least 5 anti-hypertensive drugs. The factors associated with its natural history are unknown. This study aimed to evaluate both the incidence of RfH in an cohort of patients with resistant hypertension (RH) and the factors involved in that progression. This was an observational prospective multicenter study (24 centers) with 172 patients with confirmed RH (24-h ABPM) who underwent a further 24 h ABPM study at the end of the follow-up. Prospective information was obtained from all patients in their corresponding Hypertension Units via a standard clinical protocol, and they all underwent a sleep study. Thirty patients were diagnosed with RfH (17.4%) after a mean follow-up of 57 months, despite the prescription of a greater number of long-acting thiazide-like diuretics and mineralocorticoid receptor antagonists. The factors associated with progression to RfH were: a longer period since the diagnosis of RH (OR: 1.06, 95% CI: 1.01–1.1, p = 0.007); the HbA1c concentration (OR: 1.42, 95% CI: 1.42–1.8; p = 0.005); the initial heart rate (OR: 1.05, 95% CI: 1.01–1.09, p = 0.004); and poor adherence to continuous positive airway pressure (CPAP) in cases of obstructive sleep apnea (OR: 3.36, 95% CI: 1.47–7.7, p = 0.004). In conclusion, a considerable percentage of patients evolved from the RH to the RfH phenotype despite changes in their treatment. Some easily measurable variables, such as heart rate, the time since the diagnosis, the HbA1c level, and the presence of untreated obstructive sleep apnea (or poor adherence to CPAP) have been demonstrated to be prognostic factors in the progression to RfH.

[Study objectives] Vascular damage must be diagnosed early in patients with hypertension. In this regard, endothelial dysfunction (ED) is an early sign of vascular disease and a predictor of cardiovascular diseases. In obstructive sleep apnea (OSA), intermittent hypoxia triggers ED, but mechanisms are not clear. In this context, it has been described that BK channels regulates arterial tone and that chronic and intermittent hypoxia downregulates the expression of the BK channel β1-subunit facilitating vasoconstriction. Thus, we investigated the relationship among hypoxemia, ED, and mRNA expression of the β1-subunit in patients with severe OSA. We aimed to assess (1) ED in non-hypertensive patients with OSA using laser-Doppler flowmetry, (2) BK β1-subunit mRNA expression, and (3) the impact of continuous positive airway pressure (CPAP) treatment on ED and β1-subunit regulation., [Methods] OSA patients underwent 24-hour blood pressure monitoring to exclude hypertension. Laser-Doppler flowmetry was performed to assess ED, and β1-subunit mRNA expression was evaluated using a blood test of peripheral blood leukocytes at baseline and after 3 months of CPAP treatment., [Results] In normotensive patients with OSA, endothelial function correlated with the severity of OSA. CPAP improved endothelial function in normotensive OSA patients and the speed of the arterial response was significantly correlated with β1-subunit mRNA expression. β1-subunit mRNA expression at baseline correlated inversely with its change after CPAP., [Conclusions] Sleep apnea is related to ED in normotensive patients with OSA. CPAP therapy improves endothelial function and regulates β1-subunit mRNA expression., This work was supported by two grants: 1) Instituto de Salud Carlos III, PI/0044/07, to Dr. P. Stiefel (P.S). http://www.isciii.es/ISCIII/es/contenidos/fd-investigacion/fd-financiacion/fd-convocatoriasayudas-accion-estrategica-salud/acceso-solicitud-ayudas.shtml. 2) Consejeria de Salud, Junta de Andalucía, P09-CTS-4971, to Dra. M.A Sánchez-Armengol (A.S.A). https://www.juntadeandalucia.es/temas/estudiar/becas/nacionales.html.

[Rationale:] Obesity leads to resistant hypertension and mechanisms are poorly understood, but high plasma levels of leptin have been implicated. Leptin increases blood pressure acting both centrally in the dorsomedial hypothalamus and peripherally. Sites of the peripheral hypertensive effect of leptin have not been identified. We previously reported that leptin enhanced activity of the carotid sinus nerve, which transmits chemosensory input from the carotid bodies (CBs) to the medullary centers, and this effect was abolished by nonselective blockers of Trp (transient receptor potential) channels. We searched our mouse CB transcriptome database and found that the Trpm7 (transient receptor potential melastatin 7) channel was the most abundant Trp channel., [Objective] To examine if leptin induces hypertension acting on the CB Trpm7., [Methods and Results] C57BL/6J (n=79), leptin receptor (LepRb) deficient db/db mice (n=22), and LepRb-EGFP (n=4) mice were used. CB Trpm7 and LepRb gene expression was determined and immunohistochemistry was performed; CB glomus cells were isolated and Trpm7-like current was recorded. Blood pressure was recorded continuously in (1) leptin-treated C57BL/6J mice with intact and denervated CB; (2) leptin-treated C57BL/6J mice, which also received a nonselective Trpm7 blocker FTY720 administered systemically or topically to the CB area; (3) leptin-treated C57BL/6J mice transfected with Trpm7 small hairpin RNA to the CB, and (4) Leprb deficient obese db/db mice before and after Leprb expression in CB. Leptin receptor and Trpm7 colocalized in the CB glomus cells. Leptin induced a nonselective cation current in these cells, which was inhibited by Trpm7 blockers. Leptin induced hypertension in C57BL/6J mice, which was abolished by CB denervation, Trpm 7 blockers, and Trpm7 small hairpin RNA applied to CBs. Leprb overexpression in CB of Leprb-deficient db/db mice demethylated the Trpm7 promoter, increased Trpm7 gene expression, and induced hypertension., [Conclusions] We conclude that leptin induces hypertension acting on Trmp7 in CB, which opens horizons for new therapy.

Leptin is a potent respiratory stimulant. The carotid bodies (CB) express the long functional isoform of leptin receptor, LepRb, but the role of leptin in CB has not been fully elucidated. The objectives of the current study were (1) to examine the effect of subcutaneous leptin infusion on minute ventilation (VE) and the hypoxic ventilatory response to 10% O2 (HVR) in C57BL/6J mice before and after CB denervation; (2) to express LepRb in CB of LepRb‐deficient obese db/db mice and examine its effects on breathing during sleep and wakefulness and on HVR. We found that leptin enhanced carotid sinus nerve activity at baseline and in response to 10% O2 in vivo. In C57BL/6J mice, leptin increased VE from 1.1 to 1.5 mL/min/g during normoxia (P < 0.01) and from 3.6 to 4.7 mL/min/g during hypoxia (P < 0.001), augmenting HVR from 0.23 to 0.31 mL/min/g/Δurn:x-wiley:00223751:media:tjp13266:tjp13266-math-0001 (P < 0.001). The effects of leptin on VE and HVR were abolished by CB denervation. In db/db mice, LepRb expression in CB increased VE from 1.1 to 1.3 mL/min/g during normoxia (P < 0.05) and from 2.8 to 3.2 mL/min/g during hypoxia (P < 0.02), increasing HVR. Compared to control db/db mice, LepRb transfected mice showed significantly higher VE throughout non‐rapid eye movement (20.1 vs. −27.7 mL/min respectively, P < 0.05) and rapid eye movement sleep (16.5 vs 23.4 mL/min, P < 0.05). We conclude that leptin acts in CB to augment VE and HVR, which may protect against sleep disordered breathing in obesity., This work was funded by the NIH R01s HL133100 to V.Y.P. and J.S.K.S., R01 HL128970 to V.Y.P. and A.R.S., R01 HL138932 to V.Y.P. V.Y.P. is also supported by NIEHS grant P50 ES018176 and EPA Agreements 83615201 & 83451001. C.C.E. was supported in part by ‘Beca de estancias formativas de la Consejería de Salud de Andalucía 2017. C. Caballero Eraso. Número de expediente: EF‐0128‐2016’.

Obstructive sleep apnea (OSA) is an independent cause of resistant hypertension (RH) but its association with refractory hypertension (RfH), a recently described form of severe hypertension, has not yet been investigated. This study seeks to analyze the association between the presence and severity of OSA/OSA syndrome with RfH and to compare it with a group of patients with OSA/OSA syndrome and RH. We conducted a multicenter, cross-sectional study of consecutive patients diagnosed with RH by means of 24-hour ambulatory blood pressure monitoring. Those patients with blood pressure levels ≥130/80 mm Hg, despite taking at least 5 antihypertensive drugs, were considered to have true RfH. All patients underwent a sleep study and completed a detailed clinical history related to OSA, current medication, and cardiovascular diseases. Overall, 229 patients were included (mean age, 58.3 years; 63% male), of whom 42 (18.3%) satisfied the criteria for RfH. Compared with those with RH, patients with RfH had a higher cardiovascular risk profile, higher blood pressure measurements, and a 2-fold greater risk of having both severe OSA (odds ratio, 2.1, with a prevalence of apnea-hypopnea index ≥15, 95.2% and apnea-hypopnea index ≥30, 64.3%) and OSA syndrome (apnea-hypopnea index ≥5+Epworth Sleepiness Scale10; odds ratio, 1.9; 52.4% versus 37.3%; P=0.023), as well as higher OSA severity (apnea-hypopnea index, 41.8 versus 33.8 events/h; P=0.026). Patients with RfH had an even greater prevalence and severity of OSA and OSA syndrome than RH patients, highlighting the need to identify these patients to refer them to sleep units on a preferential basis.

Obesity leads to sleep-disordered breathing (SDB) manifested by recurrent upper airway obstructions termed obstructive sleep apnea (OSA) and carbon dioxide retention due to hypoventilation. The objective of this work was to characterize breathing during sleep in C57BL6/J mice with diet-induced obesity (DIO). Arterial blood gas was measured in nine obese and nine lean mice during wakefulness. Nine male mice with DIO and six lean male C57BL/6J mice were head mounted with electroencephalogram (EEG) and electromyogram (EMG) electrodes. Sleep recordings were performed in the whole body plethysmography chamber; upper airway obstruction was characterized by the presence of inspiratory flow limitation in which airflow plateaus with increases in inspiratory effort. Obese mice showed significantly lower pH and higher partial pressure of arterial CO(2) (PaCO(2)) in arterial blood gas compared to lean mice, 7.35 ± 0.04 versus 7.46 ± 0.06 (p < 0.001) and 38 ± 8 mm Hg versus 30 ± 5 mm Hg (p < 0.001). Obese mice had similar levels of minute ventilation to lean mice during sleep and wakefulness, despite higher body weight and temperature, indicating an increase in the metabolic rate and hypoventilation. Obese mice also showed baseline hypoxemia with decreased mean oxyhemoglobin saturation across sleep/wake states. Obese mice had a higher prevalence of flow-limited breathing compared to lean mice during sleep. However, the oxygen desaturation index in lean and obese mice did not differ. We conclude that DIO in mice leads to hypoventilation. Obesity also increases the frequency of inspiratory limited breaths, but it does not translate into progression of OSA.

Rationale: General practitioners play a passive role in obstructive sleep apnea (OSA) management. Simplification of the diagnosis and use of a semiautomatic algorithm for treatment can facilitate the integration of general practitioners, which has cost advantages.Objectives: To determine differences in effectiveness between primary health care area (PHA) and in-laboratory specialized management protocols during 6 months of follow-up.Methods: A multicenter, noninferiority, randomized, controlled trial with two open parallel arms and a cost-effectiveness analysis was performed in six tertiary hospitals in Spain. Sequentially screened patients with an intermediate to high OSA probability were randomized to PHA or in-laboratory management. The PHA arm involved a portable monitor with automatic scoring and semiautomatic therapeutic decision-making. The in-laboratory arm included polysomnography and specialized therapeutic decision-making. Patients in both arms received continuous positive airway pressure treatment or sleep hygiene and dietary treatment alone. The primary outcome measure was the Epworth Sleepiness Scale. Secondary outcomes were health-related quality of life, blood pressure, incidence of cardiovascular events, hospital resource utilization, continuous positive airway pressure adherence, and within-trial costs.Measurements and Main Results: In total, 307 patients were randomized and 303 were included in the intention-to-treat analysis. Based on the Epworth Sleepiness Scale, the PHA protocol was noninferior to the in-laboratory protocol. Secondary outcome variables were similar between the protocols. The cost-effectiveness relationship favored the PHA arm, with a cost difference of €537.8 per patient.Conclusions: PHA management may be an alternative to in-laboratory management for patients with an intermediate to high OSA probability. Given the clear economic advantage of outpatient management, this finding could change established clinical practice.Clinical trial registered with www.clinicaltrials.gov (NCT02141165).

Resumen Fundamento y objetivo Realizamos un estudio sobre seguridad, costes comparados y analisis de impacto presupuestario del tratamiento ambulatorio de pacientes con cancer y trombosis venosa profunda (TVP) frente al tratamiento hospitalario. Material y metodos Estudio observacional y prospectivo de pacientes con neoplasia conocida y diagnosticados de TVP desde 2003 hasta 2007. Las variables de resultados fueron mortalidad, recidivas y hemorragias a un mes. Realizamos un analisis economico para evaluar el coste comparado de los pacientes tratados ambulatoriamente frente al procedimiento habitual. Resultados Se incluyeron 317 pacientes, 55 (17%) con cancer. La edad media (DE) de los pacientes fue de 63 (11) anos. Las complicaciones a un mes fueron: 2 sangrados, 2 recidivas y 6 muertes. De todos los pacientes, solo 7 (13,7%) necesitaron ingreso hospitalario. Todas las muertes excepto una fueron debidas a la progresion de su enfermedad de base. Cuando realizamos el analisis economico observamos que el tratamiento ambulatorio es 6 veces menos costoso que el hospitalario, lo que implicaria una reduccion de costes de un 85%. Conclusiones El tratamiento ambulatorio a traves de una consulta monografica de los pacientes con cancer y TVP es seguro y podria ahorrar importantes recursos economicos.

Patients with neuromuscular diseases usually require mechanical ventilation because of progression of their disease or after a hospitalization. In the latter situation, it is essential to optimize long-term care and to be able to transfer the patient in the best condition from the intensive care unit to home, ensuring their safety and comfort and avoiding invasive ventilation forms such as tracheostomy.

Resumen Se presenta el caso de una mujer de 20 anos diagnosticada de tromboembolismo pulmonar (EP) y trombosis de la vena subclavia derecha atribuible a la estasis provocada por la prominencia clavicular derecha. En el seguimiento a los 10 meses la paciente desarrollo una hipertension pulmonar tromboembolica cronica (HPTEC), instaurandose tratamiento con un antagonista dual del receptor de endotelina. Se han descrito muy pocos casos de trombosis venosa profunda de miembro superior debidos a alteraciones anatomicas. Lo excepcional del caso es que, ademas, la paciente desarrollo una hipertension pulmonar postembolica cronica, cuya incidencia se estima del 0,5% del total de los EP sintomaticos.

We report on a 20 year-old woman diagnosed with pulmonary embolism (PE) and right subclavian vein thrombosis attributable to stasis caused by right clavicular prominence. At the 10-months follow-up, the patient had developed chronic thromboembolic pulmonary hypertension (CTEPH), and treatment was begun with a dual endothelin receptor antagonist. Very few cases of deep venous thrombosis of upper limb have been reported in relation to anatomical abnormalities. This case is also exceptional because the patient developed a chronic thromboembolic pulmonary hypertension, whose incidence is estimated at 0.5% of all symptomatic PE.

We analyze a large population of patients to determine whether gamma glutamyl transferase (GGT) levels are increased in sleep apnea-hypopnea syndrome (OSA) and whether these levels are related to clinical characteristics or polygraphic indexes. A cross-sectional study in a population of 1744 patients referred for OSA suspicion was conducted. The following variables were determined: glucose, cholesterol, triglycerides, aspartate aminotransferase (GOT), alanine aminotransferase (GPT), GGT, body mass index, waist-hip ratio (WHR), and overnight sleep study. The 483 patients with GGT ≥40 IU/l were younger and more obese, and had a pattern of more centrally distributed fat than the 1261 with GGT

The carotid body (CB) is a key chemoreceptor organ in which glomus cells sense changes in blood O2, CO2, and pH levels. CB glomus cells have also been found to detect hypoglycemia in both non-primate mammals and humans. O2 and low-glucose responses share a common final pathway involving membrane depolarization, extracellular calcium influx, increase in cytosolic calcium concentration, and neurotransmitter secretion, which stimulates afferent sensory fibers to evoke sympathoadrenal activation. On the other hand, hypoxia and low glucose induce separate signal transduction pathways. Unlike O2 sensing, the response of the CB to low glucose is not altered by rotenone, with the low glucose-activated background cationic current unaffected by hypoxia. Responses of the CB to hypoglycemia and hypoxia can be potentiated by each other. The counter-regulatory response to hypoglycemia by the CB is essential for the brain, an organ that is particularly sensitive to low glucose. CB glucose sensing could be altered in diabetic patients, particularly those under insulin treatment, as well as in other medical conditions such as sleep apnea or obstructive pulmonary diseases, where chronic hypoxemia presents with plastic modifications in CB structure and function. The current review will focus on the following main aspects: (1) the CB as a low glucose sensor in both in vitro and in vivo models; (2) molecular and ionic mechanisms of low glucose sensing by glomus cells, (3) the interplay between low glucose and O2 sensing in CB, and (4) the role of CB low glucose sensing in the pathophysiology of cardiorespiratory and metabolic diseases, and how this may serve as a potential therapeutic target., This research was supported by the Botín Foundation and the Spanish Ministry of Economy and Innovation (SAF program).

Sarcoidosis is a systemic granulomatous disease of unknown etiology that is characterized from the point of view of pathology of the presence of noncaseating granulomas in affected organs. Typically affects young adults and is often present initially with one or more of the following conditions: 1) bilateral hilar lymphadenopathy, 2) pulmonary reticular pattern, 3) Involvement of the skin, joints and / or eyes.

Sarcoidosis is a systemic granulomatous disease that affects the lungs in 90% of cases. The stage of the disease is determined by the level of pulmonary damage as assessed by a chest x-ray. This pulmonary damage varies widely between stages I, when lymph node damage has no repercussions on lung functioning, and stage IV, in which interstitial pulmonary damage and the development of fibrosis has clear repercussions on lung functioning. Systemic corticosteroids are the drugs of choice for the treatment of sarcoidosis, although no clear consensus exists regarding when to start treatment, the correct doses, or how long treatment should be maintained. We must keep in mind that the progression of this disease is often unpredictable, with frequent cases of spontaneous remission, above all in stage I patients. However, systemic steroids have side effects and the decision to start treatment is determined by the intensity of the symptoms, especially exercise-induced dyspnoea, and the level of lung functioning deterioration. Sarcoidosis can affect both the upper and lower airways. Endobronchial damage occurs in 40% of stage I patients and approximately 70% of stage III and IV patients. Endobronchial granulomas have been described along with stenosis of the airway due to peribronchial damage. Clinically relevant airway stenosis is uncommon but difficult to treat. In the upper airway, granulomas can appear in the submucosa of the larynx, pharynx, and paranasal sinuses. Sleep apnoea has been described as a result of involvement of the epiglottis. This damage to the airway is occasionally manifested as the presence of persistent cough, with no findings in the pulmonary parenchyma. In up to 50% of cases, spirometry reveals obstructive phenomena, especially in patients with endobronchial damage due to the sarcoidosis. The treatment of choice for pulmonary sarcoidosis is oral corticosteroids. Other alternative treatments have been described, such as immunosuppressive agents (methotrexate, azathioprine, cyclophosphamide, leflunomide, cyclosporine, and chlorambucil), cytokine inhibitors (thalidomide and pentoxifylline), and immunomodulatory agents (TNF-alpha antagonists, infliximab, adalimumab, and antimalarial agents such as chloroquine) (Table 1). Currently, no clear evidence exists showing the usefulness of these drugs, and they are only indicated when the sarcoidosis does not respond to conventional treatment with oral

We report on a 20 year-old woman diagnosed with pulmonary embolism (PE) and right subclavian vein thrombosis attributable to stasis caused by right clavicular prominence. At the 10-months follow-up, the patient had developed chronic thromboembolic pulmonary hypertension (CTEPH), and treatment was begun with a dual endothelin receptor antagonist. Very few cases of deep venous thrombosis of upper limb have been reported in relation to anatomical abnormalities. This case is also exceptional because the patient developed a chronic thromboembolic pulmonary hypertension, whose incidence is estimated at 0.5% of all symptomatic PE.

This is a safety and cost comparison study with an analysis of budgetary impact of ambulatory management of patients with cancer and deep vein thrombosis (DVT) compared with hospital management.Prospective observational study of patients with known malignancy and diagnosed with DVT from 2003 to 2007. The outcome variables were mortality, relapse and bleeding in one month. We conducted an economic analysis to evaluate the comparative cost of ambulatory patients.Three hundred and seventeen patients, 55 (17%) had cancer. The mean age of patients was 63 ± 11 years. There were 2 hemorrhagic events, 2 recurrences and 6 deaths in one month of follow-up. Of all patients, only 7 (13,7%) required hospitalization. All but one deaths were due to progression of the underlying disease. Economic analysis concluded that outpatient management is 6 times less expensive than hospital management, which would imply a cost reduction of 85%.Specialized outpatient treatment of cancer patients with DVT is safe and could save significant financial resources.

Heart Rhythm disorders and suspected Sleep Apnea-Hypopnea syndrome Sleep Apnea-Hypopnea Syndrome (SAHS) is associated with several cardiovascular diseases and is a risk factor for heart rhythm disorders. A direct temporal relationship between obstructive respiratory events and the onset of non-sustained ventricular tachycardia (NSVT) and paroxysmal atrial fibrillation (AF), during sleep has been reported recently.