Acetylsalicylic acid prevents intermittent hypoxia-induced vascular remodeling in a murine model of sleep apnea

Study objectives: Chronic intermittent hypoxia (CIH), a hallmark feature of obstructive sleep apnea (OSA), induces accelerated atherogenesis as well as aorta vascular remodeling. Although the cyclooxygenase (COX) pathway has been proposed to contribute to the cardiovascular consequences of OSA, the potential benefits of a widely employed COX-inhibitor such (acetylsalicylic acid, ASA) on CIH-induced vascular pathology are unknown. Therefore, we hypothesized that a common non-selective COX inhibitor such as ASA would attenuate the aortic remodeling induced by CIH in mice. Methods: 40 wild-type C57/BL6malemice were randomly allocated to CIH or normoxic exposures (N) and treated with daily doses of ASA or placebo for 6 weeks. At the end of the experiments, intima-media thickness (IMT), elastin disorganization (ED), elastin fragmentation (EF), length between fragmented fiber endpoints (LFF), aortic wall collagen abundance (AC) and mucoid deposition (MD) were assessed. Results: Compared to N, CIH promoted significant increases in IMT (52.58 ± 2.82μm vs. 46.07 ± 4.18μm, p < 0.003), ED (25.29 ± 14.60% vs. 4.74 ± 5.37%, p < 0.001), EF (5.80 ± 2.04 vs. 3.06 ± 0.58, p < 0.001), LFF (0.65 ± 0.34% vs. 0.14 ± 0.09%, p < 0.001), AC (3.43 ± 1.52% vs. 1.67 ± 0.67%, p < 0.001) and MD (3.40 ± 2.73 μm2 vs. 1.09 ± 0.72 μm2, p < 0.006). ASA treatment mitigated the CIH-induced alterations in IMT: 44.07 ± 2.73μm; ED: 10.57 ± 12.89%; EF: 4.63 ± 0.88; LFF: 0.25 ± 0.17% and AC: 0.90 ± 0.13% (p<0.05 for all comparisons). Conclusions: ASA prevents the CIH-induced aortic vascular remodeling, and should therefore be prospectively evaluated as adjuvant treatment in patients with OSA.This work was supported by the Spanish Respiratory Society (SEPAR), SOCAP, the Associació Lleidatana de Respiratori (ALLER), and the Spanish Fondo de Investigaciones Sanitarias (PI14/00486 and PI14-00004), Instituto de Salud Carlos III (ISCIII), European Regional Development Fund (ERDF) “Una manera de hacer Europa”. DG is supported by National Institutes of Health grant HL130984

Barley-ß-glucans reduce systemic inflammation, renal injury and aortic calcification through ADAM17 and neutral-sphingomyelinase2 inhibition

In chronic kidney disease (CKD), hyperphosphatemia-induced inflammation aggravates vascular calcification (VC) by increasing vascular smooth muscle cell (VSMC) osteogenic differentiation, ADAM17-induced renal and vascular injury, and TNFα-induction of neutral-sphingomyelinase2 (nSMase2) to release pro-calcifying exosomes. This study examined anti-inflammatory β-glucans efficacy at attenuating systemic inflammation in health, and renal and vascular injury favoring VC in hyperphosphatemic CKD. In healthy adults, dietary barley β-glucans (Bβglucans) reduced leukocyte superoxide production, inflammatory ADAM17, TNFα, nSMase2, and pro-aging/pro-inflammatory STING (Stimulator of interferon genes) gene expression without decreasing circulating inflammatory cytokines, except for γ-interferon. In hyperphosphatemic rat CKD, dietary Bβglucans reduced renal and aortic ADAM17-driven inflammation attenuating CKD-progression (higher GFR and lower serum creatinine, proteinuria, kidney inflammatory infiltration and nSMase2), and TNFα-driven increases in aortic nSMase2 and calcium deposition without improving mineral homeostasis. In VSMC, Bβglucans prevented LPS- or uremic serum-induced rapid increases in ADAM17, TNFα and nSMase2, and reduced the 13-fold higher calcium deposition induced by prolonged calcifying conditions by inhibiting osteogenic differentiation and increases in nSMase2 through Dectin1-independent actions involving Bβglucans internalization. Thus, dietary Bβglucans inhibit leukocyte superoxide production and leukocyte, renal and aortic ADAM17- and nSMase2 gene expression attenuating systemic inflammation in health, and renal injury and aortic calcification despite hyperphosphatemia in CKD.A grant to A.S.D. and M.J.M. from IRBLleida and Agrotecnio Research collaborative projects from the Consell Social at Lleida University supported initial work, Instituto de Salud Carlos III and co-funded by European Union (ERDF/FEDER) (FIS PI11/00259, PI14/01452, PI17/02181), Plan de Ciencia, Tecnología e Innovación 2013–2017 y 2018–2022 del Principado de Asturias (GRUPIN14-028, IDI-2018-000152), RedInRen from ISCIII (ISCIII-RETIC REDINREN RD16/0009). Investigator support included: NC-L by GRUPIN14-028 and IDI-2018-000152, LM-A by GRUPIN14-028, SP by FICYT; MVA and PV by Educational Grant 2 A/2015 from ERA-EDTA CKD-MBD Working Group; PV and AC by ERA-EDTA fellowships 2011 and 2012; JR-C by MINECO (“Juan de la Cierva” program, FJCI-2015-23849); A.S.D. by Asociación Investigación de Fisiología Aplicada. A.S.D. and M.J.M. are members of the Campus Iberus (Ebro Valley Campus of International Excellence)

Remodelación cardiovascular inducida por hipoxia intermitente. Reversibilidad y efecto de la edad

La Síndrome d'apnea obstructiva de la son (SAOS) és una malaltia crònica prevalent en la població adulta i és considerat un problema de salut pública de primera magnitud a causa principalment a la seva morbimortalitat cardiovasculars. La hipòxia intermitent (HI) crònica és considerada el principal factor deleteri involucrat en les conseqüències cardiovasculars associades a la SAOS. El primer estudi va estar dirigit a avaluar la reversibilitat de la remodelació cardiovascular induïda per la HI en un model murí de SAOS. Les alteracions observades a nivell aòrtic i cardíac després de l'exposició a sis setmanes de HI van ser normalitzades després d'un període en condicions de normòxia, com a model translacional de l'tractament efectiu de la malaltia. Continuant en la mateixa línia d'investigació, es va estudiar l'efecte de l'edat en la remodelació cardiovascular induïda per HI. Els resultats van mostrar una protecció cardiovascular en els ratolins amb edat avançada, i en ratolins joves es va observar una remodelació cardiovascular similar a la que ocorre amb el declivi natural associat a l'envelliment. En vista del que observat, el tercer estudi va estar dirigit a definir els mecanismes moleculars que expliquen la remodelació cardiovascular induïda per hipòxia intermitent crònica observada en el segon estudi i com són modulats per l'edat. En aquest estudi es va trobar que la regulació de l'expressió gènica davant l'exposició a HI crònica és òrgan-dependent i és modulada per l'edat. El quart i últim estudi es va realitzar en pacients amb SAOS tractats amb el tractament d'elecció, pressió positiva contínua en la via aèria (CPAP). En primer lloc es va avaluar l'efecte de la CPAP en variables clíniques i biològiques; en segon lloc es va aconseguir definir un model de predicció de resposta a el tractament en termes de canvis de la pressió arterial nocturna. Els resultats van suggerir l'ús del monitoratge de la pressió arterial ambulatòria com a eina clau en la discriminació de pacients que a l'rebre tractament amb CPAP reduiran el risc cardiovascular, d'aquells pacients que tindran un efecte perjudicial a l'ésser tractats.El Síndrome de apnea obstructiva del sueño (SAOS) es una enfermedad crónica prevalente en la población adulta y es considerado un problema de salud pública de primera magnitud debido principalmente a su morbimortalidad cardiovasculares. La hipoxia intermitente (HI) crónica es considerada el principal factor deletéreo involucrado en las consecuencias cardiovasculares asociadas al SAOS. El primer estudio estuvo dirigido a evaluar la reversibilidad de la remodelación cardiovascular inducida por la HI en un modelo murino de SAOS. Las alteraciones observadas a nivel aórtico y cardíaco tras la exposición a seis semanas de HI fueron normalizadas tras un período en condiciones de normoxia, como modelo traslacional del tratamiento efectivo de la enfermedad. Continuando en la misma línea de investigación, se estudió el efecto de la edad en la remodelación cardiovascular inducida por HI. Los resultados mostraron una protección cardiovascular en los ratones con edad avanzada, y en ratones jóvenes se observó una remodelación cardiovascular similar a la que ocurre con el declive natural asociado al envejecimiento. En vista de lo observado, el tercer estudio estuvo dirigido a definir los mecanismos moleculares que explican la remodelación cardiovascular inducida por hipoxia intermitente crónica observada en el segundo estudio y como son modulados por la edad. En este estudio se encontró que la regulación de la expresión génica ante la exposición a HI crónica es órgano-dependiente y es modulada por la edad. El cuarto y último estudio se realizó en pacientes con SAOS tratados con el tratamiento de elección, presión positiva continua en la vía aérea (CPAP). En primer lugar se evaluó el efecto de la CPAP en variables clínicas y biológicas; en segundo lugar se consiguió definir un modelo de predicción de respuesta al tratamiento en términos de cambios de la presión arterial nocturna. Los resultados sugirieron el uso de la monitorización de la presión arterial ambulatoria como herramienta clave en la identificación de pacientes que se beneficiarán del tratamiento con CPAP para el control de la presión arterial.Obstructive sleep apnea syndrome (OSAS) is a chronic disease prevalent in the adult population and is considered a major public health problem due mainly to its cardiovascular morbidity and mortality. Chronic intermittent hypoxia (CIH) is considered the main deleterious factor involved in the cardiovascular consequences associated with OSAS. The first study was directed to assess the reversibility of CIH-induced cardiovascular remodeling in a murine model of OSAS. The alterations observed at the aortic and cardiac level after exposure to six weeks of CIH were normalized after a period under normoxia conditions, as a translational model of the effective treatment of the disease. Continuing in the same line of research, the effect of age on cardiovascular remodeling induced by IH was studied. The results showed cardiovascular protection in the mice with advanced age, and in young mice a cardiovascular remodeling was observed similar to the natural decline associated with aging. In view of what was observed, the third study was aimed at defining the molecular mechanisms that explain the cardiovascular remodeling induced by CIH observed in the second study and how they are modulated by age. In this study it was found that the regulation of gene expression under CIH exposure is organ-dependent and is modulated by age. The fourth and final study was conducted in patients with OSAS treated with the treatment of choice, continuous positive airway pressure (CPAP). First, the effect of CPAP on clinical and biological variables was evaluated; secondly, it was possible to define a prediction model of treatment response in terms of changes in nocturnal blood pressure. The results suggested the use of ambulatory blood pressure monitoring before CPAP treatment as a key tool in the discrimination of patients who will reduce cardiovascular risk from those patients who will have a detrimental effect when are treated

Erectile dysfunction in obstructive sleep apnea patients: A randomized trial on the effects of Continuous Positive Airway Pressure (CPAP).

OBJECTIVES:Obstructive sleep apnea (OSA) is among the least studied risk factors for erectile dysfunction (ED). We aimed to determine ED prevalence in newly-diagnosed OSA patients, describe their main characteristics and assess continuous positive airway pressure (CPAP) effects on ED. METHODS:Cross-sectional study assessing ED prevalence in OSA patients and open-label, parallel, prospective randomized controlled trial evaluating 3-month CPAP treatment effects on sexual function, satisfaction, and psychological, hormonal and biochemical profiles. Male patients newly diagnosed with moderate/severe OSA (apnea-hypopnea index >20 events·h-1), aged 18-70 years, attending the sleep unit of a Spanish hospital during 2013-2016 were considered. A total of 150 patients were recruited (75 randomized ED patients). ED was defined as scores <25 on International Index Erectile Function 15 test. Wilcoxon's matched-pairs signed-ranks and rank-sum tests were used. RESULTS:ED prevalence was 51%. Patients with ED were older (p<0.001), had greater waist-to-hip ratios (p<0.001), were more frequently undergoing pharmacological treatment (p<0.001) and had higher glucose levels (p = 0.024) than non-ED patients. Although significant increases in erectile function (mean(SD) change: +4.6(7.9); p = 0.002), overall satisfaction (+1(2.2); p = 0.035), and sexual satisfaction (+2.1(4.3); p = 0.003) were found after CPAP treatment, only differences in sexual satisfaction (p = 0.027) and erectile function (p = 0.060) were found between study arms. CPAP treatment did not impact psychological, hormonal or biochemical profiles. CONCLUSIONS:This study confirmed the relationship between OSA and ED, suggesting the potential usefulness of ED screening in OSA patients, but could not determine conclusively whether CPAP is an effective stand-alone ED treatment, regardless of positive results on sexual satisfaction. TRIAL REGISTRATION:ClinicalTrials.gov NCT03086122