SR-B1, a Key Receptor Involved in the Progression of Cardiovascular Disease: A Perspective from Mice and Human Genetic Studies

High plasma level of low-density lipoprotein (LDL) is the main driver of the initiation and progression of cardiovascular disease (CVD). Nevertheless, high-density lipoprotein (HDL) is con-sidered an anti-atherogenic lipoprotein due to its role in reverse cholesterol transport and its ability to receive cholesterol that effluxes from macrophages in the artery wall. The scavenger receptor B class type 1 (SR-B1) was identified as the high-affinity HDL receptor, which facilitates the selective uptake of cholesterol ester (CE) into the liver via HDL and is also implicated in the plasma clearance of LDL, very low-density lipoprotein (VLDL) and lipoprotein(a) (Lp(a)). Thus, SR-B1 is a multifunc-tional receptor that plays a main role in the metabolism of different lipoproteins. The aim of this review is to highlight the association between SR-B1 and CVD risk through mice and human genetic studies. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

Identificación de variantes del gen CETP en sujetos con dislipemia de etiología desconocida

La concentración elevada de colesterol transportado por lipoproteínas de baja densidad (cLDL)se ha descrito como uno de los principales factores de riesgo de padecer enfermedadcardiovascular (ECV), mientras que el colesterol transportado por lipoproteínas de altadensidad (cHDL) actúa como factor ateroprotector reduciendo el riesgo de desarrollarateroesclerosis. Sin embargo, estudios recientes desafían la presunta relación inversa entre elcHDL y ECV, sugiriendo que la asociación se ajusta más a un modelo en forma de U. En estesentido, la proteína transferidora de ésteres de colesterol (CETP) desempeña un papelimportante en el metabolismo lipoproteico y el desarrollo de la ECV, al promover laredistribución de ésteres de colesterol (EC) y triglicéridos (TG) entre las lipoproteínas de altadensidad (HDL) y las lipoproteínas de baja densidad (LDL) durante la ruta indirecta deltransporte reverso de colesterol (TRC), en el que se retorna el exceso de colesterol desde lostejidos periféricos al hígado para ser excretado en forma de sales biliares. En este trabajo, seseleccionaron 96 sujetos con valores extremos de cHDL para analizar la relación entre lospolimorfismos identificados en el gen CETP y el perfil lipídico de estos pacientes. Los análisis delas características clínicas, bioquímicas y antropométricas muestran que los sujetos con menorconcentración de cHDL presentan menores valores de cLDL y colesterol total (CT), mientrasque se observa mayor concentración de triglicéridos y mayor índice de masa corporal (IMC),además los antecedentes de ECV son significativamente superiores, evidenciando el papel decHDL como factor de protección vascular. En cuanto al análisis de las variantes genéticas deCETP, se identificaron 28, de las cuales 7 están presentes exclusivamente en el grupo convalores elevados de cHDL y 4 sólo en el grupo con baja concentración de cHDL. Se identificarondos variantes deletéreas (rs9930761 (c. 751-51 T>C) y rs1800774 (c. 1215-14 C>T)) y tresvariantes no descritas previamente (c. 6 G>A, c. 369-42 T>C y p. (Asp159=). Por otra parte, elanálisis comparativo de las frecuencias alélicas de los polimorfismos en sujetos con nivelesextremos de cHDL de nuestro estudio respecto a la población general europea muestra quedos variantes presentan diferencias significativas en ambos grupos de cHDL (c. 440-103 G>T yc. 930+29 G>A).<br /

SR-B1, a Key Receptor Involved in the Progression of Cardiovascular Disease: A Perspective from Mice and Human Genetic Studies

High plasma level of low-density lipoprotein (LDL) is the main driver of the initiation and progression of cardiovascular disease (CVD). Nevertheless, high-density lipoprotein (HDL) is considered an anti-atherogenic lipoprotein due to its role in reverse cholesterol transport and its ability to receive cholesterol that effluxes from macrophages in the artery wall. The scavenger receptor B class type 1 (SR-B1) was identified as the high-affinity HDL receptor, which facilitates the selective uptake of cholesterol ester (CE) into the liver via HDL and is also implicated in the plasma clearance of LDL, very low-density lipoprotein (VLDL) and lipoprotein(a) (Lp(a)). Thus, SR-B1 is a multifunctional receptor that plays a main role in the metabolism of different lipoproteins. The aim of this review is to highlight the association between SR-B1 and CVD risk through mice and human genetic studies.This work was supported by grants from Gobierno de Aragón, B14–7R, Spain, and the Spanish Ministry of Science and Innovation PI18/01777, PI19/00694 and CIBERCV. These projects are co-financed by Instituto de Salud Carlos III and the European Regional Development Fund (ERDF) of the European Union ‘‘A way to make Europe’’. IG-R was funded by Sara Borrell fellowship CD19/00245

Identificación de variantes polimórficas del gen SCARB1 en sujetos con dislipemia de etiología desconocida

Las lipoproteínas de alta densidad (HDL) se han descrito como factores ateroprotectores, disminuyen el riesgo de sufrir enfermedades cardiovasculares (ECV) debido a su implicación en el transporte reverso de colesterol (TRC). En este transporte juega un papel fundamental el receptor scavenger de clase B, tipo I (SR-B1), de alta afinidad por las HDL que permite el eflujo del exceso de colesterol de los tejidos periféricos para su internalización en el hígado y su posterior excreción en forma de ácidos biliares. Dado que algunos polimorfismos del gen SCARB1, que codifica para este receptor, se han relacionado con las concentraciones plasmáticas de lípidos y con el riesgo de sufrir ECV, en este trabajo se seleccionaron 96 pacientes con niveles extremos de colesterol transportado por HDL (HDLc) y se analizó la relación entre las mutaciones encontradas en la secuencia del gen y el perfil lipídico de los pacientes. Al estudiar las características clínicas y bioquímicas de ambos grupos se observó que los pacientes con menor concentración de HDL tenían los niveles de colesterol LDL y total más reducidos, los niveles de triglicéridos y el índice de masa corporal eran significativamente mayores, así como el número de incidentes cardiovasculares ocurridos en este grupo. El análisis de los polimorfismos, encontró en total veinticinco variantes genéticas, cuatro de ellas con posibles efectos patogénicos: en el grupo con niveles de HDLc altos se encontró p.(Thr378Met) y dos polimorfismos no descritos previamente (c.-177G>T y p.(Thr118Ser)), mientras que en el grupo con menores concentraciones de HDLc se identificó c.843-982G>A. Por otra parte, el análisis comparativo de nuestros datos con las frecuencias alélicas establecidas para los polimorfismos en la población europea general muestra que cinco de las variantes identificadas en nuestro estudio aparecen con una mayor frecuencia en individuos con niveles extremos de HDL (p.(Gly2Ser), p.(Pro60=), p.(Ser129Leu), c.1255-41C>G y c.*1530+786G>A). <br /

Pentamethylcyclopentadienyl halo- and alkyl-alkoxo tantalum(V) complexes. Crystal structure of TaCp*(CH2SiMe3) 2{η2-O(2-CH2-6-MeC6H3)}

Reaction of TaCp" C! 4 with MOR (M - Li, Na) in different molar ratios gives halo alkoxides TaCp" CI,(OR)4_,, (n - 3: R -tBu 1; $iPh 3 2; 2,6-Me2C6H 3 3; n -- 2: R -~Bu 4; SiPh 3 5; 2,6-Me2C6H3 6; a - !: R - SiMe 3 7) in good yields. The alkylidene complex TaCp'(CH2SiMe,02(CHSiMe ~) is hydrolyzed in the presence of traces of water to give the oxo dialkyl derivative [TaCp'(CH2SiM¢3)~O],, 8, and reacts with I equivalent of 2,6-MezC6H~NC affording a new 'q2-iminoacyi compound TaCp" (CH 2$iMe3XCHSiMe3){~ 2"C(CH 2SiMe3 ) = N(2,6"MeaC6 H 3)} 9. Reactions of TaCp "(CH 2SiMe3)a(CHSiMe3 ) with I equivalent of C6HsOH and 4-MeC6H3(OH) 2 result in the formation of the alkyl phenoxo TaCp'(CH2SiMe3)3(OC6Hs) 10 and 4-methyl pyrocatecholate TaCp'(CH2SiMe~)2(O2C6H3Me) 11, whereas the related re,",,:don with 2,6-Me2C6H 3OH leads to the cyclic alkyi-aikoxo compound TaCp (CH2SiMej)2(~2-O(2-CH2-6-MeC6H3)) 12. All the complexes were characterized by IR and NMR (tH and 13C) spectroscopy. The crystal and molecular structure of 12 has been determine~i. C~ystals of 12 are triclinic, space group P'[ with Z - 2 in a unit cell of dimensions a- 9.151(5) ~, b- 11.835(5) ~,, c- 14.045(4) A, a- 89.35(3) °, /3- 72.34(3) 0 and 'y-88.51(4) °, V- 1449(I) ~s. Final values of R -0.025 and Rw -0.0655 were obtained from 554'7 reflections measured (50'70, > 2o'(i))

Maternal separation increases alcohol-drinking behaviour and reduces endocannabinoid levels in the mouse striatum and prefrontal cortex

Altres ajuts: This study was supported by Plan Nacional sobre Drogas (2014/020) i UE Medbioinformatic project (grant number 634143).Childhood adversity is associated with an increased risk of mood, anxiety and substance use disorders. Maternal separation is a reliable rodent model of early life adversity that leads to depression-like symptoms, which may increase the vulnerability to alcohol consumption during adolescence. However, the specific alterations in the pattern of alcohol consumption induced by maternal separation and the underlying molecular mechanisms are still unclear. The purpose of this study is to evaluate the long-term effects of maternal separation with early weaning (MSEW) on emotional and social behaviour, alcohol rewarding properties, and alcohol consumption, abstinence and relapse in adolescent male C57BL/6 mice. In addition, endocannabinoid and monoamine levels were analysed in discrete brain areas. Results showed that MSEW mice presented emotional alterations related to depressive-like behaviour and modified endocannabinoid levels in the striatum and the prefrontal cortex. MSEW mice also showed impairments in alcohol-induced conditioned place preference and higher alcohol intake in a model of binge drinking. Moreover, MSEW animals displayed a higher propensity to relapse in the two-bottle choice paradigm following a period of alcohol abstinence associated with reduced monoamine levels in the striatum. Such results indicate that exposure to early life stress increased the vulnerability to alcohol binge-drinking during adolescence, which may be partially explained by decreased sensitivity to alcohol rewarding properties and the ability to potentiate alcohol intake following a period of abstinence

Association of cholesterol and oxysterols in adipose tissue with obesity and metabolic syndrome traits

Adipose tissue stores a substantial amount of body cholesterol in humans. Obesity is associated with decreased concentrations of serum cholesterol. During weight gain, adipose tissue dysfunction might be one of the causes of metabolic syndrome. The aim of this study is to evaluate cholesterol storage and oxidized metabolites in adipose tissue and their relationship with metabolic clinical characteristics

The impact of the COVID-19 pandemic in diabetes and dyslipidemia management in a Spanish region: a retrospective study of the Aragon population

IntroductionPrevious research has indicated that the COVID-19 outbreak had a negative impact on the diagnosis and management of cardiometabolic diseases. Our aim was to analyze the impact of the COVID-19 pandemic on the management of dyslipidemia and type 2 diabetes (T2D) in the Aragon region of Spain.MethodsWe conducted an observational retrospective study, which included data from all patients diagnosed with active T2D or dyslipidemia in Aragon during 2019–2021. Data was collected from the BIGAN platform, a big database that includes all healthcare data from the Aragon population. Clinical, biochemical, and pharmacological prescription information was obtained for each patient and for each year.ResultsOut of the total population of 1,330,000 in the Aragon region, 90,000 subjects were diagnosed with T2D each year, resulting in a prevalence of approximately 7%. The COVID-19 pandemic resulted in a decrease in the prevalence of this disease and a lower incidence during the year 2020. In addition, patients with T2D experienced a deterioration of their glucose profile, which led to an increase in the number of patients requiring pharmacological therapy. The prevalence of dyslipidemia was approximately 23.5% in both 2019 and 2020 and increased to 24.5% in 2021. Despite the worsening of the anthropometric profile, the lipid profile improved significantly throughout 2020 and 2021 compared to 2019. Moreover, the number of active pharmacological prescriptions increased significantly in 2021.DiscussionOur findings suggest that the overload of the health system caused by the COVID-19 pandemic has resulted in an underdiagnosis of T2D. Moreover, patients with T2D experienced a worsening of their glycemic profile, an increase in their pharmacological requirements, and lower performance of their analytical determinations. Dyslipidemic subjects improved their lipid profile although the value of lipid profile determination decreased between 2020 and 2021

The evolution of the ventilatory ratio is a prognostic factor in mechanically ventilated COVID-19 ARDS patients

Background: Mortality due to COVID-19 is high, especially in patients requiring mechanical ventilation. The purpose of the study is to investigate associations between mortality and variables measured during the first three days of mechanical ventilation in patients with COVID-19 intubated at ICU admission. Methods: Multicenter, observational, cohort study includes consecutive patients with COVID-19 admitted to 44 Spanish ICUs between February 25 and July 31, 2020, who required intubation at ICU admission and mechanical ventilation for more than three days. We collected demographic and clinical data prior to admission; information about clinical evolution at days 1 and 3 of mechanical ventilation; and outcomes. Results: Of the 2,095 patients with COVID-19 admitted to the ICU, 1,118 (53.3%) were intubated at day 1 and remained under mechanical ventilation at day three. From days 1 to 3, PaO2/FiO2 increased from 115.6 [80.0-171.2] to 180.0 [135.4-227.9] mmHg and the ventilatory ratio from 1.73 [1.33-2.25] to 1.96 [1.61-2.40]. In-hospital mortality was 38.7%. A higher increase between ICU admission and day 3 in the ventilatory ratio (OR 1.04 [CI 1.01-1.07], p = 0.030) and creatinine levels (OR 1.05 [CI 1.01-1.09], p = 0.005) and a lower increase in platelet counts (OR 0.96 [CI 0.93-1.00], p = 0.037) were independently associated with a higher risk of death. No association between mortality and the PaO2/FiO2 variation was observed (OR 0.99 [CI 0.95 to 1.02], p = 0.47). Conclusions: Higher ventilatory ratio and its increase at day 3 is associated with mortality in patients with COVID-19 receiving mechanical ventilation at ICU admission. No association was found in the PaO2/FiO2 variation

Effectiveness of an intervention for improving drug prescription in primary care patients with multimorbidity and polypharmacy:Study protocol of a cluster randomized clinical trial (Multi-PAP project)

This study was funded by the Fondo de Investigaciones Sanitarias ISCIII (Grant Numbers PI15/00276, PI15/00572, PI15/00996), REDISSEC (Project Numbers RD12/0001/0012, RD16/0001/0005), and the European Regional Development Fund ("A way to build Europe").Background: Multimorbidity is associated with negative effects both on people's health and on healthcare systems. A key problem linked to multimorbidity is polypharmacy, which in turn is associated with increased risk of partly preventable adverse effects, including mortality. The Ariadne principles describe a model of care based on a thorough assessment of diseases, treatments (and potential interactions), clinical status, context and preferences of patients with multimorbidity, with the aim of prioritizing and sharing realistic treatment goals that guide an individualized management. The aim of this study is to evaluate the effectiveness of a complex intervention that implements the Ariadne principles in a population of young-old patients with multimorbidity and polypharmacy. The intervention seeks to improve the appropriateness of prescribing in primary care (PC), as measured by the medication appropriateness index (MAI) score at 6 and 12months, as compared with usual care. Methods/Design: Design:pragmatic cluster randomized clinical trial. Unit of randomization: family physician (FP). Unit of analysis: patient. Scope: PC health centres in three autonomous communities: Aragon, Madrid, and Andalusia (Spain). Population: patients aged 65-74years with multimorbidity (≥3 chronic diseases) and polypharmacy (≥5 drugs prescribed in ≥3months). Sample size: n=400 (200 per study arm). Intervention: complex intervention based on the implementation of the Ariadne principles with two components: (1) FP training and (2) FP-patient interview. Outcomes: MAI score, health services use, quality of life (Euroqol 5D-5L), pharmacotherapy and adherence to treatment (Morisky-Green, Haynes-Sackett), and clinical and socio-demographic variables. Statistical analysis: primary outcome is the difference in MAI score between T0 and T1 and corresponding 95% confidence interval. Adjustment for confounding factors will be performed by multilevel analysis. All analyses will be carried out in accordance with the intention-to-treat principle. Discussion: It is essential to provide evidence concerning interventions on PC patients with polypharmacy and multimorbidity, conducted in the context of routine clinical practice, and involving young-old patients with significant potential for preventing negative health outcomes. Trial registration: Clinicaltrials.gov, NCT02866799Publisher PDFPeer reviewe