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1.
Drugs Today (Barc) ; 56(9): 573-582, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33025951

RESUMO

Bempedoic acid is a new, first-in-class oral ATP-citrate lyase (ACLY) inhibitor that has to be converted to its CoA thioester before it inhibits ACLY. This conversion only occurs in the liver and not in skeletal muscle. This may explain why, unlike the statins, bempedoic acid does not cause myalgia. Bempedoic acid given at a dosage of 180 mg orally once daily produces a highly significant reduction in low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol, total cholesterol, apolipoprotein B and importantly also in high-sensitivity C-reactive protein. It has recently been approved by both the Food and Drug Administration (FDA) and the European Commission for use in adult patients with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease who require additional lowering of LDL-C, and for the treatment of adults with primary hypercholesterolemia (heterozygous familial and nonfamilial) or mixed dyslipidemia, respectively.


Assuntos
ATP Citrato (pro-S)-Liase/antagonistas & inibidores , LDL-Colesterol/sangue , Ácidos Dicarboxílicos/uso terapêutico , Ácidos Graxos/uso terapêutico , Lipídeos/sangue , Humanos
2.
N Engl J Med ; 383(14): 1317-1327, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32865373

RESUMO

BACKGROUND: Evolocumab, a fully human monoclonal antibody directed against proprotein convertase subtilisin-kexin type 9, is widely used in adult patients to lower low-density lipoprotein (LDL) cholesterol levels. Its effects in pediatric patients with heterozygous familial hypercholesterolemia are not known. METHODS: We conducted a 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of evolocumab in pediatric patients with heterozygous familial hypercholesterolemia. Patients 10 to 17 years of age who had received stable lipid-lowering treatment for at least 4 weeks before screening and who had an LDL cholesterol level of 130 mg per deciliter (3.4 mmol per liter) or more and a triglyceride level of 400 mg per deciliter (4.5 mmol per liter) or less were randomly assigned in a 2:1 ratio to receive monthly subcutaneous injections of evolocumab (420 mg) or placebo. The primary end point was the percent change in LDL cholesterol level from baseline to week 24; key secondary end points were the mean percent change in LDL cholesterol level from baseline to weeks 22 and 24 and the absolute change in LDL cholesterol level from baseline to week 24. RESULTS: A total of 157 patients underwent randomization and received evolocumab (104 patients) or placebo (53 patients). At week 24, the mean percent change from baseline in LDL cholesterol level was -44.5% in the evolocumab group and -6.2% in the placebo group, for a difference of -38.3 percentage points (P<0.001). The absolute change in the LDL cholesterol level was -77.5 mg per deciliter (-2.0 mmol per liter) in the evolocumab group and -9.0 mg per deciliter (-0.2 mmol per liter) in the placebo group, for a difference of -68.6 mg per deciliter (-1.8 mmol per liter) (P<0.001). Results for all secondary lipid variables were significantly better with evolocumab than with placebo. The incidence of adverse events that occurred during the treatment period was similar in the evolocumab and placebo groups. CONCLUSIONS: In this trial involving pediatric patients with familial hypercholesterolemia, evolocumab reduced the LDL cholesterol level and other lipid variables. (Funded by Amgen; HAUSER-RCT ClinicalTrials.gov number, NCT02392559.).


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticolesterolemiantes/uso terapêutico , LDL-Colesterol/sangue , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Pró-Proteína Convertase 9/antagonistas & inibidores , Adolescente , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticolesterolemiantes/efeitos adversos , Criança , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Heterozigoto , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/genética , Lipídeos/sangue , Masculino , Resultado do Tratamento
3.
PLoS One ; 15(9): e0239573, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32970772

RESUMO

INTRODUCTION: Severe acute respiratory syndrome coronavirus2 has caused a global pandemic of coronavirus disease 2019 (COVID-19). High-density lipoproteins (HDLs), particles chiefly known for their reverse cholesterol transport function, also display pleiotropic properties, including anti-inflammatory or antioxidant functions. HDLs and low-density lipoproteins (LDLs) can neutralize lipopolysaccharides and increase bacterial clearance. HDL cholesterol (HDL-C) and LDL cholesterol (LDL-C) decrease during bacterial sepsis, and an association has been reported between low lipoprotein levels and poor patient outcomes. The goal of this study was to characterize the lipoprotein profiles of severe ICU patients hospitalized for COVID-19 pneumonia and to assess their changes during bacterial ventilator-associated pneumonia (VAP) superinfection. METHODS: A prospective study was conducted in a university hospital ICU. All consecutive patients admitted for COVID-19 pneumonia were included. Lipoprotein levels were assessed at admission and daily thereafter. The assessed outcomes were survival at 28 days and the incidence of VAP. RESULTS: A total of 48 patients were included. Upon admission, lipoprotein concentrations were low, typically under the reference values ([HDL-C] = 0.7[0.5-0.9] mmol/L; [LDL-C] = 1.8[1.3-2.3] mmol/L). A statistically significant increase in HDL-C and LDL-C over time during the ICU stay was found. There was no relationship between HDL-C and LDL-C concentrations and mortality on day 28 (log-rank p = 0.554 and p = 0.083, respectively). A comparison of alive and dead patients on day 28 did not reveal any differences in HDL-C and LDL-C concentrations over time. Bacterial VAP was frequent (64%). An association was observed between HDL-C and LDL-C concentrations on the day of the first VAP diagnosis and mortality ([HDL-C] = 0.6[0.5-0.9] mmol/L in survivors vs. [HDL-C] = 0.5[0.3-0.6] mmol/L in nonsurvivors, p = 0.036; [LDL-C] = 2.2[1.9-3.0] mmol/L in survivors vs. [LDL-C] = 1.3[0.9-2.0] mmol/L in nonsurvivors, p = 0.006). CONCLUSION: HDL-C and LDL-C concentrations upon ICU admission are low in severe COVID-19 pneumonia patients but are not associated with poor outcomes. However, low lipoprotein concentrations in the case of bacterial superinfection during ICU hospitalization are associated with mortality, which reinforces the potential role of these particles during bacterial sepsis.


Assuntos
HDL-Colesterol/sangue , LDL-Colesterol/sangue , Infecções por Coronavirus/sangue , Pneumonia Bacteriana/sangue , Pneumonia Associada à Ventilação Mecânica/sangue , Pneumonia Viral/sangue , Superinfecção/sangue , Idoso , Betacoronavirus , Infecções por Coronavirus/mortalidade , Feminino , França , Hospitais Universitários , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Bacteriana/mortalidade , Pneumonia Associada à Ventilação Mecânica/mortalidade , Pneumonia Viral/mortalidade , Estudos Prospectivos
4.
Lipids Health Dis ; 19(1): 204, 2020 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-32892746

RESUMO

BACKGROUND: The purpose of the study is to describe the blood lipid levels of patients diagnosed with coronavirus disease 2019 (COVID-19) and to analyze the correlation between blood lipid levels and the prognosis of COVID-19 patients. METHODS: In the clinical retrospective analysis, a total of 228 adults infected with COVID-19 were enrolled between January 17, 2020 and March 14, 2020, in Changsha, China. One thousand one hundred and forty healthy participants with matched age and gender were used as control. Median with interquartile range and Mann-Whitney test were adopted to describe and analyze clinical data. The Kaplan-Meier (KM) curve and Cox regression analysis were used to analyze the correlation between high-density lipoprotein cholesterol (HDL-C) and the severity of COVID-19. RESULTS: Compared with control, COVID-19 patients showed significantly lower levels of total cholesterol (TC) [median, 3.76 vs 4.65 mmol/L, P = 0.031], triglyceride [median, 1.08 vs 1.21 mmol/L, P <  0.001], low-density lipoprotein cholesterol (LDL-C) [median, 2.63 vs 2.83 mmol/L, P <  0.001], and HDL-C [median, 0.78 vs 1.37 mmol/L, P <  0.001], while compared with non-severe patients, severe COVID-19 patients only presented lower levels of HDL-C [median, 0.69 vs 0.79 mmol/L, P = 0.032]. In comparison with patients with high HDL-C, patients with low HDL-C showed a higher proportion of male (69.57% vs 45.60%, P = 0.004), higher levels of C-reactive protein (CRP) (median, 27.83 vs 12.56 mg/L, P <  0.001) and higher proportion of severe events (36.96% vs 14.84%, P = 0.001). Moreover, patients with low HDL-C at admission showed a higher risk of developing severe events compared with those with high HDL-C (Log Rank P = 0.009). After adjusting for age, gender and underlying diseases, they still had elevated possibility of developing severe cases than those with high HDL-C (HR 2.827, 95% CI 1.190-6.714, P = 0.019). CONCLUSIONS: HDL-C level was lower in COVID-19 adult patients, and low HDL-C in COVID-19 patients was correlated with a higher risk of developing severe events.


Assuntos
Betacoronavirus , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Infecções por Coronavirus/fisiopatologia , Pneumonia Viral/fisiopatologia , Adulto , Proteína C-Reativa/análise , China , Colesterol/sangue , Infecções por Coronavirus/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/sangue , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Fatores Sexuais , Triglicerídeos/sangue
5.
Medicine (Baltimore) ; 99(33): e21647, 2020 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-32872028

RESUMO

Prevalence of postpartum depression (PD) in Chinese women is rising and its associated factors are not well known. In this study we aim to explore the associations between nutritional factors in pregnancy and the risk of PD in Chinese women.A case-control study was performed in our hospital during January 2016 to June 2019. A food frequency questionnaire was designed to collect food consumption before the childbirth preceding month. Nutrition related biochemical indicators including fasting blood-glucose (GLU), total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL), high density lipoprotein (HDL), and uric acid in the third trimester of pregnancy were detected. Logistic regression model was applied to compute odds ratio (OR) and its corresponding 95% confidence interval (CI).There were 565 participants in this study, which comprised 182 individuals with PD and 383 individuals without. Patients with PD had higher odds of increased GLU (OR=2.62, 95%CI = 1.67-4.11), TC (OR = 1.73 95%CI = 1.22-2.46), TG (OR = 2.43, 95%CI = 1.55-3.81), and LDL (OR = 3.41, 95%CI = 2.09-5.57), but decreased HDL (OR = 3.41, 95%CI = 2.09-5.57) during pregnancy. With respect to uric acid, there was lack of no statistical association (OR = 2.23, 95%CI = 0.82-6.26). Food frequency questionnaire indicated a higher meat intake, but a lower vegetable, fruit, fish, and poultry intake in patients with PD during pregnancy.Increased GLU, TC, TG, and LDL, but decreased HDL in later stages of pregnancy might be associated with PD.


Assuntos
Depressão Pós-Parto/etiologia , Avaliação Nutricional , Adulto , Biomarcadores/sangue , Glicemia/análise , Estudos de Casos e Controles , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Feminino , Humanos , Gravidez , Terceiro Trimestre da Gravidez , Fatores de Risco , Triglicerídeos/sangue
6.
Int Heart J ; 61(5): 872-878, 2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-32921669

RESUMO

In-stent restenosis (ISR) still exists after drug-eluting stent (DES) implantation, even up to one year. The incidence and risk factors for neoatherosclerosis in patients with early ISR have not yet been elucidated. Here, we used optical coherence tomography (OCT) to evaluate the incidence and predictors of neoatherosclerosis in patients with early ISRs.OCT was performed on ISR lesions in 185 patients in order to detect neoatherosclerosis. The median follow-up was 180 days, and neoatherosclerosis was detected in 37% of early ISR lesions. According to the presence of neoatherosclerosis, patients with ISR were divided into two groups: neoatherosclerosis (group A, n = 69) and non-neoatherosclerosis (group B, n = 116) groups.The risk factors were similar, except for hypercholesterolemia. Moreover, the tissue characteristics were not significantly different between patients with and without neoatherosclerosis. Follow-up low-density lipoprotein-cholesterol (LDL-C) levels were divided into three grades (LDL < 70 mg/dL, 70 mg/dL≤ LDL < 100 mg/dL, and LDL ≥ 100 mg/dL). The incidence of neoatherosclerosis was significantly lower (23% versus 57%, P < 0.0001) in the LDL < 70 mg/dL group. There was no significant difference in the incidence of neoatherosclerosis in patients with lipid levels between 70 and 100 mg/dL (P = 0.53). However, neoatherosclerosis was significantly more common in patients with a follow-up LDL-C level > 100 mg/dL (45% versus 15%, P < 0.0001).In patients with early ISR lesions, the LDL-C levels may be related to the formation and progression of early neoatherosclerosis, and poor LDL-C control may be a risk factor for the occurrence of early-stage neoatherosclerosis following DES implantation.


Assuntos
LDL-Colesterol/sangue , Doença da Artéria Coronariana/epidemiologia , Reestenose Coronária/epidemiologia , Stents Farmacológicos , Hipercolesterolemia/epidemiologia , Neointima/epidemiologia , Idoso , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/cirurgia , Reestenose Coronária/diagnóstico por imagem , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/sangue , Hipercolesterolemia/tratamento farmacológico , Incidência , Masculino , Pessoa de Meia-Idade , Neointima/diagnóstico por imagem , Fatores de Risco , Tomografia de Coerência Óptica
7.
N Engl J Med ; 383(8): 711-720, 2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32813947

RESUMO

BACKGROUND: Homozygous familial hypercholesterolemia is characterized by premature cardiovascular disease caused by markedly elevated levels of low-density lipoprotein (LDL) cholesterol. This disorder is associated with genetic variants that result in virtually absent (null-null) or impaired (non-null) LDL-receptor activity. Loss-of-function variants in the gene encoding angiopoietin-like 3 (ANGPTL3) are associated with hypolipidemia and protection against atherosclerotic cardiovascular disease. Evinacumab, a monoclonal antibody against ANGPTL3, has shown potential benefit in patients with homozygous familial hypercholesterolemia. METHODS: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned in a 2:1 ratio 65 patients with homozygous familial hypercholesterolemia who were receiving stable lipid-lowering therapy to receive an intravenous infusion of evinacumab (at a dose of 15 mg per kilogram of body weight) every 4 weeks or placebo. The primary outcome was the percent change from baseline in the LDL cholesterol level at week 24. RESULTS: The mean baseline LDL cholesterol level in the two groups was 255.1 mg per deciliter, despite the receipt of maximum doses of background lipid-lowering therapy. At week 24, patients in the evinacumab group had a relative reduction from baseline in the LDL cholesterol level of 47.1%, as compared with an increase of 1.9% in the placebo group, for a between-group least-squares mean difference of -49.0 percentage points (95% confidence interval [CI], -65.0 to -33.1; P<0.001); the between-group least-squares mean absolute difference in the LDL cholesterol level was -132.1 mg per deciliter (95% CI, -175.3 to -88.9; P<0.001). The LDL cholesterol level was lower in the evinacumab group than in the placebo group in patients with null-null variants (-43.4% vs. +16.2%) and in those with non-null variants (-49.1% vs. -3.8%). Adverse events were similar in the two groups. CONCLUSIONS: In patients with homozygous familial hypercholesterolemia receiving maximum doses of lipid-lowering therapy, the reduction from baseline in the LDL cholesterol level in the evinacumab group, as compared with the small increase in the placebo group, resulted in a between-group difference of 49.0 percentage points at 24 weeks. (Funded by Regeneron Pharmaceuticals; ELIPSE HoFH ClinicalTrials.gov number, NCT03399786.).


Assuntos
Proteínas Semelhantes a Angiopoietina/antagonistas & inibidores , Anticorpos Monoclonais/uso terapêutico , Anticolesterolemiantes/uso terapêutico , LDL-Colesterol/sangue , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/sangue , Anticolesterolemiantes/efeitos adversos , Anticolesterolemiantes/sangue , Criança , Método Duplo-Cego , Feminino , Homozigoto , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/genética , Infusões Intravenosas , Análise dos Mínimos Quadrados , Masculino , Pessoa de Meia-Idade , Mutação , Receptores de LDL/metabolismo , Adulto Jovem
8.
Medicine (Baltimore) ; 99(34): e21754, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32846800

RESUMO

RATIONALE: Proprotein convertase subtilisin/kexin 9 or PCSK9 is a protein whose main function is to regulate the number of low-density lipoprotein receptors (LDLR) present on the cell surface. Loss-of-function mutations in PCSK9 have been related to low LDL-cholesterol levels and a decrease in the risk of cardiovascular events. PATIENT CONCERNS: We present the case of a 27-year-old woman, offspring of a patient with familial homozygous hypercholesterolemia, who presented with mild-moderate hypercholesterolemia. DIAGNOSIS: Genetic analysis was performed by next generation sequencing using a customized panel of 198 genes. Sanger sequencing was used to confirm the presence of the variants of interest. The genetic analysis showed a pathogenic heterozygous mutation in LDLR [exon 6:c.902A>G:p(Asp301Gly)], as well as a loss-of-function heterozygous variant in PCSK9 [exon1:c.137 G>T:p.(Arg46Leu)]. The genetic analysis of the index case's mother revealed compound heterozygosity for 2 different mutations in LDLR [c.902A>G:p.(Asp301Gly); c.1646G>T:p.(Gly549Val)] in exon 6 and in exon 11, respectively, and the same loss-of-function variant in PCSK9 that had been found in her daughter [(PCSK9:exon1:c.137G>T:p.(Arg46Leu)]. The maternal grandfather of the index case presented the same genetic variants as his granddaughter. INTERVENTIONS: The index case did not receive any specific treatment for hypercholesterolemia. The loss-of-function variant in PCSK9 protected her from higher LDL-cholesterol levels, provided she kept partial activity of the LDLR. In her mother, instead, a PCSK9 inhibitor was tried but failed to achieve lipid control. The reason for this may be the complete absence in LDL receptor activity. LDL apheresis was started afterwards, resulting in adequate lipid level control. OUTCOMES: To the date, the index case has achieved to maintain adequate total and LDL-cholesterol levels without any other intervention. She has had no known cardiovascular complication. LESSONS: Loss-of-function mutations in PCSK9 could protect from developing more severe forms of hypercholesterolemia. The finding of these mutations (LDLR-PCSK9) in three consecutive generations could imply an adaptive mechanism against the development of hypercholesterolemia.


Assuntos
Hiperlipoproteinemia Tipo II/genética , Pró-Proteína Convertase 9/genética , Adulto , LDL-Colesterol/sangue , Feminino , Humanos
9.
JAMA ; 324(7): 651-662, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32809002

RESUMO

Importance: Mental health comorbidities are increasing worldwide and worsen outcomes for people with diabetes, especially when care is fragmented. Objective: To assess whether collaborative care vs usual care lowers depressive symptoms and improves cardiometabolic indices among adults with diabetes and depression. Design, Setting, and Participants: Parallel, open-label, pragmatic randomized clinical trial conducted at 4 socioeconomically diverse clinics in India that recruited patients with type 2 diabetes; a Patient Health Questionnaire-9 score of at least 10 (range, 0-27); and hemoglobin A1c (HbA1c) of at least 8%, systolic blood pressure (SBP) of at least 140 mm Hg, or low-density lipoprotein (LDL) cholesterol of at least 130 mg/dL. The first patient was enrolled on March 9, 2015, and the last was enrolled on May 31, 2016; the final follow-up visit was July 14, 2018. Interventions: Patients randomized to the intervention group (n = 196) received 12 months of self-management support from nonphysician care coordinators, decision support electronic health records facilitating physician treatment adjustments, and specialist case reviews; they were followed up for an additional 12 months without intervention. Patients in the control group (n = 208) received usual care over 24 months. Main Outcomes and Measures: The primary outcome was the between-group difference in the percentage of patients at 24 months who had at least a 50% reduction in Symptom Checklist Depression Scale (SCL-20) scores (range, 0-4; higher scores indicate worse symptoms) and a reduction of at least 0.5 percentage points in HbA1c, 5 mm Hg in SBP, or 10 mg/dL in LDL cholesterol. Prespecified secondary outcomes were percentage of patients at 12 and 24 months who met treatment targets (HbA1c <7.0%, SBP <130 mm Hg, LDL cholesterol <100 mg/dL [<70 mg/dL if prior cardiovascular disease]) or had improvements in individual outcomes (≥50% reduction in SCL-20 score, ≥0.5-percentage point reduction in HbA1c, ≥5-mm Hg reduction in SBP, ≥10-mg/dL reduction in LDL cholesterol); percentage of patients who met all HbA1c, SBP, and LDL cholesterol targets; and mean reductions in SCL-20 score, Patient Health Questionnaire-9 score, HbA1c, SBP, and LDL cholesterol. Results: Among 404 patients randomized (mean [SD] age, 53 [8.6] years; 165 [40.8%] men), 378 (93.5%) completed the trial. A significantly greater percentage of patients in the intervention group vs the usual care group met the primary outcome (71.6% vs 57.4%; risk difference, 16.9% [95% CI, 8.5%-25.2%]). Of 16 prespecified secondary outcomes, there were no statistically significant between-group differences in improvements in 10 outcomes at 12 months and in 13 outcomes at 24 months. Serious adverse events in the intervention and usual care groups included cardiovascular events or hospitalizations (4 [2.0%] vs 7 [3.4%]), stroke (0 vs 3 [1.4%]), death (2 [1.0%] vs 7 [3.4%]), and severe hypoglycemia (8 [4.1%] vs 0). Conclusions and Relevance: Among patients with diabetes and depression in India, a 12-month collaborative care intervention, compared with usual care, resulted in statistically significant improvements in a composite measure of depressive symptoms and cardiometabolic indices at 24 months. Further research is needed to understand the generalizability of the findings to other low- and middle-income health care settings. Trial Registration: ClinicalTrials.gov Identifier: NCT02022111.


Assuntos
Pressão Sanguínea , LDL-Colesterol/sangue , Depressão/terapia , Diabetes Mellitus Tipo 2/terapia , Hemoglobina A Glicada/análise , Adulto , Idoso , Comportamento Cooperativo , Depressão/complicações , Países em Desenvolvimento , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Feminino , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Equipe de Assistência ao Paciente , Autogestão , Fatores Socioeconômicos
10.
Praxis (Bern 1994) ; 109(10): 755-762, 2020 Aug.
Artigo em Alemão | MEDLINE | ID: mdl-32752965

RESUMO

CME: Primary and Secondary Hypercholesterolemia Abstract. In patients with hypercholesterolemia and an LDL-cholesterol level >5 mmol/l, familial hypercholesterolemia (primary hypercholesterolemia) should be considered. This genetically determined illness should lead to medical therapy and screening for hypercholesterinemia in close relatives. Beside the superelevated LDL-cholesterol levels, additional clinically diagnostic findings and family anamnesis can support the diagnosis of familial hypercholesterolemia. The likelihood of familial hypercholesterolemia can be estimated using the Lipid Clinic Network Score. Additionally, a variety of exogenous factors may have an impact on lipoprotein metabolism and may lead to secondary hypercholesterolemia. Hypothyroidism, cholestasis, nephrotic syndrome or specific medications, among others, should be considered as potential factors leading to high cholesterol levels before familial hypercholesterolemia is suspected or lipid-lowering treatment is started.


Assuntos
Hipercolesterolemia , Hiperlipoproteinemia Tipo II , LDL-Colesterol , Humanos , Hipercolesterolemia/diagnóstico , Hipercolesterolemia/terapia , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/terapia , Lipídeos , Programas de Rastreamento
13.
Endocrinol. diabetes nutr. (Ed. impr.) ; 67(6): 374-382, jun.-jul. 2020. tab
Artigo em Espanhol | IBECS | ID: ibc-193362

RESUMO

BACKGROUND: The role of ADIPOQ gene rs266729 variants on weight loss after a dietary intervention are still unclear. OBJECTIVE: To analyze the effects of the ADIPOQ gene rs266729 variant n weight loss, cardiovascular risk factors, and adiponectin levels after two hypocaloric diets with different dietary fatty profiles. DESIGN: A population of 362 obese patients was enrolled in a randomized clinical trial with two diets (Diet M, monounsaturated fat-enriched diet, and Diet P, polyunsaturated-fat enriched diet). Anthropometric measurements, an assessment of nutritional intake, and biochemical tests were performed at baseline and after 12 weeks. RESULTS: Weight loss was similar with both diets. After Diet M, only subjects with CC genotype showed significant improvements in total cholesterol (CC vs. CG ± GG) -9.0 ±1.1 mU/L vs. -4.5 ± 2.4 mg/dL, p = 0.01), LDL cholesterol (-6.0 ± 1.1 mg/dL vs. -3.0 ± 0.9 mg/dL, p = 0.03), glucose (-4.7 ± 1.1 mg/dL vs. -0.6 ± 0.5 mg/dL, p = 0.01), and insulin levels (-2.6 ±1.0 mU/L vs. -0.7 ± 0.3 mU/L, p = 0.02) and in HOMA-IR (-0.5 ± 0.2 units vs. -0.2 ± 0.4 units, p = 0.03). The same improvement was reported after Diet P in all parameters, including total cholesterol (CC vs. CG±GG) (-8.0 ± 1.2mU/L vs. -2.1 ± 1.4 mg/dL, p = 0.02), LDL cholesterol (-7.3 ± 1.2 mg/dL vs. -2.1 ± 0.8 mg/dL, p = 0.02), glucose (-3.2 ± 0.1mg/dL vs. -0.2 ± 0.5 mg/dL, p = 0.01), and insulin levels (-2.5 ± 1.0 mU/L vs. -1 ± 0.6 mU/L, p = 0.02) and HOMA-IR (-0.5 ± 0.1 units vs. −0.3 ± 0.4 units, p = 0.02). Only subjects with CC genotype showed significant increases in adiponectin levels after both diets: (Diet M: 10.3 ± 2.0 ng/dL vs. Diet P: 9.3 ± 2.9 ng/dL, p = 0.43). CONCLUSION: The CC genotype of ADIPOQ gene rs266729 variant is associated to increased adiponectin levels and decreases in LDL cholesterol, glucose, insulin, and HOMA-IR levels after weight loss


ANTECEDENTES: El papel de las variantes del gen ADIPOQ en la pérdida de peso después de una intervención dietética sigue sin estar claro. OBJETIVO: Nuestro objetivo fue analizar los efectos de la variante rs266729 del gen ADIPOQ sobre la pérdida de peso, los factores de riesgo cardiovascular y los niveles de adiponectina después de 2 dietas hipocalóricas con diferentes perfiles de grasas en la dieta. DISEÑO: Una población de 362 pacientes obesos se incluyeron en un ensayo clínico aleatorizado con 2 dietas (dieta M: dieta enriquecida con grasas monoinsaturadas y dieta P: dieta enriquecida con grasas poliinsaturadas). Antes y tras 12 semanas, se realizó una evaluación antropométrica, evaluación de la ingesta nutricional y un análisis bioquímico. RESULTADOS: La pérdida de peso fue similar con ambas dietas. Después de la dieta M, solo los sujetos con genotipo CC mostraron una mejoría significativa en el colesterol total (CC vs. CG±GG) (-9,0 ± 1,1 mU/l vs. - 4,5 ± 2,4 mg/dl; p = 0,01), colesterol LDL (-6,0 ± 1,1 mg/dl vs. - 3,0 ± 0,9 mg/dl; p = 0,03), glucosa (-4,7 ± 1,1 mg/dl vs. -0,6 ± 0,5 mg/dl; p = 0,01), niveles de insulina (-2,6 ± 1,0 mU/l vs. -0,7± 0,3 mU/l; p = 0,02) y HOMA-IR (- 0,5 ± 0,2 unidades vs. -0,2 ± 0,4 unidades; p = 0,03). La misma mejora en todos los parámetros se informó después de la dieta P; niveles de colesterol total (CC vs. CG ± GG) (-8,0 ± 1,2 mU/l vs. -2,1 ± 1,4 mg/dl; p = 0,02), colesterol LDL (-7,3 ± 1,2 mg/dl vs. -2,1 ±0,8 mg/dl; p = 0,02), glucosa (-3,2 ± 0,1 mg/dl vs. -0,2 ± 0,5 mg/dl; p = 0,01), niveles de insulina (-2,5 ±1,0 mU/l vs. -1 ±0,6 mU/l; p = 0,02) y HOMA-IR (-0,5 ± 0,1 unidades vs. -0,3 ± 0,4 unidades; p = 0,02). Solo los sujetos con genotipo CC mostraron un aumento significativo de los niveles de adiponectina después de ambas dietas: (dieta M: 10,3 ± 2,0 ng/dl vs. dieta P: 9,3 ± 2,9 ng/dl; p = 0,43). CONCLUSIÓN: El genotipo CC de la variante rs266729 del gen ADIPOQ se asocia con aumentos en los niveles de adiponectina y disminución del colesterol LDL, glucosa, insulina y HOMA-IR tras la pérdida de peso


Assuntos
Humanos , Ácidos Graxos/sangue , Adiponectina/genética , Dieta Redutora/métodos , Perda de Peso , Gorduras na Dieta/uso terapêutico , Adiponectina/sangue , Obesidade/dietoterapia , Antropometria , LDL-Colesterol , Genótipo , Estudos Prospectivos , Adiponectina/metabolismo , Receptores de Adipocina/sangue , Análise de Variância
14.
Proc Natl Acad Sci U S A ; 117(31): 18521-18529, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32690708

RESUMO

Animal cells acquire cholesterol from receptor-mediated uptake of low-density lipoprotein (LDL), which releases cholesterol in lysosomes. The cholesterol moves to the endoplasmic reticulum (ER), where it inhibits production of LDL receptors, completing a feedback loop. Here we performed a CRISPR-Cas9 screen in human SV589 cells for genes required for LDL-derived cholesterol to reach the ER. We identified the gene encoding PTDSS1, an enzyme that synthesizes phosphatidylserine (PS), a phospholipid constituent of the inner layer of the plasma membrane (PM). In PTDSS1-deficient cells where PS is low, LDL cholesterol leaves lysosomes but fails to reach the ER, instead accumulating in the PM. The addition of PS restores cholesterol transport to the ER. We conclude that LDL cholesterol normally moves from lysosomes to the PM. When the PM cholesterol exceeds a threshold, excess cholesterol moves to the ER in a process requiring PS. In the ER, excess cholesterol acts to reduce cholesterol uptake, preventing toxic cholesterol accumulation. These studies reveal that one lipid-PS-controls the movement of another lipid-cholesterol-between cell membranes. We relate these findings to recent evidence indicating that PM-to-ER cholesterol transport is mediated by GRAMD1/Aster proteins that bind PS and cholesterol.


Assuntos
Membrana Celular/metabolismo , LDL-Colesterol/metabolismo , Retículo Endoplasmático/metabolismo , Lisossomos/metabolismo , Fosfatidilserinas/metabolismo , Animais , Transporte Biológico , Linhagem Celular , Colesterol/metabolismo , Humanos
15.
Proc Natl Acad Sci U S A ; 117(29): 17381-17388, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32632018

RESUMO

Adiponectin (Acrp30) is an adipokine associated with protection from cardiovascular disease, insulin resistance, and inflammation. Although its effects are conventionally attributed to binding Adipor1/2 and T-cadherin, its abundance in circulation, role in ceramide metabolism, and homology to C1q suggest an overlooked role as a lipid-binding protein, possibly generalizable to other C1q/TNF-related proteins (CTRPs) and C1q family members. To investigate this, adiponectin, representative family members, and variants were expressed in Expi293 cells and tested for binding to lipids in liposomes using density centrifugation. Binding to physiological lipids were also analyzed using gradient ultracentrifugation, liquid chromatography-mass spectrometry, and shotgun lipidomics. Interestingly, adiponectin selectively bound several anionic phospholipids and sphingolipids, including phosphatidylserine, ceramide-1-phosphate, glucosylceramide, and sulfatide, via the C1q domain in an oligomerization-dependent fashion. Binding to lipids was observed in liposomes, low-density lipoproteins, cell membranes, and plasma. Other CTRPs and C1q family members (Cbln1, CTRP1, CTRP5, and CTRP13) also bound similar lipids. These findings suggest that adiponectin and CTRPs function not only as hormones, but also as lipid opsonins, as may other C1q family proteins.


Assuntos
Adiponectina/metabolismo , Complemento C1q/metabolismo , Fosfolipídeos/metabolismo , Esfingolipídeos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Adipocinas/metabolismo , Adiponectina/genética , Animais , Ânions , Membrana Celular , LDL-Colesterol , Humanos , Metabolismo dos Lipídeos , Lipidômica , Lipoproteínas/metabolismo , Lipossomos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Opsonizantes/metabolismo , Plasma
16.
Cardiovasc Ther ; 2020: 5936748, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32636924

RESUMO

Background: Familial hypercholesterolemia (FH) is a genetic disorder characterized by high levels of low-density lipoprotein cholesterol (LDL-C). Because of underdiagnosis, acute coronary syndrome (ACS) is often the first clinical manifestation of FH. In Japan, there are few reports on the prevalence and diagnostic ratios of FH and the proportion of ACS among FH patients in clinical settings. Methods: This retrospective, observational study used anonymized data from electronic healthcare databases between April 2001 and March 2015 of patients who had ≥2 LDL-C measurements recorded after April 2009. The index date was defined as the date of the first LDL-C measurement after April 2009. The primary endpoint was the prevalence of definite or suspected FH; secondary endpoints included the proportion of FH patients hospitalized for ACS, the proportion of patients using lipid-lowering drugs (LLDs), and LDL-C levels. Results: Of the 187,781 patients screened, 1547 had definite or suspected FH (0.8%) based on data from the entire period; 832 patients with definite (n = 299, 0.16%) or suspected FH (n = 533, 0.28%) before the index date were identified in the main analysis cohort. LLDs were used in 214 definite FH patients (71.6%) and 137 suspected FH patients (25.7%). Among definite or suspected FH patients with ACS (n = 84) and without ACS (n = 748), 32.1% and 30.1% with definite FH and 3.2% and 2.4% with suspected FH had LDL-C levels < 2.6 mmol/L (<100 mg/dL), respectively. Sixty patients (7.2%) were hospitalized due to ACS at the index date. Conclusions: The prevalence of FH in this Japanese cohort of patients with ≥2 LDL-C measurements at hospitals was 0.8%, which is higher than that currently reported in epidemiological studies (0.2-0.5%). Patients with suspected FH, with or without ACS, had poorly controlled LDL-C levels and were undertreated. The proportion of FH patients who were hospitalized due to ACS was 7.2%.


Assuntos
Síndrome Coronariana Aguda/epidemiologia , Hiperlipoproteinemia Tipo II/epidemiologia , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticolesterolemiantes/uso terapêutico , Biomarcadores/sangue , LDL-Colesterol/sangue , Bases de Dados Factuais , Regulação para Baixo , Registros Eletrônicos de Saúde , Feminino , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Admissão do Paciente , Prevalência , Estudos Retrospectivos
17.
PLoS Med ; 17(7): e1003121, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32673317

RESUMO

BACKGROUND: Bempedoic acid is a first-in-class lipid-lowering drug recommended by guidelines for the treatment of hypercholesterolemia. Our objective was to estimate its average effect on plasma lipids in humans and its safety profile. METHODS AND FINDINGS: We carried out a systematic review and meta-analysis of phase II and III randomized controlled trials on bempedoic acid (PROSPERO: CRD42019129687). PubMed (Medline), Scopus, Google Scholar, and Web of Science databases were searched, with no language restriction, from inception to 5 August 2019. We included 10 RCTs (n = 3,788) comprising 26 arms (active arm [n = 2,460]; control arm [n = 1,328]). Effect sizes for changes in lipids and high-sensitivity C-reactive protein (hsCRP) serum concentration were expressed as mean differences (MDs) and 95% confidence intervals (CIs). For safety analyses, odds ratios (ORs) and 95% CIs were calculated using the Mantel-Haenszel method. Bempedoic acid significantly reduced total cholesterol (MD -14.94%; 95% CI -17.31%, -12.57%; p < 0.001), non-high-density lipoprotein cholesterol (MD -18.17%; 95% CI -21.14%, -15.19%; p < 0.001), low-density lipoprotein cholesterol (MD -22.94%; 95% CI -26.63%, -19.25%; p < 0.001), low-density lipoprotein particle number (MD -20.67%; 95% CI -23.84%, -17.48%; p < 0.001), apolipoprotein B (MD -15.18%; 95% CI -17.41%, -12.95%; p < 0.001), high-density lipoprotein cholesterol (MD -5.83%; 95% CI -6.14%, -5.52%; p < 0.001), high-density lipoprotein particle number (MD -3.21%; 95% CI -6.40%, -0.02%; p = 0.049), and hsCRP (MD -27.03%; 95% CI -31.42%, -22.64%; p < 0.001). Bempedoic acid did not significantly modify triglyceride level (MD -1.51%; 95% CI -3.75%, 0.74%; p = 0.189), very-low-density lipoprotein particle number (MD 3.79%; 95% CI -9.81%, 17.39%; p = 0.585), and apolipoprotein A-1 (MD -1.83%; 95% CI -5.23%, 1.56%; p = 0.290). Treatment with bempedoic acid was positively associated with an increased risk of discontinuation of treatment (OR 1.37; 95% CI 1.06, 1.76; p = 0.015), elevated serum uric acid (OR 3.55; 95% CI 1.03, 12.27; p = 0.045), elevated liver enzymes (OR 4.28; 95% CI 1.34, 13.71; p = 0.014), and elevated creatine kinase (OR 3.79; 95% CI 1.06, 13.51; p = 0.04), though it was strongly associated with a decreased risk of new onset or worsening diabetes (OR 0.59; 95% CI 0.39, 0.90; p = 0.01). The main limitation of this meta-analysis is related to the relatively small number of individuals involved in the studies, which were often short or middle term in length. CONCLUSIONS: Our results show that bempedoic acid has favorable effects on lipid profile and hsCRP levels and an acceptable safety profile. Further well-designed studies are needed to explore its longer-term safety.


Assuntos
Anticolesterolemiantes/uso terapêutico , Ácidos Dicarboxílicos/uso terapêutico , Ácidos Graxos/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Anticolesterolemiantes/efeitos adversos , Apolipoproteínas B/sangue , Colesterol/sangue , LDL-Colesterol/sangue , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Ácidos Dicarboxílicos/efeitos adversos , Ácidos Graxos/efeitos adversos , Humanos , Hipercolesterolemia/sangue , Fragmentos de Peptídeos/sangue , Ensaios Clínicos Controlados Aleatórios como Assunto
18.
Intern Med ; 59(14): 1705-1710, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32669515

RESUMO

Objective Lipoprotein (a), or Lp (a), has been shown to be associated with the development of chronic kidney disease (CKD) in populations of various ethnicities. This study aimed to investigate the association between serum Lp (a) and CKD in Japanese patients. Methods A total of 6,130 subjects who underwent a serum Lp (a) level assessment for any reason (e.g. any type of surgery requiring prolonged bed rest or risk factors for atherosclerosis, such as hypertension or diabetes) were retrospectively investigated at Kanazawa University Hospital from April 2004 to March 2014. Of these, 1,895 subjects were excluded because of the lack of clinical data. Subjects were assessed for Lp (a), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, hypertension, diabetes, smoking, body mass index (BMI), coronary artery disease (CAD), and CKD (stage ≥3). Results When the study subjects were divided into quartiles of Lp (a) levels, significant trends were observed with regard to the presence of CKD (p = 2.7×10-13). A multiple regression analysis showed that Lp (a) was significantly associated with CKD [odds ratio (OR), 1.12; 95% confidence interval (CI), 1.08-1.17; p = 1.3×10-7, per 10 mg/dL], independent of other classical risk factors, including age, gender, BMI, hypertension, diabetes, smoking, LDL cholesterol, and triglycerides. Under these conditions, Lp (a) was significantly associated with CAD (OR = 1.11, 95% CI = 1.06-1.16; p = 1.7×10-6, per 10 mg/dL), independent of other risk factors. Conclusion Serum Lp (a) was associated with CKD, independent of other classical risk factors in a Japanese population.


Assuntos
Hiperlipidemias/complicações , Lipoproteína(a)/sangue , Insuficiência Renal Crônica/etiologia , Adulto , Idoso , Doenças Cardiovasculares/complicações , LDL-Colesterol/sangue , Doença da Artéria Coronariana/sangue , Feminino , Hospitalização , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Razão de Chances , Curva ROC , Análise de Regressão , Estudos Retrospectivos , Fatores de Risco , Triglicerídeos/sangue
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