Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 28.308
Filtrar
1.
Mol Genet Genomic Med ; 12(3): e2410, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38433605

RESUMO

BACKGROUND: Familial hypercholesterolemia (MIM: PS143890) is a genetic disorder characterized by an increase in blood cholesterol. LDLR is one of the genes which their defect contributes to the disorder. Affected individuals may carry a heterozygous variant or homozygous/compound heterozygous variants and those with biallelic pathogenic variants present more severe symptoms. METHOD: We report an Egyptian family with familial hypercholesterolemia. Both the proband and parents have the disorder while a sibling is unaffected. Exome sequencing was performed to identify the causal variant. RESULTS: LINE-1 insertion in exon 7 of LDLR was identified. Both parents have a heterozygous variant while the proband has a homozygous variant. The unaffected sibling did not carry the variant. DISCUSSION: This insertion may contribute to the high prevalence of hypercholesterolemia in Egypt and the finding underscores the importance of implementing mobile element insertion caller in routine bioinformatics pipeline.


Assuntos
Hipercolesterolemia , Hiperlipoproteinemia Tipo II , Humanos , Biologia Computacional , Egito , Éxons , Hiperlipoproteinemia Tipo II/genética , Elementos Nucleotídeos Longos e Dispersos
2.
Rapid Commun Mass Spectrom ; 38(9): e9723, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38504484

RESUMO

RATIONALE: Hypercholesterolemia is an important risk factor for cardiovascular diseases and death. This study performed pseudo-targeted lipidomics to identify differentially expressed plasma lipids in hypercholesterolemia, to provide a scientific basis for the diagnosis and pathogenesis of hypercholesterolemia. METHODS: Pseudo-targeted lipidomic analyses of plasma lipids from 20 patients with hypercholesterolemia and 20 normal control subjects were performed using liquid chromatography-mass spectrometry. Differentially expressed lipids were identified by principal component analysis and orthogonal partial least squares discriminant analysis. Receiver operating characteristic curves were used to identify differentially expressed lipids with high diagnostic value. The Kyoto Encyclopedia of Genes and Genomes pathway database was used to identify enriched metabolic pathways. RESULTS: We identified 13 differentially expressed lipids in hypercholesterolemia using variable importance of projection > 1 and p < 0.05 as threshold parameters. The levels of eight sphingomyelins and cholesterol sulfate were higher and those of three triacylglycerols and lysophosphatidylcholine were reduced in hypercholesterolemia. Seven differentially expressed plasma lipids showed high diagnostic value for hypercholesterolemia. Functional enrichment analyses showed that pathways related to necroptosis, sphingolipid signaling, sphingolipid metabolism, and steroid hormone biosynthesis were enriched. CONCLUSIONS: This pseudo-targeted lipidomics study demonstrated that multiple sphingomyelins and cholesterol sulfate were differentially expressed in the plasma of patients with hypercholesterolemia. We also identified seven plasma lipids, including six sphingomyelins and cholesterol sulfate, with high diagnostic value.


Assuntos
Hipercolesterolemia , Lipidômica , Humanos , Lipidômica/métodos , Hipercolesterolemia/diagnóstico , Esfingomielinas , Triglicerídeos , Biomarcadores
4.
Sci Rep ; 14(1): 6522, 2024 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-38499796

RESUMO

To evaluate the efficacy and nutrition of single-anastomosis duodenal-ileal bypass with sleeve gastrectomy (SADI-S) in Chinese obese patients in the first postoperative year. Clinical data of 66 obese patients who underwent SADI-S surgery at China-Japan Union Hospital of Jilin University from November 2018 to May 2022 were retrospectively collected. The weight, body mass index (BMI), percentage of excess weight loss (%EWL), and percentage of total weight loss (%TWL) were recorded at 3, 6, and 12 months after surgery. Moreover, metabolic disease remission and nutrient deficiencies were assessed at 1 year postoperatively. Overall, 66 patients (38 males and 28 females) were recruited, with a mean age of 35 (18-61) years and an average preoperative BMI of 42.94 kg/m2. Before surgery, 38 patients had type 2 diabetes mellitus (T2DM), 46 patients had hyperuricemia (HUA), 45 patients had hypertension (HTN), 35 patients had hyperlipidemia, 12 patients had hypercholesterolemia, 12 patients had hyper-low-density lipoproteinemia, and 14 patients had gastroesophageal reflux disease symptoms (GERD). All patients had undergone a DaVinci robotic or laparoscopic SADI-S surgery, and none converted to laparotomy or died. Four patients developed postoperative complications and were cured and discharged after conservative treatment or surgical treatment. At 3, 6 and 12 months, the average %EWL was 62.07 ± 26.56, 85.93 ± 27.92, and 106.65 ± 29.65%, %TWL was 22.67 ± 4.94, 32.10 ± 5.18, and 40.56 ± 7.89%, respectively. Fasting blood glucose (FBG), glycated hemoglobin (HbA1c), uric acid (UA), triglycerides (TG), blood pressure (BP), and other indexes were significantly lower after one year post-surgery compared with the preoperative period (P < 0.05). The remission rates of T2DM, HUA, HTN, hypertriglyceridemia, hypercholesterolemia, and hyper-low-density lipoproteinemia 1 year after surgery were 100, 65.2, 62.2, 94.3, 100, and100%, respectively. One year after surgery, the remission rate of GERD was 71.4% (10/14), the rate of new occurrence of GERD was 12.1% (8/66), and the overall incidence rate was 18.2% (12/66). Except for vitamin B12(vit B12), the other nutrient indexes were significantly decreased after 1 year of surgery relative to levels before surgery (P < 0.05). The deficiency rates for vitamin A (vit A), vitamin E (vit E), zinc ion (Zn), and folic acid (FA) were higher (45.5, 25.8, 24.2, and 16.7%, respectively); however, there were no related clinical symptoms. SADI-S had significant effects on weight loss and metabolic disease remission. The main nutrient deficiencies after SADI-S were vit A, vit E, Zn, and FA deficiencies. The long-term efficacy and safety of SADI-S warrant further follow-up.


Assuntos
Diabetes Mellitus Tipo 2 , Derivação Gástrica , Refluxo Gastroesofágico , Hipercolesterolemia , Hipertensão , Obesidade Mórbida , Masculino , Feminino , Humanos , Adulto , Obesidade Mórbida/complicações , Diabetes Mellitus Tipo 2/complicações , Estudos Retrospectivos , Hipercolesterolemia/complicações , Íleo/cirurgia , Obesidade/complicações , Anastomose Cirúrgica/efeitos adversos , Gastrectomia/efeitos adversos , Hipertensão/complicações , Redução de Peso/fisiologia , Refluxo Gastroesofágico/complicações , Derivação Gástrica/efeitos adversos , Resultado do Tratamento
6.
Nat Commun ; 15(1): 2451, 2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38503751

RESUMO

The connection between triglyceride-rich lipoproteins and cardiometabolic multimorbidity, characterized by the concurrence of at least two of type 2 diabetes, ischemic heart disease, and stroke, has not been definitively established. We aim to examine the prospective associations between serum remnant cholesterol, triglycerides, and the risks of progression from first cardiometabolic disease to multimorbidity via multistate modeling in the UK Biobank. We also evaluate the causality of these associations via Mendelian randomization using 13 biologically relevant SNPs as the genetic instruments. Here we show that elevated remnant cholesterol and triglycerides are significantly associated with gradually higher risks of cardiometabolic multimorbidity, particularly the progression of ischemic heart disease to the multimorbidity of ischemic heart disease and type 2 diabetes. These results advocate for effective management of remnant cholesterol and triglycerides as a potential strategy in mitigating the risks of cardiometabolic multimorbidity.


Assuntos
Diabetes Mellitus Tipo 2 , Hipercolesterolemia , Isquemia Miocárdica , Humanos , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Fatores de Risco , Multimorbidade , Triglicerídeos , Colesterol , Isquemia Miocárdica/epidemiologia , Isquemia Miocárdica/genética
7.
Lipids Health Dis ; 23(1): 83, 2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38509578

RESUMO

OBJECTIVE: To enhance the detection, management and monitoring of Chinese children afflicted with sitosterolemia by examining the physical characteristics and genetic makeup of pediatric patients. METHODS: In this group, 26 children were diagnosed with sitosterolemia, 24 of whom underwent genetic analysis. Patient family medical history, physical symptoms, tests for liver function, lipid levels, standard blood tests, phytosterol levels, cardiac/carotid artery ultrasounds, fundus examinations, and treatment were collected. RESULTS: The majority (19, 73.1%) of the 26 patients exhibited xanthomas as the most prevalent manifestation. The second most common symptoms were joint pain (7, 26.9%) and stunted growth (4, 15.4%). Among the 24 (92.3%) patients whose genetics were analyzed, 16 (66.7%) harbored ABCG5 variants (type 2 sitosterolemia), and nearly one-third (8, 33.3%) harbored ABCG8 variants (type 1 sitosterolemia). Additionally, the most common pathogenic ABCG5 variant was c.1166G > A (p.Arg389His), which was found in 10 patients (66.7%). Further analysis did not indicate any significant differences in pathological traits among those carrying ABCG5 and ABCG8 variations (P > 0.05). Interestingly, there was a greater abundance of nonsense variations in ABCG5 than in ABCG8 (P = 0.09), and a greater frequency of splicing variations in ABCG8 than ABCG5 (P = 0.01). Following a change in diet or a combination of ezetimibe, the levels of cholesterol and low-density lipoprotein were markedly decreased compared to the levels reported before treatment. CONCLUSION: Sitosterolemia should be considered for individuals presenting with xanthomas and increased cholesterol levels. Phytosterol testing and genetic analysis are important for early detection. Managing one's diet and taking ezetimibe can well control blood lipids.


Assuntos
Hipercolesterolemia , Enteropatias , Erros Inatos do Metabolismo Lipídico , Fitosteróis , Fitosteróis/efeitos adversos , Xantomatose , Humanos , Criança , Lipoproteínas/genética , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Fitosteróis/genética , Colesterol , Ezetimiba/uso terapêutico
8.
Aging (Albany NY) ; 16(5): 4095-4115, 2024 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-38441531

RESUMO

FoxO6, an identified factor, induces hyperlipidemia and hepatic steatosis during aging by activating hepatic lipoprotein secretion and lipogenesis leading to increased ApoC3 concentrations in the bloodstream. However, the intricate mechanisms underlying hepatic steatosis induced by elevated FoxO6 under hyperglycemic conditions remain intricate and require further elucidation. In order to delineate the regulatory pathway involving ApoC3 controlled by FoxO6 and its resultant functional impacts, we employed a spectrum of models including liver cell cultures, aged rats subjected to HFD, transgenic mice overexpressing FoxO6 (FoxO6-Tg), and FoxO6 knockout mice (FoxO6-KO). Our findings indicate that FoxO6 triggered ApoC3-driven lipid accumulation in the livers of aged rats on an HFD and in FoxO6-Tg, consequently leading to hepatic steatosis and hyperglycemia. Conversely, the absence of FoxO6 attenuated the expression of genes involved in lipogenesis, resulting in diminished hepatic lipid accumulation and mitigated hyperlipidemia in murine models. Additionally, the upregulation of FoxO6 due to elevated glucose levels led to increased ApoC3 expression, consequently instigating cellular triglyceride mediated lipid accumulation. The transcriptional activation of FoxO6 induced by both the HFD and high glucose levels resulted in hepatic steatosis by upregulating ApoC3 and genes associated with gluconeogenesis in aged rats and liver cell cultures. Our conclusions indicate that the upregulation of ApoC3 by FoxO6 promotes the development of hyperlipidemia, hyperglycemia, and hepatic steatosis in vivo, and in vitro. Taken together, our findings underscore the significance of FoxO6 in driving hyperlipidemia and hepatic steatosis specifically under hyperglycemic states by enhancing the expression of ApoC3 in aged rats.


Assuntos
Fígado Gorduroso , Hipercolesterolemia , Hiperglicemia , Hiperlipidemias , Animais , Camundongos , Ratos , Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/metabolismo , Glucose/metabolismo , Hiperglicemia/metabolismo , Hiperlipidemias/metabolismo , Fígado/metabolismo , Camundongos Knockout , Camundongos Transgênicos , Fatores de Transcrição/metabolismo , Triglicerídeos/metabolismo , Regulação para Cima , Fatores de Transcrição Forkhead/metabolismo , Apolipoproteína C-III/metabolismo
10.
Hipertens. riesgo vasc ; 41(1): 58-61, Ene-Mar, 2024. ilus
Artigo em Inglês | IBECS | ID: ibc-ADZ-276

RESUMO

Atropine, a competitive antagonist of acetylcholine muscarinic receptors, is commonly used to treat severe bradycardia by blocking parasympathetic activity. We present a rare case of hypertensive emergency following atropine administration, with only one previous report in the literature. A 78-year-old woman with essential hypertension and hypercholesterolemia was admitted to the cardiac intensive care unit for non-ST segment elevation myocardial infarction. During coronary angiography, an occlusion of the right coronary artery was identified. While removing the diagnostic catheter through the right radial artery, the patient experienced intense pain and discomfort, accompanied by a vasovagal reflex characterized by bradycardia and hypotension. Intravenous atropine (0.5mg) was administered, leading to a rapid rise in heart rate with frequent ventricular ectopy. Subsequently, a progressive and exaggerated elevation in arterial blood pressure occurred, peaking at 294/121mmHg approximately 10min after atropine administration. The patient developed hypertensive acute pulmonary edema, successfully treated with intravenous nitroglycerine (10mg) and furosemide (60mg). Blood pressure normalized after approximately 14min. The exact mechanism of atropine-induced hypertensive emergency remains unknown. While hypertensive emergencies with atropine are exceedingly rare, healthcare professionals should be aware of this potential effect and be prepared for prompt intervention.(AU)


La atropina, un antagonista competitivo de los receptores muscarínicos de acetilcolina, se utiliza comúnmente para tratar la bradicardia severa al bloquear la actividad parasimpática. Presentamos un caso raro de emergencia hipertensiva después de la administración de atropina, con solo un informe previo en la literatura. Una mujer de 78 años con hipertensión esencial e hipercolesterolemia fue ingresada en la unidad de cuidados intensivos cardíacos por infarto agudo de miocardio sin elevación del segmento ST. Durante la angiografía coronaria, se identificó una oclusión de la arteria coronaria derecha. Mientras se retiraba el catéter diagnóstico a través de la arteria radial derecha, la paciente experimentó un intenso dolor y malestar, acompañado de un reflejo vasovagal caracterizado por bradicardia e hipotensión. Se administró atropina intravenosa (0,5 mg), lo que provocó un rápido aumento de la frecuencia cardíaca con frecuente ectopia ventricular. Posteriormente, ocurrió una elevación progresiva y exagerada de la presión arterial, alcanzando un máximo de 294/121 mmHg aproximadamente 10 minutos después de la administración de atropina. La paciente desarrolló edema pulmonar agudo hipertensivo, tratado con éxito con nitroglicerina intravenosa (10 mg) y furosemida (60 mg). La presión arterial se normalizó después de aproximadamente 14 minutos. El mecanismo exacto de la emergencia hipertensiva inducida por atropina sigue siendo desconocido. Aunque las emergencias hipertensivas con atropina son excepcionalmente raras, los profesionales de la salud deben estar al tanto de este efecto potencial y estar preparados para intervenir rápidamente.(AU)


Assuntos
Humanos , Feminino , Idoso , Atropina/administração & dosagem , Atropina/efeitos adversos , Bradicardia , Hipercolesterolemia , Angiografia Coronária , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Pacientes Internados , Exame Físico , Hipertensão , Pressão Arterial
11.
Sci Rep ; 14(1): 4596, 2024 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-38409335

RESUMO

The relationship between remnant cholesterol (RC) and homeostasis model assessment-insulin resistance (HOMA-IR) in the context of metabolic-associated fatty liver disease (MAFLD) remains an area of ambiguity. This investigation was designed to elucidate the potential association between RC and HOMA-IR in a cohort of American adults diagnosed with MAFLD. Data from 5533 participants were procured from the 2017-2018 US National Health and Nutrition Examination (NHANES) databases. A weighted linear regression model was employed to analyze the association between RC and HOMA-IR in the context of MAFLD. Preliminary analysis revealed that 44.67% of the participants were diagnosed with MAFLD, with a higher prevalence observed in individuals aged 50-64 years (31.84%, p < 0.0001) and in males compared to females (53.48% vs. 46.52%, p < 0.0001). A positive correlation was identified between RC and HOMA-IR in MAFLD patients. The threshold effect analysis model indicated a breakpoint at RC = 30 mg/dl, with a more pronounced positive correlation when RC < 30 mg/dl (ß = 0.17, p < 0.001). Receiver operating characteristic analysis further demonstrated that among all lipid parameters, RC exhibited the largest area under the curve. The study findings suggest a positive correlation between RC and HOMA-IR in MAFLD patients, indicating that elevated RC may serve as an independent risk factor for MAFLD.


Assuntos
Hipercolesterolemia , Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica , Adulto , Feminino , Masculino , Humanos , Inquéritos Nutricionais , Colesterol
13.
Phytomedicine ; 125: 155299, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38301301

RESUMO

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) rapidly becomes the leading cause of end-stage liver disease or liver transplantation. Nowadays, there has no approved drug for NAFLD treatment. Diosgenin as the structural analogue of cholesterol attenuates hypercholesterolemia by inhibiting cholesterol metabolism, which is an important pathogenesis in NAFLD progression. However, there has been no few report concerning its effects on NAFLD so far. METHODS: Using a high-fat diet & 10% fructose-feeding mice, we evaluated the anti-NAFLD effects of diosgenin. Transcriptome sequencing, LC/MS analysis, molecular docking simulation, molecular dynamics simulations and Luci fluorescent reporter gene analysis were used to evaluate pathways related to cholesterol metabolism. RESULTS: Diosgenin treatment ameliorated hepatic dysfunction and inhibited NAFLD formation including lipid accumulation, inflammation aggregation and fibrosis formation through regulating cholesterol metabolism. For the first time, diosgenin was structurally similar to cholesterol, down-regulated expression of CYP7A1 and regulated cholesterol metabolism in the liver (p < 0.01) and further affecting bile acids like CDCA, CA and TCA in the liver and feces. Besides, diosgenin decreased expression of NPC1L1 and suppressed cholesterol transport (p < 0.05). Molecular docking and molecular dynamics further proved that diosgenin was more strongly bound to CYP7A1. Luci fluorescent reporter gene analysis revealed that diosgenin concentration-dependently inhibited the enzymes activity of CYP7A1. CONCLUSION: Our findings demonstrated that diosgenin was identified as a specific regulator of cholesterol metabolism, which pave way for the design of novel clinical therapeutic strategies.


Assuntos
Diosgenina , Hipercolesterolemia , Hepatopatia Gordurosa não Alcoólica , Camundongos , Animais , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/patologia , Diosgenina/farmacologia , Diosgenina/metabolismo , Simulação de Acoplamento Molecular , Fígado , Colesterol/metabolismo , Hipercolesterolemia/tratamento farmacológico , Metabolismo dos Lipídeos , Dieta Hiperlipídica/efeitos adversos
14.
J Clin Apher ; 39(1): e22105, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38334173

RESUMO

INTRODUCTION: Lipoprotein X (Lp-X) is an abnormal lipoprotein found in multiple disease conditions, including liver dysfunction and cholestasis. High Lp-X concentrations can interfere with some laboratory testing that may result in spurious results. The detection of Lp-X can be challenging, and there is currently a lack of consensus regarding the management of Lp-X other than treating the underlying disease. CASE PRESENTATION: A 42-year-old female with Hodgkin's lymphoma treated with dexamethasone, high dose cytarabine and cisplatin and vanishing bile duct syndrome confirmed by liver biopsy presented with cholestasis, pseudohyponatremia (sodium, 113 mmol/L; reference range 136-146 mmL/L; serum osmolality, 303 mOsm/kg), and hypercholesterolemia (> 2800 mg/dL, reference range < 200 mg/dL). Lp-X was confirmed by lipoprotein electrophoresis (EP). Although she did not manifest any specific signs or symptoms, therapeutic plasma exchange (TPE) was initiated based on laboratory findings of extreme hypercholesterolemia, spuriously abnormal serum sodium, and HDL values, and the potential for short- and long-term sequelae such as hyperviscosity syndrome, xanthoma, and neuropathy. During the hospitalization, she was treated with four 1.0 plasma volume TPE over 6 days using 5% albumin for replacement fluid. After the first TPE, total cholesterol (TC) decreased to 383 mg/dL and sodium was measured at 131 mmol/L. The patient was transitioned into outpatient maintenance TPE to eliminate the potential of Lp-X reappearance while the underlying disease was treated. Serial follow-up laboratory testing with lipoprotein EP showed the disappearance of Lp-X after nine TPEs over a 10-week period. LITERATURE REVIEW: There are seven and four case reports of Lp-X treated with TPE and lipoprotein apheresis (LA), respectively. While all previous case reports showed a reduction in TC levels, none had monitored the disappearance of Lp-X after completing a course of therapeutic apheresis. CONCLUSION: Clinicians should have a heightened suspicion for the presence of abnormal Lp-X in patients with cholestasis, hypercholesterolemia, and pseudohyponatremia. Once Lp-X is confirmed by lipoprotein EP, TPE should be initiated to reduce TC level and remove abnormal Lp-X. Most LA techniques are not expected to be beneficial since Lp-X lacks apolipoprotein B. Therefore, we suggest that inpatient course of TPE be performed every other day until serum sodium, TC and HDL levels become normalized. Outpatient maintenance TPE may also be considered to keep Lp-X levels low while the underlying disease is treated. Serum sodium, TC, and HDL levels should be monitored while on maintenance TPE.


Assuntos
Colestase , Hipercolesterolemia , Feminino , Humanos , Adulto , Hipercolesterolemia/complicações , Hipercolesterolemia/terapia , Lipoproteína-X , Troca Plasmática , Colestase/etiologia , Colestase/terapia , Lipoproteínas , Sódio , Ductos Biliares
15.
Int J Cardiol ; 402: 131857, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38360103

RESUMO

BACKGROUND AND AIMS: Lowering the blood concentration of low-density lipoprotein cholesterol (LDL-C), is a cornerstone in preventing atherosclerotic cardiovascular disease (ASCVD). Current European guidelines recommends LDL-C < 1.4 mmol/L for secondary prevention in high-risk patients. The aim of this study is to investigate monitoring and treatment of hypercholesterolemia one year after a ASCVD event. METHODS: Danish patients with hypercholesterolemia and an incident ASCVD event from 2015 to 2020 were included in this nationwide cohort study. Patients' LDL-C measurements and lipid-lowering treatment were followed for one year after ASCVD event, or until death or migration. Imputation was used to estimate absolute LDL-values when patients were unmeasured. RESULTS: A total of 139,043 patients were included in the study with a mean follow-up time of 10.4 months. During the one-year period, 120,020 (86%) patients had their LDL-C measured at least once, 83,723 (60%) patients were measured at least twice. During the period one to six months after ASCVD event 25,999 (19%) achieved an LDL-C < 1.4 mmol/L, 93,349 (67%) failed to achieve an LDL-C < 1.4 mmol/L, and 196,950 (14%) had died or migrated. Missing LDL-C values were estimated via imputation. At the end of month twelve, 60,583 (44%) patients were in statin monotherapy, 2926 (2%) were treated with other lipid-lowering treatment, 42,869 (31%) were in no treatment, and 32,665 (23%) had died or migrated. CONCLUSIONS: Many Danish patients are not appropriately followed-up with LDL-C measurements, and a substantial number of patients are not in lipid-lowering treatment one year after an ASCVD event.


Assuntos
Anticolesterolemiantes , Aterosclerose , Doenças Cardiovasculares , Inibidores de Hidroximetilglutaril-CoA Redutases , Hipercolesterolemia , Humanos , Hipercolesterolemia/diagnóstico , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/epidemiologia , LDL-Colesterol , Estudos de Coortes , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Aterosclerose/diagnóstico , Aterosclerose/tratamento farmacológico , Aterosclerose/epidemiologia , Dinamarca/epidemiologia , Anticolesterolemiantes/uso terapêutico
16.
Kardiol Pol ; 82(2): 144-155, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38348620

RESUMO

Heterozygous familial hypercholesterolemia (heFH) is an autosomal dominant lipid metabolism disorder. Its prevalence is 1:250-1:300 people in the population. Patients with heFH have an up to 13-fold increased risk of premature coronary artery disease (CAD). If left untreated, men and women with heFH typically develop early CAD before the ages of 55 and 60, respectively. There is evidence that coronary artery calcification (CAC) and aortic valve calcification (AoVC) are more prevalent in FH patients than in the general population. It is documented that CAC and AoVC are predictors of increased risk of cardiovascular morbidity and mortality in heFH patients, like in the general population. However, the etiology and pathogenesis of vascular calcification in FH patients is not well understood. Risk factors for vascular calcification include age, increased levels of atherogenic lipoproteins, Lp(a), increased blood pressure, and inflammation. There are convincing data from clinical studies and animal atherosclerotic mouse models using low-density lipoprotein receptor (LDL-R) knockout mice that the vascular calcification processes in FH are associated with LDL-R mutations, probably partly due to a higher total cholesterol burden of FH subjects. Data from animal models as well as clinical studies indicate that the Wnt/beta-catenin pathway components and LDL receptor-related proteins 5 and 6 (LRP-5/6) might be involved in calcification processes in FH patients. The purpose of the review is to describe the prevalence of coronary and aortic calcification and its risk factors in FH patients. The review covers data about the role of the Wnt/beta-catenin pathway and factors modulating calcification processes.


Assuntos
Estenose da Valva Aórtica , Valva Aórtica/patologia , Calcinose , Doença da Artéria Coronariana , Hipercolesterolemia , Hiperlipoproteinemia Tipo II , Calcificação Vascular , Masculino , Humanos , Feminino , Animais , Camundongos , Valva Aórtica/metabolismo , beta Catenina/metabolismo , beta Catenina/uso terapêutico , Estenose da Valva Aórtica/complicações , Hiperlipoproteinemia Tipo II/complicações , Hipercolesterolemia/complicações , Calcificação Vascular/etiologia , Doença da Artéria Coronariana/complicações
17.
Gene ; 908: 148295, 2024 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-38387707

RESUMO

Intramuscular fat (IMF) deposition profoundly influences meat quality and economic value in beef cattle production. Meanwhile, contemporary developments in epigenetics have opened new outlooks for understanding the molecular basics of IMF regulation, and it has become a key area of research for world scholars. Therefore, the aim of this paper was to provide insight and synthesis into the intricate relationship between epigenetic mechanisms and IMF deposition in beef cattle. The methodology involves a thorough analysis of existing literature, including pertinent books, academic journals, and online resources, to provide a comprehensive overview of the role of epigenetic studies in IMF deposition in beef cattle. This review summarizes the contemporary studies in epigenetic mechanisms in IMF regulation, high-resolution epigenomic mapping, single-cell epigenomics, multi-omics integration, epigenome editing approaches, longitudinal studies in cattle growth, environmental epigenetics, machine learning in epigenetics, ethical and regulatory considerations, and translation to industry practices from perspectives of IMF deposition in beef cattle. Moreover, this paper highlights DNA methylation, histone modifications, acetylation, phosphorylation, ubiquitylation, non-coding RNAs, DNA hydroxymethylation, epigenetic readers, writers, and erasers, chromatin immunoprecipitation followed by sequencing, whole genome bisulfite sequencing, epigenome-wide association studies, and their profound impact on the expression of crucial genes governing adipogenesis and lipid metabolism. Nutrition and stress also have significant influences on epigenetic modifications and IMF deposition. The key findings underscore the pivotal role of epigenetic studies in understanding and enhancing IMF deposition in beef cattle, with implications for precision livestock farming and ethical livestock management. In conclusion, this review highlights the crucial significance of epigenetic pathways and environmental factors in affecting IMF deposition in beef cattle, providing insightful information for improving the economics and meat quality of cattle production.


Assuntos
Epigenômica , Hipercolesterolemia , Bovinos/genética , Animais , Músculo Esquelético/metabolismo , Regulação da Expressão Gênica , Adipogenia/genética , Hipercolesterolemia/metabolismo , Epigênese Genética
18.
Lancet Diabetes Endocrinol ; 12(3): 174-183, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38310920

RESUMO

BACKGROUND: Currently available injectable drugs that target proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce serum LDL cholesterol and improve cardiovascular outcomes. This phase 2 study assessed NNC0385-0434, an oral PCSK9 inhibitor, in individuals receiving oral lipid-lowering therapy. METHODS: In this randomised, double-blind, placebo-controlled and active-controlled trial, 42 research sites across seven countries (Belgium, Germany, Greece, Japan, the Netherlands, Poland, and the USA) recruited individuals with established atherosclerotic cardiovascular disease (aged ≥40 years) or at high risk of atherosclerotic cardiovascular disease (aged >50 years), who had LDL cholesterol concentration of at least 1·8 mmol/L and were receiving maximum tolerated statins and stable lipid-lowering therapy. The study randomly allocated participants (3:1) with an interactive web response system to receive either NNC0385-0434 (15 mg, 40 mg, or 100 mg) once a day co-formulated with the oral absorption enhancer sodium N-[8-(2-hydroxybenzoyl)amino] caprylate (500 mg); placebo; or open-label evolocumab (140 mg) every 2 weeks administered subcutaneously. Blinding was performed within each dose level. The primary endpoint was percentage change from baseline in LDL cholesterol measured by ß quantification at week 12. All randomly assigned participants received at least one dose of treatment and were included in both safety and efficacy analyses. The trial was registered on ClinicalTrials.gov, NCT04992065, and is completed. FINDINGS: Between Aug 16, 2021, and Jan 28, 2022, we randomly assigned 267 patients to one of the three NNC0385-0434 dose cohorts (n=53 per cohort), matching placebo (n=54), or open-label evolocumab (n=54). The study population comprised 82 (31%) women and 185 (69%) men; mean age was 64·3 years (SD 9·0). Baseline mean LDL cholesterol concentration was 2·7 mmol/L (SD 0·8). Treatment with NNC0385-0434 resulted in reductions in LDL cholesterol from baseline to week 12, of 32·0 percentage points (95% CI 20·9 to 43·0) in the 15 mg cohort, 44·9 percentage points (33·8 to 56·0) in the 40 mg cohort, and 61·8 percentage points (50·7 to 72·9) in the 100 mg cohort, compared with the placebo group (p<0·0001 for each). Patients treated with evolocumab had similar LDL cholesterol reductions (59·6% [SE 4·1] decrease from baseline) to patients receiving NNC0385-0434 100 mg (56·2% [4·0]). The estimated treatment difference between NNC0385-0434 100 mg and evolocumab 140 mg was 3·4 percentage points [95% CI -7·8 to 14·7]. The most frequently reported adverse event was COVID-19, which affected 31 (12%) of 267 patients, with similar numbers across treatment groups. Investigative sites reported gastrointestinal disorders as the most frequent treatment-related adverse event (26 patients and 35 events total in the three NNC0385 cohorts and one patient and one event each in the placebo and evolocumab cohorts). No deaths or treatment-related serious adverse events occurred. INTERPRETATION: This study showed excellent 12-week LDL cholesterol lowering efficacy and good patient tolerance of an oral PCSK9 inhibitor, NNC0835-0434, similar to an injectable drug. However, the sponsor chose to discontinue further development of NNC0835-0434 due to portfolio considerations. FUNDING: Novo Nordisk.


Assuntos
Anticolesterolemiantes , Doenças Cardiovasculares , Hipercolesterolemia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Anticorpos Monoclonais , Anticolesterolemiantes/uso terapêutico , Anticolesterolemiantes/efeitos adversos , Doenças Cardiovasculares/induzido quimicamente , LDL-Colesterol , Método Duplo-Cego , Hipercolesterolemia/tratamento farmacológico , Pró-Proteína Convertase 9 , Resultado do Tratamento
19.
JAMA Pediatr ; 178(3): 283-293, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38315470

RESUMO

Importance: Many pediatric patients with heterozygous familial hypercholesterolemia (HeFH) cannot reach recommended low-density lipoprotein cholesterol (LDL-C) concentrations on statins alone and require adjunct lipid-lowering therapy (LLT); the use of alirocumab in pediatric patients requires evaluation. Objective: To assess the efficacy of alirocumab in pediatric patients with inadequately controlled HeFH. Design, Setting, and Participants: This was a phase 3, randomized clinical trial conducted between May 2018 and August 2022 at 43 centers in 24 countries. Pediatric patients aged 8 to 17 years with HeFH, LDL-C 130 mg/dL or greater, and receiving statins or other LLTs were included. Following consecutive enrollment into dosing cohorts, 25 of 99 patients screened for dosing every 2 weeks (Q2W) failed screening; 25 of 104 patients screened for dosing every 4 weeks (Q4W) failed screening. A total of 70 of 74 Q2W patients (95%) and 75 of 79 Q4W patients (95%) completed the double-blind period. Interventions: Patients were randomized 2:1 to subcutaneous alirocumab or placebo and Q2W or Q4W. Dosage was based on weight (40 mg for Q2W or 150 mg for Q4W if <50 kg; 75 mg for Q2W or 300 mg for Q4W if ≥50 kg) and adjusted at week 12 if LDL-C was 110 mg/dL or greater at week 8. After the 24-week double-blind period, patients could receive alirocumab in an 80-week open-label period. Main Outcomes and Measures: The primary end point was percent change in LDL-C from baseline to week 24 in each cohort. Results: Among 153 patients randomized to receive alirocumab or placebo (mean [range] age, 12.9 [8-17] years; 87 [56.9%] female), alirocumab showed statistically significant reductions in LDL-C vs placebo in both cohorts at week 24. Least squares mean difference in percentage change from baseline was -43.3% (97.5% CI, -56.0 to -30.7; P < .001) Q2W and -33.8% (97.5% CI, -46.4 to -21.2; P < .001) Q4W. Hierarchical analysis of secondary efficacy end points demonstrated significant improvements in other lipid parameters at weeks 12 and 24 with alirocumab. Two patients receiving alirocumab Q4W experienced adverse events leading to discontinuation. No significant difference in adverse event incidence was observed between treatment groups. Open-label period findings were consistent with the double-blind period. Conclusions and Relevance: The findings in this study indicate that alirocumab Q2W or Q4W significantly may be useful for reducing LDL-C and other lipid parameters and be well tolerated in pediatric patients with HeFH inadequately controlled with statins. Trial Registration: ClinicalTrials.gov Identifier: NCT03510884.


Assuntos
Anticorpos Monoclonais Humanizados , Anticolesterolemiantes , Inibidores de Hidroximetilglutaril-CoA Redutases , Hipercolesterolemia , Hiperlipoproteinemia Tipo II , Humanos , Feminino , Criança , Masculino , LDL-Colesterol , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Anticorpos Monoclonais/efeitos adversos , Resultado do Tratamento , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hipercolesterolemia/induzido quimicamente , Hipercolesterolemia/tratamento farmacológico , Método Duplo-Cego , Anticolesterolemiantes/uso terapêutico
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...