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1.
Gene ; 762: 145102, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-32882331

RESUMO

The Angiotensin system is implicated in the pathogenesis of COVID-19. First, ACE2 is the cellular receptor for SARS-CoV-2, and expression of the ACE2 gene could regulate the individuals susceptibility to infection. In addition, the balance between ACE1 and ACE2 activity has been implicated in the pathogenesis of respiratory diseases and could play a role in the severity of COVID-19. Functional ACE1/ACE2 gene polymorphisms have been associated with the risk of cardiovascular and pulmonary diseases, and could thus also contribute to the outcome of COVID-19. We studied 204 COVID-19 patients (137 non-severe and 67 severe-ICU cases) and 536 age-matched controls. The ACE1 insertion/deletion and ACE2 rs2285666 polymorphism were determined. Variables frequencies were compared between the groups by logistic regression. We also sequenced the ACE2 coding nucleotides in a group of patients. Severe COVID-19 was associated with hypertension male gender (p < 0.001), hypertension (p = 0.006), hypercholesterolaemia (p = 0.046), and the ACE1-DD genotype (p = 0.049). In the multiple logistic regression hypertension (p = 0.02, OR = 2.26, 95%CI = 1.12-4.63) and male gender (p = 0.002; OR = 3.15, 95%CI = 1.56-6.66) remained as independent significant predictors of severity. The ACE2 polymorphism was not associated with the disease outcome. The ACE2 sequencing showed no coding sequence variants that could explain an increased risk of developing COVID-19. In conclusion, an adverse outcome of COVID-19 was associated with male gender, hypertension, hypercholesterolemia and the ACE1 genotype. Our work suggested that the ACE1-I/D might influence COVID-19 severity, but the effect was dependent on the hypertensive status. This result requires further validation in other large cohorts.


Assuntos
Infecções por Coronavirus/genética , Peptidil Dipeptidase A/genética , Pneumonia Viral/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus , Estudos de Casos e Controles , Feminino , Técnicas de Genotipagem , Humanos , Hipercolesterolemia/complicações , Hipertensão/complicações , Mutação INDEL , Masculino , Pessoa de Meia-Idade , Pandemias , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Espanha , Adulto Jovem
2.
Medicine (Baltimore) ; 99(38): e22225, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32957361

RESUMO

BACKGROUND: Coronary heart disease (CHD) is the leading cause of death globally. Angina pectoris is closely associated with coronary artery insufficiency, which seriously affects the quality of life and work of patients. Hypercholesterolemia and hypertension (HTN) are risk factors for CHD angina pectoris. The correlation between hypercholesterolemia with or without HTN and the severity of coronary arteries has not been clarified. OBJECTIVE: To explore the correlation between hypercholesterolemia and the degree of coronary artery stenosis (CAS) of CHD angina pectoris, and to further research the influence of HTN on total cholesterol level and CAS, so as to provide guidance for clinical prevention and treatment. METHODS: A multicenter, retrospective clinical study was conducted in the medical records management system of 6 hospitals in Tianjin. Patients who were suffered from CHD angina pectoris and aged from 35 to 75 years old are involved. They hospitalized in the Department of Cardiology between September 1, 2014, and September 1, 2019, and underwent coronary angiography. We divide patients into 3 groups based on the total cholesterol level, the degree of CAS is evaluated by Gensini score, and further divide them into 6 subgroups based on with or without HTN. Collect and analyze the demographics, laboratory information, clinical outcome data, and coronary angiographic data of patients. CONCLUSION: Through clinical research data, the study will help to provide guidance for the prevention and treatment of CHD angina pectoris complicated with diseases and promote further research.


Assuntos
Angina Pectoris/etiologia , Estenose Coronária/etiologia , Hipercolesterolemia/complicações , Hipertensão/complicações , Estudos Clínicos como Assunto , Humanos , Estudos Multicêntricos como Assunto , Estudos Retrospectivos
3.
Med Hypotheses ; 143: 110127, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32759008

RESUMO

Fenofibrate, which is a PPAR-alfpha agonist, increases the level of sulfatide. In this letter we hypothesize on the background of various findings that this is beneficial against COVID-19. Fenofibrate has been used for decades against hypercholesterolemia and has no serious side effects. Therefore, a trial giving fenofibrate to patients with corona virus infection is recommended.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/tratamento farmacológico , Fenofibrato/farmacologia , Hipolipemiantes/farmacologia , Pandemias , Pneumonia Viral/tratamento farmacológico , Sulfoglicoesfingolipídeos/sangue , Adulto , Envelhecimento/sangue , Criança , Reposicionamento de Medicamentos , Fenofibrato/uso terapêutico , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/complicações , Hipertensão/sangue , Hipertensão/complicações , Hipolipemiantes/uso terapêutico , PPAR alfa/antagonistas & inibidores , Internalização do Vírus
4.
PLoS One ; 15(6): e0234131, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32502216

RESUMO

BACKGROUND: Low plasma testosterone, either spontaneous or as a result of androgen deprivation therapy for prostate cancer, is associated with an increased risk of cardiovascular events. The underlying mechanism in humans is not understood. Experimental studies in mice have shown that castration facilitates atherogenesis and may increase signs of plaque vulnerability. Pigs used for translational atherosclerosis research have frequently been castrated for practical or commercial reasons, but the effect of castration on atherosclerosis has never been systematically evaluated in pigs. OBJECTIVE: To study the effect of castration on atherosclerotic plaque burden and type in genetically modified minipigs with hypercholesterolemia. METHODS: Newborn male Yucatan minipigs with transgenic overexpression of a human gain-of-function mutant of proprotein convertase subtilisin/kexin type 9 were randomized to undergo orchiectomy (n = 8) or serve as controls (n = 6). Minipigs were started on high-fat diet at 3 months of age and the amount and composition of atherosclerotic lesions were analyzed at 12 months of age. Plasma lipid profiles and behavioral parameters were also assessed. RESULTS: Plasma lipids were slightly affected to a more atherogenic profile by orchiectomy, but atherosclerotic lesion size was unaltered in the LAD, thoracic aorta, abdominal aorta, and iliac arteries. The distribution of lesion types (xanthomas, pathological intimal thickening and fibroatheromas) were also not statistically different between groups in any of the examined vascular territories. The abdominal aorta developed the most advanced stages of disease with reproducible fibroatheroma formation, and here it was found that the area of necrotic core was significantly increased in orchiectomized pigs compared with controls. Orchiectomy also reduced aggressive behavior. CONCLUSIONS: Castration does not alter the burden of atherosclerosis in hypercholesterolemic Yucatan minipigs, but may increase necrotic core area in fibroatheromas.


Assuntos
Aterosclerose/patologia , Hipercolesterolemia/patologia , Animais , Animais Geneticamente Modificados , Aorta/patologia , Aterosclerose/complicações , Dieta Hiperlipídica , Modelos Animais de Doenças , Humanos , Hipercolesterolemia/complicações , Hipercolesterolemia/genética , Artéria Ilíaca/patologia , Lipídeos/sangue , Masculino , Necrose , Orquiectomia , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/metabolismo , Suínos , Porco Miniatura , Testosterona/sangue
5.
Cardiovasc Pathol ; 49: 107241, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32554057

RESUMO

In order to accelerate development of atherosclerosis(AS) in miniature swine models, varieties of strategies and methods have been explored. In addition to traditional methods such as high cholesterol feeding and balloon injury, new methods such as familial hypercholesterolemia induced by gene editing and intramural injection have been applied in recent years. Although it has been claimed that these methods have successfully aggravated lesion areas and stenosis, lesion features induced by different strategies have shown heterogeneity in morphology. In addition, time consumption, high cost, and unavailability are problems that restrict application of these AS models. Here, we summarize strategies and methods to accelerate AS models and further analyze their values, advantages, and shortcomings.


Assuntos
Artérias/patologia , Aterosclerose/etiologia , Placa Aterosclerótica , Angioplastia com Balão , Animais , Animais Geneticamente Modificados , Artérias/metabolismo , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Dieta Hiperlipídica , Modelos Animais de Doenças , Progressão da Doença , Edição de Genes , Predisposição Genética para Doença , Hipercolesterolemia/complicações , Hipercolesterolemia/genética , Suínos , Porco Miniatura/genética , Fatores de Tempo
6.
PLoS One ; 15(4): e0231209, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32251440

RESUMO

As survival of acute lymphoblastic leukemia (ALL) exceeds 90%, limiting therapy-related toxicity has become a key challenge. Cardio-metabolic dysfunction is a challenge during and after childhood ALL therapy. In a single center study, we measured triglycerides (TG), total cholesterol (TC), high (HDL) and low density lipoproteins (LDL) levels at diagnosis and assessed the association with BMI, early therapy response, on-therapy hyperlipidemia and the toxicities; thromboembolism, osteonecrosis and pancreatitis. We included 127 children (1.0-17.9 years) all treated according to the NOPHO ALL2008 protocol. Dyslipidemia was identified at ALL-diagnosis in 99% of the patients, dominated by reduced HDL levels (98%) and mild hypertriglyceridemia (61%). Hypertriglyceridemia was not associated with body mass index (P = 0.71). Five percent of patients had mild hypercholesterolemia, 14% had mild hypocholesterolemia, 13% had decreased and 1% elevated LDL-levels. Increased TG and TC levels at ALL-diagnosis were not associated with any on-therapy lipid levels. Lipid levels and BMI were not associated to MRD after induction therapy; However, BMI and hypercholesterolemia were associated with worse risk group stratification (P<0.045 for all). The cumulative incidence of thromboembolism was increased both for patients with hypo- (20.0%) and hypercholesterolemia (16.7%) compared to patients with normal TC levels (2.2%) at diagnosis (P = 0.0074). In conclusion, dyslipidemic changes were present prior to ALL-therapy in children with ALL but did not seem to affect dysmetabolic traits during therapy and were not predictive of on-therapy toxicities apart from an association between dyscholesterolemia at time of ALL-diagnosis and risk of thromboembolism. However, the latter should be interpreted with caution due to low number in the groups.


Assuntos
Dislipidemias/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Adolescente , Asparaginase/metabolismo , Índice de Massa Corporal , Criança , Pré-Escolar , Dislipidemias/epidemiologia , Feminino , Humanos , Hipercolesterolemia/complicações , Hipercolesterolemia/epidemiologia , Hipertrigliceridemia/complicações , Hipertrigliceridemia/epidemiologia , Lactente , Masculino , Osteonecrose/complicações , Pancreatite/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Estudos Retrospectivos , Risco , Esteroides/metabolismo , Tromboembolia/complicações , Resultado do Tratamento
7.
Metabolism ; 106: 154205, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32184090

RESUMO

BACKGROUND: Cardiovascular diseases (CVDs), with highest mortality and morbidity rates, are the major cause of death in the world. Due to the limited information on heart tissue changes, mediated by hypercholesterolemia, we planned to investigate molecular mechanisms of endoplasmic reticulum (ER) stress and related cell death in high cholesterol fed rabbit model and possible beneficial effects of α-tocopherol. METHODS: Molecular changes in rabbit heart tissue and cultured cardiomyocytes (H9c2 cells) were measured by western blotting, qRT-PCR, immunflouresence and flow cytometry experiments. Histological modifications were assessed by light and electron microscopes, while degradation of mitochondria was quantified through confocal microscope. RESULTS: Feeding rabbits 2% cholesterol diet for 8 weeks and treatment of cultured cardiomyocytes with 10 µg/mL cholesterol for 3 h induced excessive autophagic activity via IRE1/JNK pathway. While no change in ER-associated degradation (ERAD) and apoptotic cell death were determined, electron and confocal microscopy analyses in cholesterol supplemented rabbits revealed significant parameters of autophagic cell death, including cytoplasmic autophagosomes, autolysosomes and organelle loss in juxtanuclear area as well as mitochondria engulfment by autophagosome. Either inhibition of ER stress or JNK in cultured cardiomyocytes or α-tocopherol supplementation in rabbits could counteract the effects of cholesterol. CONCLUSION: Our findings underline the essential role of hypercholesterolemia in stimulating IRE1/JNK branch of ER stress response which then leads to autophagic cell death in heart tissue. Results also showed α-tocopherol as a promising regulator of autophagic cell death in cardiomyocytes.


Assuntos
Morte Celular Autofágica/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Colesterol/farmacologia , Coração/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Animais , Células Cultivadas , Colesterol/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Coração/fisiologia , Humanos , Hipercolesterolemia/complicações , Hipercolesterolemia/metabolismo , Hipercolesterolemia/patologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Proteínas de Membrana/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/fisiologia , Proteínas Serina-Treonina Quinases/metabolismo , Coelhos , Ratos
8.
Circ Arrhythm Electrophysiol ; 13(4): e007614, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32189516

RESUMO

BACKGROUND: Heart rate variability (HRV) and pulse rate variability are indices of autonomic cardiac modulation. Increased pericardial fat is associated with worse cardiovascular outcomes. We hypothesized that progressive increases in pericardial fat volume and inflammation prospectively dampen HRV in hypercholesterolemic pigs. METHODS: WT (wild type) or PCSK9 (proprotein convertase subtilisin-like/kexin type-9) gain-of-function Ossabaw mini-pigs were studied in vivo before and after 3 and 6 months of a normal diet (WT-normal diet, n=4; PCSK9-normal diet, n=6) or high-fat diet (HFD; WT-HFD, n=3; PCSK9-HFD, n=6). The arterial pulse waveform was obtained from an arterial telemetry transmitter to analyze HRV indices, including SD (SD of all pulse-to-pulse intervals over a single 5-minute period), root mean square of successive differences, proportion >50 ms of normal-to-normal R-R intervals, and the calculated ratio of low-to-high frequency distributions (low-frequency power/high-frequency power). Pericardial fat volumes were evaluated using multidetector computed tomography and its inflammation by gene expression of TNF (tumor necrosis factor)-α. Plasma lipid panel and norepinephrine level were also measured. RESULTS: At diet completion, hypercholesterolemic PCSK9-HFD had significantly (P<0.05 versus baseline) depressed HRV (SD of all pulse-to-pulse intervals over a single 5-minute period, root mean square of successive differences, proportion >50 ms, high-frequency power, low-frequency power), and both HFD groups had higher sympathovagal balance (SD of all pulse-to-pulse intervals over a single 5-minute period/root mean square of successive differences, low-frequency power/high-frequency power) compared with normal diet. Pericardial fat volumes and LDL (low-density lipoprotein) cholesterol concentrations correlated inversely with HRV and directly with sympathovagal balance, while sympathovagal balance correlated directly with plasma norepinephrine. Pericardial fat TNF-α expression was upregulated in PCSK9-HFD, colocalized with nerve fibers, and correlated inversely with root mean square of successive differences and proportion >50 ms. CONCLUSIONS: Progressive pericardial fat expansion and inflammation are associated with a fall in HRV in Ossabaw mini-pigs, implying aggravated autonomic imbalance. Hence, pericardial fat accumulation is associated with alterations in HRV and the autonomic nervous system. Visual Overview: A visual overview is available for this article.


Assuntos
Tecido Adiposo/fisiopatologia , Adiposidade , Arritmias Cardíacas/etiologia , Sistema Nervoso Autônomo/fisiopatologia , Frequência Cardíaca , Hipercolesterolemia/complicações , Inflamação/etiologia , Pericárdio/fisiopatologia , Tecido Adiposo/metabolismo , Animais , Animais Geneticamente Modificados , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatologia , Sistema Nervoso Autônomo/metabolismo , Colesterol/sangue , Modelos Animais de Doenças , Hipercolesterolemia/metabolismo , Hipercolesterolemia/fisiopatologia , Inflamação/metabolismo , Inflamação/fisiopatologia , Mediadores da Inflamação/metabolismo , Masculino , Norepinefrina/sangue , Pericárdio/metabolismo , Suínos , Porco Miniatura/genética , Fatores de Tempo , Fator de Necrose Tumoral alfa/metabolismo
9.
N Engl J Med ; 382(16): 1507-1519, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32187462

RESUMO

BACKGROUND: Inclisiran inhibits hepatic synthesis of proprotein convertase subtilisin-kexin type 9. Previous studies suggest that inclisiran might provide sustained reductions in low-density lipoprotein (LDL) cholesterol levels with infrequent dosing. METHODS: We enrolled patients with atherosclerotic cardiovascular disease (ORION-10 trial) and patients with atherosclerotic cardiovascular disease or an atherosclerotic cardiovascular disease risk equivalent (ORION-11 trial) who had elevated LDL cholesterol levels despite receiving statin therapy at the maximum tolerated dose. Patients were randomly assigned in a 1:1 ratio to receive either inclisiran (284 mg) or placebo, administered by subcutaneous injection on day 1, day 90, and every 6 months thereafter over a period of 540 days. The coprimary end points in each trial were the placebo-corrected percentage change in LDL cholesterol level from baseline to day 510 and the time-adjusted percentage change in LDL cholesterol level from baseline after day 90 and up to day 540. RESULTS: A total of 1561 and 1617 patients underwent randomization in the ORION-10 and ORION-11 trials, respectively. Mean (±SD) LDL cholesterol levels at baseline were 104.7±38.3 mg per deciliter (2.71±0.99 mmol per liter) and 105.5±39.1 mg per deciliter (2.73±1.01 mmol per liter), respectively. At day 510, inclisiran reduced LDL cholesterol levels by 52.3% (95% confidence interval [CI], 48.8 to 55.7) in the ORION-10 trial and by 49.9% (95% CI, 46.6 to 53.1) in the ORION-11 trial, with corresponding time-adjusted reductions of 53.8% (95% CI, 51.3 to 56.2) and 49.2% (95% CI, 46.8 to 51.6) (P<0.001 for all comparisons vs. placebo). Adverse events were generally similar in the inclisiran and placebo groups in each trial, although injection-site adverse events were more frequent with inclisiran than with placebo (2.6% vs. 0.9% in the ORION-10 trial and 4.7% vs. 0.5% in the ORION-11 trial); such reactions were generally mild, and none were severe or persistent. CONCLUSIONS: Reductions in LDL cholesterol levels of approximately 50% were obtained with inclisiran, administered subcutaneously every 6 months. More injection-site adverse events occurred with inclisiran than with placebo. (Funded by the Medicines Company; ORION-10 and ORION-11 ClinicalTrials.gov numbers, NCT03399370 and NCT03400800.).


Assuntos
Anticolesterolemiantes/uso terapêutico , LDL-Colesterol/sangue , Doença da Artéria Coronariana/tratamento farmacológico , Hipercolesterolemia/tratamento farmacológico , Pró-Proteína Convertase 9/antagonistas & inibidores , RNA Interferente Pequeno/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Anticolesterolemiantes/efeitos adversos , Anticolesterolemiantes/farmacocinética , Doenças Cardiovasculares , Doença da Artéria Coronariana/complicações , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/sangue , Hipercolesterolemia/complicações , Injeções Subcutâneas/efeitos adversos , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , RNA Interferente Pequeno/efeitos adversos , RNA Interferente Pequeno/farmacocinética , Fatores de Risco
10.
Herz ; 45(1): 24-29, 2020 Feb.
Artigo em Alemão | MEDLINE | ID: mdl-31970461

RESUMO

Cardiovascular diseases are among the leading causes of death worldwide. Apart from a few exceptions heart attack, stroke and peripheral arterial occlusive disease first occur in later adulthood. The cornerstone for these diseases, however, is already laid by accelerated vascular aging in childhood. Apart from pediatric medical preventive check-ups, the medical care of the parents should also be a reason for taking action. A detailed family history enables many conclusions to be drawn about the cardiovascular risk of the next generation This requires targeted diagnostics and appropriate interventions in childhood ranging from lifestyle measures up to pharmaceutical therapy. In this context the current guidelines on the diagnostics and treatment of hypercholesterolemia and arterial hypertension in children and adolescents are also presented.


Assuntos
Doenças Cardiovasculares , Hipercolesterolemia , Hipertensão , Estilo de Vida , Infarto do Miocárdio , Adolescente , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Criança , Humanos , Hipercolesterolemia/complicações , Hipercolesterolemia/tratamento farmacológico , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/prevenção & controle , Fatores de Risco
11.
Life Sci ; 243: 117275, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31926242

RESUMO

AIMS: Imatinib is an effective tyrosine kinase inhibitor which has different therapeutic actions. The recent work demonstrated the possible beneficial effects of imatinib on the progression of atherosclerosis, endothelial dysfunction, and hypercholesterolemia-associated liver damage in rabbits. MAIN METHODS: Animals had been distributed in 4 groups: group 1 (non-treated): animals fed regular diet; group 2 high cholesterol [HC]: animals fed 1% cholesterol supplemented diet for 30 days; group 3 (HC-Imatinib): animals fed 1% cholesterol supplemented diet+imatinib (0.01 g/kg daily, p.o) for 30 days; group 4 (Imatinib): animals fed regular diet with imatinib (0.01 g/kg daily, p.o). After thirty days, tissue samples and blood were isolated to be detected biochemically, histologically, and for in vitro analysis. KEY FINDINGS: HC exhibited significant elevations in serum lipid parameters, CRP, ALT, AST and ALP. Additionally, HC induced significant increases for aortic and hepatic MDA, aortic NO and hepatic PDGFR-ß, while significantly exhibited reductions in aortic and hepatic GSH, SOD and hepatic PPARγ1. Moreover, HC produced impairment in ACh-enhanced aortic relaxation and aortic pathological changes. Histopathological examination of HC-fed rabbits revealed hepatic steatosis compared with non-treated group. Imatinib administration exhibited significant decreases in serum lipid parameters, CRP, ALT, AST and ALP. Additionally, imatinib induced significant decreases for aortic and hepatic MDA, aortic NO and hepatic PDGFR-ß, while significantly exhibited elevations in aortic and hepatic GSH, SOD and hepatic PPARγ1 compared with HC animals. Furthermore, imatinib significantly protected against HC produced attenuation in ACh-induced aortic relaxation and pathological changes in aortic and hepatic tissues. Interestingly, imatinib could return serum CRP, ALP, hepatic SOD and PDGFR-ß to basal values. SIGNIFICANCE: The recent observation reports that imatinib could have beneficial effect against atherosclerosis progression, vascular malfunction, and liver damage in high cholesterol diet (HCD)-fed rabbits.


Assuntos
Aterosclerose/prevenção & controle , Endotélio Vascular/efeitos dos fármacos , Hipercolesterolemia/complicações , Mesilato de Imatinib/uso terapêutico , Fígado/efeitos dos fármacos , Fígado/patologia , Animais , Aorta/enzimologia , Aorta/metabolismo , Aorta/patologia , Aterosclerose/etiologia , Peso Corporal , Proteína C-Reativa/metabolismo , Colesterol na Dieta/administração & dosagem , Dieta , Endotélio Vascular/fisiopatologia , Enzimas/sangue , Enzimas/metabolismo , Mesilato de Imatinib/farmacologia , Lipídeos/sangue , Masculino , Coelhos
12.
Clin Sci (Lond) ; 134(2): 225-237, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-31934720

RESUMO

Circulating factors have been implicated in the pathogenesis of minimal change disease (MCD), and may have direct effects on cholesterol metabolism. This study investigated the pathogenesis of hypercholesterolemia in an IL-13 overexpression rat model of MCD prior to the onset of proteinuria, so as to establish the direct contribution of IL-13, especially with regard to hepatic cholesterol handling. In this model of MCD, the temporal relationship between hypercholesterolemia and proteinuria was first identified. Plasma proprotein convertase subtilisin/kexin type 9 (Pcsk9) and liver ATP-binding cassette sub-family G member 5 (Abcg5) were measured using ELISA. Liver Ldlr and liver X receptor alpha (Lxra) were quantified with Western blot. Abcg5-mediated cholesterol efflux in IL-13-stimulated rat primary hepatocytes was measured using taurocholate as cholesterol acceptor. The role of Lxra was validated using a luciferase assay in Lxre-luciferase-transfected IL-13-stimulated hepatocytes. IL-13-transfected rats developed hypercholesterolemia prior to proteinuria, with 35% of rats hypercholesterolemic but only 11% proteinuric by Day 20 (P = 0.04). These pre-proteinuric hypercholesterolemic rats showed elevations in total and LDL-cholesterol, but not hypertriglyceridemia or hepatic steatosis. The hypercholesterolemia was associated with increased hepatic Pcsk9 synthesis and enhanced circulating Pcsk9 levels, which correlated strongly with plasma total cholesterol (r = 0.73, P<0.001). The hypercholesterolemia was also contributed by decreased Abcg5 expression and activity, due to reduced Lxra expression. Lxra expression correlated with plasma total cholesterol levels (r = -0.52, P = 0.01), and overexpression of pLxra in rat hepatocytes abrogated the IL-13-mediated down-regulation of Lxre-driven gene expression. In conclusion, we have shown that IL-13 induced changes in hepatic cholesterol handling in a cytokine-induced rat model of MCD, resulting in hypercholesterolemia which can precede the onset of proteinuria.


Assuntos
Colesterol/metabolismo , Hipercolesterolemia/metabolismo , Interleucina-13/metabolismo , Fígado/metabolismo , Nefrose Lipoide/metabolismo , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Colesterol/sangue , Modelos Animais de Doenças , Regulação para Baixo , Hipercolesterolemia/sangue , Hipercolesterolemia/complicações , Lipoproteínas/metabolismo , Receptores X do Fígado/metabolismo , Masculino , Nefrose Lipoide/sangue , Nefrose Lipoide/complicações , Pró-Proteína Convertase 9/metabolismo , Proteinúria/complicações , Proteinúria/metabolismo , Ratos Wistar , Proteínas de Ligação a Elemento Regulador de Esterol/metabolismo
13.
Arterioscler Thromb Vasc Biol ; 40(3): 638-655, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31893948

RESUMO

OBJECTIVE: Although often studied independently, little is known about how aortic valve endothelial cells and valve interstitial cells interact collaborate to maintain tissue homeostasis or drive valve calcific pathogenesis. Inflammatory signaling is a recognized initiator of valve calcification, but the cell-type-specific downstream mechanisms have not been elucidated. In this study, we test how inflammatory signaling via NFκB (nuclear factor κ-light-chain enhancer of activated B cells) activity coordinates unique and shared mechanisms of valve endothelial cells and valve interstitial cells differentiation during calcific progression. Approach and Results: Activated NFκB was present throughout the calcific aortic valve disease (CAVD) process in both endothelial and interstitial cell populations in an established mouse model of hypercholesterolemia-induced CAVD and in human CAVD. NFκB activity induces endothelial to mesenchymal transformation in 3-dimensional cultured aortic valve endothelial cells and subsequent osteogenic calcification of transformed cells. Similarly, 3-dimensional cultured valve interstitial cells calcified via NFκB-mediated osteogenic differentiation. NFκB-mediated endothelial to mesenchymal transformation was directly demonstrated in vivo during CAVD via genetic lineage tracking. Genetic deletion of NFκB in either whole valves or valve endothelium only was sufficient to prevent valve-specific molecular and cellular mechanisms of CAVD in vivo despite the persistence of a CAVD inducing environment. CONCLUSIONS: Our results identify NFκB signaling as an essential molecular regulator for both valve endothelial and interstitial participation in CAVD pathogenesis. Direct demonstration of valve endothelial cell endothelial to mesenchymal transformation transmigration in vivo during CAVD highlights a new cellular population for further investigation in CAVD morbidity. The efficacy of valve-specific NFκB modulation in inhibiting hypercholesterolemic CAVD suggests potential benefits of multicell type integrated investigation for biological therapeutic development and evaluation for CAVD.


Assuntos
Valva Aórtica/metabolismo , Calcinose/metabolismo , Diferenciação Celular , Células Endoteliais/metabolismo , Doenças das Valvas Cardíacas/metabolismo , NF-kappa B/metabolismo , Osteogênese , Animais , Valva Aórtica/patologia , Calcinose/etiologia , Calcinose/patologia , Células Cultivadas , Microambiente Celular , Modelos Animais de Doenças , Células Endoteliais/patologia , Doenças das Valvas Cardíacas/etiologia , Doenças das Valvas Cardíacas/genética , Doenças das Valvas Cardíacas/patologia , Humanos , Hipercolesterolemia/complicações , Hipercolesterolemia/genética , Hipercolesterolemia/metabolismo , Quinase I-kappa B/genética , Quinase I-kappa B/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , NF-kappa B/genética , Fatores de Transcrição NFATC/genética , Fatores de Transcrição NFATC/metabolismo , Receptores de LDL/genética , Receptores de LDL/metabolismo , Transdução de Sinais , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo
14.
J Periodontal Res ; 55(3): 453-463, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31994219

RESUMO

BACKGROUND AND OBJECTIVES: Periodontitis can corroborate with development and progression of atherosclerosis and a possible bidirectional interaction between both pathologies has been hypothesized. The aim of this work was to study the interactions between diet-induced hypercholesterolemia and ligature-induced periodontitis in Wistar rats submitted to both conditions. MATERIAL AND METHODS: Animals were divided into four experimental groups: C (control: standard diet without periodontitis), Perio (periodontitis plus standard diet), HC (high cholesterol diet without periodontitis), and HC + Perio (high cholesterol diet plus periodontitis). The diets were offered for 45 days and a silk ligature was applied in the lower first molars of Perio and HC-Perio animals on day 34 and maintained for 11 days until euthanasia. The mandibles were excised, and alveolar bone loss was determined by macroscopic and micro-tomographic (µ-CT) imaging. Blood samples were obtained, and platelet aggregation was induced in plasma rich in platelets by adenosine diphosphate (ADP) and collagen. Endothelium-dependent vascular reactivity and protein expression of endothelial (eNOS), phosphorylated endothelial (peNOS), and inducible (iNOS) nitric oxide synthases were evaluated in aorta samples. RESULTS: The HC diet combined with periodontitis (HC + Perio group) was associated with an increased alveolar bone loss, when compared to the other groups. Both in Perio and HC groups, platelet aggregation induced by ADP or collagen was increased, while maximum aortic relaxation induced by acetylcholine was decreased. Periodontitis or HC diet alone decreased the expression of peNOS and HC diet increased the expression of iNOS. In contrast, no additive or synergistic effects were found in vascular reactivity or in platelet aggregation when the two conditions were associated (HC + Perio group). CONCLUSION: Hypercholesterolemia accelerated the process of bone loss induced by periodontitis while a high cholesterol diet or periodontitis individually increased platelet aggregation and vascular reactivity in rats without additive or synergistic effects, when associated.


Assuntos
Perda do Osso Alveolar/fisiopatologia , Hipercolesterolemia/complicações , Periodontite/complicações , Agregação Plaquetária , Animais , Colesterol na Dieta , Dieta , Ratos , Ratos Wistar
15.
Med Care ; 58(1): 59-64, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31688551

RESUMO

INTRODUCTION: Hypertension, hypercholesterolemia, and type II diabetes are leading cardiovascular risk factors in the United States, and Latinos are disproportionately burdened by these chronic health conditions. The extent to which Latinos overall and by language spoken at home report health behavior modification following diagnosis is poorly understood. METHODS: Our inclusion criteria included participants sampled in the 2011-2016 waves of the National Health and Nutrition Examination Survey who self-identified as Latinos, were 20 years of age or above, and reported a diagnosis of hypertension, hypercholesterolemia or diabetes (N=2027). We examined associations between the language spoken at home and report of adoption of 3 recommended health behaviors in the past year: weight loss, leisure-time physical activity (LTPA) and smoking cessation. Separate log-binomial models were fit to estimate prevalence ratios (PRs) for each health behavior. RESULTS: Approximately one third (28%) of study participants had been diagnosed with diabetes and more than half reported a diagnosis of hypercholesterolemia (65%) or hypertension (60%). Most Latinos met the highest levels of smoking cessation criteria (82%), whereas less than a third met LTPA recommendations (29%) or attempted weight loss (24%) in the past year. Fully adjusted outcome specific models showed that exclusively speaking English at home was associated with a higher probability of reporting weight loss attempt and LTPA compared with Spanish only speakers, although only LTPA was statistically significant [weight loss PR: 1.23, 95% confidence interval (CI): 0.92, 1.65; LTPA PR: 1.74; 95% CI: 1.37, 2.20; smoking cessation PR: 0.93, 95% CI: 0.86, 1.01]. CONCLUSIONS: Our findings provide new evidence on patterns of behavioral modification in a population-based sample of Latinos diagnosed with chronic health conditions. Findings suggest the need to promote language and culturally relevant initiatives to increase the adoption of health-enhancing behaviors and improve chronic disease management among Spanish-speaking Latinos.


Assuntos
Doenças Cardiovasculares/etnologia , Doenças Cardiovasculares/psicologia , Comportamentos Relacionados com a Saúde , Hispano-Americanos/psicologia , Comportamento de Redução do Risco , Adulto , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/etnologia , Diabetes Mellitus Tipo 2/psicologia , Feminino , Humanos , Hipercolesterolemia/complicações , Hipercolesterolemia/etnologia , Hipercolesterolemia/psicologia , Hipertensão/complicações , Hipertensão/etnologia , Hipertensão/psicologia , Masculino , Inquéritos Nutricionais , Fatores de Risco , Estados Unidos , Adulto Jovem
16.
Am Heart J ; 220: 203-212, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31841795

RESUMO

BACKGROUND: People living with human immunodeficiency virus (PLHIV) are at higher risk of atherosclerotic cardiovascular disease (ASCVD) due to traditional and HIV- or antiretroviral treatment (ART)-related risk factors. The use of high-intensity statin therapy is often limited by comorbidities and drug-drug interactions with ART. Herein, we present the design and baseline characteristics of the BEIJERINCK study, which will assess the safety and efficacy of evolocumab in PLHIV and hypercholesterolemia/mixed dyslipidemia. METHODS: Randomized, double-blind, placebo-controlled, multinational trial that investigates monthly subcutaneous evolocumab 420 mg versus placebo in PLHIV with hypercholesterolemia/mixed dyslipidemia who are treated with maximally-tolerated statin therapy. The primary outcome is the baseline to week 24 percent change in low density lipoprotein cholesterol (LDL-C). Secondary outcomes include achievement of LDL-C < 70 mg/dL and percent change in other plasma lipid and lipoprotein levels. Safety will also be examined. RESULTS: This study enrolled and dosed 464 patients who had a mean age of 56.4 years and were mostly male (82.5%). Mean duration with HIV was 17.4 years, and, by design, HIV viral load at screening was ≤50 copies/mL. ASCVD was documented in 35.6% of patients. Mean LDL-C of enrolled patients at baseline was 133.3 mg/dL. Statin use was prevalent (79.3% overall) with 74.6% receiving moderate or high-intensity statins. In total, 20.7% of patients did not receive statins due to intolerance/contraindications. CONCLUSIONS: The BEIJERINCK study is the first clinical trial to examine the lipid-lowering efficacy and safety of a fully human PCSK9 monoclonal antibody inhibitor in a moderate/high cardiovascular risk population of PLHIV.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Anticolesterolemiantes/administração & dosagem , LDL-Colesterol/sangue , Infecções por HIV/complicações , Hipercolesterolemia/tratamento farmacológico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticolesterolemiantes/efeitos adversos , Método Duplo-Cego , Esquema de Medicação , Dislipidemias/sangue , Dislipidemias/complicações , Dislipidemias/tratamento farmacológico , Feminino , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Sobreviventes de Longo Prazo ao HIV , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/complicações , Masculino , Pessoa de Meia-Idade , Pró-Proteína Convertase 9/antagonistas & inibidores , Valores de Referência , Carga Viral
17.
Rev. cient. Esc. Univ. Cienc. Salud ; 6(2): 17-26, jun.-dic. 2019. tab
Artigo em Espanhol | LILACS | ID: biblio-1117034

RESUMO

Introducción: La hipertensión arterial causa millones de fallecimientos anualmente. Su origen es heterogéneo; implicando factores, tanto modificables como no modificables. Objetivos Identificar los factores de riesgo asociados a hipertensión arterial en estudiantes de la Universidad Nacional Autónoma de Honduras en el Valle de Sula (UNAH-VS) en el II y III trimestre del 2018. Pacientes y métodos Se realizó un estudio cuantitativo de casos y controles con una proporción 1:1 durante el II y III trimestre del año 2018 en el Área de Salud de la Subdirección de Desarrollo Estudiantil, Cultura, Arte y Deporte (SUDECAD) de la UNAH-VS. Mediante un muestreo no probabilístico por conveniencia, se obtuvo una muestra de 34 universitarios, casos, diagnosticados con hipertensión arterial y 34 controles que no padecían la enfermedad. Resultados 24 (35.29%) de los pacientes eran hombres. Los factores con una importante asociación a la enfermedad son el antecedente familiar de hipertensión familiar en primer grado (OR: 3.8 IC: 95%, 1.3 ­ 11.2), la obesidad (OR: 5.1 IC: 95%, 1.6 ­ 16.5), el sedentarismo (OR: 4.8 IC: 95%, 1.6 ­ 14.2), la dieta no saludable (OR: 7.6 IC: 95%, 1.5 ­ 37.8), la hipertrigliceridemia (OR: 5.2 IC: 95%, 1.7 ­ 15.9) y la hipercolesterolemia (OR: 7.3 IC: 95%, 2.2 ­ 23.5). Conclusiones En los factores de riesgo no modificables, el antecedente familiar de la enfermedad fue el más importante. En los factores de riesgo modificables, predominaron aquellos asociados fuertemente a riesgo cardiovascular...(AU)


Assuntos
Humanos , Masculino , Feminino , Adulto , Hiperlipoproteinemia Tipo IV , Hipertensão , Dislipidemias , Hipercolesterolemia/complicações
18.
Biomed Res Int ; 2019: 3708497, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781614

RESUMO

Hypercholesterolaemia is associated with oxidative stress and endothelial dysfunction and leads to the development of atherosclerosis. Naringin exhibits cardiovascular protective and antioxidant properties. Therefore, the aim of this study was to assess the effect of naringin administration on vascular oxidative stress and endothelial dysfunction in hypercholesterolaemic rats and to elucidate its underlying mechanism. Sprague Dawley rats were fed a diet with 1.5% cholesterol (HCD) for 8 weeks to induce hypercholesterolaemia. Naringin (100 mg/kg body weight) was orally administrated to rats during the last 4 weeks of the diet treatment. After 8 weeks, the thoracic aorta was isolated to determine vascular function and nitric oxide (NO) levels. The aortic superoxide anion (O2 -) level was detected using dihydroethidium (DHE) fluorescence staining. Protein expression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits, and inducible nitric oxide synthase (iNOS), as well as oxidative damage markers, was also evaluated in aortae. Naringin treatment of hypercholesterolaemic rats enhanced aortic NO levels, restored endothelium-dependent responses to acetylcholine (ACh), and reduced aortic O2 - levels. Furthermore, naringin treatment decreased LOX-1, NADPH oxidase subunits (p47phox, Nox2, and Nox4), and iNOS as well as oxidative damage markers (3-nitrotyrosine (3-NT) and 4-hydroxynonenal (4-HNE)) expression in aortic tissues from hypercholesterolaemic rats. These results demonstrate that naringin treatment improves endothelium dysfunction in hypercholesterolaemic rats, at least partially by decreasing oxidative stress via downregulation of LOX-1 and NADPH oxidase.


Assuntos
Aterosclerose/tratamento farmacológico , Cardiotônicos/farmacologia , Flavanonas/farmacologia , Hipercolesterolemia/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Animais , Aorta/efeitos dos fármacos , Aorta/patologia , Aterosclerose/etiologia , Aterosclerose/genética , Aterosclerose/patologia , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hipercolesterolemia/complicações , Hipercolesterolemia/genética , Hipercolesterolemia/patologia , NADPH Oxidase 2/genética , NADPH Oxidase 4/genética , NADPH Oxidases/genética , Óxido Nítrico/genética , Óxido Nítrico Sintase Tipo II/genética , Ratos , Receptores Depuradores Classe E/genética
19.
Radiat Oncol ; 14(1): 204, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31727075

RESUMO

BACKGROUND: Breast cancer (BC) radiotherapy (RT) can induce cardiotoxicity, with adverse events often observed many years after BC RT. Subclinical left ventricular (LV) dysfunction can be detected early after BC RT with global longitudinal strain (GLS) measurement based on 2D speckle-tracking echocardiography. This 6-month follow-up analysis from the BACCARAT prospective study aimed to investigate the association between cardiac radiation doses and subclinical LV dysfunction based on GLS reduction. METHODS: The patient study group consisted of 79 BC patients (64 left-sided BC, 15 right-sided BC) treated with RT without chemotherapy. Echocardiographic parameters, including GLS, were measured before RT and 6 months post-RT. The association between subclinical LV dysfunction, defined as GLS reduction > 10%, and radiation doses to whole heart and the LV were performed based on logistic regressions. Non-radiation factors associated with subclinical LV dysfunction including age, BMI, hypertension, hypercholesterolemia and endocrine therapy were considered for multivariate analyses. RESULTS: A mean decrease of 6% in GLS was observed (- 15.1% ± 3.2% at 6 months vs. - 16.1% ± 2.7% before RT, p = 0.01). For left-sided patients, mean heart and LV doses were 3.1 ± 1.3 Gy and 6.7 ± 3.4 Gy respectively. For right-sided patients, mean heart dose was 0.7 ± 0.5 Gy and median LV dose was 0.1 Gy. Associations between GLS reduction > 10% (37 patients) and mean doses to the heart and the LV as well as the V20 were observed in univariate analysis (Odds Ratio = 1.37[1.01-1.86], p = 0.04 for Dmean Heart; OR = 1.14 [1.01-1.28], p = 0.03 for Dmean LV; OR = 1.08 [1.01-1.14], p = 0.02 for LV V20). In multivariate analysis, these associations did not remain significant after adjustment for non-radiation factors. Further exploratory analysis allowed identifying a subgroup of patients (LV V20 > 15%) for whom a significant association with subclinical LV dysfunction was found (adjusted OR = 3.97 [1.01-15.70], p = 0.048). CONCLUSIONS: This analysis indicated that subclinical LV dysfunction defined as a GLS decrease > 10% is associated with cardiac doses, but adjustment for non-radiation factors such as endocrine therapy lead to no longer statistically significant relationships. However, LV dosimetry may be promising to identify high-risk subpopulations. Larger and longer follow-up studies are required to further investigate these associations. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02605512, Registered 6 November 2015 - Retrospectively registered.


Assuntos
Neoplasias da Mama/complicações , Neoplasias da Mama/radioterapia , Coração/efeitos da radiação , Disfunção Ventricular Esquerda/complicações , Disfunção Ventricular Esquerda/diagnóstico , Adulto , Idoso , Índice de Massa Corporal , Cardiotoxicidade , Diagnóstico Precoce , Ecocardiografia , Feminino , Seguimentos , Humanos , Hipercolesterolemia/complicações , Hipertensão/complicações , Processamento de Imagem Assistida por Computador , Imageamento Tridimensional , Pessoa de Meia-Idade , Análise Multivariada , Estudos Prospectivos , Radiometria , Radioterapia Conformacional , Análise de Regressão , Estudos Retrospectivos , Fatores de Risco
20.
Recenti Prog Med ; 110(9): 401-411, 2019 Sep.
Artigo em Italiano | MEDLINE | ID: mdl-31593176

RESUMO

Elevated levels of LDL-C represent a major risk factor for cardiovascular (CV) disease and recent guidelines recommended early and appropriate interventions in hypercholesterolemic patients in order to reduce the risk of CV events. The current lipid lowering therapies (mainly statins and ezetimibe) not always allow patients to reach their appropriate LDL-C goals. This is particularly true in patients affected by genetic forms of hypercholesterolemia as well as in those who need to attain low LDL-C due to their high cardiovascular risk. In this context, the recent availability of monoclonal antibodies directed against the PCSK9 protein (PCSK9i) represent a novel therapeutic strategy to control resistant forms of hypercholesterolemia. In this review, we will examine the clinical pharmacology of PCSK9i and we will dedicated particular attention to review the results of the two pivotal cardiovascular prevention trials, FOURIER and ODISSEY OUTCOMES that demonstrated the benefit of PCSK9i in prevention of cardiovascular events in patients at very high risk not at LDL-C goal with conventional LDL-lowering therapies. The PCSK9i has been approved for use in Italy under specific criteria and following a strict prescription procedures. We will examine the epidemiology of use of PCSK9i in Italy and will underlying the potential factors influencing the access and availability to this therapy.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Hipercolesterolemia/tratamento farmacológico , Pró-Proteína Convertase 9/antagonistas & inibidores , Anticolesterolemiantes/farmacologia , LDL-Colesterol/sangue , Acesso aos Serviços de Saúde , Humanos , Hipercolesterolemia/complicações , Itália , Pró-Proteína Convertase 9/metabolismo , Fatores de Risco
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