RESUMO
OBJECTIVE: Dietary sodium intake represents a risk factor for cardiovascular disease and mortality. The study sought to analyse the sodium content of effervescent dietary supplements and drugs in Germany and the USA. DESIGN: Comparative cross-sectional study. SETTING AND METHODS: The sodium content of 39 dietary supplement effervescent tablets available in Germany was measured in May and June 2022 using optical emission spectrometry with inductively coupled argon plasma. The sodium content of 33 common pharmacy-only effervescent tablets (over-the-counter (OTC) drugs) in Germany was obtained from the summary of product characteristics. We compared the sodium content of the measured German dietary supplement effervescent tablets to that of 51 dietary supplement effervescent tablets available in the USA (data: National Institutes of Health's Dietary Supplement Label Database). RESULTS: The measured sodium content in the German dietary supplements was 283.9±122.6 mg sodium/tablet, equivalent to 14±6% of the maximum recommended daily sodium intake (MRDSI). Vitamin products had the highest (378.3±112.8 mg, 19±6% of MRDSI), and calcium products had the lowest mean sodium content (170.4±113.2 mg, 9±6% of MRDSI). Vitamin products contained significantly more sodium than magnesium (378.3 mg vs 232.7 mg; p=0.004), calcium (378.3 mg vs 170.4 mg; p=0.006) and mineral products (378.3 mg vs 191.6 mg; p=0.048). The sodium content measured in products available in Germany was higher when compared with the declared sodium content on the label of the products sold in the USA (283.9 mg vs 190.0 mg; p<0.001). The median summary of product characteristics-declared sodium content of a single dose of the German OTC drugs was 157.0 mg (IQR: 98.9-417.3 mg); pain/common cold drugs contained the most sodium (median: 452.1 mg; IQR: 351.3-474.0 mg). CONCLUSION: Effervescent tablets of nutritional supplements and OTC drugs contain high amounts of sodium, which often is not disclosed.
Assuntos
Medicamentos sem Prescrição , Sódio , Humanos , Estudos Transversais , Cálcio , Suplementos Nutricionais/análise , Vitaminas , ComprimidosRESUMO
Endpoints of large-scale trials in chronic heart failure have mostly been defined to evaluate treatments with regard to hospitalizations and mortality. However, patients with heart failure are also affected by very severe reductions in exercise capacity and quality of life. We aimed to evaluate the effects of heart failure treatments on these endpoints using available evidence from randomized trials. Interventions with evidence for improvements in exercise capacity include physical exercise, intravenous iron supplementation in patients with iron deficiency, and - with less certainty - testosterone in highly selected patients. Erythropoiesis-stimulating agents have been reported to improve exercise capacity in anaemic patients with heart failure. Sinus rhythm may have some advantage when compared with atrial fibrillation, particularly in patients undergoing pulmonary vein isolation. Studies assessing treatments for heart failure co-morbidities such as sleep-disordered breathing, diabetes mellitus, chronic kidney disease and depression have reported improvements of exercise capacity and quality of life; however, the available data are limited and not always consistent. The available evidence for positive effects of pharmacologic interventions using angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and mineralocorticoid receptor antagonists on exercise capacity and quality of life is limited. Studies with ivabradine and with sacubitril/valsartan suggest beneficial effects at improving quality of life; however, the evidence base is limited in particular for exercise capacity. The data for heart failure with preserved ejection fraction are even less positive, only sacubitril/valsartan and spironolactone have shown some effectiveness at improving quality of life. In conclusion, the evidence for state-of-the-art heart failure treatments with regard to exercise capacity and quality of life is limited and appears not robust enough to permit recommendations for heart failure. The treatment of co-morbidities may be important for these patient-related outcomes. Additional studies on functional capacity and quality of life in heart failure are required.
Assuntos
Insuficiência Cardíaca , Qualidade de Vida , Aminobutiratos , Antagonistas de Receptores de Angiotensina , Combinação de Medicamentos , Tolerância ao Exercício , Humanos , Volume Sistólico , TetrazóisRESUMO
Coronary artery disease (CAD) is the most frequent cause of morbidity and mortality worldwide. Lifestyle modifications and drug treatment of cardiovascular risk factors are able to effectively prevent CAD. The basis of prevention is the assessment of the individual cardiovascular risk, e.g. by using a validated risk score. Documented evidence for prevention of CAD is available for the control of hypertension using angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB) and calcium antagonists, for the treatment of hypercholesterolemia using statins, ezetimibe and proprotein convertase subtilisin-kexin type 9 (PCSK-9) inhibitors and for the treatment of type 2 diabetes mellitus with metformin, sodium-glucose transporter 2 (SGLT-2) inhibitors and glucagon-like peptide 1 (GLP-1) agonists. There is no positive benefit-risk ratio for people with a low risk in the use of acetylsalicylic acid in primary prevention, in contrast to the positive recommendations for secondary prevention. There is no evidence for the efficacy of primary prevention with beta blockers, dipeptidyl peptidase 4 (DPP-4) inhibitors, glitazones, sulfonylureas or insulin. Similarly, there is no evidence for drug treatment of obesity, any supplementation with vitamins or hormone preparations or omega3 fatty acids.
Assuntos
Doença da Artéria Coronariana , Diabetes Mellitus Tipo 2 , Prevenção Primária , Doença da Artéria Coronariana/prevenção & controle , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon , Humanos , HipoglicemiantesRESUMO
Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) reduce cardiovascular events in coronary artery disease (CAD). Their costs exceed that of established oral lipid-lowering agents. Previous cost-effectiveness assessments have been inconsistent. Markov cohort state transitions models for stable CAD patients were calculated using information from 1530 participants of the Ludwigshafen Risk and Cardiovascular Health Study (LURIC) with known causes of deaths. Non-fatal to fatal event rates, drug prices, direct treatment costs, and utility weights were from public sources. At an assumed relative risk reduction of 32.5% and an annual drug price of 8500 Euros, QALYs gained were 1.23 and 1.20, savings were 2390 and 2410 Euros, and ICERs were 112,530 and 108,660 Euros in women and men, respectively. When the annual cost of this medication was set at 1600 Euros, corresponding ICERs were 21,180 and 20,450 Euros. PCSK9i treatment is cost-effective in stable CAD at a threshold of 150,000 Euro and annual costs of 8500 Euros. As the broad use of PCSK9i therapy in CAD would have a disruptive impact on the healthcare budget, treatment should be focused on very high risk patients (≥3 comorbidities, annual risk of 10%); alternatively, and for lower risk, significant cost reductions would be needed.
Assuntos
Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/economia , Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/economia , Custos de Medicamentos , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/economia , Inibidores de PCSK9 , Inibidores de Serina Proteinase/administração & dosagem , Inibidores de Serina Proteinase/economia , Idoso , Anticolesterolemiantes/efeitos adversos , Biomarcadores/sangue , Colesterol/sangue , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/epidemiologia , Redução de Custos , Análise Custo-Benefício , Esquema de Medicação , Feminino , Alemanha/epidemiologia , Humanos , Hiperlipidemias/sangue , Hiperlipidemias/epidemiologia , Masculino , Cadeias de Markov , Pessoa de Meia-Idade , Modelos Econômicos , Pró-Proteína Convertase 9/metabolismo , Anos de Vida Ajustados por Qualidade de Vida , Medição de Risco , Fatores de Risco , Inibidores de Serina Proteinase/efeitos adversos , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Hypertriglyceridemia affects 15-20% of the adult population and is associated with overweight, metabolic syndrome, and diabetes mellitus. It is often discovered incidentally. METHODS: This review is based on pertinent publications retrieved by a selective literature search, including current guidelines on hypertriglyceridemia. RESULTS: Elevated triglyceride (TG) levels are causally linked to cardiovascular disease; TG levels above 1000 mg/dL (11.4 mmol/L) can induce acute pancreatitis. The individual risk of cardiovascular disease and of pancreatitis must be estimated in order to decide whether, and how, hypertriglyceridemia should be treated. Lifestyle modifications (cessation of alcohol consumption, reduced intake of rapidly metabolized carbohydrates), weight loss, and blood sugar control are the most effective ways to lower TG levels. The need to lower the low-density lipoprotein (LDL) concentration must be determined on the basis of the cardiovascular risk, independently of the success of the lifestyle changes. Few patients need specific drug treatment to lower the TG level. Fibrates can lower TG concentrations, but their efficacy in combination with statins has not been clearly shown in endpoint studies. A daily dose of 2-4 g omega-3 fatty acids can also lower TG levels. To date, only a single large-scale randomized, blinded trial has shown the efficacy of 4 g of eicosapentaenoic acid ethyl ester per day in lowering the risk in high-risk patients (number needed to treat = 21). Patients with the very rare purely genetic types of hypertriglyceridemia (familial chylomicronemia syndrome) should be treated in specialized outpatient clinics. CONCLUSION: Hypertriglyceridemia is causally linked to cardiovascular disease and pancreatitis. Lifestyle modifications play a paramount role in its treatment.
Assuntos
Hipertrigliceridemia/diagnóstico , Hipertrigliceridemia/terapia , Doenças Cardiovasculares/epidemiologia , Humanos , Hipertrigliceridemia/epidemiologia , Pancreatite/epidemiologia , Guias de Prática Clínica como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Comportamento de Redução do RiscoRESUMO
BACKGROUND AND AIMS: Statin-associated muscle symptoms (SAMS) frequently cause statin non-adherence, switching and discontinuation, contributing to adverse cardiovascular (CV) outcomes. Therefore, the management of SAMS is key in the effective treatment of patients with cardiovascular disease (CVD), through achievement of maximum-tolerated statin dosing and other practical aspects. The aim of this article is to provide practical, focused advice for healthcare professionals on the management of patients with SAMS. METHODS: An expert working group combined current evidence, published guidelines and experiences surrounding a number of topics concerning SAMS to provide recommendations on how to best assess and manage this condition and reach the highest tolerated dose of statin for each individual patient. RESULTS: The group collaborated to provide guidance on definitions in the SAMS field, psychological issues, re-challenging and switching treatments, as well as interpretation of current guidelines and optimal treatment of SAMS in different patient populations. An algorithm was developed to guide the management of patients with SAMS. In addition, the expert working group considered some of the more complex scenarios in a series of frequently asked questions and suggested answers. CONCLUSIONS: The expert working group gave recommendations for healthcare professionals on the management of SAMS but highlighted the importance of tailoring the treatment approach to each individual patient. Evidence supporting the role of nutraceuticals and complementary therapies, such as vitamin D, was lacking, however the majority of the group favoured combination therapy with ezetimibe and the addition of PCSK9 inhibitors in high-risk patients.
Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Gerenciamento Clínico , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Doenças Musculares/prevenção & controle , Guias de Prática Clínica como Assunto , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Doenças Musculares/induzido quimicamenteRESUMO
BACKGROUND: Vitamin B deficiency is common in elderly people and has been associated with an increased risk of developing age-related diseases. B-vitamins are essential for the synthesis and stability of DNA. Telomers are the end caps of chromosomes that shorten progressively with age, and short telomers are associated with DNA instability. OBJECTIVE: In the present randomized intervention study, we investigated whether the one-carbon metabolism is related to telomere length, a surrogate marker for cellular aging. DESIGN: Sixty-five subjects (>54 years) were randomly assigned to receive either a daily combination of vitamin D3 (1200 IU), folic acid (0.5 mg), vitamin B12 (0.5 mg), vitamin B6 (50 mg) and calcium carbonate (456 mg) (group A) or vitamin D3 and calcium carbonate alone (group B). Blood testing was performed at baseline and after 1 year of supplementation. The concentrations of several metabolites of the one-carbon pathway, as well as relative telomere length (RTL) and 5,10-methylenetetrahydrofolate reductase C677T genotype, were analyzed. RESULTS: At baseline, age- and gender-adjusted RTL correlated with total folate and 5-methyltetrahydrofolate (5-methylTHF). Subjects with RTL above the median had higher concentrations of total folate and 5-methylTHF compared to subjects below the median. At study end, gender- and age-adjusted RTL correlated in group A with methylmalonic acid (MMA; r = -0.460, p = 0.0012) and choline (r = 0.434, p = 0.0021) and in group B with 5,10-methenyltetrahydrofolate (r = 0.455, p = 0.026) and dimethylglycine (DMG; r = -0.386, p = 0.047). Subjects in the group A with RTL above the median had lower MMA and higher choline compared to subjects below the median. CONCLUSIONS: The present pilot study suggests a functional relationship between one-carbon metabolism and telomere length. This conclusion is supported by several correlations that were modified by B-vitamin supplementation. In agreement with our hypothesis, the availability of nucleotides and methylation groups seems to impact telomere length. Due to the small sample size and the limitations of the study, further studies should confirm the present results in a larger cohort.
Assuntos
Carbono/metabolismo , Suplementos Nutricionais , Homeostase do Telômero , Telômero/ultraestrutura , Complexo Vitamínico B/administração & dosagem , Vitamina D/administração & dosagem , Idoso , Biomarcadores/sangue , Índice de Massa Corporal , Carbonato de Cálcio/administração & dosagem , Colina/sangue , Estudos Transversais , Método Duplo-Cego , Feminino , Ácido Fólico/administração & dosagem , Ácido Fólico/sangue , Humanos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/sangue , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Ácido Metilmalônico/sangue , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Sarcosina/análogos & derivados , Sarcosina/sangue , Tetra-Hidrofolatos/sangue , Vitamina B 12/administração & dosagem , Vitamina B 12/sangue , Vitamina B 6/administração & dosagem , Vitamina B 6/sangue , Complexo Vitamínico B/sangue , Vitamina D/sangueRESUMO
BACKGROUND: The potential for global collaborations to better inform public health policy regarding major non-communicable diseases has been successfully demonstrated by several large-scale international consortia. However, the true public health impact of familial hypercholesterolaemia (FH), a common genetic disorder associated with premature cardiovascular disease, is yet to be reliably ascertained using similar approaches. The European Atherosclerosis Society FH Studies Collaboration (EAS FHSC) is a new initiative of international stakeholders which will help establish a global FH registry to generate large-scale, robust data on the burden of FH worldwide. METHODS: The EAS FHSC will maximise the potential exploitation of currently available and future FH data (retrospective and prospective) by bringing together regional/national/international data sources with access to individuals with a clinical and/or genetic diagnosis of heterozygous or homozygous FH. A novel bespoke electronic platform and FH Data Warehouse will be developed to allow secure data sharing, validation, cleaning, pooling, harmonisation and analysis irrespective of the source or format. Standard statistical procedures will allow us to investigate cross-sectional associations, patterns of real-world practice, trends over time, and analyse risk and outcomes (e.g. cardiovascular outcomes, all-cause death), accounting for potential confounders and subgroup effects. CONCLUSIONS: The EAS FHSC represents an excellent opportunity to integrate individual efforts across the world to tackle the global burden of FH. The information garnered from the registry will help reduce gaps in knowledge, inform best practices, assist in clinical trials design, support clinical guidelines and policies development, and ultimately improve the care of FH patients.
Assuntos
Prestação Integrada de Cuidados de Saúde , Hiperlipoproteinemia Tipo II/terapia , Cooperação Internacional , Lacunas da Prática Profissional , Sistema de Registros , Projetos de Pesquisa , Acesso à Informação , Comportamento Cooperativo , Mineração de Dados , Prestação Integrada de Cuidados de Saúde/organização & administração , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/mortalidade , Armazenamento e Recuperação da Informação , Objetivos Organizacionais , Resultado do TratamentoRESUMO
PURPOSE: Deficiencies of folate, vitamins B12 and D are common age-related conditions. Vitamin B12 and folate are necessary for DNA methylation. Telomeres appear to be regulated by DNA methylation. Here, we study the effect of B vitamins supplementation on telomere length and global DNA methylation in a prospective study. METHODS: In total, 60 elderly subjects were supplemented for 1 year with either vitamin B12, B6, folate, vitamin D and calcium (group A n = 31) or only vitamin D and calcium (group B n = 29). LINE-1 methylation, relative telomere length (T/S), vitamin B12, folate, homocysteine (tHcy) , 5-methyltetrahydrofolate (5-methylTHF), S-adenosylhomocysteine (SAH), S-adenosylmethionine (SAM), cystathionine and vitamin D were quantified before and after supplementation. RESULTS: At baseline, tHcy was high, vitamin D was low, and T/S did not differ between groups A and B. Vitamin supplementation increased LINE-1 methylation in group A at site 317 but reduced LINE-1 methylation in group B at site 327. There was no correlation between T/S and LINE-1 methylation at baseline. Multiple backward regression analysis revealed baseline tHcy and 5-methylTHF are significant predictors of T/S. After supplementation in group B but not in group A, LINE-1 methylation correlated inversely with T/S, and LINE-1 methylation variation was an independent predictor of T/S variation. B vitamins decreased tHcy significantly in group A. Multiple backward regression analysis showed 5-methylTHF in group A and tHcy in group B were significant predictors for LINE-1 methylation. At baseline, the lower LINE-1 methylation observed in subjects with 5-methylTHF >10 nmol/l was in agreement with a reduced methyl group transfer due to a lower SAM formation. In group B, an increase in telomere length was correlated with lower LINE-1 methylation. Subjects with hyperhomocysteinemia >12 µmol/L had compared to those with normal tHcy a reduced LINE-1 methylation accompanied by a higher SAM and SAH (that inhibits demethylation of SAM) as well as lower 5-methylTHF. Additionally, subjects with tHcy > 12 µmol/L had longer telomeres when compared with subjects having tHcy < 12 µmol/L. CONCLUSIONS: The results suggest a possible effect of B vitamins for telomere biology in blood cells. Suboptimal B vitamins status and hyperhomocysteinemia are associated with altered DNA methylation and telomere length. These data have to be confirmed in future studies.
Assuntos
Células Sanguíneas/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Suplementos Nutricionais , Elementos Nucleotídeos Longos e Dispersos/genética , Telômero/ultraestrutura , Complexo Vitamínico B/administração & dosagem , Idoso , Cálcio/administração & dosagem , Cálcio/sangue , Estudos Transversais , Feminino , Ácido Fólico/administração & dosagem , Ácido Fólico/sangue , Homocisteína/sangue , Humanos , Hiper-Homocisteinemia/tratamento farmacológico , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , S-Adenosil-Homocisteína/sangue , S-Adenosilmetionina/sangue , Tetra-Hidrofolatos/sangue , Vitamina B 12/administração & dosagem , Vitamina B 12/sangue , Vitamina B 6/administração & dosagem , Vitamina B 6/sangue , Complexo Vitamínico B/sangue , Vitamina D/administração & dosagem , Vitamina D/sangueRESUMO
Loop diuretics are used for fluid control in patients with heart failure. Furosemide and torasemide may exert differential effects on myocardial fibrosis. Here, we studied the effects of torasemide and furosemide on atrial fibrosis and remodeling during atrial fibrillation. In primary neonatal cardiac fibroblasts, torasemide (50µM, 24h) but not furosemide (50µM, 24h) reduced the expression of connective tissue growth factor (CTGF; 65±6%) and the pro-fibrotic miR-21 (44±23%), as well as the expression of lysyl oxidase (LOX; 57±8%), a regulator of collagen crosslinking. Mineralocorticoid receptor (MR) expression and activity were not altered. Torasemide but not furosemide inhibited human aldosterone synthase (CYP11B2) activity in transfected lung fibroblasts (V79MZ cells) by 75±1.8%. The selective CYP11B2 inhibitor SL242 mimicked the torasemide effects. Mice with cardiac overexpression of Rac1 GTPase (RacET), which develop atrial fibrosis and spontaneous AF with aging, were treated long-term (8months) with torasemide (10mg/kg/day), furosemide (40mg/kg/day) or vehicle. Treatment with torasemide but not furosemide prevented atrial fibrosis in RacET as well as the up-regulation of CTGF, LOX, and miR-2, whereas MR expression and activity remained unaffected. These effects correlated with a reduced prevalence of atrial fibrillation (33% RacET+Tora vs. 80% RacET). Torasemide but not furosemide inhibits CYP11B2 activity and reduces the expression of CTGF, LOX, and miR-21. These effects are associated with prevention of atrial fibrosis and a reduced prevalence of atrial fibrillation in mice.
Assuntos
Fibrilação Atrial/tratamento farmacológico , Cardiotônicos/farmacologia , Citocromo P-450 CYP11B2/antagonistas & inibidores , Sulfonamidas/farmacologia , Aldosterona/metabolismo , Animais , Fibrilação Atrial/enzimologia , Remodelamento Atrial/efeitos dos fármacos , Células Cultivadas , Fator de Crescimento do Tecido Conjuntivo/genética , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Citocromo P-450 CYP11B2/metabolismo , Avaliação Pré-Clínica de Medicamentos , Colágenos Fibrilares/metabolismo , Fibroblastos/metabolismo , Fibrose , Concentração Inibidora 50 , Camundongos , Camundongos Transgênicos , MicroRNAs/genética , MicroRNAs/metabolismo , Proteína-Lisina 6-Oxidase/genética , Proteína-Lisina 6-Oxidase/metabolismo , Ratos Sprague-Dawley , TorasemidaRESUMO
Statin-associated muscle symptoms (SAMS) are one of the principal reasons for statin non-adherence and/or discontinuation, contributing to adverse cardiovascular outcomes. This European Atherosclerosis Society (EAS) Consensus Panel overviews current understanding of the pathophysiology of statin-associated myopathy, and provides guidance for diagnosis and management of SAMS. Statin-associated myopathy, with significant elevation of serum creatine kinase (CK), is a rare but serious side effect of statins, affecting 1 per 1000 to 1 per 10 000 people on standard statin doses. Statin-associated muscle symptoms cover a broader range of clinical presentations, usually with normal or minimally elevated CK levels, with a prevalence of 7-29% in registries and observational studies. Preclinical studies show that statins decrease mitochondrial function, attenuate energy production, and alter muscle protein degradation, thereby providing a potential link between statins and muscle symptoms; controlled mechanistic and genetic studies in humans are necessary to further understanding. The Panel proposes to identify SAMS by symptoms typical of statin myalgia (i.e. muscle pain or aching) and their temporal association with discontinuation and response to repetitive statin re-challenge. In people with SAMS, the Panel recommends the use of a maximally tolerated statin dose combined with non-statin lipid-lowering therapies to attain recommended low-density lipoprotein cholesterol targets. The Panel recommends a structured work-up to identify individuals with clinically relevant SAMS generally to at least three different statins, so that they can be offered therapeutic regimens to satisfactorily address their cardiovascular risk. Further research into the underlying pathophysiological mechanisms may offer future therapeutic potential.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Doenças Musculares/induzido quimicamente , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Terapias Complementares , Consenso , Creatina Quinase/metabolismo , Dieta , Predisposição Genética para Doença/etiologia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Hipolipemiantes/uso terapêutico , Mitocôndrias Musculares , Doenças Mitocondriais/complicações , Doenças Musculares/diagnóstico , Doenças Musculares/terapia , Pró-Proteína Convertase 9 , Pró-Proteína Convertases/antagonistas & inibidores , Fatores de Risco , Serina EndopeptidasesRESUMO
OBJECTIVE: Epidemiologic studies suggest that elevated postprandial triglycerides (ppTG) are associated with future cardiovascular events. Monocyte activation plays an important role in vascular diseases. Omega-3 fatty acids (n3-FA) lower fasting TG levels. The effects of n3-FA on ppTG and the role of ppTG for monocyte activation are insufficiently understood. METHODS AND RESULTS: 23 healthy volunteers and 30 non-diabetic patients with documented coronary artery disease were subjected to an oral TG tolerance test (OTTT) consisting of 80 g cream fat or to water as control (H(2)O). Patients were treated with 4 g n3-FA/day or placebo for 3 weeks in a randomized, placebo-controlled, double-blind, crossover study. Relative postprandial TG increase reached its maximum 4 h after fat intake (185.1 ± 10.9% of baseline). n3-FA reduced fasting TG from 137.1 ± 12.9 to 112.2 ± 8.6 mg/dl (p < 0.05), and maximum ppTG concentrations from 243.6 ± 24.6 to 205.8 ± 17.1 mg/dl (p < 0.05), while relative TG increase (192.8 ± 12.7%) was comparable to placebo. Relative monocytopenia and neutrophilia were detected following fat intake, which was unaffected by n3-FA and also detectable in the H(2)O group. Serum chemotactic cytokine (MCP1 and fractalkine) concentrations and monocyte migration were not affected by fat intake or n3-FA. Monocyte activation markers CD11b and CD14, monocyte subpopulations CD16(+)CD14(high) and CD16(+)CD14(low), sICAM serum levels and markers of oxidative stress remained unchanged by fat intake or n3-FA. CONCLUSION: The postprandial TG increase does not stimulate monocytes beyond their circadian activation patterns. n3-FA reduce fasting TG and the postprandial TG increase. n3-FA may therefore allow to prospectively study whether selected patients benefit from TG-lowering independent of LDL- and HDL-cholesterol.
Assuntos
Doença da Artéria Coronariana/fisiopatologia , Ácidos Graxos Ômega-3/uso terapêutico , Monócitos/fisiologia , Triglicerídeos/sangue , Adulto , Idoso , Quimiocina CCL2/sangue , Quimiocina CX3CL1/sangue , Colesterol , Doença da Artéria Coronariana/tratamento farmacológico , Gorduras na Dieta , Ácidos Graxos Ômega-3/farmacologia , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Período Pós-Prandial/efeitos dos fármacosRESUMO
Ambivalent effects of interleukin-6 on the pathogenesis of ischaemic stroke have been reported. However, to date, the long-term actions of interleukin-6 after stroke have not been investigated. Here, we subjected interleukin-6 knockout (IL-6(-/-)) and wild-type control mice to mild brain ischaemia by 30-min filamentous middle cerebral artery occlusion/reperfusion. While ischaemic tissue damage was comparable at early time points, IL-6(-/-) mice showed significantly increased chronic lesion volumes as well as worse long-term functional outcome. In particular, IL-6(-/-) mice displayed an impaired angiogenic response to brain ischaemia with reduced numbers of newly generated endothelial cells and decreased density of perfused microvessels along with lower absolute regional cerebral blood flow and reduced vessel responsivity in ischaemic striatum at 4 weeks. Similarly, the early genomic activation of angiogenesis-related gene networks was strongly reduced and the ischaemia-induced signal transducer and activator of transcription 3 activation observed in wild-type mice was almost absent in IL-6(-/-) mice. In addition, systemic neoangiogenesis was impaired in IL-6(-/-) mice. Transplantation of interleukin-6 competent bone marrow into IL-6(-/-) mice (IL-6(chi)) did not rescue interleukin-6 messenger RNA expression or the early transcriptional activation of angiogenesis after stroke. Accordingly, chronic stroke outcome in IL-6(chi) mice recapitulated the major effects of interleukin-6 deficiency on post-stroke regeneration with significantly enhanced lesion volumes and reduced vessel densities. Additional in vitro experiments yielded complementary evidence, which showed that after stroke resident brain cells serve as the major source of interleukin-6 in a self-amplifying network. Treatment of primary cortical neurons, mixed glial cultures or immortalized brain endothelia with interleukin 6-induced robust interleukin-6 messenger RNA transcription in each case, whereas oxygen-glucose deprivation did not. However, oxygen-glucose deprivation of organotypic brain slices resulted in strong upregulation of interleukin-6 messenger RNA along with increased transcription of key angiogenesis-associated genes. In conclusion, interleukin-6 produced locally by resident brain cells promotes post-stroke angiogenesis and thereby affords long-term histological and functional protection.
Assuntos
Infarto da Artéria Cerebral Média/complicações , Interleucina-6/metabolismo , Neovascularização Patológica/etiologia , Análise de Variância , Proteínas Angiogênicas/genética , Proteínas Angiogênicas/metabolismo , Animais , Transplante de Medula Óssea/métodos , Encéfalo/patologia , Proteínas de Ligação ao Cálcio/metabolismo , Células Cultivadas , Córtex Cerebral/citologia , Receptor gp130 de Citocina/genética , Receptor gp130 de Citocina/metabolismo , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Embrião de Mamíferos , Células Endoteliais/patologia , Endotelina-1/genética , Endotelina-1/metabolismo , Ensaio de Imunoadsorção Enzimática , Transtornos Neurológicos da Marcha/etiologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/genética , Glucose/deficiência , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Hipóxia/complicações , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Infarto da Artéria Cerebral Média/cirurgia , Interleucina-6/genética , Camundongos , Camundongos Knockout/genética , Proteínas dos Microfilamentos/metabolismo , Neovascularização Patológica/metabolismo , Neuroglia/fisiologia , Neurônios/efeitos dos fármacos , Análise de Sequência com Séries de Oligonucleotídeos , Imagem de Perfusão , Receptor trkB/genética , Receptor trkB/metabolismo , Teste de Desempenho do Rota-Rod , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Sais de Tetrazólio , TiazóisAssuntos
Fármacos Cardiovasculares/administração & dosagem , Doenças Cardiovasculares/prevenção & controle , Ácidos Graxos Ômega-3/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Margarina , Infarto do Miocárdio/complicações , Feminino , Humanos , MasculinoRESUMO
Low-density lipoproteins (LDL) are atherogenic and represent a strong cardiovascular risk factor. Therefore, LDL-cholesterol (LDL-C) remains the primary target in lipid lowering therapy. However, since many cardiovascular events occur despite an optimal LDL-C, it is necessary to focus on the remaining cardiovascular risk. Treatment of low high-density lipoprotein-cholesterol (HDL-C) and high triglycerides (TG) are options to achieve cardiovascular risk reduction beyond LDL. HDL mediates reverse cholesterol transport and exerts several other athero-protective effects. Epidemiologic evidence has shown that low HDL-cholesterol (HDL-C) is a strong and independent cardiovascular risk marker. However, since the anti-atherogenic effects of HDL particles rather depend on their functionality rather than on their cholesterol content, an increase in HDL-C concentration does not always have to result in a clinical benefit. Besides established strategies to increase HDL-C, e.g. with fibrates and nicotinic acid, CETP (Cholesteryl ester transfer protein)-inhibition is a promising new therapeutic option. The failure of torcetrapib, the first CETP-inhibitor, seems to be attributed to "off-target" effects. Treatment with the newer CETP-inhibitors dalcetrapib and anacetrapib has been shown to be efficacious and safe - but their usefulness in clinical practice remains to be determined in ongoing clinical endpoint trials. TG concentrations have been shown to correlate with cardiovascular risk. However, interpretation of plasma TG concentrations remains difficult due to considerable intra-individual variability of plasma concentrations. Post-prandial triglyceride concentrations may be better predictors of cardiovascular risk than fasting TG. In patients with hypertriglyceridemia, achievement of the LDL-C goal remains the primary lipid target. The basis of therapy in patients with hypertriglyceridemia are life style modifications. In addition, non-HDL-C should be addressed. For selected patients, treatment with fibrates, nicotinic acid or omega-3 fatty acids are available to lower TG concentrations. In summary, the focus of lipid therapy is the reduction of cardiovascular risk rather than the modification of lipoprotein sub-fractions. Ongoing research points towards a shift of the focus from the HDL-C concentrations to parameters of HDL function and from fasting TG to TG kinetics.
Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Dislipidemias/tratamento farmacológico , Dislipidemias/metabolismo , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Feminino , Humanos , Lipoproteínas LDL/sangue , Lipoproteínas LDL/metabolismo , Masculino , Fatores de RiscoRESUMO
AIMS: 'Functional foods' supplemented with plant sterol esters (PSE) and plant stanol esters (PSA) are therapeutic options for the management of hypercholesterolaemia. However, their effects on blood monocytes, endothelial function, atherogenesis, and sterol tissue concentrations are poorly understood. METHODS AND RESULTS: Male apoE-/- mice (n= 30) were randomized to three different diets for 6 weeks (n= 10 per group): high-cholesterol (1.25%) western-type diet (WTD), WTD + 2% PSE, and WTD + 2% PSA. Both supplements reduced serum cholesterol. WTD + PSE resulted in increased plant sterol serum concentrations and increased inflammatory Ly-6C(high) monocyte numbers. WTD + PSA increased plant stanol serum concentrations and Ly-6C-monocyte numbers, but decreased vascular superoxide release, lipid hydroperoxides, and inflammatory cytokines in aortic tissue, in plasma, and in circulating monocytes. Despite reduced serum cholesterol concentrations, both supplements impaired endothelial vasodilation compared with WTD. WTD + PSA reduced the development of atherosclerotic lesions compared with WTD alone (12.7 ± 3.7 vs. 28.3 ± 3.5%), and WTD + PSE was less effective (17.5 ± 3.7%). WTD + PSE and WTD + PSA reduced the cholesterol content in the liver, but not in the brain. However, WTD + PSE and WTD + PSA increased plant sterol and plant stanol concentrations in the liver as well as in the brain. CONCLUSION: PSE and PSA supplementation reduced serum cholesterol, but increased plant sterol and plant stanol concentrations. Elevated levels of PSE and PSA were associated with endothelial dysfunction and increased central nervous system depositions. Atherosclerotic lesion retardation was more pronounced in WTD + PSA, coinciding with higher regenerative monocyte numbers, decreased oxidative stress, and decreased inflammatory cytokines compared with WTD + PSE.
Assuntos
Colesterol na Dieta/farmacocinética , Suplementos Nutricionais/efeitos adversos , Fitosteróis/administração & dosagem , Fitosteróis/efeitos adversos , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Aterosclerose/etiologia , Aterosclerose/patologia , Aterosclerose/fisiopatologia , Aterosclerose/prevenção & controle , Colesterol/sangue , Citocinas/metabolismo , Dieta Aterogênica , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Mediadores da Inflamação/metabolismo , Absorção Intestinal/efeitos dos fármacos , Peróxidos Lipídicos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/citologia , Monócitos/efeitos dos fármacos , NADP/metabolismo , Fitosteróis/farmacocinética , Superóxidos/metabolismoAssuntos
Alimentos Fortificados , Hipercolesterolemia/dietoterapia , Hipercolesterolemia/metabolismo , Fitosteróis/uso terapêutico , Fitoterapia/métodos , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , LDL-Colesterol/metabolismo , Gorduras na Dieta/metabolismo , Suplementos Nutricionais , Feminino , Humanos , Hipercolesterolemia/complicações , Estilo de Vida , Masculino , Medicamentos sem Prescrição/uso terapêutico , Fitosteróis/efeitos adversos , Guias de Prática Clínica como AssuntoRESUMO
OBJECTIVES: The purpose of this study was to evaluate vascular effects of diet supplementation with plant sterol esters (PSE). BACKGROUND: Plant sterol esters are used as food supplements to reduce cholesterol levels. Their effects on endothelial function, stroke, or atherogenesis are not known. METHODS: In mice, plasma sterol concentrations were correlated with endothelial function, cerebral lesion size, and atherosclerosis. Plasma and tissue sterol concentrations were measured by gas-liquid chromatography-mass spectrometry in 82 consecutive patients with aortic stenosis. RESULTS: Compared with those fed with normal chow (NC), wild-type mice fed with NC supplemented with 2% PSE showed increased plant sterol but equal cholesterol plasma concentrations. The PSE supplementation impaired endothelium-dependent vasorelaxation and increased cerebral lesion size after middle cerebral artery occlusion. To test the effects of cholesterol-lowering by PSE, apolipoprotein E (ApoE)-/- mice were randomized to Western-type diet (WTD) with the addition of PSE or ezetimibe (EZE). Compared with WTD, both interventions reduced plaque sizes; however, WTD + PSE showed larger plaques compared with WTD + EZE (20.4 +/- 2.1% vs. 10.0 +/- 1.5%). Plant sterol plasma concentration strongly correlated with increased atherosclerotic lesion formation (r = 0.50). Furthermore, we examined plasma and aortic valve concentrations of plant sterol in 82 consecutive patients with aortic stenosis. Patients eating PSE-supplemented margarine (n = 10) showed increased plasma concentrations and 5-fold higher sterol concentrations in aortic valve tissue. CONCLUSIONS: Food supplementation with PSE impairs endothelial function, aggravates ischemic brain injury, effects atherogenesis in mice, and leads to increased tissue sterol concentrations in humans. Therefore, prospective studies are warranted that evaluate not only effects on cholesterol reduction, but also on clinical endpoints.