A red wine intervention does not modify plasma trimethylamine N-oxide but is associated with broad shifts in the plasma metabolome and gut microbiota composition.

BACKGROUND: Gut microbiota profiles are closely related to cardiovascular diseases through mechanisms that include the reported deleterious effects of metabolites, such as trimethylamine N-oxide (TMAO), which have been studied as diagnostic and therapeutic targets. Moderate red wine (RW) consumption is reportedly cardioprotective, possibly by affecting the gut microbiota. OBJECTIVES: To investigate the effects of RW consumption on the gut microbiota, plasma TMAO, and the plasma metabolome in men with documented coronary artery disease (CAD) using a multiomics assessment in a crossover trial. METHODS: We conducted a randomized, crossover, controlled trial involving 42 men (average age, 60 y) with documented CAD comparing 3-wk RW consumption (250 mL/d, 5 d/wk) with an equal period of alcohol abstention, both preceded by a 2-wk washout period. The gut microbiota was analyzed via 16S rRNA high-throughput sequencing. Plasma TMAO was evaluated by LC-MS/MS. The plasma metabolome of 20 randomly selected participants was evaluated by ultra-high-performance LC-MS/MS. The effect of RW consumption was assessed by individual comparisons using paired tests during the abstention and RW periods. RESULTS: Plasma TMAO did not differ between RW intervention and alcohol abstention, and TMAO concentrations showed low intraindividual concordance over time, with an intraclass correlation coefficient of 0.049 during the control period. After RW consumption, there was significant remodeling of the gut microbiota, with a difference in ß diversity and predominance of Parasutterella, Ruminococcaceae, several Bacteroides species, and Prevotella. Plasma metabolomic analysis revealed significant changes in metabolites after RW consumption, consistent with improved redox homeostasis. CONCLUSIONS: Modulation of the gut microbiota may contribute to the putative cardiovascular benefits of moderate RW consumption. The low intraindividual concordance of TMAO presents challenges regarding its role as a cardiovascular risk biomarker at the individual level. This study was registered at clinical trials.gov as NCT03232099.

Intestinal Microbiota and Cardiovascular Diseases

Abstract Recently, gut microbiota has emerged as an important mediator of several diseases such as diabetes, atherosclerosis, arterial hypertension, obesity, cancers and neuropsychiatric diseases including Alzheimer, autism and depression. Intestinal microbiota is formed by bacteria, fungi and viruses and its main function is to facilitate the absorption and metabolism of foods (protein, fat and carbohydrate). One example of the multiple actions of the gut microbiota is the bidirectional relationship between the intestine and the brain, the so-called "gut/brain axis". Furthermore, metabolites produced by gut microbiota can induce effects locally or at distance, which suggests that the intestine is an endocrine organ. Given the participation of the gut microbiota in several diseases, there is great interest in strategies that may positively affect the gut flora and prevent or even treat diseases. Among these strategies, lifestyle change, but specially diet modulation has gained importance. In this article, we review the mechanisms through which intestinal microbiota participates in cardiovascular diseases and possible therapeutic interventions.

Red wine and equivalent oral pharmacological doses of resveratrol delay vascular aging but do not extend life span in rats.

OBJECTIVE: To investigate, in male Wistar rats, the effects of long-term moderate red wine (RW) consumption (equivalent to ∼0.15 mg% resveratrol RS), or RS in low (L, 0.15 mg%) or high (H, 400 mg%) doses in chow. BACKGROUND: Both RW and RS exhibit cardioprotection. RS extends lifespan in obese rats. It is unclear whether RW consumption or low-dose RS delay vascular aging and prolong life span in the absence of overt risk factors. METHODS: Endpoints were aerobic performance, exercise capacity, aging biomarkers (p53,p16,p21, telomere length and telomerase activity in aortic homogenates), vascular reactivity. Data were compared with controls (C) given regular chow. RESULTS: Expressions of p53 decreased ∼50% ∼with RW and LRS (p < 0.05 vs. C), p16 by ∼29% with RW (p < 0.05 vs. C) and p21 was unaltered. RW and LRS increased telomere length >6.5-fold vs. C, and telomerase activity increased with LRS and HRS. All treatments increased aerobic capacity (C 32.5 ± 1.2, RW 38.7 ± 1.7, LRS 38.5 ± 1.6, HRS 38.3 ± 1.8 mlO(2) min(-1) kg(-1)), and RW or LRS also improved time of exercise tolerance vs. C (p < 0.05). Endothelium-dependent relaxation improved with all treatments vs. C. Life span, however, was unaltered with each treatment vs. C = 673 ± 30 days, p = NS. CONCLUSIONS: RW and LRS can preserve vascular function indexes in normal rats, although not extending life span. These effects were translated into better aerobic performance and exercise capacity.

Effect of exercise training on plasma levels and functional properties of high-density lipoprotein cholesterol in the metabolic syndrome.

Intense lifestyle modifications can change the high-density lipoprotein (HDL) cholesterol concentration. The aim of the present study was to analyze the early effects of short-term exercise training, without any specific diet, on the HDL cholesterol plasma levels and HDL functional characteristics in patients with the metabolic syndrome (MS). We studied 30 sedentary subjects, 20 with and 10 without the MS. The patients with the MS underwent moderate intensity exercise training for 3 months on bicycle ergometers. Blood was sampled before and after training for biochemical analysis, paraoxonase-1 activity, and HDL subfraction composition and antioxidative capacity. Lipid transfer to HDL was assayed in vitro using a labeled nanoemulsion as the lipid donor. At baseline, the MS group had greater triglyceride levels and a lower HDL cholesterol concentration and lower paraoxonase-1 activity than did the controls. Training decreased the plasma triglycerides but did not change the low-density lipoprotein or HDL cholesterol levels. Nonetheless, exercise training increased the HDL subfractions' antioxidative capacity and paraoxonase-1 activity. After training, the MS group had compositional changes in the smallest HDL subfractions associated with increased free cholesterol and cholesterol ester transfers to HDL, reaching normal values. In conclusion, the present investigation has added relevant information about the dissociation between the quantitative and qualitative aspects of HDL after short-term exercise training without any specific diet in those with the MS, highlighting the importance of evaluating the functional aspects of the lipoproteins, in addition to their plasma levels.

[Lack of knowledge of Guidelines for Prevention of Atherosclerosis in Childhood and Adolescence by pediatricians in the city of São Paulo]. / Desconhecimento da diretriz de prevenção da aterosclerose na infância e adolescência por pediatras em São Paulo.

OBJECTIVE: To report the extent of knowledge of pediatricians in São Paulo concerning the Guidelines. METHODS: At pediatric events or hospitals, pediatricians were given a questionnaire about the time of training, work, dedication in the area of pediatrics, and academic performance for reply to multiple choice questions with information drawn from the Guidelines. The Chi -square and the Chi -square of linear trend tests were chosen for statistical calculations. RESULTS: Among 370 pediatricians surveyed, 65.7% had no previous knowledge of the Guidelines. The cut-off for the hits was > or = 70% (> or = 5 correct replies). Only 136 pediatricians (36.7%) reached the cut-off and no gender differences were found in knowledge (p = 0.25). Among 187 professionals involved in academic activities, 45 (24%) hit the cut-off and about 183 participants from non-academic activities, 23 (12.7%) reached > or = 5 hit points (p <0.001). Pediatricians in the public sector had better knowledge about preventive measures for atherosclerosis risk factors (46.1%, p = 0.01). Awareness of the Guidelines was independent from training time. CONCLUSION: The majority of pediatricians in the city of São Paulo were not familiar with the Guidelines for Prevention of Atherosclerosis in Childhood and Adolescence and individual strategies were rarely found. Medical education and adequate disclosure of the Guidelines are necessary for active control of populational risk factors.

Desconhecimento da diretriz de prevenção da aterosclerose na infância e adolescência por pediatras em São Paulo / Lack of knowledge of guidelines for prevention of atherosclerosis in childhood and adolescence by pediatricians in the city of São Paulo

OBJETIVO: Relatar a extensão do conhecimento de pediatras de São Paulo sobre a diretriz. MÉTODOS: Durante eventos de pediatria ou nos locais de trabalho, pediatras responderam um questionário contendo informações sobre o tempo de formação, local de trabalho, dedicação dentro da área de pediatria, atuação em área acadêmica e questões de múltipla escolha com informações retiradas da diretriz. As diferenças de expressão e associações foram consideradas significantes estatisticamente quando p<0,05. Todas as análises foram realizadas usando teste de Quiquadrado e teste de Quiquadrado de tendência linear por meio dos Softwares Primer of Biostatistics ou SPSS for Windows. RESULTADOS: Dos 370 pediatras entrevistados, 65,7 por cento afirmaram não ter tido conhecimento prévio da diretriz. O valor de corte para os acertos foi maior ou igual a 70 por cento (maior ou igual a cinco questões corretas). Apenas 136 pediatras (36,7 por cento) alcançaram tal valor e dentre esses não havia relação no conhecimento da diretriz quanto aos sexos (p=0,25). Dos 187 profissionais envolvidos em atividades acadêmicas, 45 (24 por cento) acertaram o valor de corte e dos 183 não participantes de atividades acadêmicas, 23 (12,7 por cento) acertaram maior ou igual a cinco questões (p<0,001). Pediatras do setor público apresentaram melhor conhecimento da prática preventiva da aterosclerose (46,1 por cento; p=0,01). O desconhecimento da diretriz foi independente do tempo de formação. CONCLUSÃO: A meta da diretriz de servir como referência para o estabelecimento de estratégias individuais e populacionais no controle dos fatores de risco para a aterosclerose desde a infância não foi alcançada na cidade de São Paulo. A divulgação mais adequada e cursos de educação médica continuada em que o conhecimento da diretriz se torne mais efetivo são sugeridos para corrigir tais achados.

OBJECTIVE: To report the extent of knowledge of pediatricians in São Paulo concerning the Guidelines. METHODS: At pediatric events or hospitals, pediatricians were given a questionnaire about the time of training, work, dedication in the area of pediatrics, and academic performance for reply to multiple choice questions with information drawn from the Guidelines. The Chi -square and the Chi -square of linear trend tests were chosen for statistical calculations. RESULTS: Among 370 pediatricians surveyed, 65.7 percent had no previous knowledge of the Guidelines. The cut-off for the hits was > or = 70 percent (> or = 5 correct replies). Only 136 pediatricians (36.7 percent) reached the cut-off and no gender differences were found in knowledge (p = 0.25). Among 187 professionals involved in academic activities, 45 (24 percent) hit the cut-off and about 183 participants from non-academic activities, 23 (12.7 percent) reached > or = 5 hit points (p <0.001). Pediatricians in the public sector had better knowledge about preventive measures for atherosclerosis risk factors (46.1 percent, p = 0.01). Awareness of the Guidelines was independent from training time. CONCLUSION: The majority of pediatricians in the city of São Paulo were not familiar with the Guidelines for Prevention of Atherosclerosis in Childhood and Adolescence and individual strategies were rarely found. Medical education and adequade disclosure of the Guidelines are necessary for active control of populational risk factors.

Prognostic value of left atrial volume in patients who underwent dobutamine stress echocardiography for known or suspected coronary artery disease.

BACKGROUND: Left atrial volume indexed (LAVI) has been reported as a predictor of cardiovascular events. We sought to determine the prognostic value of LAVI for predicting the outcome of patients who underwent dobutamine stress echocardiography (DSE) for known or suspected coronary artery disease (CAD). METHODS: From January 2000 to July 2005, we studied 981 patients who underwent DSE and off-line measurements of LAVI. The value of DSE over clinical and LAVI data was examined using a stepwise log-rank test. RESULTS: During a median follow-up of 24 months, 56 (6%) events occurred. By univariate analysis, predictors of events were male sex, diabetes mellitus, previous myocardial infarction, left ventricular ejection fraction (LVEF), left atrial diameter indexed, LAVI, and abnormal DSE. By multivariate analysis, independent predictors were LVEF (relative risk [RR] = 0.98, 95% CI 0.95-1.00), LAVI (RR = 1.04, 95% CI 1.02-1.05), and abnormal DSE (RR = 2.70, 95% CI 1.28-5.69). In an incremental multivariate model, LAVI was additional to clinical data for predicting events (chi(2) 36.8, P < .001). The addition of DSE to clinical and LAVI yielded incremental information (chi(2) 55.3, P < .001). The 3-year event-free survival in patients with normal DSE and LAVI < or =33 mL/m(2) was 96%; with abnormal DSE and LAVI < or =33 mL/m(2), 91%; with normal DSE and LAVI >34 mL/m(2), 83%; and with abnormal DSE and LAVI >34 mL/m(2), 51%. CONCLUSION: Left atrial volume indexed provides independent prognostic information in patients who underwent DSE for known or suspected CAD. Among patients with normal DSE, those with larger LAVI had worse outcome, and among patients with abnormal DSE, LAVI was still predictive.

Vascular and metabolic response to statin in the mildly hypertensive hypercholesterolemic elderly.

INTRODUCTION: Much evidence indicates the importance of the endothelium and hypercholesterolemia in atherosclerosis, as well as the decline in endothelial function with aging. However, it is unclear if treating dyslipidemia in elderly patients improves endothelial function and reduces C-reactive protein levels. OBJECTIVES: To evaluate vasomotor function, lipids and C-reactive protein in mildly hypertensive and hypercholesterolemic elderly patients treated with atorvastatin. METHODS: Forty-seven elderly Brazilian subjects (> or = 65 years old) with LDL cholesterol (LDL-c) > or = 130 mg/dL were randomly assigned, in a double-blinded manner, to receive either placebo (n = 23) or 20 mg/day of atorvastatin (n = 24) for 4 weeks. Exclusion criteria included diabetes, serious hypertension, obesity, steroid use, hormone replacement, and statin use within the previous six months. All patients underwent clinical examinations, laboratory tests (glucose, lipids, liver enzymes, creatine phosphokinase and high sensitivity C-reactive protein) and assessment of vasomotor function by high-resolution ultrasound examination of the brachial artery (flow-mediated dilation and sublingual nitrate), both before and after treatment. RESULTS: The patients were 65 to 91 years old; there was no significant difference between basal flow-mediated dilation of placebo (7.3 +/- 6.1%) and atorvastatin (4.5 +/- 5.1%; p = 0.20). The same was observed after treatment (6.6 +/- 6.2 vs. 5.0 +/- 5.6; p = 0.55). The initial nitrate dilatation (8.1 +/- 5.4% vs. 10.8 +/- 7.5%; p = 0.24) and that after 4 week treatment (7.1 +/- 4.7% vs. 8.6 +/- 5.0%; p = 0.37) were similar. Atorvastatin produced a reduction of 20% of the C-reactive protein and 42% in the LDL-c; however, there were no changes in the flow-mediated dilation. CONCLUSIONS: Atorvastatin produced a significant change of lipids and C-reactive protein; however, there were no changes in vasomotor function, suggesting the existence of intrinsic age-related vessel alterations.

Characterization of high density lipoprotein particles in familial apolipoprotein A-I deficiency.

Our aim was to characterize HDL subspecies and fat-soluble vitamin levels in a kindred with familial apolipoprotein A-I (apoA-I) deficiency. Sequencing of the APOA1 gene revealed a nonsense mutation at codon -2, Q[-2]X, with two documented homozygotes, eight heterozygotes, and two normal subjects in the kindred. Homozygotes presented markedly decreased HDL cholesterol levels, undetectable plasma apoA-1, tuboeruptive and planar xanthomas, mild corneal arcus and opacification, and severe premature coronary artery disease. In both homozygotes, analysis of HDL particles by two-dimensional gel electrophoresis revealed undetectable apoA-I, decreased amounts of small alpha-3 migrating apoA-II particles, and only modestly decreased normal amounts of slow alpha migrating apoA-IV- and apoE-containing HDL, while in the eight heterozygotes, there was loss of large alpha-1 HDL particles. There were no significant decreases in plasma fat-soluble vitamin levels noted in either homozygotes or heterozygotes compared with normal control subjects. Our data indicate that isolated apoA-I deficiency results in marked HDL deficiency with very low apoA-II alpha-3 HDL particles, modest reductions in the separate and distinct plasma apoA-IV and apoE HDL particles, tuboeruptive xanthomas, premature coronary atherosclerosis, and no evidence of fat malabsorption.

Vascular and metabolic response to statin in the mildly hypertensive hypercholesterolemic elderly

INTRODUCTION: Much evidence indicates the importance of the endothelium and hypercholesterolemia in atherosclerosis, as well as the decline in endothelial function with aging. However, it is unclear if treating dyslipidemia in elderly patients improves endothelial function and reduces C-reactive protein levels. OBJECTIVES: To evaluate vasomotor function, lipids and C-reactive protein in mildly hypertensive and hypercholesterolemic elderly patients treated with atorvastatin. METHODS: Forty-seven elderly Brazilian subjects (> 65 years old) with LDL cholesterol (LDL-c) > 130 mg/dL were randomly assigned, in a double-blinded manner, to receive either placebo (n = 23) or 20 mg/day of atorvastatin (n = 24) for 4 weeks. Exclusion criteria included diabetes, serious hypertension, obesity, steroid use, hormone replacement, and statin use within the previous six months. All patients underwent clinical examinations, laboratory tests (glucose, lipids, liver enzymes, creatine phosphokinase and high sensitivity C-reactive protein) and assessment of vasomotor function by high-resolution ultrasound examination of the brachial artery (flow-mediated dilation and sublingual nitrate), both before and after treatment. RESULTS: The patients were 65 to 91 years old; there was no significant difference between basal flow-mediated dilation of placebo (7.3 ± 6.1 percent) and atorvastatin (4.5 ± 5.1 percent; p = 0.20). The same was observed after treatment (6.6 ± 6.2 vs. 5.0 ± 5.6; p = 0.55). The initial nitrate dilatation (8.1 ± 5.4 percent vs. 10.8 ± 7.5 percent; p = 0.24) and that after 4 week treatment (7.1 ± 4.7 percent vs. 8.6 ± 5.0 percent; p = 0.37) were similar. Atorvastatin produced a reduction of 20 percent of the C-reactive protein and 42 percent in the LDL-c; however, there were no changes in the flow-mediated dilation. CONCLUSIONS: Atorvastatin produced a significant change of lipids and C-reactive protein; however, there were no changes in vasomotor ...

Enhanced inflammatory response to coronary stenting marks the development of clinically relevant restenosis.

OBJECTIVES: The aims of this study were to investigate the effect of coronary stenting on the release of cytokines and cell-mediated immunity factors and to evaluate the association between inflammation and clinical outcomes at 6 months. BACKGROUND: Circulating levels of inflammatory markers and cytokines are elevated in patients with acute coronary syndromes and are related to an unfavorable outcome. The aims of this study were to investigate the effect of coronary stenting on the release of cytokines and cell-mediated immunity factors and to evaluate the association between inflammation and clinical outcomes at 6 months. METHODS: Forty patients with single native coronary artery disease treated with stenting were enrolled. Peripheral venous blood samples were collected before and 6 h, 48 h, and 12 weeks after stenting. Serum concentrations of high-sensitivity C-reactive protein, interleukin-6, interleukin-8, tumor necrosis factor-alpha (markers of inflammation) and serum-soluble interleukin-2 receptor for T-lymphocyte activation (sIL2-R, marker of cell-mediated immunity) were measured. Patients also were evaluated clinically one, 3, and 6 months post-stenting or when they presented with cardiovascular symptoms to identify major adverse cardiac events (cardiac death, MI, revascularization). RESULTS: Concentrations of interleukins 6 and 8 and tumor necrosis factor-alpha peaked at 6 h (11.0, 12.6, and 5.3 pg/ml, respectively). The peak level of high-sensitivity C-reactive protein (2.77 mg/dL) occurred 48 h post stenting, while sIL2-R peaked (495 U/ml) at 12 weeks. Patients who experienced restenosis had higher levels of C-reactive protein at 48 h (4.94 vs. 1.84 mg/dl; P = 0.043) and of IL-8 at 6 h (26.75 vs. 13.55 pg/mL; P = 0.048) than those without restenosis. CONCLUSIONS: Proinflammatory cytokines and inflammatory markers are released into the peripheral circulation early after coronary stenting, and increased levels of some are associated with clinically relevant restenosis.

Accumulation of chylomicron remnants and impaired vascular reactivity occur in subjects with isolated low HDL cholesterol: effects of niacin treatment.

Fasting hypertriglyceridemia relates with high-density lipoprotein (HDL) cholesterol, but it is not known whether low HDL cholesterol is associated with disturbances of chylomicron metabolism. To clarify this issue this metabolism was studied in subjects with low HDL cholesterol together with vascular reactivity and evaluation of no-flush niacin treatment. Thirty men with HDL < 1.04 mmol/L and no other risk factors for coronary artery disease (CAD) and 11 normal controls with HDL > 1.04 mmol/L were studied. The plasma kinetics of a chylomicron-like emulsion labeled with 14C-cholesterol oleate (CO) and 3H-triolein (TG) was determined and the fractional clearance rate (FCR, min(-1)) was calculated. Vascular reactivity was evaluated using high-resolution ultrasonography. CO FCR was markedly reduced in the low HDL group compared to controls (3.6 x 10(-3) +/- 5.1 x 10(-3) min(-1) versus 12.2 x 10(-3) +/- 8.4 x 10(-3) min(-1), p < 0.001) but TG FCR was similar. Flow-mediated dilation (FMD) was diminished in low HDL (7.4 +/- 4.1 versus 12.8 +/- 4.6%, p < 0.001), whereas nitrate-mediated dilation was similar. Twenty-two low HDL subjects with reduced FMD were randomized into two groups, one given 1.5 g/day niacin and a placebo group. After 3-month treatment, plasma lipids and chylomicron kinetics were not changed by niacin treatment but FMD improved to normal values (5.44 +/- 1.89 to 11.13 +/- 3.4%, p < 0.01). In conclusion, isolated low HDL cholesterol subjects may also bear chylomicron remnant accumulation and endothelial dysfunction, which highlight the importance of their preventive treatment.