Effects of two lipid lowering therapies on immune responses in hyperlipidemic subjects.

AIMS: To compare the effects of two of the most effective lipid-lowering therapies with similar LDL-cholesterol reduction capacity on the innate and adaptive immune responses through the evaluation of autoantibodies anti-oxidized LDL (anti-oxLDL Abs) and electronegative LDL [LDL(-)] levels. MAIN METHODS: We performed a prospective, randomized, open label study, with parallel arms and blinded endpoints. One hundred and twelve subjects completed the study protocol and received rosuvastatin 40 mg or ezetimibe/simvastatin 10/40 mg for 12 weeks. Lipids, apolipoproteins, LDL(-), and anti-oxLDL Abs (IgG) were assayed at baseline and end of study. KEY FINDINGS: Main clinical and laboratory characteristics were comparable at baseline. Lipid modifications were similar in both treatment arms, however, a significant raise in anti-oxLDL Abs levels was observed in subjects treated with rosuvastatin (p=0.026 vs. baseline), but not in those receiving simvastatin/ezetimibe. (p=0.233 vs. baseline), thus suggesting modulation of adaptive immunity by a potent statin. Titers of LDL(-) were not modified by the treatments. SIGNIFICANCE: Considering atherosclerosis as an immune disease, this study adds new information, showing that under similar LDL-cholesterol reduction, the choice of lipid-lowering therapy can differently modulate adaptive immune responses.

The role of soluble fiber intake in patients under highly effective lipid-lowering therapy.

BACKGROUND: It has been demonstrated that statins can increase intestinal sterol absorption. Augments in phytosterolemia seems related to cardiovascular disease. OBJECTIVE: We examined the role of soluble fiber intake in endogenous cholesterol synthesis and in sterol absorption among subjects under highly effective lipid-lowering therapy. DESIGN: In an open label, randomized, parallel-design study with blinded endpoints, subjects with primary hypercholesterolemia (n = 116) were assigned to receive during 12 weeks, a daily dose of 25 g of fiber (corresponding to 6 g of soluble fibers) plus rosuvastatin 40 mg (n = 28), rosuvastatin 40 mg alone (n = 30), sinvastatin 40 mg plus ezetimibe 10 mg plus 25 g of fiber (n = 28), or sinvastatin 40 mg plus ezetimibe 10 mg (n = 30) alone. RESULTS: The four assigned therapies produced similar changes in total cholesterol, LDL-cholesterol, and triglycerides (p < 0.001 vs. baseline) and did not change HDL-cholesterol. Fiber intake decreased plasma campesterol (p < 0.001 vs. baseline), particularly among those patients receiving ezetimibe (p < 0.05 vs. other groups), and ß-sitosterol (p = 0.03 vs. baseline), with a trend for lower levels in the group receiving fiber plus ezetimibe (p = 0.07). Treatment with rosuvastatin alone or combined with soluble fiber was associated with decreased levels of desmosterol (p = 0.003 vs. other groups). Compared to non-fiber supplemented individuals, those treated with fibers had weight loss (p = 0.04), reduced body mass index (p = 0.002) and blood glucose (p = 0.047). CONCLUSION: Among subjects treated with highly effective lipid-lowering therapy, the intake of 25 g of fibers added favorable effects, mainly by reducing phytosterolemia. Additional benefits include improvement in blood glucose and anthropometric parameters.

Impaired glucose tolerance plus hyperlipidaemia induced by diet promotes retina microaneurysms in New Zealand rabbits.

UNLABELLED: With the increasing prevalence of diabetes mellitus and metabolic syndrome worldwide, experimental models are required to better understand the pathophysiology and therapeutic approaches to preserve pancreatic beta cells, attenuate atherosclerosis and protect target organs. The aims of this study were to develop an experimental model of impaired glucose tolerance combined with hypercholesterolaemia induced by diet and assess metabolic alterations and target organ lesions. New Zealand male rabbits were fed high-fat/high-sucrose (10/40%) and cholesterol-enriched diet for 24 weeks, when they were sacrificed. Biochemistry, fundus photographs with fluorescein angiography and pathological analyses were performed. Cholesterol-fed and normal animals of same age were compared. RESULTS: The animals with diet-induced impaired glucose tolerance combined with hypercholesterolaemia gained weight, increased blood glucose, total cholesterol, LDL-C and triglycerides and decreased HDL-C (P < 0.05 vs. baseline). Fructosamine levels and the homeostasis model assessment of insulin resistance (HOMA-IR) index were increased, while there was a reduction in the HOMA-ß (P < 0.05 for all vs. baseline). Histomorphologic findings of this model were aortic atherosclerosis, hepatic steatofibrosis and glomerular macrophage infiltration. Early clinical features of diabetic retinopathy with hyperfluorescent dots consistent with presence of retina microaneurysms were seen since week 12, progressing up to the end of the experiment (P < 0.0005 vs. baseline and 12 weeks). Our model reproduced several metabolic characteristics of human diabetes mellitus and promoted early signs of retinopathy. This non-expensive model is suitable for studying mechanistic pathways and allowing novel strategic approaches.

Resident peritoneal inflammatory cells are pivotal in the development of experimental atherosclerosis.

AIM: Based on evidence that ionizing radiation can ameliorate chronic and autoimmune diseases in patients and experimental animals, we investigated the effects of radiation on the induction and development of experimental atherogenesis. METHODS: Male New Zealand rabbits were divided into 5 groups and given an atherogenic diet for 90 days. Peritoneal and thoracic areas (9 Gy) were irradiated on the 1st and 45th days for groups 1 and 2, the 45th day for groups 3 and 4, and not at all for group 5. Prior to irradiation, the peritoneal cavity of animals from groups 1 and 3 was washed with buffered saline. Cells collected by peritoneal washing were reinfused into the peritoneal cavity of the same animal after irradiation. Animals from groups 2 and 4 were intraperitoneally injected with saline as a control. RESULTS: Despite similar lipid profiles among the experimental groups, the percentage of aortas covered by plaques was remarkably reduced (p<0.001) among animals submitted to irradiation (groups 2 and 4). These differences were completely abolished in irradiated animals reconstituted with their own peritoneal cells. CONCLUSIONS: These findings point to an important role of resident inflammatory peritoneal cells in experimental atherogenesis.

Early increase in autoantibodies against human oxidized low-density lipoprotein in hypertensive patients after blood pressure control.

BACKGROUND: Oxidized lipoproteins and antioxidized low-density lipoprotein (anti-oxLDL) antibodies (Abs) have been detected in plasma in response to blood pressure (BP) elevation, suggesting the participation of the adaptive immune system. Therefore, treatment of hypertension may act on the immune response by decreasing oxidation stimuli. However, this issue has not been addressed. Thus, we have here analyzed anti-oxLDL Abs in untreated (naive) hypertensive patients shortly after initiation of antihypertensive therapeutic regimens. METHODS: Titers of anti-oxLDL Abs were measured in subjects with recently diagnosed hypertension on stage 1 (n = 94), in primary prevention of coronary disease, with no other risk factors, and naive of antihypertensive medication at entry. Subjects were randomly assigned to receive perindopril, hydrochlorothiazide (HCTZ), or indapamide (INDA) for 12 weeks, with additional perindopril if necessary to achieve BP control. Abs against copper-oxidized LDL were measured by enzyme-linked immunosorbent assay. RESULTS: Twelve-week antihypertensive treatment reduced both office-based and 24-h ambulatory BP measurements (P < 0.0005). The decrease in BP was accompanied by reduction in thiobarbituric acid-reactive substances (TBARS) (P < 0.05), increase in anti-oxLDL Ab titers (P < 0.005), and improvement in flow-mediated dilation (FMD) (P < 0.0005), independently of treatment. Although BP was reduced, we observed favorable changes in anti-oxLDL titers and FMD. CONCLUSIONS: We observed that anti-oxLDL Ab titers increase after antihypertensive therapy in primary prevention when achieving BP targets. Our results are in agreement with the concept that propensity to oxidation is increased by essential hypertension and anti-oxLDL Abs may be protective and potential biomarkers for the follow-up of hypertension treatment.

Early glucometabolic profile in patients with acute coronary syndromes and metabolic syndrome.

BACKGROUND: Patients with metabolic syndrome (MetS) are at high coronary risk and beta-cell dysfunction or insulin resistance might predict an additional risk for early cardiovascular events. OBJECTIVE: This study aimed to evaluate early glucometabolic alterations in patients with MetS, but without previously known type 2 diabetes, after acute coronary syndrome. METHODS: A total of 114 patients were submitted to an oral glucose tolerance test (OGTT) 1-3 days after hospital discharge due to myocardial infarction or unstable angina. Based on the OGTT, we defined three groups of patients: normal glucose tolerance (NGT; n=26), impaired glucose tolerance (IGT; n=39), or diabetes (DM; n=49). The homeostasis model assessment (HOMA-IR) was used to measure insulin resistance; beta-cell responsiveness was assessed by the insulinogenic index at 30 min (DeltaI30/DeltaG30). RESULTS: Based on the HOMA-IR, patients with DM were more insulin-resistant than those with NGT or IGT (p<0.001). According to the insulinogenic index, the beta-cell responsiveness was also impaired in subjects with DM (p<0.001 vs NGT or IGT). CONCLUSION: High rates of glucometabolic alterations were found after acute coronary syndrome in patients with MetS. As these abnormalities markedly increase the risk for adverse outcomes, early OGTT among MetS patients might be used to identify those at the highest coronary risk.

Perfil glicometabólico inicial em pacientes com síndrome coronariana aguda e síndrome metabólica / Perfil glucometabólico inicial en pacientes con síndrome coronario agudo y síndrome metabólico / Early glucometabolic profile in patients with acute coronary syndromes and metabolic syndrome

FUNDAMENTO: Pacientes com síndrome metabólica (SM) têm alto risco coronariano e a disfunção da célula beta ou resistência à insulina pode prever um risco adicional de eventos cardiovasculares precoces. OBJETIVO: Avaliar as alterações glicometabólicas precoces em pacientes com SM, mas sem diagnóstico de diabete tipo 2, após síndrome coronariana aguda. MÉTODOS: Um total de 114 pacientes foi submetido ao teste oral de tolerância à glicose (TOTG), 1-3 dias da alta hospitalar, após infarto agudo do miocárdio ou angina instável. Baseado no TOTG, definimos três grupos de pacientes: tolerância normal à glicose (TNG; n=26), tolerância alterada à glicose (TAG; n=39) ou diabetes mellitus (DM; n=49). O Modelo de Avaliação da Homeostase (HOMA-IR) foi usado para estimar a resistência à insulina; a responsividade da célula beta foi avaliada através do índice insulinogênico de 30 minutos (ΔI30/ΔG30). RESULTADOS: Baseado no HOMA-IR, os pacientes com DM eram mais insulino-resistentes do que aqueles com TNG ou TAG (p<0,001). De acordo com o índice insulinogênico, a responsividade da célula beta também estava alterada em indivíduos com DM (p<0,001 vs TNG ou TAG). CONCLUSÃO: Altas taxas de alterações glicometabólicas foram encontradas após síndrome coronariana aguda em pacientes com SM. Como essas anormalidades acentuadamente aumentam o risco de desfechos adversos, o TOTG precoce pode ser utilizado em pacientes com SM para identificar aqueles que apresentam maior risco coronariano.

BACKGROUND: Patients with metabolic syndrome (MetS) are at high coronary risk and beta-cell dysfunction or insulin resistance might predict an additional risk for early cardiovascular events. OBJECTIVE: This study aimed to evaluate early glucometabolic alterations in patients with MetS, but without previously known type 2 diabetes, after acute coronary syndrome. METHODS: A total of 114 patients were submitted to an oral glucose tolerance test (OGTT) 1-3 days after hospital discharge due to myocardial infarction or unstable angina. Based on the OGTT, we defined three groups of patients: normal glucose tolerance (NGT; n=26), impaired glucose tolerance (IGT; n=39), or diabetes (DM; n=49). The homeostasis model assessment (HOMA-IR) was used to measure insulin resistance; beta-cell responsiveness was assessed by the insulinogenic index at 30 min (ΔI30/ΔG30). RESULTS: Based on the HOMA-IR, patients with DM were more insulin-resistant than those with NGT or IGT (p<0.001). According to the insulinogenic index, the beta-cell responsiveness was also impaired in subjects with DM (p<0.001 vs NGT or IGT). CONCLUSION: High rates of glucometabolic alterations were found after acute coronary syndrome in patients with MetS. As these abnormalities markedly increase the risk for adverse outcomes, early OGTT among MetS patients might be used to identify those at the highest coronary risk.

FUNDAMENTO: Pacientes con síndrome metabólico (SM) tienen alto riesgo coronario y la disfunción de la célula beta o la resistencia a la insulina puede prever un riesgo adicional de eventos cardiovasculares precoces. OBJETIVO: Evaluar las alteraciones glucometabólicas precoces en pacientes con SM, pero sin diagnóstico de diabetes tipo 2, tras el síndrome coronario agudo. MÉTODOS: Un total de 114 pacientes fue sometido a la prueba oral de tolerancia a la glucosa (POTG), de un a tres días tras el alta hospitalaria, y luego de infarto agudo de miocardio o angina inestable. Basado en el POTG, definimos tres grupos de pacientes: tolerancia normal a la glucosa (TNG; n=26), tolerancia alterada a la glucosa (TAG; n=39) o diabetes mellitus (DM; n=49). Se utilizó el Modelo de Evaluación de la Homeostasis (HOMA-IR) para estimarse la resistencia a la insulina; se evaluó la responsividad de la célula beta a través del índice insulinogénico de 30 minutos (ΔI30/ΔG30). RESULTADOS: Basado en el HOMA-IR, los pacientes con DM se mostraban más insulinoresistentes que los individuos con TNG o TAG (p<0,001). De acuerdo con el índice insulinogénico, la responsividad de la célula beta también estaba alterada en individuos con DM (p<0,001 vs. TNG o TAG). CONCLUSIONES: Se encontraron altas tasas de alteraciones glucometabólicas tras el síndrome coronario agudo en pacientes con SM. Como esas anormalidades incrementan acentuadamente el riesgo de desenlaces adversos, el POTG precoz se puede utilizar en pacientes con SM para identificar a los que presentan mayor riesgo coronario.

Association of lipoprotein lipase D9N polymorphism with myocardial infarction in type 2 diabetes: the genetics, outcomes, and lipids in type 2 diabetes (GOLD) study.

The association of polymorphisms affecting lipid metabolism with the risk of myocardial infarction (MI) in type 2 diabetes mellitus was investigated. The Genetics, Outcomes and Lipids in type 2 Diabetes (GOLD) Study is a prospective, multicenter study, conducted on 990 patients presenting diabetes and MI (n=386), or diabetes without previous manifestation of stroke, peripheral or coronary arterial disease (n=604), recruited from 27 institutions in Brazil. APO A1 (A/G -75 and C/T +83) and APO C3 (C/G 3'UTR) non-coding sequences, CETP (Taq 1B), LPL (D9N), APO E (epsilon2, epsilon3, epsilon4,), PON-1 (Q192R), and two LCAT variants Arg(147)-->Trp and Tyr(171)-->Stop were tested by PCR-RFLP. There was a higher prevalence of LPL DN genotype (19% vs.12%, p=0.03) and a higher frequency of the N allele (11% vs. 7%) among subjects with MI when compared to controls, with an odds ratio of MI for carriers of 9N allele of 2.46 (95% CI=1.79-3.39, p<0.0001). This association was present in men and women, in non-smokers and in hypertensive patients. A logistic regression model including gender, duration of diabetes, systolic blood pressure, HDL-C, left ventricle hypertrophy and D9N polymorphism showed that the latter still remained significantly associated with MI (OR=1.50, 95% CI=1.02-2.25, p=0.049). These findings suggest that D9N polymorphism can be a useful risk marker for myocardial infarction and that further potential candidate genes should be screened for exploratory analysis and for future therapeutic intervention in diabetes.

Prevalence of myocardial infarction is related to hyperhomocysteinemia but not influenced by C677T methylenetetrahydrofolate reductase and A2756G methionine synthase polymorphisms in diabetic and non-diabetic subjects.

BACKGROUND: Hyperhomocysteinemia has emerged as a novel risk factor for myocardial infarction (MI). Some mechanisms proposed to explain its relationship with coronary events are also shared by major coronary risk factors. We examined whether C677T methylenetetrahydrofolate reductase and A2756G methionine synthase polymorphisms could affect the relative risk for MI. METHODS: A sample of 196 individuals was divided into four groups (diabetics with MI, n=43; diabetics without MI, n=50; non-diabetics with MI, n=47; non-diabetics without MI, n=56) and compared regarding the prevalence of the polymorphisms, risk factors, and biochemical parameters. RESULTS: Higher prevalence of hyperhomocysteinemia was found in MI patients (p<0.05 vs. non-MI subjects), in males (p<0.001 vs. female) and in those > or = 65 years (p=0.01 vs. <65 years). Homocysteine was negatively associated with HDL-C (p<0.05) and glucose, although results did not reach significance (p=0.06). Similar distribution of studied polymorphisms was seen in all groups, which presented normal folate and vitamin B12 serum levels. CONCLUSIONS: Higher homocysteinemia was predominantly observed in men, presenting low HDL-C, and at advancing age. Methylenetetrahydrofolate reductase and methionine synthase polymorphisms did not contribute to risk assessment in diabetic and non-diabetic subjects presenting normal folate levels.

A doença arterial coronariana sob o prisma da genética molecular / A genetic view of the coronary artery disease

A biologia molecular evolui de forma vertiginosa e atualmente é tida como ferramenta indispensável na compreensão de doenças complexas e multifatoriais como a doença arterial coronariana. Tal abordagem gera uma nova forma de avaliação de doenças conhecidas e propicia a criação de novas técnicas, novos métodos diagnósticos e possíveis abordagens terapêuticas, interferindo diariamente no desfecho clínico final do paciente. O número de publicações em genética cardiovascular aumentou cinco vezes nos últimos 20 anos e a descoberta de novos polimorfismos e mutações bem como marcadores de inflamação, coagulação e genes relacionados ao metabolismo lipídico contribuem para se conhecer cada vez mais os aspectos intrínsecos envolvidos na aterosclerose. Este artigo irá abordar os principais avanços nessa área, identificando os polimorfismos mais comuns e sua relevância clínica segundo grandes ensaios e meta-análises,bem como fazer um breve racional acerca do desenho atual dos ensaios clínicos em biologia molecular