RESUMO
Multiple factors regulate glucagon-like peptide-1 (GLP-1) secretion, but a group of apparently healthy subjects showed blunted responses of GLP-1 secretion in our previous study. In this study, we examined whether the reduction in GLP-1 secretory capacity is associated with increased extent of coronary artery stenosis in non-diabetic patients. Non-diabetic patients who were admitted for coronary angiography without a history of coronary interventions were enrolled. Coronary artery stenosis was quantified by Gensini score (GS), and GS ≥ 10 was used as an outcome variable based on its predictive value for cardiovascular events. The patients (mean age, 66.5 ± 8.8 years; 71% males, n = 173) underwent oral 75 g-glucose tolerant tests for determination of glucose, insulin and active GLP-1 levels. The area under the curve of plasma active GLP-1 (AUC-GLP-1) was determined as an index of GLP-1 secretory capacity. AUC-GLP-1 was not correlated with fasting glucose, AUC-glucose, serum lipids or indices of insulin sensitivity. In multivariate logistic regression analysis for GS ≥ 10, AUC-GLP-1 < median, age and hypertension were selected as explanatory variables, though fasting GLP-1 level was not selected. The findings suggest that reduction in GLP-1 secretory capacity is a novel independent risk factor of coronary stenosis.
Assuntos
Estenose Coronária/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Idoso , Área Sob a Curva , Feminino , Humanos , Modelos Logísticos , Masculino , Análise Multivariada , Fatores de RiscoAssuntos
Cardiomiopatias/diagnóstico , Cardiomiopatias/tratamento farmacológico , Infecções por Bactérias Gram-Positivas/diagnóstico , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Sarcoidose Pulmonar/diagnóstico , Sarcoidose Pulmonar/tratamento farmacológico , Corticosteroides/uso terapêutico , Adulto , Antimaláricos/uso terapêutico , Cardiomiopatias/epidemiologia , Cardiomiopatias/microbiologia , Diagnóstico Precoce , Feminino , Predisposição Genética para Doença , Infecções por Bactérias Gram-Positivas/epidemiologia , Infecções por Bactérias Gram-Positivas/microbiologia , Humanos , Imunossupressores/uso terapêutico , Incidência , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Prevalência , Propionibacterium acnes/genética , Sarcoidose Pulmonar/epidemiologia , Sarcoidose Pulmonar/microbiologia , Adulto JovemAssuntos
Neoplasias Cardíacas/induzido quimicamente , Linfoma/induzido quimicamente , Metotrexato/efeitos adversos , Febre Reumática/tratamento farmacológico , Idoso de 80 Anos ou mais , Antirreumáticos/efeitos adversos , Biópsia , Diagnóstico Diferencial , Feminino , Átrios do Coração , Neoplasias Cardíacas/diagnóstico , Ventrículos do Coração , Humanos , Linfoma/diagnóstico , Imagem Cinética por Ressonância Magnética/métodos , Miocárdio/patologia , Tomografia Computadorizada por Raios X/métodosRESUMO
AIMS: The EXPAND study examined the real-world efficacy and safety of rivaroxaban for the prevention of stroke and systemic embolism (SE) in Japanese patients with non-valvular atrial fibrillation (NVAF). METHODS AND RESULTS: This multicenter, prospective, non-interventional, observational, cohort study was conducted at 684 medical centers in Japan. A total of 7141 NVAF patients ≥20â¯years of age (mean, 71.6⯱â¯9.4â¯years) who were being or about to be treated with rivaroxaban (10â¯mg/day, 43.5%; 15â¯mg/day, 56.5%) were followed for an average of 897.1 (±206.8) days with a high follow-up rate (99.65%). The mean CHADS2 score at baseline was 2.1 (1.3) (0-1, 37%; 2, 29%; ≥3, 34%). The total incidence rate of symptomatic stroke and SE (primary efficacy endpoint) was 1.0%/year, and 0.5%, 0.9%, and 1.7%/year for those with CHADS2 scores of 0-1, 2, and ≥3, respectively. Cumulative incidence rates for major bleeding (primary safety endpoint) and non-major bleeding (secondary safety endpoint) were 1.2%/year and 4.9%/year, respectively. Differences were noted between new and current users only for major bleeding event rate (1.7% vs. 1.1%/year, Pâ¯=â¯0.0024). Comparisons with previous studies suggested that rivaroxaban is effective and safe for low-risk patients (0-1 CHADS2), as shown for warfarin in the XANTUS international prospective post-marketing study. CONCLUSIONS: The EXPAND study demonstrated that low dosages of rivaroxaban for Japanese NVAF patients in real-world clinical practice, including those with CHADS2 scores 0-1, resulted in low rates of stroke and SE, and major and non-major bleeding.
Assuntos
Fibrilação Atrial/diagnóstico por imagem , Fibrilação Atrial/tratamento farmacológico , Inibidores do Fator Xa/uso terapêutico , Rivaroxabana/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Fibrilação Atrial/epidemiologia , Estudos de Coortes , Feminino , Seguimentos , Hemorragia/induzido quimicamente , Hemorragia/diagnóstico por imagem , Hemorragia/epidemiologia , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Rivaroxabana/efeitos adversos , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/prevenção & controle , Resultado do TratamentoRESUMO
OBJECTIVE: To develop and validate a scoring system for selection of patients who should proceed to endocrinologic examinations of primary aldosteronism in newly diagnosed hypertensive patients. METHODS: A multivariate logistic regression analysis for primary aldosteronism was undertaken by use of seven possible primary aldosteronism markers, age less than 40 years, female sex, moderate-to-severe hypertension, hypokalemia, serum Na minus Cl at least 40âmmol/l, serum uric acid 237.92âµmol/l or less (4.0âmg/dl), and urine pH (U-pH) at least 7.0, in consecutive outpatients newly diagnosed with hypertension. The diagnostic criteria of primary aldosteronism were plasma aldosterone concentration-to-plasma renin activity ratio [ARR, (ng/dl)/(ng/ml per h)] at least 20 and at least one positive result in four types of challenge tests. RESULTS: Of 130 patients, 24 were diagnosed with primary aldosteronism. The area under the receiver operating characteristic curve (AUC) for a logistic model incorporating all possible primary aldosteronism markers was 0.73 [95% confidence interval (CI): 0.61-0.85]. Removing high U-pH, female sex, and hypokalemia from the full model decreased the AUC by 0.059, 0.035, and 0.011, respectively. We devised pH of urine, female sex, low serum K (PFK) score, in which one point each was assigned to high U-pH, female sex, and hypokalemia. The prevalences of primary aldosteronism in patients with 0, 1, 2, and 3 points were 11, 14, 42, and 60%, respectively. In external validation datasets (nâ=â106), AUC of PFK score was significantly higher than that of hypokalemia alone (0.73, 95% CI: 0.63-0.83 vs. 0.53, 95% CI: 0.44-0.63, Pâ<â0.01). CONCLUSION: PFK score may be a better parameter than hypokalemia alone for identifying patients with a high probability of having primary aldosteronism.
Assuntos
Hiperaldosteronismo/diagnóstico , Hipertensão/etiologia , Potássio/sangue , Adulto , Aldosterona/sangue , Área Sob a Curva , Biomarcadores/sangue , Biomarcadores/urina , Feminino , Humanos , Concentração de Íons de Hidrogênio , Hiperaldosteronismo/sangue , Hiperaldosteronismo/complicações , Hiperaldosteronismo/urina , Hipopotassemia/sangue , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Curva ROC , Renina/sangue , Fatores Sexuais , UrináliseRESUMO
The use of rivaroxaban, a factor Xa inhibitor, has been increasing for prevention of ischemic stroke and systemic embolism in patients with non-valvular atrial fibrillation (AF) in Japan. We conducted the nationwide multicenter study, termed as the EXPAND Study, to address its effectiveness and safety in the real-world practice of patients with non-valvular AF in Japan. The EXPAND Study is a prospective, non-interventional, observational cohort study to evaluate the effectiveness and safety of rivaroxaban in non-valvular AF patients in a real-world clinical practice. A total of 7,178 patients with non-valvular AF were enrolled in 684 medical institutes between November 20, 2012 and June 30, 2014. As for the baseline demographic and clinical characteristics of 7,164 patients, the proportion of female patients was 32.2%, and those of patients with creatinine clearance < 50 mL/min and non-paroxysmal (persistent or permanent) AF were 21.8% and 55.1%, respectively. The proportions of patients complicated with hypertension, congestive heart failure, diabetes mellitus, and a history of ischemic stroke were 70.9%, 25.9%, 24.3%, and 20.2%, respectively. The proportions of patients with a CHADS2 score ≤ 1 and a CHA2DS2-VASc score ≤ 1 were 37.3% and 13.6%, respectively. They were followed up until March 31, 2016 for a mean follow-up period of approximately 2.5 years. The findings of the EXPAND Study will help to establish an appropriate treatment with rivaroxaban for Japanese patients with non-valvular AF.
Assuntos
Fibrilação Atrial/tratamento farmacológico , Embolia/tratamento farmacológico , Inibidores do Fator Xa/uso terapêutico , Fator Xa/metabolismo , Projetos de Pesquisa , Rivaroxabana/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Idoso , Fibrilação Atrial/complicações , Fibrilação Atrial/epidemiologia , Ensaios Clínicos como Assunto , Estudos de Coortes , Demografia , Embolia/complicações , Embolia/epidemiologia , Feminino , Humanos , Japão/epidemiologia , Masculino , Prevalência , Reprodutibilidade dos Testes , Rivaroxabana/farmacologia , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/epidemiologia , Resultado do TratamentoRESUMO
OBJECTIVE: Chronic kidney disease is a risk factor of coronary events, however, its impact on coronary artery stenosis has not yet been clarified with the use of a large database. We examined the association between a reduced glomerular filtration rate (GFR) and the overall severity of coronary stenosis. METHODS: We enrolled 1,150 patients [mean age, 68±12 (SD) years; 66.6% men] who consecutively underwent coronary angiography for suspected stable angina pectoris. The overall severity of stenosis in the coronary arteries was assessed by the Gensini score (GS), and its logarithmic values (log-GS) were used for statistical analyses since the GS does not follow a normal distribution. RESULTS: The log-GS was significantly larger in men than in women (2.5±1.5 vs. 1.9±1.7), while the estimated GFR (eGFR) and comorbidities were comparable between both sexes. A multivariate regression analysis indicated that age, smoking, eGFR, HDL-cholesterol and HbA1c were independent explanatory variables of the log-GS in men, although the eGFR explained only 1.2% of the log-GS variation. In women, the eGFR was not included in the significant explanatory variables shown by the multivariate analysis. However, the sex difference in the regression for the eGFR-log-GS relationship was not statistically significant. CONCLUSION: A reduced eGFR is a significant, but minor, determinant of the overall severity of coronary artery stenosis in men and potentially women.
Assuntos
Estenose Coronária/fisiopatologia , Taxa de Filtração Glomerular , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Angina Estável/diagnóstico por imagem , HDL-Colesterol , Comorbidade , Angiografia Coronária , Estenose Coronária/diagnóstico por imagem , Estenose Coronária/epidemiologia , Vasos Coronários/diagnóstico por imagem , Feminino , Hemoglobina E/análogos & derivados , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Fatores de Risco , Índice de Gravidade de Doença , Fatores Sexuais , Fumar/epidemiologiaRESUMO
OBJECTIVES: This study aimed to examine:1) whether nicorandil protects the ischemic myocardium by activating sarcolemmal adenosine triphosphate (ATP)-sensitive K(+) (sarcK(ATP)) channels or the mitochondrial K(ATP) (mitoK(ATP)) channels, and 2) whether protein kinase C (PKC) activity is necessary for cardioprotection afforded by nicorandil. BACKGROUND: Nicorandil is a hybrid of nitrate and a K(ATP) channel opener that activates the sarcK(ATP) and mitoK(ATP) channels. Both of these K(ATP) channels are regulated by PKC, and this kinase may be activated by nitric oxide and also by oxygen free radicals (OFR) generated after mitoK(ATP) channel opening. METHODS: In isolated rabbit hearts, infarction was induced by 30-min global ischemia/2-h reperfusion with monitoring of the activation recovery interval (ARI), an index of action potential duration. Protein kinase C translocation was assessed by Western blotting. RESULTS: Nicorandil did not change ARI before ischemia, but it accelerated ARI shortening after the onset of ischemia and reduced infarct size by 90%. A sarcK(ATP) channel selective blocker, HMR1098, abolished acceleration of ischemia-induced ARI-shortening by nicorandil and eliminated 40% of nicorandil-induced infarct size limitation. A mitoK(ATP) channel selective blocker, 5-hydroxydecanoate, abolished the protection afforded by nicorandil without affecting ARI. Cardioprotection by nicorandil was inhibited neither by an OFR scavenger, N-2-mercaptopropionylglycine nor by a PKC inhibitor, calphostin C, at a dose that was capable of inhibiting PKC- epsilon translocation after preconditioning. CONCLUSIONS: Both the sarcK(ATP) and mitoK(ATP) channels are involved in anti-infarct tolerance afforded by nicorandil, but PKC activation induced by nitric oxide or OFR generation, if any, does not play a crucial role.
Assuntos
Glicina/análogos & derivados , Mitocôndrias Cardíacas/fisiologia , Isquemia Miocárdica/fisiopatologia , Nicorandil/farmacologia , Canais de Potássio/fisiologia , Proteína Quinase C/fisiologia , Sarcolema/fisiologia , Animais , Benzamidas , Ácidos Decanoicos/farmacologia , Inibidores Enzimáticos/farmacologia , Glicina/farmacologia , Hemodinâmica/efeitos dos fármacos , Hidroxiácidos/farmacologia , Técnicas In Vitro , Masculino , Isquemia Miocárdica/tratamento farmacológico , Naftalenos/farmacologia , Nicorandil/uso terapêutico , Coelhos , Compostos de Sulfidrila/farmacologiaRESUMO
We examined whether the mitochondrial ATP-sensitive K channel (K(ATP)) is an effector downstream of protein kinase C-epsilon (PKC-epsilon) in the mechanism of preconditioning (PC) in isolated rabbit hearts. PC with two cycles of 5-min ischemia/5-min reperfusion before 30-min global ischemia reduced infarction from 50.3 +/- 6.8% of the left ventricle to 20.3 +/- 3.7%. PC significantly increased PKC-epsilon protein in the particulate fraction from 51 +/- 4% of the total to 60 +/- 4%, whereas no translocation was observed for PKC-delta and PKC-alpha. In mitochondria separated from the other particulate fractions, PC increased the PKC-epsilon level by 50%. Infusion of 5-hydroxydecanoate (5-HD), a mitochondrial K(ATP) blocker, after PC abolished the cardioprotection of PC, whereas PKC-epsilon translocation by PC was not interfered with 5-HD. Diazoxide, a mitochondrial K(ATP) opener, infused 10 min before ischemia limited infarct size to 5.2 +/- 1.4%, but this agent neither translocated PKC-epsilon by itself nor accelerated PKC-epsilon translocation after ischemia. Together with the results of earlier studies showing mitochondrial K(ATP) opening by PKC, the present results suggest that mitochondrial K(ATP)-mediated cardioprotection occurs subsequent to PKC-epsilon activation by PC.
Assuntos
Precondicionamento Isquêmico Miocárdico , Isoenzimas/metabolismo , Mitocôndrias Cardíacas/metabolismo , Miocárdio/metabolismo , Canais de Potássio/metabolismo , Proteína Quinase C/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Ácidos Decanoicos/farmacologia , Diazóxido/farmacologia , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Hemodinâmica , Hidroxiácidos/farmacologia , Técnicas In Vitro , Masculino , Mitocôndrias Cardíacas/efeitos dos fármacos , Isquemia Miocárdica/metabolismo , Miocárdio/química , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio/efeitos dos fármacos , Proteína Quinase C-alfa , Proteína Quinase C-delta , Proteína Quinase C-épsilon , Transporte Proteico/efeitos dos fármacos , Transporte Proteico/fisiologia , Coelhos , Frações Subcelulares/química , Vasodilatadores/farmacologiaRESUMO
The hypothesis that blockade of angiotensin II type 1 (AT1) receptors after myocardial infarction prevents coronary endothelial vasomotor dysfunction by suppressing oxygen free radical production was examined. Rabbits underwent coronary ligation or a sham operation with or without infusion of valsartan, an AT 1 receptor blocker. Two weeks after the operation, the heart was isolated from each rabbit and perfused with buffer in the Langendorff mode, and coronary flow responses to acetylcholine and sodium nitroprusside were assessed. The ratio of heart weight to body weight and the lipid peroxide level in the myocardium were increased by 30 and 50%, respectively, 2 weeks after infarction. The coronary flow response to acetylcholine (10(-8) to 10(-5) M) was reduced by 50% in the hearts with infarction compared with the sham controls, although coronary flow responses to sodium nitroprusside were similar. The coronary flow response to acetylcholine in the hearts with infarction was restored by concurrent infusion of N -2-mercaptopropionyl-glycine, a free radical scavenger. Valsartan (10 mg/kg/d) infused after infarction prevented both ventricular remodeling and elevation of the tissue lipid peroxide level and preserved coronary flow response to acetylcholine. In conclusion, long-term AT1 receptor blockade after infarction protects the coronary arteries from endothelial vasomotor dysfunction through suppression of free radical production.