RESUMO
BACKGROUND:: Left ventricular dysfunction as part of takotsubo syndrome is reversible, and the long-term prognosis appears favorable. However, life-threatening complications are not uncommon during the acute phase, and it remains unclear whether renal dysfunction is a factor in complications suffered by hospitalized patients with takotsubo syndrome. The present study was conducted to investigate the implications of renal dysfunction in this setting. METHODS:: Data from 61 consecutive patients (male, 21; female, 40) diagnosed with takotsubo syndrome at our hospital between years 2010 and 2016 were evaluated retrospectively. In-hospital complications by definition were all-cause deaths and severe pump failure (Killip class ≥III). RESULTS:: Overall, 30 patients (49%) developed renal dysfunction. In the 32 patients (52%) who suffered in-hospital complications (mortality, 10; severe pump failure, 22), estimated glomerular filtration rate (eGFR) was significantly lower by comparison (51.3±29.8 vs. 69.5±29.0; p=0.019). Low eGFR (<30 ml/min per 1.73m2) proved independently predictive of in-hospital complications (hazard ratio =2.84, 95% confidence interval: 1.20-6.69) in multivariate Cox hazard analysis, also showing a significant association with peak event rate of Kaplan-Meier curve (log-rank test, p=0.0073). Similarly, patients with chronic kidney disease were at significantly greater risk of in-hospital complications (hazard ratio=2.49, 95% confidence interval: 1.01-5.98), relative to non-compromised counterparts (eGFR >60 ml/min per 1.73m2). CONCLUSION:: Renal dysfunction is a simple but useful means of predicting complications in hospitalized patients with takotsubo syndrome, especially those with chronic kidney disease.
Assuntos
Taxa de Filtração Glomerular/fisiologia , Pacientes Internados , Insuficiência Renal Crônica/etiologia , Cardiomiopatia de Takotsubo/complicações , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Incidência , Japão/epidemiologia , Masculino , Prognóstico , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/fisiopatologia , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida/tendências , Cardiomiopatia de Takotsubo/mortalidadeRESUMO
BACKGROUND: We recently reported that serum levels of pentosidine, one of the well-defined advanced glycation end products (AGE), was an independent prognostic factor for heart failure. Receptor for AGEs (RAGE) is expressed in a variety of tissues, and RAGE has a C-truncated secretory isoform of the receptor protein, termed soluble RAGE. In the present study, we measured serum soluble RAGE levels in patients and examined whether serum soluble RAGE predicts prognosis in patients with heart failure. METHODS AND RESULTS: Serum soluble RAGE concentration was measured in 160 patients with heart failure by a competitive enzyme-linked immunosorbent assay. Patients were prospectively followed during a median follow-up period of 872 days with end points of cardiac death or rehospitalization. Serum soluble RAGE level increased with advancing New York Heart Association functional class. Serum soluble RAGE level was also higher in patients with cardiac events than in event free patients. From the receiver operating characteristic curve analysis, the cutoff value of serum soluble RAGE level was determined as 1220 pg/mL. Kaplan-Meier analysis clearly demonstrated that the high soluble RAGE group had a significantly higher incidence of cardiac events than occurred in the low serum soluble RAGE group (P = .0004). In the multivariate Cox proportional hazard analysis, soluble RAGE and serum pentosidine were independent risk factors for cardiac events (soluble RAGE: HR 1.90, 95% CI 1.16-3.09, P = .010; pentosidine: HR 1.59, 95% CI 1.11-2.29, P = .012). CONCLUSIONS: Serum soluble RAGE level is an independent prognostic factor for heart failure, and this novel marker may be useful for risk stratification of patients with heart failure.
Assuntos
Produtos Finais de Glicação Avançada/sangue , Insuficiência Cardíaca/fisiopatologia , Idoso , Biomarcadores , Progressão da Doença , Feminino , Produtos Finais de Glicação Avançada/farmacologia , Indicadores Básicos de Saúde , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/mortalidade , Humanos , Masculino , Prognóstico , Estudos Prospectivos , Curva ROC , Medição de Risco , Índice de Gravidade de Doença , Volume Sistólico , UltrassonografiaRESUMO
BACKGROUND: The G alpha q protein-coupled receptor (GPCR) signaling pathway, which includes diacylglycerol (DAG) and protein kinase C (PKC), plays a critical role in the development of cardiac hypertrophy and heart failure (HF). It has been reported that the expression of a constitutively active mutant of the G protein alpha q subunit in the hearts of transgenic mice (G alpha q-TG) induces cardiac hypertrophy and lethal HF. DAG kinase (DGK) catalyzes DAG and controls its cellular levels, thus acting as a regulator of GPCR signaling. It has been found that transgenic mice with cardiac-specific overexpression of DGK zeta (DGK zeta-TG) inhibit GPCR agonist-induced activation of the DAG-PKC signaling and subsequent cardiac hypertrophy, so this study tested the hypothesis that DGK zeta could rescue G alpha q-TG mice from developing HF. METHODS AND RESULTS: Double transgenic mice (G alpha q/DGK zeta-TG) with cardiac-specific overexpression of both DGK zeta and G alpha q were generated by crossing G alpha q-TG with DGK zeta-TG mice, and the pathophysiological consequences were analyzed. DGK zeta prevented cardiac dysfunction, determined by dilatation of left ventricular (LV) dimensions, reduction of LV fractional shortening, and marked increases in LV end-diastolic pressure in G alpha q-TG mice. Translocation of PKC isoforms, phosphorylation activity of c-jun N-terminal kinase and p38 mitogen-activated protein kinase in G alpha q-TG mice were attenuated by DGK zeta. DGK zeta improved the survival rate of G alpha q-TG mice. CONCLUSIONS: These results demonstrate the first evidence that DGK zeta blocks cardiac dysfunction and progression to lethal HF by activated G alpha q protein without detectable adverse effects in the in-vivo heart and suggest that DGK zeta is a novel therapeutic target for HF.
Assuntos
Cardiomegalia/enzimologia , Diacilglicerol Quinase/metabolismo , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Insuficiência Cardíaca/enzimologia , Miocárdio/enzimologia , Transdução de Sinais , Animais , Cardiomegalia/genética , Cardiomegalia/patologia , Diacilglicerol Quinase/genética , Modelos Animais de Doenças , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Camundongos , Camundongos Transgênicos , Miocárdio/patologia , Especificidade de Órgãos/genética , Proteína Quinase C/genética , Proteína Quinase C/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismoRESUMO
BACKGROUND: Pentraxin 3 (PTX3) is a novel inflammatory marker produced by endothelial cells, smooth muscle cells, and macrophages. The purpose of the present study was to examine the clinical significance of plasma PTX3 levels in patients with heart failure. METHODS: We measured the plasma PTX3 levels in 196 patients with heart failure and 60 control subjects without heart failure by sandwich enzyme-linked immunosorbent assay. Patients were prospectively followed during a median follow-up period of 655 days with the end points of cardiac death or progressive heart failure requiring rehospitalization. RESULTS: Plasma PTX3 concentrations were higher in patients with heart failure than in control subjects (P < .0001) and increased as the severity of New York Heart Association functional class advanced (P < .0001). A total of 63 cardiac events occurred during a follow-up period, and cardiac event-free rate was markedly lower in patients with high PTX3 levels than in those with normal PTX3 levels (44.7% vs 89.2%, P < .0001). The multivariate Cox proportional hazard analysis demonstrated that the plasma PTX3 level, but not the high-sensitive C-reactive protein, was the independent predictor of cardiac events (hazard ratio 1.20, 95% CI 1.03-1.40, P = .0162). Patients were divided into 4 groups based on plasma PTX3 values from first to fourth quartile. The highest fourth quartile of plasma PTX3 levels was associated with the highest risk of cardiac events (9.23-fold compared with the first quartile). CONCLUSIONS: The plasma PTX3 level provides important prognostic information for the risk stratification of patients with heart failure.
Assuntos
Proteína C-Reativa/análise , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/mortalidade , Mediadores da Inflamação/sangue , Componente Amiloide P Sérico/análise , Vasculite/sangue , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Progressão da Doença , Feminino , Insuficiência Cardíaca/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Probabilidade , Prognóstico , Modelos de Riscos Proporcionais , Valores de Referência , Medição de Risco , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Estatísticas não Paramétricas , Análise de SobrevidaRESUMO
BACKGROUND: Heart-type fatty acid-binding protein (H-FABP) is a small cytosolic protein that is released into the circulation when the myocardium is injured. This study examined whether serial measurement of the H-FABP level provides additional prognostic information. METHODS AND RESULTS: Serum H-FABP levels were measured in 113 consecutive chronic heart failure (CHF) patients at both admission and discharge. The following 3 patterns of changes were identified. In 41 patients, H-FABP levels (<4.3 ng/ml) at both admission and discharge were normal (Group 1). The remaining 72 patients had high initial H-FABP levels (> or =4.3 ng/ml) at admission, and in 21 of them (29%), H-FABP decreased to the normal range at discharge (Group 2), whereas 51 had persistently high H-FABP levels despite improvement in symptoms and signs of CHF (Group 3). There were 33 cardiac events (29%) during the follow-up period, and Group 3 had significantly higher cardiac event rates than Groups 1 and 2 (p=0.0002). Group 3 had the highest cardiac risk among the groups (hazard ratio 5.68, p=0.012). CONCLUSION: Serial measurement of the H-FABP level is a new monitoring tool that provides information to guide optimal therapy and management of CHF patients.
Assuntos
Proteínas de Ligação a Ácido Graxo/sangue , Insuficiência Cardíaca/sangue , Valor Preditivo dos Testes , Idoso , Proteína 3 Ligante de Ácido Graxo , Feminino , Insuficiência Cardíaca/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Miocárdio , Prognóstico , Resultado do TratamentoRESUMO
BACKGROUND: Clinical markers to predict adverse outcome have not yet been established for patients with preserved left ventricular (LV) systolic function. The present study was designed to examine whether carboxy-terminal telopeptide of type I collagen (ICTP), a marker of collagen degradation, is useful for determining the prognosis of such patients. METHODS AND RESULTS: Serum levels of ICTP were measured at admission in 156 consecutive patients hospitalized for chronic heart failure (CHF). Patients were divided into 2 groups based on the LV ejection fraction (LVEF): reduced LV systolic function group (LVEF <50%, n=92) and preserved LV systolic function group (LVEF > or =50%, n=64). In preserved LV systolic function group, cardiac event-free rates were significantly lower in high ICTP group than in low ICTP group (p<0.001). The area under the receiver operating characteristic curve of ICTP in the preserved LV systolic function group was markedly larger than that in the reduced LV systolic function group. Cox multivariate analysis also revealed that ICTP was an independent predictor of cardiac events in the preserved LV systolic function group. CONCLUSION: Serum ICTP level is highly reliable for risk stratifying CHF patients with preserved LV systolic function.
Assuntos
Colágeno Tipo I/sangue , Insuficiência Cardíaca/sangue , Peptídeos/sangue , Função Ventricular Esquerda , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Feminino , Seguimentos , Insuficiência Cardíaca/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida , SístoleRESUMO
BACKGROUND: Pentosidine, one of the advanced glycation end products (AGE), is generated by nonenzymatic glycation and oxidation of proteins. The receptor of AGE (RAGE) is expressed in a variety of tissue, and interaction of AGE with RAGE induces oxidative stress and activation of intracellular signaling, causing production of cytokines and mediators of inflammation. We investigated whether serum pentosidine is a risk factor for heart failure. METHODS AND RESULTS: Serum pentosidine concentration was measured in 141 patients with heart failure and 18 control subjects by a competitive enzyme-linked immunosorbent assay. Patients were prospectively followed during a median follow-up period of 479 days with end points of cardiac death or rehospitalization. Serum concentration of pentosidine was significantly higher in New York Heart Association (NYHA) Class III/IV patients than in NYHA class I/II patients (P < .0001). Serum pentosidine was also higher in patients with cardiac events than in event-free patients (P < .001). In the univariate Cox proportional hazard analysis, age, NYHA class, pentosidine, creatinine, uric acid, B-type natriuretic peptide, left ventricular end-systolic volume, and left ventricular mass were significant risk factors to predict cardiac events. In the multivariate Cox analysis, serum pentosidine concentration was an independent risk factor for cardiac events (hazard ratio 1.88, 95% confidence interval 1.23-2.69, P = .002). The highest 4th quartile of pentosidine was associated with the highest risk of cardiac events (4.52-fold). CONCLUSIONS: Serum pentosidine concentration is an independent prognostic factor for heart failure, and this new marker may be useful for risk stratification of patients with heart failure. Patients were divided into 4 groups based on the serum pentosidine levels.
Assuntos
Arginina/análogos & derivados , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/epidemiologia , Lisina/análogos & derivados , Idoso , Arginina/sangue , Biomarcadores/sangue , Cardiotônicos/uso terapêutico , Estudos de Casos e Controles , Comorbidade , Complicações do Diabetes/epidemiologia , Digoxina/uso terapêutico , Diuréticos/uso terapêutico , Feminino , Seguimentos , Insuficiência Cardíaca/classificação , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/tratamento farmacológico , Hospitalização/estatística & dados numéricos , Humanos , Japão/epidemiologia , Lisina/sangue , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Insuficiência Renal/epidemiologia , Fatores de Risco , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Análise de SobrevidaRESUMO
BACKGROUND: Heart-type fatty acid-binding protein (H-FABP) is a small cytosolic protein and released into the circulation when the myocardium is injured. Previous studies have demonstrated that both H-FABP and troponin T (TnT) are detectable in venous blood samples in chronic heart failure (CHF) patients, suggesting the presence of ongoing myocardial damage (OMD). We hypothesized that a cytosolic marker (H-FABP) is more sensitive than a myofibrillar component (TnT) in the detection of OMD in CHF. METHODS AND RESULTS: We measured serum H-FABP and TnT levels in 126 consecutive CHF patients at admission, and patients were followed-up with a mean period of 474 +/- 328 days. Cutoff values for H-FABP (4.3 ng/mL) and TnT (0.01 ng/mL) were determined from previous studies. Positive rate of H-FABP was higher than that of TnT in all CHF patients (46% [58/126] versus 26% [33/126], P < .0001), and in severe CHF (New York Heart Association III/IV) patients (69% [34/49] versus 47% [23/49], P = .0121). There were 27 cardiac events during a follow-up period. In patients with cardiac events, H-FABP was more frequently detected than TnT (88% [24/27] versus 44% [12/27], P = .0103). There were 33 patients with positive H-FABP among 93 patients with negative TnT. Those patients had more severe New York Heart Association class, higher levels of brain natriuretic peptide, and higher rates of cardiac events (36% versus 5%, P < .0001) compared with those both H-FABP and TnT were negative. Kaplan-Meier analysis demonstrated that in patients with negative TnT, positive H-FABP group had higher risk for cardiac events than negative H-FABP group (P < .0001). A multivariate analysis with Cox proportional hazard model showed that H-FABP was the only independent predictor of cardiac events (hazard ratio 15.677, P = .0001). The area under the receiver operating characteristic curve was larger for H-FABP than for TnT (0.779 versus 0.581; P = .009), suggesting that H-FABP had greater predictive capacity for cardiac events than TnT. CONCLUSIONS: H-FABP was more sensitive to detect OMD and could identify patients at high risk more effectively than TnT.
Assuntos
Proteínas de Ligação a Ácido Graxo/sangue , Insuficiência Cardíaca/sangue , Troponina T/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Proteína 3 Ligante de Ácido Graxo , Feminino , Seguimentos , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Prognóstico , Estudos Prospectivos , Curva ROC , Radioimunoensaio , Medição de Risco , Índice de Gravidade de Doença , Função Ventricular Esquerda/fisiologiaRESUMO
BACKGROUND: Iodine-123-metaiodobenzylguanidine ((123)I-MIBG) can assess cardiac sympathetic nervous function. Heart-type fatty acid binding protein (H-FABP) has been used as a marker of ongoing myocardial damage. The prognostic value of combination (123)I-MIBG imaging and H-FABP in heart failure is unknown. METHODS AND RESULTS: We prospectively enrolled consecutive 104 patients with heart failure in whom we quantified (123)I-MIBG scintigraphy, simultaneously measured serum H-FABP and plasma brain natriuretic peptide (BNP) levels, and analyzed clinical outcomes. The multivariate Cox regression analysis revealed that augmented H-FABP level and decreased heart to mediastinum ratio of (123)I-MIBG at 240 minutes (delayed H/M ratio), but not BNP, were the independent predictors for cardiac events. The cutoff values for H-FABP and delayed H/M ratio were determined from the receiver operating characteristic curves as 5.2 ng/mL for H-FABP and 1.73 for delayed H/M ratio. The cardiac event rate was markedly higher in patients with both H-FABP and delayed H/M ratio of (123)I-MIBG was abnormal. Conversely, no cardiac events occurred in patients with both H-FABP level and delayed H/M ratio were normal. CONCLUSION: H-FABP adds independent prognostic information to delayed H/M ratio of (123)I-MIBG imaging, and the combination of these approaches may improve the accuracy of prognostic determination in heart failure.
Assuntos
Insuficiência Cardíaca/diagnóstico , Coração/inervação , 3-Iodobenzilguanidina , Idoso , Proteína 3 Ligante de Ácido Graxo , Proteínas de Ligação a Ácido Graxo/sangue , Feminino , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Cintilografia , Compostos Radiofarmacêuticos , Sistema Nervoso Simpático/fisiopatologiaRESUMO
PURPOSE: Oxidative stress plays an important role in the pathogenesis of cardiovascular diseases. Azelnidipine is a novel dihydropyridine calcium channel blocker. Several studies have demonstrated that some dihydropyridine calcium channel blockers have antioxidant effects. We evaluated the antioxidant effects of azelnidipine compared to another dihyropyridine calcium channel blocker, nifedipine, in neonatal rat cardiomyocytes. MATERIALS AND METHODS: We examined effects of azelnidipine and nifedipine on the H(2)O(2)-induced mitogen-activated protein kinase (MAPK) activity and cell death in neonatal rat cardiomyocytes. RESULTS: Extracellular signal-regulated protein kinases (ERK), p38 MAPK and c-Jun NH(2)-terminal kinases (JNK) were activated by H(2)O(2) stimulation. Azelnidipine and nifedipine did not affect the H(2)O(2)-induced activation of ERK and p38 MAPK. In contrast, azelnidipine, but not nifedipine, inhibited the H(2)O(2)-induced JNK activation. The numbers of viable cell were significantly decreased by H(2)O(2) treatments (65.8 +/- 4.11% of control, P < 0.0001). Azelnidipine, but not nifedipine, inhibited the H(2)O(2)-induced cell death (azelnidipine: 76.0 +/- 4.66% of control, P < 0.05; nifedipine: 70.7 +/- 4.01% of control, P = 0.32). CONCLUSION: Azelnidipine inhibited the H(2)O(2)-induced JNK activation and cardiac cell death. Azelnidipine may have cardioprotective effects against oxidative stress.
Assuntos
Ácido Azetidinocarboxílico/análogos & derivados , Di-Hidropiridinas/farmacologia , Peróxido de Hidrogênio/toxicidade , Miócitos Cardíacos/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Ácido Azetidinocarboxílico/farmacologia , Western Blotting , Bloqueadores dos Canais de Cálcio/farmacologia , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , MAP Quinase Quinase 4/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Nifedipino/farmacologia , Ratos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Left ventricular (LV) remodeling, including cardiomyocyte necrosis, scar formation, LV geometric changes, and cardiomyocyte hypertrophy, contributes to cardiac dysfunction and mortality after myocardial infarction (MI). Although precise cellular signaling mechanisms for LV remodeling are not fully elucidated, G(q) protein-coupled receptor signaling pathway, including diacylglycerol (DAG) and PKC, are involved in this process. DAG kinase (DGK) phosphorylates DAG and controls cellular DAG levels, thus acting as a negative regulator of PKC and subsequent cellular signaling. We previously reported that DGK inhibited angiotensin II and phenylephrine-induced activation of the DAG-PKC signaling and subsequent cardiac hypertrophy. The purpose of this study was to examine whether DGK modifies LV remodeling after MI. Left anterior descending coronary artery was ligated in transgenic mice with cardiac-specific overexpression of DGKzeta (DGKzeta-TG) and wild-type (WT) mice. LV chamber dilatation (4.12 +/- 0.10 vs. 4.53 +/- 0.32 mm, P < 0.01), reduction of LV systolic function (34.8 +/- 8.3% vs. 28.3 +/- 4.8%, P < 0.01), and increases in LV weight (95 +/- 3.6 vs. 111 +/- 4.1 mg, P < 0.05) and lung weight (160 +/- 15 vs. 221 +/- 25 mg, P < 0.05) at 4 wk after MI were attenuated in DGKzeta-TG mice compared with WT mice. In the noninfarct area, fibrosis fraction (0.51 +/- 0.04, P < 0.01) and upregulation of profibrotic genes, such as transforming growth factor-beta1 (P < 0.01), collagen type I (P < 0.05), and collagen type III (P < 0.01), were blocked in DGKzeta-TG mice. The survival rate at 4 wk after MI was higher in DGKzeta-TG mice than in WT mice (61% vs. 37%, P < 0.01). In conclusion, these results demonstrate the first evidence that DGKzeta suppresses LV structural remodeling and fibrosis and improves survival after MI. DGKzeta may be a potential novel therapeutic target to prevent LV remodeling after MI.
Assuntos
Diacilglicerol Quinase/metabolismo , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Remodelação Ventricular , Animais , Fator Natriurético Atrial/metabolismo , Colágeno/metabolismo , Diacilglicerol Quinase/genética , Modelos Animais de Doenças , Regulação para Baixo , Fibrose , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Isoenzimas , Camundongos , Camundongos Transgênicos , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miocárdio/patologia , Cadeias Pesadas de Miosina/metabolismo , Peptídeo Natriurético Encefálico/metabolismo , Proteína Quinase C/metabolismo , Transporte Proteico , RNA Mensageiro , Fatores de Tempo , Fator de Crescimento Transformador beta1/metabolismo , Regulação para Cima , Função Ventricular EsquerdaRESUMO
OBJECTIVES: Congestive heart failure (CHF) is the major cause of death and hospitalization in the elderly population. Simple markers that can be measured anywhere at low cost are necessary to identify patients at high risk. Recent studies have reported that hyperuricemia is a prognostic marker for CHF. However, it is not yet known whether serum levels of uric acid may provide prognostic information in the elderly population. Therefore, this study tried to identify the clinical characteristics of elderly CHF patients (+/-70 years) in our institution and to evaluate whether uric acid levels can effectively estimate the prognosis for elderly CHF patients. METHODS AND RESULTS: Uric acid levels were analyzed in 247 CHF patients, and patients were followed up for 451 +/- 235 days (mean +/- SD). Elderly CHF patients aged > or =70 years (123 patients) had higher rate of hypertension, lower current smoking rate and higher uric acid levels than those aged < 70 years (124 patients). There were 72 cardiac events including cardiac deaths and readmissions for worsening CHF. Multivariate analysis with the Cox proportional hazard model showed that uric acid was the only independent predictor of cardiac events (hazard ratio 1.544, 95% confidence interval 1.215-2.582, p < 0.0001) in the elderly with CHF. The highest quartile of uric acid level was associated with the highest risk of cardiac events (a 4.45-fold compared to the lowest quartile). Kaplan-Meier analysis revealed that uric acid levels effectively risk stratified elderly CHF patients for cardiac events. CONCLUSIONS: These findings suggest that measurement of uric acid levels in elderly CHF patients may add valuable prognostic information to predict cardiac events.
Assuntos
Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/fisiopatologia , Hiperuricemia/complicações , Idoso , Biomarcadores/sangue , Feminino , Insuficiência Cardíaca/complicações , Humanos , Hiperuricemia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Ácido Úrico/sangueRESUMO
BACKGROUND: It is now evident that inflammation after vascular injury has significant impact on the restenosis after revascularization procedures such as angioplasty, stenting, and bypass grafting. However, the mechanisms that regulate inflammation and repair after vascular injury are incompletely understood. Here, we report that vascular injury-mediated cytokine expression, reactive oxygen species (ROS) production, as well as subsequent neointimal formation requires Toll-like receptor-2 (TLR-2) mediated signaling pathway in vivo. METHODS AND RESULTS: Vascular injury was induced by cuff-placement around the femoral artery in non-transgenic littermates (NLC) and TLR-2 knockout (TLR-2KO) mice. After cuff-placement in NLC mice, expression of TLR-2 was significantly increased in both smooth muscle medial layer and adventitia. Interestingly, we found that inflammatory genes expression such as tumor necrosis factor-alpha, interleukin-1beta (IL-1beta), IL-6, and monocyte chemoattractant protein-1 were markedly decreased in TLR-2KO mice compared with NLC mice. In addition, ROS production after vascular injury was attenuated in TLR-2KO mice compared with NLC mice. Since we observed the significant role of endogenous TLR-2 activation in regulating inflammatory responses and ROS production after vascular injury, we determined whether inhibition of endogenous TLR-2 activation can inhibit neointimal proliferation after vascular injury. Neointimal hyperplasia was markedly suppressed in TLR-2KO mice compared with WT mice at both 2 and 4 weeks after vascular injury. CONCLUSIONS: These findings suggested that endogenous TLR-2 activation might play a central role in the regulation of vascular inflammation as well as subsequent neointimal formation in injured vessels.
Assuntos
Artéria Femoral/metabolismo , Inflamação/fisiopatologia , Espécies Reativas de Oxigênio/metabolismo , Receptor 2 Toll-Like/fisiologia , Túnica Íntima/patologia , Animais , Pressão Sanguínea/fisiologia , Peso Corporal/fisiologia , Citocinas/genética , Feminino , Artéria Femoral/lesões , Regulação da Expressão Gênica , Frequência Cardíaca/fisiologia , Inflamação/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Receptor 2 Toll-Like/genética , Túnica Íntima/metabolismoRESUMO
BACKGROUND: Diacylglycerol is a lipid second messenger that accumulates in cardiomyocytes when stimulated by Gqalpha protein-coupled receptor (GPCR) agonists such as angiotensin II, phenylephrine, and others. Diacylglycerol functions as a potent activator of protein kinase C (PKC) and is catalyzed by diacylglycerol kinase (DGK) to form phosphatidic acid and inactivated. However, the functional roles of DGK have not been previously examined in the heart. We hypothesized that DGK might prevent GPCR agonist-induced activation of diacylglycerol downstream signaling cascades and subsequent cardiac hypertrophy. METHODS AND RESULTS: To test this hypothesis, we generated transgenic (DGKzeta-TG) mice with cardiac-specific overexpression of DGKzeta. There were no differences in heart size and heart weight between DGKzeta-TG and wild-type littermate mice. The left ventricular function was normal in DGKzeta-TG mice. Continuous administration of subpressor doses of angiotensin II and phenylephrine caused PKC translocation, gene induction of atrial natriuretic factor, and subsequent cardiac hypertrophy in WT mice. However, in DGKzeta-TG mice, neither translocation of PKC nor upregulation of atrial natriuretic factor gene expression was observed after angiotensin II and phenylephrine infusion. Furthermore, in DGKzeta-TG mice, angiotensin II and phenylephrine failed to increase cross-sectional cardiomyocyte areas and heart to body weight ratios. Phenylephrine-induced increases in myocardial diacylglycerol levels were completely blocked in DGKzeta-TG mouse hearts, suggesting that DGKzeta regulated PKC activity by controlling cellular diacylglycerol levels. CONCLUSIONS: These results demonstrated the first evidence that DGKzeta negatively regulated the hypertrophic signaling cascade and resultant cardiac hypertrophy in response to GPCR agonists without detectable adverse effects in in vivo hearts.
Assuntos
Cardiomegalia/prevenção & controle , Diacilglicerol Quinase/farmacologia , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP , Proteínas Heterotriméricas de Ligação ao GTP/agonistas , Miocárdio/metabolismo , Angiotensina II/farmacologia , Animais , Diacilglicerol Quinase/genética , Diglicerídeos/metabolismo , Camundongos , Camundongos Transgênicos , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Fenilefrina/farmacologia , Regiões Promotoras Genéticas , Proteína Quinase C/metabolismo , RNA Mensageiro/análise , Ratos , Transdução de Sinais/efeitos dos fármacos , Miosinas Ventriculares/genéticaRESUMO
UNLABELLED: Iodine-123-metaiodobenzylguanidine (123I-MIBG) has been used to assess the integrity and function of the cardiac sympathetic nervous system in patients with heart failure. Heart-type fatty acid binding protein (H-FABP) is released into the circulation when the myocardium is injured, and H-FABP has been recently used as a novel marker for the diagnosis of ongoing myocardial damage. OBJECTIVE: The aim of the present study was to compare cardiac sympathetic nervous activity assessed by 123I-MIBG imaging with serum levels of H-FABP in patients with heart failure. METHODS: Fifty patients with chronic heart failure were studied. 123I-MIBG imaging was carried out at 30 min (early) and 240 min (delayed) after the tracer injection. We measured serum levels of H-FABP using a sandwich enzyme linked immunosorbent assay. RESULTS: Heart to mediastinum (H/M) ratios of 123I-MIBG decreased and washout rate increased with higher New York Heart Association (NYHA) functional class. H-FABP, norepinephrine and brain natriuretic peptide (BNP) levels increased as the severity of NYHA class advanced. Delayed H/M ratio was significantly correlated with H-FABP (r = -0.296, p = 0.029) and BNP (r = -0.335, p = 0.0213). Myocardial washout rate of 123I-MIBG was also correlated with H-FABP (r = 0.469, p < 0.001), norepinephrine (r = 0.433, p = 0.005), and BNP (r = 0.465, p = 0.001). CONCLUSIONS: These data suggest that cardiac sympathetic nervous activation was associated with ongoing cardiomyocyte damage characterized by an elevated serum level of H-FABP in patients with heart failure. 123I-MIBG imaging is an appropriate approach to evaluate non-invasively not only cardiac sympathetic nervous activity, but also latent ongoing myocardial damage in the failing heart.
Assuntos
3-Iodobenzilguanidina , Cardiomiopatias/sangue , Cardiomiopatias/diagnóstico por imagem , Proteínas de Ligação a Ácido Graxo/sangue , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/diagnóstico por imagem , Sistema Nervoso Simpático/diagnóstico por imagem , Idoso , Cardiomiopatias/complicações , Feminino , Insuficiência Cardíaca/complicações , Humanos , Masculino , Cintilografia , Compostos Radiofarmacêuticos , Estatística como AssuntoRESUMO
BACKGROUND: Cystatin C, a novel endogenous marker of glomerular filtration rate, has been reported as more sensitive to detect renal insufficiency than creatinine. The purpose of the present study was to examine the clinical significance of serum cystatin C level in patients with mild to moderate heart failure. METHODS AND RESULTS: Serum levels of cystatin C were measured by an enzyme immunoassay in 140 patients with heart failure and 64 control subjects without heart failure. Patients were prospectively followed during a median follow-up period of 480 days, with the end points of cardiac death and progressive heart failure requiring rehospitalization. Serum levels of cystatin C were higher in patients with heart failure than in control subjects (1.14 +/- 0.60 ng/mL versus 0.72 +/- 0.14 ng/mL, P < .001). The Cox multivariate proportional hazard analysis revealed that a change of 1 standard deviation (SD) in cystatin C level was the one of independent predictor for cardiac events (hazard ratio, 1.94; 95% confidence interval, 1.29-6.64; P < .01). The cardiac event rate was markedly higher in patients with elevated cystatin C level (> or =1.0 ng/mL) than in those with normal level (< or =1.0 ng/mL) (38.7% versus 10.3%, P < 0.001). Furthermore in patients with normal creatinine levels (n = 91), the cardiac event rate was similarly higher in patients with elevated cystatin C than in those with normal levels (29.2% versus 7.5%, P = .002). CONCLUSION: Elevation of serum cystatin C, a new marker of renal function, provides promising prognostic information for clinical outcome in patients with mild to moderate heart failure.
Assuntos
Cistatinas/sangue , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/fisiopatologia , Rim/fisiopatologia , Idoso , Biomarcadores/sangue , Creatinina/metabolismo , Cistatina C , Cistatinas/metabolismo , Feminino , Seguimentos , Taxa de Filtração Glomerular , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/mortalidade , Humanos , Rim/metabolismo , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Readmissão do Paciente , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Estudos Prospectivos , Índice de Gravidade de Doença , Análise de SobrevidaRESUMO
Increased cardiovascular mortality is an unresolved problem of chronic renal failure. Cardiac hypertrophy, observed in many patients with chronic renal failure, is a major risk factor for cardiovascular death. The purpose of the present study was to examine the effects of pitavastatin on cardiac hypertrophy in a progressive renal injury rat model by subtotal nephrectomy (SNx). Because we previously reported that angiotensin II played a pivotal role in cardiac hypertrophy of SNx rats, we first investigated the effects of pitavastatin on angiotensin II-induced activation of extracellular signal-regulated kinase (ERK) and serum response element (SRE) DNA-binding activity using neonatal rat cardiomyocytes. Angiotensin II-induced ERK activation was attenuated by pretreatment with pitavastatin. Luciferase assay revealed that angiotensin II-induced increase in SRE DNA-binding activity was inhibited by pitavastatin. We next examined the effect of pitavastatin on cardiac hypertrophy of SNx rats in vivo. Treatment with pitavastatin prevented ERK activation and cardiac hypertrophy in SNx rats without changes in blood pressure. The increased expression of atrial natriuretic factor mRNA in SNx rat hearts was significantly attenuated by the treatment with pitavastatin. These results suggest that pitavastatin has a beneficial effect on cardiac hypertrophy in renal failure through preventing the activation of ERK.
Assuntos
Cardiomegalia/prevenção & controle , Inibidores Enzimáticos/farmacologia , Rim/patologia , Quinolinas/farmacologia , Angiotensina II/farmacologia , Animais , Animais Recém-Nascidos , Fator Natriurético Atrial/genética , Pressão Sanguínea/efeitos dos fármacos , Cardiomegalia/fisiopatologia , Células Cultivadas , Modelos Animais de Doenças , Progressão da Doença , Ativação Enzimática/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Rim/metabolismo , Rim/cirurgia , Masculino , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Nefrectomia , Fosforilação/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Vasoconstritores/farmacologiaRESUMO
BACKGROUND AND OBJECTIVES: Heart-type fatty acid binding protein (H-FABP) is released into the circulation from the damaged myocardium of patients with severe chronic heart failure. Chronic heart failure is the most frequent cause of death and disability in the elderly. However, there are no data for the prognostic value of H-FABP in the elderly population. This study investigated whether H-FABP can effectively predict the prognosis in elderly patients (> or = 70 years) with chronic heart failure. METHODS: Serum H-FABP levels were measured in 90 chronic heart failure patients > or =70 years old (mean age 77 +/- 4 years, range 70-92 years), and patients were followed-up for 421 +/- 326 days. RESULTS: There were 35 cardiac events (38.9%) including cardiac deaths and readmissions for worsening chronic heart failure. Multivariate analysis with the Cox proportional hazard model showed that H-FABP was the only independent predictor of cardiac events (chi2 = 6.640, p = 0.0100). Kaplan-Meier analysis revealed that H-FABP effectively risk stratified elderly patients with chronic heart failure for cardiac events. CONCLUSIONS: These findings suggest that H-FABP is a reliable marker for prognosis in elderly patients with chronic heart failure.
Assuntos
Proteínas de Transporte/sangue , Insuficiência Cardíaca/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Doença Crônica , Proteínas de Ligação a Ácido Graxo , Feminino , Humanos , Masculino , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Risco , Índice de Gravidade de DoençaRESUMO
BACKGROUND: The aim of the present study was to prospectively study whether a combination of markers for myocardial cell injury and left ventricular overload at admission can reliably risk stratify patients hospitalized for chronic heart failure (CHF). METHODS AND RESULTS: Serum concentrations of heart-type fatty acid binding protein (H-FABP) and plasma concentrations of brain natriuretic peptide (BNP) were measured at admission in 186 consecutive patients hospitalized for CHF. During a mean follow-up period of 534+/-350 days, there were 44 cardiac events, including 16 cardiac deaths and 28 readmissions for worsening heart failure. Normal upper limits for H-FABP and BNP values were determined from the receiver operating characteristic curves (4.3 ng/ml for H-FABP and 200 pg/ml for BNP). A stepwise Cox regression analysis demonstrated that high H-FABP (hazard ratio 5.416, p = 0.0002) and high BNP (hazard ratio 2.411, p = 0.0463) were independent predictors of cardiac events. High concentrations of both H-FABP and BNP at admission were associated with the highest incidence of cardiac mortality and cardiac events. Kaplan-Meier analysis also showed that the combination of H-FABP and BNP concentrations could reliably stratify patients for cardiac events. CONCLUSION: Combined measurement of H-FABP and BNP concentrations at admission may be a highly reliable evaluation for risk stratifying patients hospitalized for CHF.
Assuntos
Proteínas de Transporte/sangue , Insuficiência Cardíaca/sangue , Peptídeo Natriurético Encefálico/sangue , Seleção de Pacientes , Idoso , Biomarcadores/sangue , Proteínas de Ligação a Ácido Graxo , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de RiscoRESUMO
BACKGROUND: Diacylglycerol (DAG) is a lipid second messenger that transiently accumulates in cells stimulated by endothelin-1 (ET-1) and other Galphaq protein-coupled receptor agonists. Diacylglycerol kinase (DGK) is thought to be an enzyme that controls the cellular levels of DAG by converting it to phosphatidic acid; however, the functional role of DGK has not been examined in cardiomyocytes. Because DGK inactivates DAG, a strong activator of protein kinase C (PKC), we hypothesized that DGK inhibited ET-1-induced activation of a DAG-PKC signaling cascade and subsequent cardiomyocyte hypertrophy. METHODS AND RESULTS: Real-time reverse transcription-polymerase chain reaction demonstrated a significant increase of DGK-zeta mRNA by ET-1 in cardiomyocytes. To determine the functional role of DGK-zeta, we overexpressed DGK-zeta in cardiomyocytes using a recombinant adenovirus encoding rat DGK-zeta (Ad-DGKzeta). ET-1-induced translocation of PKC-epsilon was blocked by Ad-DGKzeta (P<0.01). Ad-DGKzeta also inhibited ET-1-induced activation of extracellular signal-regulated kinase (P<0.01). Luciferase reporter assay revealed that ET-1-mediated increase of activator protein-1 (AP1) DNA-binding activity was significantly inhibited by DGK-zeta (P<0.01). In cardiomyocytes transfected with DGK-zeta, ET-1 failed to cause gene induction of atrial natriuretic factor, increases in [3H]-leucine uptake, and increases in cardiomyocyte surface area. CONCLUSIONS: We demonstrated for the first time that DGK-zeta blocked ET-1-induced activation of the PKC-epsilon-ERK-AP1 signaling pathway, atrial natriuretic factor gene induction, and resultant cardiomyocyte hypertrophy. DGK-zeta might act as a negative regulator of hypertrophic program in response to ET-1, possibly by controlling cellular DAG levels.