Additive clinical value of serum brain-derived neurotrophic factor for prediction of chronic heart failure outcome.

The importance of the central nervous system in cardiovascular events has been recognized. Recently, brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family, is involved in depression mechanisms and also in stress and anxiety. Because BDNF is reported about cardioprotective role, we elucidated whether BDNF is associated with cardiovascular events in patients with chronic heart failure (CHF). We examined serum BDNF levels in 134 patients with CHF and 23 control subjects. The patients were followed to register cardiac events for a median of 426 days. BDNF was significantly lower in CHF patients than in control subjects (25.8 ± 8.4 vs 14.7 ± 8.4, P < 0.0001). Serum BDNF was also lower in patients with cardiac events than in event-free patients (16.1 ± 8.0 vs 12.5 ± 8.5, P < 0.0001). The cutoff value of BDNF was determined by performing receiver operating characteristic curve analysis. Kaplan-Meier analysis demonstrated that patients with low levels of BDNF experienced higher rates of cardiac events than those with high levels of BDNF. Multivariate Cox hazard analysis demonstrated that low BDNF levels (≤12.4 ng/mL) were an independent prognostic factor for cardiac events (hazard ratio 2.932, 95 % confidence interval 1.622-5.301; P = 0.0004). Adding levels of BDNF to the model with BNP levels, age, and eGFR for the prediction of cardiac events yielded significant net reclassification improvement of 0.429 (P < 0.001) and an integrated discrimination improvement of 0.101 (P < 0.001). Low serum BDNF levels were found in patients with CHF, and these levels were found to be independently associated with an increased risk of cardiac events.

Deficiency of Senescence Marker Protein 30 Exacerbates Cardiac Injury after Ischemia/Reperfusion.

Early myocardial reperfusion is an effective therapy but ischemia/reperfusion (I/R) causes lethal myocardial injury. The aging heart was reported to show greater cardiac damage after I/R injury than that observed in young hearts. Senescence marker protein 30 (SMP30), whose expression decreases with age, plays a role in reducing oxidative stress and apoptosis. However, the impact of SMP30 on myocardial I/R injury remains to be determined. In this study, the left anterior descending coronary artery was occluded for 30 min, followed by reperfusion in wild-type (WT) and SMP30 knockout (KO) mice. After I/R, cardiomyocyte apoptosis and the ratio of infarct area/area at risk were higher, left ventricular fractional shortening was lower, and reactive oxygen species (ROS) generation was enhanced in SMP30 KO mice. Moreover, the previously increased phosphorylation of GSK-3ß and Akt was lower in SMP30 KO mice than in WT mice. In cardiomyocytes, silencing of SMP30 expression attenuated Akt and GSK-3ß phosphorylation, and increased Bax to Bcl-2 ratio and cardiomyocyte apoptosis induced by hydrogen peroxide. These results suggested that SMP30 deficiency augments myocardial I/R injury through ROS generation and attenuation of Akt activation.

High-mobility group box 1-mediated heat shock protein beta 1 expression attenuates mitochondrial dysfunction and apoptosis.

AIMS: Apoptosis of cardiomyocytes is thought to account for doxorubicin cardiotoxicity as it contributes to loss of myocardial tissue and contractile dysfunction. Given that high-mobility group box 1 (HMGB1) is a nuclear DNA-binding protein capable of inhibiting apoptosis, we aimed to clarify the role of HMGB1 in heat shock protein beta 1 (HSPB1) expression during doxorubicin-induced cardiomyopathy. METHODS AND RESULTS: Mitochondrial damage, cardiomyocyte apoptosis, and cardiac dysfunction after doxorubicin administration were significantly attenuated in mice with cardiac-specific overexpression of HMGB1 (HMGB1-Tg) compared with wild type (WT) -mice. HSPB1 levels after doxorubicin administration were significantly higher in HMGB1-Tg mice than in WT mice. Transfection with HMGB1 increased the expression of HSPB1 at both the protein and mRNA levels, and HMGB1 inhibited mitochondrial dysfunction and apoptosis after exposure of cardiomyocytes to doxorubicin. HSPB1 silencing abrogated the inhibitory effect of HMGB1 on cardiomyocyte apoptosis. Doxorubicin increased the binding of HMGB1 to heat shock factor 2 and enhanced heat shock element promoter activity. Moreover, HMGB1 overexpression greatly enhanced heat shock element promoter activity. Silencing of heat shock factor 2 attenuated HMGB1-dependent HSPB1 expression and abrogated the ability of HMGB1 to suppress cleaved caspase-3 accumulation after doxorubicin stimulation. CONCLUSIONS: We report the first in vivo and in vitro evidence that cardiac HMGB1 increases HSPB1 expression and attenuates cardiomyocyte apoptosis associated with doxorubicin-induced cardiomyopathy. Cardiac HMGB1 increases HSPB1 expression in cardiomyocytes in a heat shock factor 2-dependent manner.

A novel mouse model of aortic valve stenosis induced by direct wire injury.

OBJECTIVE: The response-to-tissue-injury theory is currently the favorite paradigm to investigate valve pathology. To the best of our knowledge, there are currently no in vivo valve injury models. There are few calcific aortic valve stenosis (AVS) models that develop hemodynamically significant stenosis. Here, we investigated the effect of direct mechanical injury on aortic valves in vivo and developed a novel mouse model of calcific AVS. APPROACH AND RESULTS: Aortic valve injury was created by inserting and moving a spring guidewire under echocardiographic guidance into the left ventricle of male C57/BL6 mice via right common carotid artery. Serial echocardiographic measurements revealed that aortic velocity was increased 1 week after injury and persistently increased until 16 weeks after injury. AVS mice showed a higher heart weight/body weight ratio and decreased left ventricular fractioning shortening 4 weeks after injury, compared with sham mice. We found remarkable proliferation of valve leaflets 4 weeks after injury. Proliferative valves showed increased production of reactive oxygen species and expression of inflammatory cytokines and osteochondrogenic factors. Alizarin red staining showed valvular calcification 12 weeks after injury. CONCLUSIONS: We report a novel calcific AVS model to support the response-to-tissue-injury theory. This model may be a valuable tool for analyzing the mechanism of AVS and assessing therapeutic options.

Midkine exacerbates pressure overload-induced cardiac remodeling.

Midkine is a multifunctional growth factor, and its serum levels are increased with the functional severity of heart failure. This study aimed to examine the role of midkine in heart failure pathogenesis. Midkine expression levels were increased in the kidney and lung after transverse aortic constriction (TAC) surgery, but not sufficiently increased in the heart. After TAC, phosphorylation of extracellular signal-regulated kinase1/2 and AKT, and the expression levels of foetal genes in the heart were considerably increased in transgenic mice with cardiac-specific overexpression of midkine (MK-Tg) compared with wild-type (WT) mice. MK-Tg mice showed more severe cardiac hypertrophy and dysfunction, and showed lower survival rate after TAC than WT mice. We conclude that midkine plays a critical role in cardiac hypertrophy and remodelling.

Impact of serum omentin-1 levels on cardiac prognosis in patients with heart failure.

BACKGROUND: Various adipokines are reported to be associated with the development of heart failure (HF) through insulin resistance and chronic inflammation. Omentin-1 is a novel adipokine and is associated with incident coronary artery disease. However, it remains unclear whether serum omentin-1 levels are associated with cardiac prognosis in patients with HF. METHODS: We measured serum omentin-1 levels at admission in 136 consecutive patients with HF, and 20 control subjects without signs of significant heart disease. We prospectively followed patients with HF to endpoints of cardiac death or re-hospitalization for worsening HF. RESULTS: Serum omentin-1 levels were markedly lower in HF patients with cardiac events compared with to without. The patients who were in New York Heart Association (NYHA) functional class IV showed significantly lower serum omentin-1 levels compared to those in class II and III, whereas serum omentin-1 levels did not correlate with serum brain natriuretic peptide levels (r = 0.217, P = 0.011). We divided the HF patients into three groups based on the tertiles of serum omentin-1 level (low T1, middle T2, and high T3). Multivariate Cox hazard analysis showed that the lowest serum omentin-1 level (T1) was independently associated with cardiac events after adjustment for confounding factors (hazard ratio 5.78, 95% confidence interval 1.20-12.79). We divided the HF patients into two groups according to the median serum omentin-1 levels. Kaplan-Meier analysis revealed that the patients with low serum omentin-1 levels had a higher risk of cardiac events compared with those with high serum omentin-1 levels (log-rank test p < 0.001). CONCLUSION: Decreased serum omentin-1 levels were associated with a poor cardiac outcome in patients with HF.

Diacylglycerol kinase α exacerbates cardiac injury after ischemia/reperfusion.

Early coronary reperfusion of the ischemic myocardium is a desired therapeutic goal for the preservation of myocardial function. However, reperfusion itself causes additional myocardium injuries. Activation of the diacylglycerol-protein kinase C (DAG-PKC) cascade has been implicated in the cardioprotective effects occurring after ischemia/reperfusion (I/R). DAG kinase (DGK) controls cellular DAG levels by converting DAG to phosphatidic acid, and may act as an endogenous regulator of DAG-PKC signaling. In the present study, we examined the functional role of DGKα in cardiac injury after I/R in in vivo mouse hearts. We generated transgenic mice with cardiac-specific overexpression of DGKα (DGKα-TG). The left anterior descending coronary artery was transiently occluded for 20 min and reperfused for 24 h in DGKα-TG mice and wild-type littermate (WT) mice. The levels of phosphorylation activity of PKCε, extracellular-signal regulated kinase (ERK) 1/2, and p70 ribosomal S6 kinase (p70S6K) were increased after I/R in WT mouse hearts. However, in DGKα-TG mice, activation of PKCε, ERK1/2, and p70S6K was attenuated compared to WT mice. After 24 h, Evans blue/triphenyltetrazolium chloride double staining and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining showed that DGKα-TG mice had significantly larger myocardial infarctions and larger numbers of TUNEL-positive cardiomyocytes than WT mice. Echocardiography and cardiac catheterization revealed that left ventricular systolic function was more severely depressed in DGKα-TG mice than in WT mice after I/R. These findings suggest that DGKα exacerbates I/R injury by inhibiting the cardioprotective effects of PKCε, ERK1/2, and p70S6K activation.

Combined assessment of myocardial damage and electrical disturbance in chronic heart failure.

AIM: To investigate feasibility of combined assessment of biochemical and electrophysiological myocardial impairment markers risk-stratifying patients with chronic heart failure (CHF). METHODS: Serum levels of heart-type fatty acid binding protein (H-FABP) as a marker of ongoing myocardial damage and QRS duration on electrocardiogram were measured at admission in 322 consecutive patients with CHF. A prolonged QRS duration was defined as 120 ms or longer. The cut-off value for H-FABP level (4.5 ng/mL) was determined from a previous study. Patients were prospectively followed during a median follow up period of 534 d. The primary endpoint was cardiac deaths and rehospitalization for worsening CHF. RESULTS: There were 117 primary events, including 27 cardiac deaths and 90 rehospitalizations. Patients were stratified into four groups according to H-FABP level and QRS duration (≥ 120 ms). Multivariate analysis demonstrated that high H-FABP levels [hazard ratio (HR) = 1.745, P = 0.021] and QRS prolongation (HR 1.612, P = 0.0258) were independent predictors of cardiac events. Kaplan-Meier analysis demonstrated that the combination of high H-FABP levels and QRS prolongation could be used to reliably stratify patients at high risk for cardiac events (log rank test P < 0.0001). CONCLUSION: Combined assessment of myocardial damage and electrical disturbance can be used to risk-stratify patients with CHF.

Impact of restrictive lung disorder on cardiovascular mortality in a general population: The Yamagata (Takahata) study.

BACKGROUND: Obstructive lung disorder (OLD) is known to be associated with cardiovascular disease. However, the impact of restrictive lung disorder (RLD) on cardiovascular mortality has not been fully investigated in the apparently healthy general population. OBJECTIVES: To clarify whether RLD is associated with cardiovascular mortality in the general population. METHODS AND RESULTS: This community-based cohort study included 3247 subjects who participated in an annual health check in Takahata. We performed spirometry in registered subjects and found that 194 (6%) had RLD, 262 (8%) had OLD, and 73 (2%) had RLD and OLD (Mixed). During a 10-year follow-up, there were 210 deaths, including 57 cardiovascular deaths. Cardiovascular mortality of subjects with RLD was significantly higher than that of subjects with normal lung function. Although the subjects with RLD were younger, comprised fewer smokers, and were more likely to be female than those with OLD, cardiovascular mortality of subjects with RLD was comparable to that of subjects with OLD. Subjects with RLD had a higher prevalence of atrial fibrillation (AF) than those with OLD, and the prevalence of AF was increased with advanced severity of RLD. Multivariate Cox proportional hazard analysis revealed that RLD was an independent predictor of cardiovascular death (hazard ratio 2.61, 95% confidence interval, 1.22-5.21) after adjustment for confounders, but OLD was not. The net reclassification improvement and integrated discrimination improvement were significantly increased by the addition of RLD to conventional cardiovascular risk factors. CONCLUSION: The presence of RLD was associated with cardiovascular mortality in the general population.

Midkine Deteriorates Cardiac Remodeling via Epidermal Growth Factor Receptor Signaling in Chronic Kidney Disease.

In chronic kidney disease, activation of the epidermal growth factor receptor (EGFR) leads to cardiac hypertrophy, which affects morbidity and mortality. In patients with renal insufficiency and heart failure, the expression of midkine, a heparin-binding growth factor, is increased. Therefore, we investigated the association between midkine and EGFR in the induction of cardiac hypertrophy and dysfunction in chronic kidney disease. We performed subtotal nephrectomies in midkine-knockout mice and wild-type mice. We found that subtotal nephrectomy-induced cardiac hypertrophy and phosphorylation of extracellular signal-regulated kinase 1/2 and AKT were attenuated in midkine-knockout mice compared with wild-type mice. An antiphosphotyrosine receptor antibody array was used to demonstrate that EGFR phosphorylation in the heart was also lower in midkine-knockout mice than in wild-type mice. Midkine induced EGFR, extracellular signal-regulated kinase 1/2, and AKT phosphorylation and led to hypertrophy in neonatal rat cardiomyocytes. Pretreatment with EGFR inhibitors or EGFR silencing suppressed midkine-stimulated phosphorylation of extracellular signal-regulated kinase 1/2 and AKT, induction of fetal cardiac gene expression, and hypertrophy in cardiomyocytes. To confirm the association between midkine and EGFR in vivo, mice subjected to subtotal nephrectomy were treated with the EGFR inhibitor gefitinib. Gefitinib treatment attenuated subtotal nephrectomy-induced cardiac hypertrophy. These results indicate that midkine might be a key mediator of cardiorenal interactions through EGFR activation, which plays a crucial role in cardiac hypertrophy in chronic kidney disease.

HECT-Type Ubiquitin E3 Ligase ITCH Interacts With Thioredoxin-Interacting Protein and Ameliorates Reactive Oxygen Species-Induced Cardiotoxicity.

BACKGROUND: The homologous to the E6-AP carboxyl terminus (HECT)-type ubiquitin E3 ligase ITCH is an enzyme that plays a pivotal role in posttranslational modification by ubiquitin proteasomal protein degradation. Thioredoxin-interacting protein (TXNIP) is a negative regulator of the thioredoxin system and an endogenous reactive oxygen species scavenger. In the present study, we focused on the functional role of ubiquitin E3 ligase ITCH and its interaction with TXNIP to elucidate the mechanism of cardiotoxicity induced by reactive oxygen species, such as doxorubicin and hydrogen peroxide. METHODS AND RESULTS: Protein interaction between TXNIP and ITCH in cardiomyocyte was confirmed by immunoprecipitation assays. Overexpression of ITCH increased proteasomal TXNIP degradation and augmented thioredoxin activity, leading to inhibition of reactive oxygen species generation, p38 MAPK, p53, and subsequent intrinsic pathway cardiomyocyte apoptosis in reactive oxygen species-induced cardiotoxicity. Conversely, knockdown of ITCH using small interfering RNA inhibited TXNIP degradation and resulted in a subsequent increase in cardiomyocyte apoptosis. Next, we generated a transgenic mouse with cardiac-specific overexpression of ITCH, called the ITCH-Tg mouse. The expression level of TXNIP in the myocardium in ITCH-Tg mice was significantly lower than WT littermates. In ITCH-Tg mice, cardiac dysfunction and remodeling were restored compared with WT littermates after doxorubicin injection and myocardial infarction surgery. Kaplan-Meier analysis revealed that ITCH-Tg mice had a higher survival rate than WT littermates after doxorubicin injection and myocardial infarction surgery. CONCLUSION: We demonstrated, for the first time, that ITCH targets TXNIP for ubiquitin-proteasome degradation in cardiomyocytes and ameliorates reactive oxygen species-induced cardiotoxicity through the thioredoxin system.

The role of macrophage transcription factor MafB in atherosclerotic plaque stability.

BACKGROUND AND AIMS: Macrophage differentiation is associated with the development of atherosclerosis and plaque vulnerability and is regulated by transcription factor MafB. We previously reported that MafB attenuates macrophage apoptosis, which is associated with atherosclerotic plaque instability. The aim of this study was to elucidate the role of MafB in the progression of atherosclerotic plaque. METHODS: We generated macrophage-specific dominant-negative (DN) MafB transgenic mice and intercrossed DN-MafB mice with apolipoprotein E (ApoE) knockout (KO) mice. RESULTS: There was no significant difference in advanced atherosclerotic lesion area between DN-MafB/ApoE KO mice and littermate control ApoE KO mice 9 weeks after high-cholesterol diet. However, DN-MafB/ApoE KO mice showed significantly larger necrotic cores and lower collagen content in atherosclerotic plaques than ApoE KO mice. Although there was no difference in intraplaque macrophage infiltration and efferocytosis, DN-MafB/ApoE KO mice showed significantly more apoptotic macrophages at the plaque edges than did ApoE KO mice. Real-time PCR analysis revealed that peritoneal macrophages of DN-MafB/ApoE KO mice had a greater increase in matrix metalloproteinase-9 and mRNA expression of inflammatory/M1 macrophage markers (tissue necrosis factor-α, interleukin-6, CD11c, and p47phox) after lipopolysaccharide stimulation than those of ApoE KO mice. CONCLUSION: Macrophage-specific inhibition of MafB may destabilize atherosclerotic plaques in advanced lesions.

Sarcopenia evaluated by fat-free mass index is an important prognostic factor in patients with chronic heart failure.

BACKGROUND AND AIM: Chronic heart failure (CHF) is a major cause of morbidity and mortality, and cardiac cachexia and sarcopenia are serious complications associated with weight loss and increased catabolism. Fat-free mass index (FFMI) is an indicator of resting energy expenditure and is used for the clinical diagnosis of sarcopenia. In the present study, we investigated the impact of sarcopenia, as evaluated by FFMI, on cardiac prognosis in patients with CHF. METHODS AND RESULTS: We calculated FFMI in 267 CHF patients who were prospectively followed until they died due to cardiac event, or until they were re-hospitalized. Fat-free mass (FFM) was estimated by the formula [FFM (kg)=7.38+0.02908×urinary creatinine (mg/day)] and normalized by the square of the patient's height in meters to calculate FFMI. During the follow-up periods, there were 83 cardiac events, including 19 cardiac deaths. FFMI was lower in patients with cardiac events than in those without (17.0 kg/m(2) vs. 17.6 kg/m(2), P=0.045). Multivariate Cox hazard analysis revealed that decreased FFMI was associated with an unfavorable outcome (adjusted hazard ratio 0.68, 95% confidence interval 0.47-0.98). The patients were divided into two groups according to their median FFMI. The Kaplan-Meier analysis revealed that significantly higher cardiac event rate was observed in the low-FFMI group (log-rank test, P=0.017). CONCLUSIONS: Decreased FFMI was associated with an unfavorable prognosis in patients with CHF.

Left atrial appendage dysfunction in acute cerebral embolism patients with sinus rhythm: correlation with pulse wave tissue Doppler imaging.

To evaluate left atrial appendage (LAA) dysfunction using left atrial pulse-wave tissue Doppler imaging (PW-TDI) in acute cerebral embolism (ACE) patients with sinus rhythm (SR), transthoracic (TTE) and transesophageal echocardiograhy (TEE) were performed in 60 consecutive patients with SR without obvious left ventricular dysfunction within 2 weeks after ACE. Two groups were identified: LAA dysfunction [LAA emptying peak flow velocity (LAA-eV) <0.55 m/s, n = 20, age 65 ± 10 years] and without LAA dysfunction (LAA-eV ≥ 0.55 m/s, n = 40, age 64 ± 10 years) on TEE. Left atrial wall motion velocity (WMV) was obtained from PW-TDI, with the sample volume placed at the left atrial anterior wall adjacent to ascending aortic inferior wall from the long axis view on TTE. WMVs showed triphasic waves: after the P wave (La') during systole (Ls'), and during early diastole. La' and Ls' were significantly lower in the group with versus without LAA dysfunction (4.9 ± 1.4 vs. 7.7 ± 1.8 cm/s, p < 0.0001; 5.3 ± 2.0 vs. 6.7 ± 1.9 cm/s, p < 0.001, respectively) and prevalence of paroxysmal atrial fibrillation, left atrial volume index, and serum levels of brain natriuretic peptide were significantly higher (60 vs. 15 %, p < 0.001; 32 ± 13 vs. 24 ± 13 ml/m(2), p < 0.05; 174 ± 279 vs. 48 ± 68 pg/ml, p < 0.01, respectively). La' was an independent predictor of LAA dysfunction (OR 0.380, 95 % CI 0.156-0.925, p < 0.05), and was significantly correlated with LAA-eV (r = 0.594, p < 0.0001) and LAA fractional area change (r = 0.682, p < 0.0001). The optimal cut-off value for LAA-eV < 0.55 m/s was 5.5 cm/s (sensitivity 83 %, specificity 88 %). La' is a useful and convenient strong predictor of LAA dysfunction in ACE patients with SR.

The obesity paradox is not observed in chronic heart failure patients with metabolic syndrome.

INTRODUCTION: Although being overweight or obese is a risk factor for cardiovascular disease, obese subjects often live longer than their lean peers, and this is known as the obesity paradox. We investigated the impact of obesity on cardiac prognosis in chronic heart failure (CHF) patients, with or without metabolic syndrome. DESIGN AND METHODS: We divided 374 consecutive CHF patients into two groups according to their mean body mass index (BMI) and prospectively followed them for 2 years. RESULTS: There were 126 cardiac events, including 32 cardiac deaths and 94 re-hospitalizations. Kaplan-Meier analysis revealed a significantly lower cardiac event rate in the higher BMI group (log-rank test P < 0.001) in all patients and those patients without metabolic syndrome. There was no association between BMI and cardiac prognosis in patients with metabolic syndrome. Cox hazard analysis revealed that a higher BMI was associated with favorable cardiac outcomes in all patients and patients without metabolic syndrome, after adjusting for confounding factors. However, this finding did not extend to patients with metabolic syndrome. CONCLUSIONS: The advantages of obesity are not found in CHF patients with metabolic syndrome.

Association of renal tubular damage with cardio-renal anemia syndrome in patients with heart failure.

BACKGROUND: Cardio-renal anemia syndrome (CRAS) has begun to gather attention as a vicious circle since chronic heart failure (CHF), chronic kidney disease (CKD), and anemia are all able to be caused and exacerbated by each other. However, it remains unclear whether renal tubular damage (RTD), another type of kidney dysfunction, is associated with this vicious circle. The aim of the present study was to assess the association of RTD with CRAS in patients with CHF. METHODS AND RESULTS: We included 300 consecutive patients with CHF. RTD was defined as a urinary ß2-microglobulin to creatinine ratio ≥ 300 µg/g. Patients with RTD had lower serum iron and higher levels of high sensitivity C-reactive protein than those without it. Multivariate logistic analysis showed that RTD was closely associated with anemia in patients with CHF, after adjustment for confounding factors. During a median period of 1,098 days, there were 86 cardiac events, including 14 cardiac deaths and 72 re-hospitalizations for worsening heart failure. Net reclassification improvement was significantly improved by addition of RTD to the model including age, New York Heart Association functional class, brain natriuretic peptide, anemia, and CKD. All patients were divided into 3 groups: CRAS+RTD group, CRAS group, and control group. Kaplan-Meier analysis demonstrated that CRAS+RTD had the greatest risk in patients with CHF. CONCLUSIONS: RTD was associated with normocytic anemia, accompanying iron deficiency and inflammation. RTD added prognostic information to conventional CRAS, suggesting the importance of RTD in cardio-renal anemia interaction.

Association of plasma thioredoxin-1 with renal tubular damage and cardiac prognosis in patients with chronic heart failure.

BACKGROUND: Thioredoxin-1 (Trx-1) is an abundant 12.5 kDa redox protein expressed in almost all eukaryotic cells that protect against the development of heart failure and kidney dysfunction. Plasma Trx-1 levels are considered as a reliable marker for oxidative stress. However, it remains to be determined whether plasma Trx-1 levels can predict cardiac prognosis in patients with chronic heart failure (CHF). METHODS AND RESULTS: We measured plasma Trx-1 levels and urinary ß2-microglobulin-creatinine ratio (UBCR), a marker for renal tubular damage, in 156 consecutive patients with CHF and 17 control subjects. The patients were prospectively followed for a median follow-up period of 627 days and 46 cardiac events were observed. The patients with cardiac events had significantly higher plasma Trx-1 levels and UBCR levels than the cardiac event-free patients. Multivariate Cox proportional hazard analysis revealed that an elevated Trx-1 level was independently associated with poor outcome in patients with CHF after adjustment for confounding factors (hazard ratio, 1.74; 95% confidence interval, 1.33-2.29; p < 0.0001). UBCR was increased with higher plasma Trx-1 levels. Kaplan-Meier analysis demonstrated that the highest Trx-1 tertile was associated with the highest risk of cardiac events. CONCLUSION: Plasma Trx-1 level was associated with renal tubular damage and cardiac prognosis, suggesting that it could be a useful marker to identify patients at high risk for comorbid heart failure and renal tubular damage.

Prognostic value of myocardial damage markers in patients with chronic heart failure with atrial fibrillation.

OBJECTIVE: The aim of the present study was to examine the relationship between myocardial damage caused by atrial fibrillation (AF) and subsequent cardiovascular events in AF patients with chronic heart failure (CHF). METHODS AND RESULTS: We measured the serum levels of heart-type fatty acid binding protein (H-FABP) and high-sensitivity troponin T in 402 consecutive CHF patients with chronic AF (CHF-AF, n=201) or sinus rhythm (CHF-SR, n=201). The patients with CHF-AF had higher H-FABP and troponin T levels than those with CHF-SR. In order to examine the prognostic value of myocardial damage markers in CHF-AF and CHF-SR patients, we followed the above patients and analyzed their clinical outcomes. A multivariate Cox proportional hazard analysis revealed that both the serum H-FABP and troponin T levels independently predicted subsequent cardiovascular events. A Kaplan-Meier analysis demonstrated that the rate of cardiovascular events was higher in the patients with elevated H-FABP and troponin T levels. The optimal cut-off values for the myocardial damage markers of cardiovascular events were higher in the CHF-AF patients than in the CHF-SR patients (H-FABP, 5.4 vs. 4.6 ng/mL and troponin T, 0.030 vs. 0.013 ng/mL). CONCLUSION: Myocardial damage advances in association with the presence of AF and is associated with subsequent cardiovascular events in both CHF-AF and CHF-SR patients. In this study, the cut-off values for the myocardial damage markers were higher in the CHF-AF patients than in the CHF-SR patients.

Electrocardiographic left ventricular hypertrophy Cornell product is a feasible predictor of cardiac prognosis in patients with chronic heart failure.

BACKGROUND: Left ventricular hypertrophy (LVH) is an independent risk factor for cardiovascular disease and is associated with heart failure development. The Cornell product is an easily measured electrocardiographic parameter for assessing LVH. However, it is undetermined whether the Cornell product can predict the cardiac prognosis of chronic heart failure (CHF) patients. METHODS AND RESULTS: We performed standard 12-lead electrocardiography and calculated the Cornell product in 432 consecutive CHF patients. LV geometry was assessed as normal, concentric remodeling, concentric or eccentric hypertrophy. The Cornell product was significantly higher in patients with eccentric hypertrophy, and increased with advancing New York Heart Association functional class. During a median follow-up of 660 days, there were 121 cardiac events including 36 cardiac deaths and 85 re-hospitalizations for worsening heart failure. Multivariate Cox proportional hazard analysis showed that the Cornell product was an independent predictor of cardiac events in CHF patients. Patients in the highest quartile of Cornell product had a higher prevalence of LV eccentric hypertrophy (22, 29, 33 and 67 % for quartiles one through four). Kaplan-Meier analysis demonstrated that the highest quartile of Cornell product was associated with the greatest risk among CHF patients. CONCLUSION: The Cornell product is associated with LV eccentric hypertrophy and can be used to predict future cardiac events in CHF patients.

Association of heart-type fatty acid-binding protein with cardiovascular risk factors and all-cause mortality in the general population: the Takahata study.

BACKGROUND: Despite many recent advances in medicine, preventing the development of cardiovascular diseases remains a challenge. Heart-type fatty acid-binding protein (H-FABP) is a marker of ongoing myocardial damage and has been reported to be a useful indicator for future cardiovascular events. However, it remains to be determined whether H-FABP can predict all-cause and cardiovascular deaths in the general population. METHODS AND RESULTS: This longitudinal cohort study included 3,503 subjects who participated in a community-based health checkup with a 7-year follow-up. Serum H-FABP was measured in registered subjects. The results demonstrated that higher H-FABP levels were associated with increasing numbers of cardiovascular risk factors, including hypertension, diabetes mellitus, obesity, and metabolic syndrome. There were 158 deaths during the follow-up period, including 50 cardiovascular deaths. Deceased subjects had higher H-FABP levels compared to surviving subjects. Multivariate Cox proportional hazard regression analysis revealed that H-FABP is an independent predictor of all-cause and cardiovascular deaths after adjustments for confounding factors. Subjects were divided into four quartiles according to H-FABP level, and Kaplan-Meier analysis demonstrated that the highest H-FABP quartile was associated with the greatest risks for all-cause and cardiovascular deaths. Net reclassification index and integrated discrimination index were significantly increased by addition of H-FABP to cardiovascular risk factors. CONCLUSIONS: H-FABP level was increased in association with greater numbers of cardiovascular risk factors and was an independent risk factor for all-cause and cardiovascular deaths. H-FABP could be a useful indicator for the early identification of high-risk subjects in the general population.