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

AbstractBackgroundThioredoxin-1 (Trx-1) is an abundant 12.5kDa 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 resultsWe measured plasma Trx-1 levels and urinary β2-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.ConclusionPlasma 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

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

AbstractAimsApoptosis 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 resultsMitochondrial 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.ConclusionsWe 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

Synthesis, Structure, and Characterization of In10-Containing Open-Wells–Dawson Polyoxometalate

We have successfully synthesized K17{[{KIn2(μ-OH)2}(α,α-Si2W18O66)]2[In6(μ-OH)13(H2O)8]}·35H2O (potassium salt of In10-open), an open-Wells–Dawson polyoxometalate (POM) containing ten indium metal atoms. This novel compound was characterized by X-ray crystallography, 29Si NMR, FTIR, complete elemental analysis, and TG/DTA. X-ray crystallography results for {[{KIn2(μ-OH)2}(α,α-Si2W18O66)]2[In6(μ-OH)13(H2O)8]}17− (In10-open) revealed two open-Wells–Dawson units containing two In3+ ions and a K+ ion, [{KIn2(μ-OH)2}(α,α-Si2W18O66)]11−, connected by an In6-hydroxide cluster moiety, [In6(μ-OH)13(H2O)8]5+. In10-open is the first example of an open-Wells–Dawson POM containing a fifth-period element. Moreover, to the best of our knowledge, it exhibits the highest nuclearity among the indium-containing POMs reported to date

Heart-type fatty acid binding protein and high-sensitivity troponin T are myocardial damage markers that could predict adverse clinical outcomes in patients with peripheral artery disease

Background: Despite many recent advances in endovascular therapy (EVT), peripheral artery disease (PAD) is an increasing health problem with high mortality. Heart-type fatty acid-binding protein (H-FABP) and high-sensitivity troponin T (hsTnT) are markers of ongoing myocardial damage and have been reported to be useful indicators of future cardiovascular events. However, it remains to be determined whether H-FABP and hsTnT can predict adverse clinical outcomes in patients with PAD. Methods and results: We enrolled 208 de novo PAD patients who underwent EVT. Serum H-FABP and hsTnT were measured in all patients before EVT. During the median follow-up period of 694 days, there were 40 major adverse cardiovascular and cerebrovascular events (MACCEs) including all-cause deaths, and re-hospitalizations due to cardiovascular and cerebrovascular diseases and amputations. H-FABP and hsTnT were found to be higher in patients with critical limb ischemia (CLI) compared to those without this condition. Multivariate Cox proportional hazard regression analysis revealed that both H-FABP and hsTnT were independent predictors of MACCEs after adjustment for confounding factors. Kaplan–Meier analysis demonstrated that patients in the highest tertile according to H-FABP levels, as well as those in the highest hsTnT tertile, were at greatest risk for MACCEs. The net reclassification index was significantly improved by the addition of H-FABP as well as the addition of hsTnT to traditional risk factors. Conclusion: The myocardial damage markers H-FABP and hsTnT were increased in PAD patients with CLI and could predict MACCEs in PAD patients

Increased epicardial adipose tissue volume predicts insulin resistance and coronary artery disease in non-obese subjects without metabolic syndrome

Background/objectives: Epicardial adipose tissue (EAT) reportedly secretes various adipokines that evoke insulin resistance in patients with obesity or metabolic syndrome. However, it remains unclear whether EAT also plays a role in the development of insulin resistance in lean subjects. The purpose of this study was to investigate the impact of EAT volume on the presence of insulin resistance and coronary artery disease in non-obese subjects without metabolic syndrome. Methods: We prospectively studied 624 consecutive patients who underwent multidetector computed tomography (MDCT) and measured EAT volume between January 2009 and June 2011. Obesity was defined as body mass index ≥25 kg/m2, and metabolic syndrome was defined according to the National Cholesterol Education Program Adult Treatment Panel III criteria. After we excluded 385 patients with obesity or metabolic syndrome, 239 patients were enrolled in the present study. Results: There were 102 (42.7%) subjects with insulin resistance (homeostasis model assessment ratio [HOMA-R] >2.5) and 88 (36.8%) subjects with coronary artery disease. After adjusting for age, gender, and body mass index, increased EAT volume (≥35 ml mean EAT volume) was independently associated with insulin resistance (odds ratio 2.6, 95% confidence interval 1.5–4.8). Furthermore, increased EAT volume was also associated with coronary artery disease (odds ratio 1.9, 95% confidence interval 1.0–3.6) after adjustment of age, gender, body mass index, and the presence of insulin resistance. Conclusion: Increased EAT volume may play a key role in the development of insulin resistance and coronary artery disease, even in non-obese subjects without metabolic syndrome

Association of the Aspartate Aminotransferase to Alanine Aminotransferase Ratio with BNP Level and Cardiovascular Mortality in the General Population: The Yamagata Study 10-Year Follow-Up

Background. Early identification of high risk subjects for cardiovascular disease in health check-up is still unmet medical need. Cardiovascular disease is characterized by the superior increase in aspartate aminotransferase (AST) to alanine aminotransferase (ALT). However, the association of AST/ALT ratio with brain natriuretic peptide (BNP) levels and cardiovascular mortality remains unclear in the general population. Methods and Results. This longitudinal cohort study included 3,494 Japanese subjects who participated in a community-based health check-up, with a 10-year follow-up. The AST/ALT ratio increased with increasing BNP levels. And multivariate logistic analysis showed that the AST/ALT ratio was significantly associated with a high BNP (≥100 pg/mL). There were 250 all-cause deaths including 79 cardiovascular deaths. Multivariate Cox proportional hazard regression analysis revealed that a high AST/ALT ratio (>90 percentile) was an independent predictor of all-cause and cardiovascular mortality after adjustment for confounding factors. Kaplan-Meier analysis demonstrated that cardiovascular mortality was higher in subjects with a high AST/ALT ratio than in those without. Conclusions. The AST/ALT ratio was associated with an increase in BNP and was predictive of cardiovascular mortality in a general population. Measuring the AST/ALT ratio during routine health check-ups may be a simple and cost-effective marker for cardiovascular mortality