Heart failure: mechanisms for progression 781 of circulating proBNP1-108 with our immunodepletion process, we are now able to assess the remaining "true" BNP and NT-proBNP molecules and evaluate their clinical relevance.

Purpose: Although indoxyl sulfate (IS), one of a uremic toxin, is suggested be a novel prognostic marker in patients with chronic kidney disease, its clinical characteristics has remained uncertain in patients with heart failure (HF) and preserved renal function (RF). We aimed to determine the clinical characteristics of IS in patients with HF. Methods: We studied 726 participants without overt HF and renal disease from a community-living, and prospectively enrolled 154 consecutive hospitalized acute and chronic heart failure (CHF) patients with preserved RF (eGFR >40 ml/min/1.73 m2) (24 acute HF patients and 130 CHF patients, respectively). We also performed right heart catheterization (RHC) in CHF patients (n = 105). Results: The plasma IS (PIS) levels in patients with CHF were significantly higher than that of healthy population matched with gender and eGFR of HF patients (0.79 [25th to 75th IQR: 0.45-1.19] μg/ml vs. 0.07 [0.04-0.11] μg/ml, respectively, p<0.001) (Figure A.), PIS levels were significantly correlated with right atrial pressure (r = 0.19, p = 0.028) and cardiac output (r = -0.30, p<0.001) in RHC study. Echocardiography revealed that LV mass index in High IS group (≥0.79 μg/ml) was significantly higher than that of Low IS group (<0.79 μg/ml) (Figure B.) in CHF patients. Interestingly, of 24 acute HF patients, PIS levels at discharge were significantly elevated compared with the baseline, as preliminary data (0.67 [0.36-0.90] μg/ml to 0.94 [0.76-1.68] μg/ml, p = 0.005) (Figure C). Figure 1 Figure 1 Conclusions: The plasma IS levels were suggested to be related to renal perfusion pressure with the prevalence of cardiac hypertrophy. From the change of IS levels during HF hospitalization, IS might be a novel marker to predict remote renal and cardiac status in patients with heart failure.

The ubiquitin–proteasome system contributes to regulation of apoptosis degrading apoptosis-regulatory proteins. Marked accumulation of ubiquitinated proteins in cardiomyocytes of human failing hearts suggested impaired ubiquitin–proteasome system in heart failure. Since cardiomyocyte apoptosis contributes to the progression of cardiac dysfunction in pressure-overloaded hearts, we investigated the role of ubiquitin–proteasome system in such conditions. We found that proteasome activities already depressed before the onset of cardiac dysfunction in pressure-overloaded hearts of mice. Cardiomyocyte apoptosis was observed along with depression of proteasome activities and elevation of proapoptotic/antiapoptotic protein ratio in failing hearts. In cultured cardiomyocytes, pharmacological inhibition of proteasome accumulated proapoptotic proteins such as p53 and Bax. Gene silencing of these proapoptotic proteins by RNA interference prevented the accumulation of respective proteins and attenuated cardiomyocyte apoptosis induced by proteasome inhibition. We conclude that depression of proteasome activities contributes to cardiac dysfunction resulting from cardiomyocyte apoptosis through accumulation of proapoptotic proteins by impaired degradation.

OBJECTIVES We investigated the effects of erythropoietin (EPO) on neovascularization and cardiac function after myocardial infarction (MI).BACKGROUND Erythropoietin exerts antiapoptotic effects and mobilizes endothelial progenitor cells (EPCs).METHODS We intravenously administered EPO (1,000 IU/kg) immediately [EPO(0) group], 6 h [EPO(6h) group], or 1 week [EPO(1wk) group] after the permanent ligation of the coronary artery in dogs. Control animals received saline immediately after the ligation.RESULTS The infarct size 6 h after MI was significantly smaller in the EPO(0) group than in the control group (61.5 +/- 6.0% vs. 22.9 +/- 2.2%). One week after MT, the circulating CD34-positive mononuclear cell numbers in both the EPO(0) and the EPO(6h) groups were significantly higher than in the control group. In the ischemic region, the capillary density and myocardial blood flow 4 weeks after MI was significantly higher in both the EPO(0) and the EPO(6h) groups than in the control group. Four weeks after MI, left ventricular (LV) ejection fraction in the EPO(6h) (48.6 +/- 1.9%) group was significantly higher than that in either the control (41.9 +/- 0.9%) or the EPO(1wk) (42.6 +/- 1.2%) group but significantly lower than that in the EPO(0) group (56.1 +/- 2.3%). The LV end-diastolic pressure 4 weeks after MI in both the EPO(0) and the EPO(6h) groups was significantly lower than either the control or the EPO(1wk) group. Hematologic parameters did not differ among the groups.CONCLUSIONS In addition to its acute infarct size-limiting effect, EPO enhances neovascularization, likely via EPC mobilization, and improves cardiac dysfunction in the chronic phase, although it has time-window limitations.

Objective: The effects of long-acting calcium channel blockers (CCBs) on pressure overload-induced cardiac remodeling are seldom studied in animals. We evaluated the effects of benidipine, a long-acting CCB, on cardiac remodeling.Methods: Rat neonatal cardiac myocytes were used to examine the influence of benidipine on protein synthesis. Cardiac remodeling was induced in C5 7 B6/J mice by transverse aortic constriction (TAC). Then the effects of benidipine (10 mg/kg/d) were assessed on myocardial hypertrophy and heart failure, cardiac histology, and gene expression.Results: Benidipine significantly inhibited protein synthesis by cardiac myocytes stimulated with phenylephrine (PE), and this effect was partially abolished by cotreatment with a nitric oxide synthase (NOS) inhibitor [N(G)-nitro-L-arginine methylester (L-NAME)]. Four weeks after the onset of pressure overload, benidipine therapy potently inhibited cardiac hypertrophy and prevented heart failure. The heart to body weight ratio was 6.89 +/- 0.48 mg/g in treated mice vs. 8.76 +/- 0.33 mg/g in untreated mice (P<0.01), and the lung to body weight ratio was 7.39 +/- 0.93 mg/g vs. 10.53 +/- 0.99 mg/g, respectively (P<0.05). Left ventricular fractional shortening (LVFS) was improved on echocardiography. Plasma NO levels were increased, while B type natriuretic peptide, protein inhibitor of neuronal NOS, and procollagen IV alpha were down-regulated in benidipine-treated mice.Conclusion: These results indicate that benidipine inhibits cardiac remodeling due to pressure overload at least partly by acting on the nitric oxide signaling pathway. (C) 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

The opening of mitochondrial ATP-sensitive K+ (mitoK(ATP)) channels triggers or mediates the infarct size (IS)-limiting effect of ischemic preconditioning (IP). Because ecto-5'-nucleotidase related to IP is activated by PKC, we tested whether the opening of mitoK(ATP) channels activates PKC and contributes to either activation of ecto-5'-nucleotidase or IS-limiting effect. In dogs, IP procedure decreased IS and activated ecto-5'-nucleotidase, both of which were mimicked by transient exposure to either cromakalim or diazoxide, and these effects were blunted by either GF109203X (a PKC inhibitor) or 5-hydroxydecanoate (a mitoK(ATP) channel blocker), but not by HMR-1098 (a surface sarcolenmal K(ATP) channel blocker). Either cromakalim or diazoxide activated both PKC and ecto-5'-nucleotidase, which was blunted by either GF109203X or 5-hydroxydecanoate, but not by HMR-1098. We concluded that the opening of mitoK(ATP) channels contributes to either activation of ecto-5'-nucleotidase or the infarct size-limiting effect via activation of PKC in canine hearts.

Rapid nongenomic actions of aldosterone independent of mineralocorticoid receptors (MRs) on vascular tone are divergent. Until now, the rapid nongenomic actions of aldosterone on vascular tone of coronary artery and cardiac function in the in vivo ischemic hearts were not still fully estimated. Furthermore, although aldosterone can modulate protein kinase C (PKC) activity, there is no clear consensus whether PKC is involved in the nongenomic actions of aldosterone on the ischemic hearts. In open chest dogs, the selective infusion of aldosterone into the left anterior descending coronary artery (LAD) reduced coronary blood flow (CBF) in the nonischemic hearts in a dose-dependent manner. Also, in the ischemic state that CBF was decreased to 33% of the baseline, the intracoronary administration of aldosterone (0.1 nmol/L) rapidly decreased CBF (37.4±3.8 to 19.3±5.2 mL/100 g/min; P<0.05), along with decreases in fractional shortening (FS) (8.4±0.7 to 5.4±0.4%; P<0.05) and lactate extraction rate (LER) (−31.7±2.9 to −41.4±3.7%; P<0.05). The decrease in CBF was reproduced by the infusion of bovine serum albumin-conjugated aldosterone. Notably, these aldosterone-induced deteriorations of myocardial contractile and metabolic functions were blunted by the co-administration of GF109203X, an inhibitor of PKC, but not spironolactone. In addition, aldosterone activated vascular PKC. These results indicate that aldosterone nongenomically induces vasoconstriction via PKC-dependent pathways possibly through membrane receptors, which leads to the worsening of the cardiac contractile and metabolic functions in the ischemic hearts. Elevation of plasma or cardiac aldosterone levels may be deleterious to ischemic heart disease through its nongenomic effects.