BackgroundThe efficacy of pharmacological interventions to prevent sudden arrhythmic death in patients with chronic heart failure remains limited. Evidence now suggests increased ventricular expression of hyperpolarization‐activated cation (HCN) channels in hypertrophied and failing hearts contributes to their arrythmicity. Still, the role of induced HCN channel expression in the enhanced arrhythmicity associated with heart failure and the capacity of HCN channel blockade to prevent lethal arrhythmias remains undetermined.Methods and ResultsWe examined the effects of ivabradine, a specific HCN channel blocker, on survival and arrhythmicity in transgenic mice (dnNRSF‐Tg) expressing a cardiac‐specific dominant‐negative form of neuron‐restrictive silencer factor, a useful mouse model of dilated cardiomyopathy leading to sudden death. Ivabradine (7 mg/kg per day orally) significantly reduced ventricular tachyarrhythmias and improved survival among dnNRSF‐Tg mice while having no significant effect on heart rate or cardiac structure or function. Ivabradine most likely prevented the increase in automaticity otherwise seen in dnNRSF‐Tg ventricular myocytes. Moreover, cardiac‐specific overexpression of HCN2 in mice (HCN2‐Tg) made hearts highly susceptible to arrhythmias induced by chronic β‐adrenergic stimulation. Indeed, ventricular myocytes isolated from HCN2‐Tg mice were highly susceptible to β‐adrenergic stimulation‐induced abnormal automaticity, which was inhibited by ivabradine.ConclusionsHCN channel blockade by ivabradine reduces lethal arrhythmias associated with dilated cardiomyopathy in mice. Conversely, cardiac‐specific overexpression of HCN2 channels increases arrhythmogenicity of β‐adrenergic stimulation. Our findings demonstrate the contribution of HCN channels to the increased arrhythmicity seen in failing hearts and suggest HCN channel blockade is a potentially useful approach to preventing sudden death in patients with heart failure.

Background: Remote ischemic preconditioning (RIPC) induced by transient limb ischemia is a powerful innate mechanism of cardioprotection against ischemia. Several described mechanisms explain how RIPC may act through neural pathways or humoral factors; however, the mechanistic pathway linking the remote organ to the heart has not yet been fully elucidated. This study aimed to investigate the mechanisms underlying the RIPC-induced production of Janus kinase (JAK)-signal transducer and activator of the transcription (STAT)-activating cytokines and cardioprotection by using mouse and human models of RIPC. Methods and Results:Screened circulating cardioprotective JAK-STAT-activating cytokines in mice unexpectedly revealed increased serum erythropoietin (EPO) levels after RIP induced by transient ischemia. In mice, RIPC rapidly upregulated EPO mRNA and its main transcriptional factor, hypoxia-inducible factor-1α (HIF1α), in the kidney. Laser Doppler blood flowmetry revealed a prompt reduction of renal blood flow (RBF) after RIPC. RIPC activated cardioprotective signaling pathways and the anti-apoptotic Bcl-xL pathway in the heart, and reduced infarct size. In mice, these effects were abolished by administration of an EPO-neutralizing antibody. Renal nerve denervation also abolished RIPC-induced RBF reduction, EPO production, and cardioprotection. In humans, transient limb ischemia of the upper arm reduced RBF and increased serum EPO levels. Conclusions:Based on the present data, we propose a novel RIPC mechanism in which inhibition of infarct size by RIPC is produced through the renal nerve-mediated reduction of RBF associated with activation of the HIF1α-EPO pathway. 1558OBA T et al. Hypoxia Inducible Factor-1α (HIF1α) Immunohistochemical StainingMouse kidneys were harvested 1 h after RIPC. Embedded sections were deparaffinized, and endogenous peroxidase activity was inhibited by treating the sections with 0.3% H2O2 in PBS for 10 min. After several washes with PBS, the sections were incubated for 20 min with blocking solution (Jackson ImmunoResearch) to block non-specific binding, followed by overnight incubation at 4°C with the purified anti-hypoxia inducible factor-1α (HIF1α) antibody (Abcam). Subsequently, the sections were incubated with an alkaline phosphatase-conjugated goat anti-rabbit IgG antibody for 30 min. Signal amplification was achieved by incubating the slides for 30 min with Vectastain Elite Avidin-Biotin Complex solution (Vectastain ABC Kit, Vector), followed by incubation with Vectastain diaminobenzidine solution as the chromagen marker (Dako). 28 For a negative staining control, goat serum was used in place of the HIF1α antibody. Renal Blood Flow (RBF) MonitoringMouse RBF was measured at 0 min and every 2 min during and after RIPC induction, using a laser Doppler blood flow imager (Laser Doppler Perfusion Imager System, moorLDI TMMark 2, Moor Instruments). Before RBF scanning in the right kidney, mice were placed on a heating pad at 37°C to minimize temperature variations. In control mice, a sham...

Methyl-CpG-binding protein 2 (MeCP2) is an epigenetic regulator of gene expression that is essential for normal brain development. Mutations in MeCP2 lead to disrupted neuronal function and can cause Rett syndrome (RTT), a neurodevelopmental disorder. Previous studies reported cardiac dysfunction, including arrhythmias in both RTT patients and animal models of RTT. In addition, recent studies indicate that MeCP2 may be involved in cardiac development and dysfunction, but its role in the developing and adult heart remains unknown. In this study, we found that Mecp2-null ESCs could differentiate into cardiomyocytes, but the development and further differentiation of cardiovascular progenitors were significantly affected in MeCP2 deficiency. In addition, we revealed that loss of MeCP2 led to dysregulation of endogenous cardiac genes and myocardial structural alterations, although Mecp2-null mice did not exhibit obvious cardiac functional abnormalities. Furthermore, we detected methylation of the CpG islands in the Tbx5 locus, and showed that MeCP2 could target these sequences. Taken together, these results suggest that MeCP2 is an important regulator of the gene-expression program responsible for maintaining normal cardiac development and cardiomyocyte structure.

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The present study demonstrated that area and metabolic activity in VAT and SAT could be differently regulated, suggesting the involvement of AGEs and PEDF in adipose tissue inflammation.

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Objective— Endothelial dysfunction is an initial step in atherosclerotic cardiovascular disease. However, involvement of vascular inflammation in endothelial dysfunction is not fully investigated in humans because of the lack of diagnostic modality to noninvasively evaluate vascular inflammation. We assessed the relationship between endothelial function and vascular inflammation evaluated by [ 18 F]-fluorodeoxyglucose-positron emission tomography/computed tomographic imaging. Approach and Results— We examined endothelial function and vascular inflammation by flow-mediated dilation (FMD) of the brachial artery and [ 18 F]-fluorodeoxyglucose-positron emission tomography/computed tomographic imaging of carotid arteries, respectively, in 145 subjects (95 men and 50 women; mean age, 61.8±9.5 years) who underwent a risk-screening test for cardiovascular disease in Kurume University Hospital. Vascular inflammation was measured by blood-normalized standardized uptake value, known as a target:background ratio (TBR). We investigated whether absolute changes from baseline of %FMD after antihypertensive treatment for 6 months (Δ%FMD) were correlated with those of TBR in 33 drug-naive patients with essential hypertension. Multiple logistic regression analysis revealed that age (odds ratio, 1.767 for 10-year increase), male sex (odds ratio, 0.434), low-density lipoprotein-cholesterol (odds ratio, 1.630 for 26-mg/dL increase), and TBR values (odds ratio, 1.759 for 0.2 increase) were independently associated with %FMD in 145 patients. There was an inverse correlation between Δ%FMD and ΔTBR; ΔTBR was a sole independent associate of Δ%FMD in hypertensive patients ( r =−0.558; P <0.001). Conclusions— The present study showed that vascular inflammation in the carotid arteries evaluated by [ 18 F]-fluorodeoxyglucose-positron emission tomography/computed tomography was one of the independent correlates of decreased %FMD, thus suggesting the association of vascular inflammation with endothelial dysfunction in humans.

The present study suggests that switching DPP-4 inhibitors to tofogliflozin ameliorates arterial stiffness in T2DM patients partly via improvement of liver function. Baseline serum levels of AGEs may identify patients who improve arterial stiffness more after treatment with tofogliflozin.