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Background: The prevalence of atrial fibrillation (AF) increases in patients with hypertension and heart failure in which endothelial function is impaired. Oxidative stress in atrial tissues is involved in the development of AF. Statins have pleiotropic effects including antioxidant effects. Thus, we developed hypertensive heart failure in rats by the chronic inhibition of NO synthesis and we investigated the role of the statin in atrial remodeling. Methods and Results: Ten-week-old male Wistar-Kyoto rats were randomly divided into four groups: the control (no treatment), the L-NAME (received L-NAME, an inhibitor of NO synthase, 1 g/L in drinking water), the L-NAME+atorvastatin (L(a low dose)) (5 mg/kg/day) and the L-NAME+atorvastatin (H(a high dose)) (20 mg/kg/day). Chronic inhibition of NO synthesis increased systolic blood pressure (control group: 138±5 mmHg; L-NAME group: 212±8 mmHg L+atorvastatin (L) group: 210±6 seconds , L+atorvastatin (H): 208±6 seconds) and decreased LV dP/dt max/LVSP (control group: 54±3, L-NAME group: 36±8, L+atorvastatin (L) group: 40±3, L+atorvastatin (H) group: 38±6 1/second), whereas co-administration of atorvastatin did not affect them. The sustained duration of AF was always induced by transesophageal burst pacing (The pacing pulse used for induction of AF was rectanglar in shape, of 60V and 6ms-width. The atrium was paced at a cycle length of 12ms (83Hz) for 30seconds) and it was prolonged by L-NAME, which was prevented by atorvastatin in a dose-dependent manner (control: 8.8 ± 1.0 seconds, L-NAME: 20.7 ± 3.0 seconds, L+atorvastatin (L): 12.8 ± 3.2 seconds , L+atorvastatin (H): 8.8 ± 2.6 seconds). The chronic inhibition of NO synthesis increased the extent of fibrosis and markers of oxidative stresses such as proteins modified with 4-hydroxy-trans-2-nonenal and p47phox and rac1 in left atrial tissue, either of which was prevented by atorvastatin. Conclusion: Atorvastatin attenuates oxidative stresses in atrium and prevents atrial electrical and morphological remodeling in rat hypertensive failing hearts without hemodynamic changes. Statin may be beneficial in patients with coronary heart disease and atrial fibrillation, and may contribute to the prevention of the onset of heart failure.

Background Liposome is a nano-size particle that can delay the drug degradation and induce the drug to the specific tissues including ischemia/reperfused myocardium. Coating liposome with polyethylene-glycol (PEG) prolongs the residence time in the blood stream. Although adenosine reduces myocardial infarct size in clinical trials, its half-time is extremely short and a high-dose of adenosine administration causes both hypotension and bradycardia. In this study, we investigated whether PEGylated liposomal adenosine minimizes systemic hemodynamic effects of adenosine and maximize cardioprotective effects against ischemia/reperfusion injury. Methods and Results We obtained PEGylated liposomal adenosine (average diameter: 126.2+/−42.9 nm) by the remote loading method. In rats, the intravenous administration of free adenosine (450 μg/kg/min for 10 minutes) decreased mean blood pressure and heart rate by 22.7% and 15.4% compared with the baseline, respectively. PEGylated liposomal adenosine at the same dose did not significantly change either mean blood pressure or heart rate compared with the baseline. Next, we produced myocardial infarction (MI) in male rats by 30-minutes of ligation of the left anterior descending coronary artery followed by reperfusion. We evaluated the accumulation of liposome in the hearts and infarct size 72 hours after the MI. Fluorescence microscopy revealed the accumulation of fluorescent-labeled PEGylated liposomes in ischemic, but not non-ischemic area. PEGylated liposomal adenosine (450 μg/kg/min), free adenosine (450 μg/kg/min) or free-PEGylated liposome was intravenously administered for 10 minutes starting 5 minutes before the onset of reperfusion. PEGylated liposomal adenosine significantly (p Conculusion PEGylated liposomal adenosine attenuated the systemic hemodynamic effects of adenosine and augmented cardioprotection against ischemia/repefusion injury. Nano-size PEGylated liposomal adenosine is a promising candidate for the adjunctive therapy for AMI.

Background Cardiomyocytes mainly consist of sarcomere structure and marked sarcomere disorganization is a well-documented characteristic of cardiomyocytes in the failing myocardium. Among several constituents of sarcomeres, myosin regulatory light chain 2 (MLC2v) affects physiological cardiac sarcomere formation and heart development through its phosphorylation. Exact upstream kinase of MLC2v in cardiomyocytes however, have not been elucidated so far. Mathods and Results We identified a novel cardiac-specific gene whose expression was upregulated in failing myocardium and was also correlated with the values of pulmonary arterial pressure of each patient. This gene has kinase domain and MLC2v was identified as a putative substrate by in vitro kinase reaction using mouse heart extracts and recombinant protein of this gene. Therefore, we termed this novel gene as a cardiac-specific myosin light chain kinase (cardiac-MLCK, gene symbol: MYLK3 ). To further investigate the function of cardiac-MLCK, we targeted cardiac-MLCK using specific siRNAs in cultured neonatal rat cardiomyocytes. Reduced expression of cardiac-MLCK caused the impairment of sarcomere reassembly on epinephrine treatment. Also knockdown of cardiac-MLCK expression in zebrafish embryos using specific morpholino antisense oligonucleotides led to dilation of the cardiac ventricle with incomplete sarcomere formation. We also analyzed the nature of cardiac-MLCK and MLC2v in mouse models of heart failure. Expression levels of cardiac-MLCK proteins and phosphorylation levels of MLC2v were severely reduced in the failing heart of trans-aortic constriction mice. Conclusions We identified a novel cardiac-MLCK which contributed mainly to cardiac MLC2v phosphorylation. Attenuation of cardiac-MLCK expression caused severe sarcomere disorganization both in vitro and in vivo implies its important roles in cardiac functions. Our results suggest that cardiac-MLCK mRNA expression may be upregulated to compensate for the lower expression and reduced phosphorylation of MLC2v in failing myocardium. As a possible therapeutic modality in patients with CHF, upregulation of cardiac-MLCK may promote sarcomere assembly and enhanced contractility of the failing heart

Backgrounds; Since AMP-activated protein kinase (AMPK) is activated in the pressure-overloaded hypertrophic hearts, we investigated whether the activation of AMPK caused by metformin attenuates the progression of heart failure induced by rapid pacing in dogs and decreases cellular damage caused by oxidative stress in neonatal rat cardiac myocytes. Methods and Results; Heart failure was induced by right ventricular (RV) pacing at 230 bpm for 4 weeks in dogs. Treatment of dogs with metformin (100mg/kg/day, orally, n=8, Met group) for 4 weeks prevented significantly the progression of pacing-induced heart failure evaluated by echocardiographical and hemodynamic measurement compared with the control group (n=8). Left ventricular (LV) diastolic and systolic dimension (LVDd and LVDs) were smaller (32.8±0.4 and 26.7±0.9 mm, respectively) and fractional shortening (FS) and ejection fraction (EF) were preserved in Met group (18.6±1.8 and 45.5±3.5 %, respectively) compared with the control group (LVDd and LVDs; 36.5±1.0 and 33.0±1.0 mm, FS and EF; 9.6±0.7 and 27.0±1.9 %, p2 O 2 exposure (50μmol/L). These effects were blunted by an AMPK inhibitor, compound-C (20μmol/L), suggesting that the activation of AMPK increased the cellular viability during H 2 O 2 exposure. Conclusions; Metformin that activates AMPK prevented the progression of heart failure induced by rapid pacing in dogs and attenuated the cellular damage against H 2 O 2 exposure in cardiac myocytes. AMPK may be one of new targets for preventing heart failure in clinical settings.