Effects Of Aliskiren On The Atrial Fibrillation Substrate In Dogs With Ventricular Tachypacing-Induced Congestive Heart Failure

Objective To characterize the alterations of atrial electrophysiology, size and contractility in the canine atrial fibrillation (AF) model with ventricular tachypacing-induced congestive heart failure (CHF).Methods Fifteen mongrel dogs were randomly divided into experiment group and control group. In experimental dogs (n=9), the right ventricle was paced at 240 beats per minute for 25±3 days to induce CHF, while no pacing was performed in the control group. Transthoracic echocardiography was performed at baseline and before the end-study. At the terminal study, atrial electrophysiological parameters were measured in right atrial appendage (RAA), posterior wall of right atrium (RAPW), coronary sinus (CS), left atrial appendage (LAA), posterior wall of left atrium (LAPW) and left superior pulmonary vein (LSPV) with endocardial leads. AF was induced by programmed electrical stimulation and burst pacing. AF inducibility and mean AF duration (DAF) was determined.Results Study was completed in 7 dogs in the experiment group. Atrial systolic and diastolic areas increased significantly after 25+3 days of rapid ventricular pacing (P＜0.01). Left and right atrial fractional area shortening (FAS) substantially decreased (left atrial:(35.7+1.9)%vs (20.7±2.7)%, P<0.01; right atrial:(35.0±2.3)%vs (18.0±2.3)%, P<0.01). Left ventricular ejection fraction (LVEF) decreased from (65.3±2.1)%to (31.6±2.8)%(P<0.01). Effective refractory periods (ERP) at 400ms and 300ms cycle lengths in both LA and RA were significantly prolonged in dogs with CHF. AERP dispersion increased significantly and conduction velocity decreased apparently. CHF increased DAF from 13+9 seconds in control dogs to 687±290 seconds (P<0.01). DAF and LA systolic and diastolic areas were highly correlated in HF dogs(r=0.797,0.828; P＜0.05 for each). Similar findings were observed for RA areas (r=0.770,0.829; P＜0.05 for each). FAS in both atria negatively correlated with DAF (p＜0.05).Conclusion Ventricular tachypacing-induced CHF strongly increases duration of induced AF, which is correlated with the structural and functional abnormalities in both atria. Objective To assess the effects of direct rennin inhibitor aliskiren on arrhythmogenic atrial remodeling and associated mitogen-activated protein kinase (MAPK) changes in a dog model of congestive heart failure (CHF).Methods For this study,21 mongrel dogs were randomly assigned to the control group (CTL, n=6), the ventricular tachypacing group (VTP, n=9), and the aliskiren group (AL, n=6). In the group VTP and AL, pacing at 220～ 240 beats per minute was maintained for 3 weeks. At the end of the experiments, histopathologic studies were performed to identify the fibrosis of atria. AngiotensinⅡconcentration in atrial tissue was determined by radio-immunity. The messenger ribonucleic acid (mRNA) level of ERK1 was measured by reverse transcription polymerase chain reaction (RT-PCR), and normalized to the mRNA level of GAPDH. The protein expression of ERK1/2, JNK and p38MAPK in atrial myocardium were detected by Western blot.Results Atrial tissue from the paced dogs showed a large amount of interstitial fibrosis distributed throughout the tissue, evidence by Masson trichrome stain. In addition, heterogeneity in the size and arrangement of atrial myocytes was found in these tissues. But these pathological abnormal findings were attenuated in the aliskiren-treated dogs. Consisted with the pathological findings, atrial angiotensinⅡconcentrations and MAPK expression were increased by tachypacing, with substantial changes in phosphorylated forms of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38-kinase. Aliskiren significantly reduced tachypacing-induced changes in atrial angiotensinⅡand ERK1 mRNA expression (LA AngⅡ:group AL 11.25±1.74 vs group CTL 25.20±4.64, P<0.01; ERK1 mRNA:group AL 0.92±0.09 vs group VTP 1.45±0.14, P<0.01). The protein expression of ERK1/2 in atrial tissue was significantly decreased in group AL compared with group VTP (p44:group AL 0.32±0.09 vs group VTP 0.75±0.11, P<0.01; p42:group AL 0.34±0.09 vs group VTP 0.83±0.12, P<0.01). Aliskiren did not alter tachypacing-induced changes in phosphorylated forms of JNK and p38.Conclusion CHF-induced increases in angiotensinⅡcontent and MAPK activation contribute to arrhythmogenic atrial structural remodeling. Direct rennin inhibitor aliskiren interferes with signal transduction leading to the AF substrate in CHF and may represent a useful new component to AF therapy.