piperidines and Atrial-Remodeling

Atrial fibrillation (AF) commonly occurs after surgery and is associated with atrial remodeling. TRPV4 is functionally expressed in the heart, and its activation affects cardiac structure and functions. We hypothesized that TRPV4 blockade alleviates atrial remodeling and reduces AF induction in sterile pericarditis (SP) rats. TRPV4 antagonist GSK2193874 or vehicle was orally administered 1 day before pericardiotomy. AF susceptibility and atrial function were assessed using in vivo electrophysiology, ex vivo optical mapping, patch clamp, and molecular biology on day 3 after surgery. TRPV4 expression increased in the atria of SP rats and patients with AF. GSK2193874 significantly reduced AF vulnerability in vivo and the frequency of atrial ectopy and AF with a reentrant pattern ex vivo. Mechanistically, GSK2193874 reversed the abnormal action potential duration (APD) prolongation in atrial myocytes through the regulation of voltage-gated K+ currents (IK); reduced the activation of atrial fibroblasts by inhibiting P38, AKT, and STAT3 pathways; and alleviated the infiltration of immune cells. Our results reveal that TRPV4 blockade prevented abnormal changes in atrial myocyte electrophysiology and ameliorated atrial fibrosis and inflammation in SP rats; therefore, it might be a promising strategy to treat AF, particularly postoperative AF.

Topics: Action Potentials; Aged; Animals; Atrial Fibrillation; Atrial Remodeling; Female; Fibrosis; Heart Atria; Heart Rate; Humans; Inflammation; Male; Middle Aged; Myocytes, Cardiac; Pericarditis; Piperidines; Quinolines; Rats; Rats, Sprague-Dawley; TRPV Cation Channels

Ibrutinib is a novel antitumor drug that targets Bruton tyrosine kinase for treatment of chronic lymphocytic leukemia. Atrial fibrillation (AF) occurs in 5%-9% of patients during treatment, but the underlying mechanisms remain unclear.. The purpose of this study was to develop a mouse model of ibrutinib-induced AF and investigate its proarrhythmic mechanisms.. In C57BI/6 mice in the ibrutinib and control groups, ibrutinib (25 mg/kg/d) or vehicle (hydroxypropy1-β-cyclodextrin), respectively, was administered orally for 4 weeks. Transesophageal burst stimulation then was used to induced AF. To evaluate the underlying mechanism of AF, cardiac echocardiography was performed. Ca. Compared with the control group, the ibrutinib group showed (1) a higher incidence and longer duration of AF with transesophageal burst stimulation; (2) increased left atrial mass, as indicated by echocardiography; (3) significant myocardial fibrosis in the left atrium on Masson trichrome staining; (4) Ca. The present study established a mouse model of AF by oral administration of ibrutinib for 4 weeks. The arrhythmogenic mechanisms underlying this model likely are associated with structural remodeling and Ca

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Antineoplastic Agents; Atrial Fibrillation; Atrial Remodeling; Calcium; Calcium Signaling; Disease Models, Animal; Echocardiography; Heart Atria; Leukemia, Lymphocytic, Chronic, B-Cell; Mice; Myocytes, Cardiac; Piperidines; Pyrazoles; Pyrimidines

There is increasing evidence implicating atrial mitochondrial dysfunction in the pathogenesis of atrial fibrillation. In this study, we explored whether alogliptin, a dipeptidyl peptidase-4 inhibitor, can prevent mitochondrial dysfunction and atrial remodeling in a diabetic rabbit model.. A total of 90 rabbits were randomized into 3 groups as follows: control group (n=30), alloxan-induced diabetes mellitus group (n=30), and alogliptin-treated (12.5 mg/kg per day for 8 weeks) diabetes mellitus group (n=30). Echocardiographic and hemodynamic assessments were performed in vivo. The serum concentrations of glucagon-like peptide-1, insulin, and inflammatory and oxidative stress markers were measured. Electrophysiological properties of Langendorff-perfused rabbit hearts were assessed. Mitochondrial morphology, respiratory function, membrane potential, and reactive oxygen species generation rate were assessed. The protein expression of transforming growth factor β1, nuclear factor κB p65, and mitochondrial biogenesis-related proteins were measured by Western blot analysis. Diabetic rabbits exhibited left ventricular hypertrophy and left atrial dilation without obvious hemodynamic abnormalities, and all of these changes were attenuated by alogliptin. Compared with the control group, higher atrial fibrillation inducibility in the diabetes mellitus group was observed, and markedly reduced by alogliptin. Alogliptin decreased mitochondrial reactive oxygen species production rate, prevented mitochondrial membrane depolarization, and alleviated mitochondrial swelling in diabetic rabbits. It also improved mitochondrial biogenesis by peroxisome proliferator-activated receptor-γ coactivator 1α/nuclear respiratory factor-1/mitochondrial transcription factor A signaling regulated by adiponectin/AMP-activated protein kinase.. Dipeptidyl peptidase-4 inhibitors can prevent atrial fibrillation by reversing electrophysiological abnormalities, improving mitochondrial function, and promoting mitochondrial biogenesis.

Topics: Animals; Atrial Fibrillation; Atrial Remodeling; Diabetes Mellitus, Experimental; Dipeptidyl-Peptidase IV Inhibitors; Fibrosis; Heart Atria; Heart Rate; Membrane Potential, Mitochondrial; Mitochondria, Heart; NF-E2-Related Factor 1; Organelle Biogenesis; Oxidative Stress; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Piperidines; Rabbits; Time Factors; Transcription Factor RelA; Transforming Growth Factor beta1; Uracil; Ventricular Function