Abstract 3863: Deletion Of Integrin Alpha7 Leads To Altered Cardiac Conduction And Sudden Death Associated With Connexin43 Downregulation
Effective propagation of the electrical impulse throughout the myocardium is highly dependent on cell-to-cell and cell-to-extracellular matrix interactions. Increasing evidence indicates that dysregulation of cellular adhesion is a critical determinant in the genesis of arrhythmia. Null mutations in the integrin α7 gene, an essential mediator of cellular adhesion in cardiac and skeletal muscles, have been linked to myopathy in humans, however, the in vivo role of the integrin α7 subunit in the heart is undefined. The mouse model of integrin α7 deletion dies prematurely at one year of age. We therefore analysed the cardiac phenotype in integrin α7 deficient mice (α7−/−) to determine whether their premature death was associated with altered cardiac conduction. One year old integrin α7−/− mice exhibited altered cardiac conduction characterised by spontaneous atrial fibrillation and prolonged QTc duration (α7−/−: 25.7±0.74ms, α7+/+: 19.5±0.61ms; n=6; p<0.001, QTc=QT/(RR/100)1/2). The abnormal cardiac conduction was associated with downregulation of connexin43. However, no significant changes were observed in the expression of ion chanels that have been linked to long QT syndrome or atrial fibrillation (kv1.1, kv1.5, kcne1, kcnq1, erg1, Cav1.2 and Cav1.3). In addition, α7−/− mice displayed increased susceptibility to drug-induced arrhythmias: treatment with ouabain (2mg/kg BW) in combination with isoprenaline (2.5mg/kg BW) induced atrial fibrillation and ventricular tachycardia and eventually death in 6 month-old integrin α7−/− mice, but not in α7+/+ mice. Interestingly, α7−/− also displayed concentric ventricular hypertrophy with increased septal wall thickness and reduced left ventricular end-diastolic diameter starting from 6 months of age. These structural changes were accompanied by an increase in myocyte size and increased ERK1/2 phosphorylation. In conclusion, deletion of the integrin α7 gene in mice leads to ventricular hypertrophy and to abnormal cardiac conduction. The integrin α7 deficient mice have a marked propensity to lethal arrhythmias through alterations in gap junctions but not ion channels. The integrin α7 knockout model provides new insight into the link between the extracellular matrix and cardiac conduction.