AIMS: The progression of pathological @entity5707 and contributes to the occurrence of malignant @entity943 and @entity1164 . The underlying molecular mechanisms remain unclear, however. Our aim was to examine the role of the renin- @entity7774 system (RAS) in the mechanism underlying arrhythmogenic @entity299 using a transgenic @entity19 expressing a cardiac-specific dominant-negative form of neuron-restrictive silencer factor (dnNRSF-Tg). This @entity19 model exhibits progressive @entity299 leading to lethal @entity943 . METHODS AND RESULTS: Subcutaneous administration of @entity17162 , a direct renin inhibitor, significantly suppressed the progression of pathological @entity299 and improved survival among dnNRSF-Tg @entity19 while reducing arrhythmogenicity. Genetic deletion of the angiotensin type 1a receptor (AT1aR) similarly suppressed @entity299 and @entity944 . In optical mapping analyses, spontaneous @entity1165 ( @entity1165 ) and fibrillation (VF) initiated by breakthrough-type excitations originating from focal activation sites and maintained by functional re-entry were observed in dnNRSF-Tg hearts. Under constant pacing, dnNRSF-Tg hearts exhibited markedly slowed conduction velocity, which likely contributes to the arrhythmogenic substrate. Aliskiren treatment increased conduction velocity and reduced the incidence of sustained @entity1165 . These effects were associated with suppression of cardiac @entity82 and restoration of @entity16899 expression in dnNRSF-Tg ventricles. CONCLUSION: Renin inhibition or genetic deletion of AT1aR suppresses pathological @entity299 that leads to the generation of substrates maintaining @entity1165 /VF and reduces the occurrence of @entity944 in dnNRSF-Tg @entity19 . These findings demonstrate the significant contribution of RAS activation to the progression of arrhythmogenic substrates.

The renin-angiotensin system promotes arrhythmogenic substrates and lethal XXXX in @entity19 with non-ischaemic cardiomyopathy.

@entity1164 :: ('MESH:D016757', 'Disease') :: ['sudden cardiac death'] @entity16899 :: ('14609(Tax:10090)', 'Gene') :: ['connexin 43'] @entity82 :: ('MESH:D005355', 'Disease') :: ['fibrosis'] @entity1165 :: ('MESH:D017180', 'Disease') :: ['VT', 'ventricular tachycardia'] @entity7774 :: ('MESH:D000809', 'Chemical') :: ['angiotensin'] @entity19 :: ('10090', 'Species') :: ['mice', 'mouse'] @entity17162 :: ('MESH:C446481', 'Chemical') :: ['aliskiren'] @entity944 :: ('MESH:D003645', 'Disease') :: ['sudden death'] @entity5707 :: ('MESH:D020257', 'Disease') :: ['left ventricular remodelling leads to cardiac dysfunction'] @entity299 :: ('MESH:D006331', 'Disease') :: ['cardiac remodelling', 'cardiac dysfunction'] @entity943 :: ('MESH:D001145', 'Disease') :: ['arrhythmias']
@entity943 :: (MESH:D001145,Disease) :: ['arrhythmias']
