Structural and electrical ventricular remodeling in rat acute myocarditis and subsequent heart failure.
OBJECTIVE
We reported that experimental autoimmune myocarditis (EAM) rats showed dramatic changes in ventricular action potential and enhanced arrhythmogenicity in the acute phase, but mechanisms for this are still unclear. To investigate the mechanisms of cardiac remodeling in acute myocarditis and subsequent heart failure, physiological and molecular changes were evaluated along the time course of EAM.


METHODS
Six-week-old Lewis rats were immunized with porcine cardiac myosin. On days 14, 21, 35 and 60 after immunization, histology, hemodynamics and electrophysiological parameters (i.e., effective refractory period (ERP), monophasic action potential duration (MAPD) and PVC inducibility) were evaluated and compared with control rats. After these studies, the expression levels of Kv(+) and L-Ca(2+) channels, ion transporters and BNP expressions in the left ventricle were examined by quantitative real time RT-PCR and Western blot analysis.


RESULTS
EAM rats showed acute myocarditis with massive infiltration of the mononuclear cells on days 14 and 21. Subsequently, a chronic dilated cardiomyopathy (DCM)-like structural change was observed on day 60. Hemodynamic parameters were worse in EAM than controls. ERP and MAPD were longer in EAM than controls, with a peak on day 21, which was parallel to PVC inducibility. mRNA levels of Kv4.2, Kv1.5, KChIP2, frequenin and SERCA2a, and the protein levels of Kv4.2 and Kv1.5, were reduced, especially in the acute phase.


CONCLUSIONS
The initial reduction of Ito-related molecules, such as the expression levels of Kv4.2, 1.5, frequenin and KChIP2, and the prolongation of MAPD are considered to be a key mechanism of ventricular remodeling and cause the characteristic clinical findings in EAM in the acute inflammatory phase and chronic DCM phase.
Department of Internal Medicine, Kitasato University School of Medicine, 1-15-1, Kitasato, Sagamihara, 228-8111, Japan. wakisaka@med.kitasato-u.ac.jp
Yuko
Y
Wakisaka
Shinichi
S
Niwano
Hiroe
H
Niwano
Junko
J
Saito
Tohru
T
Yoshida
Shoji
S
Hirasawa
Hideaki
H
Kawada
Tohru
T
Izumi
D000208:Acute Disease; D000818:Animals; D004594:Electrophysiology; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006352:Heart Ventricles / Q000473:pathology; D006439:Hemodynamics; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D008297:Male; D009205:Myocarditis / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D009929:Organ Size; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011917:Rats, Inbred Lew; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020257:Ventricular Remodeling
D007473:Ion Channels; D012333:RNA, Messenger