Electrical remodelling precedes heart failure in an endothelin-1-induced model of cardiomyopathy.
OBJECTIVE
Binary transgenic (BT) mice with doxycycline (DOX)-suppressible cardiac-specific overexpression of endothelin-1 (ET-1) exhibit progressive heart failure (HF), QRS prolongation, and death following DOX withdrawal. However, the molecular basis and reversibility of the electrophysiological abnormalities in this model were not known. Here, we assess the mechanisms underlying ET-1-mediated electrical remodelling, and its role in HF.


RESULTS
BT vs. non-BT littermate controls were withdrawn from DOX and serially studied with ultrasound biomicroscopy, octapolar catheters, multielectrode epicardial mapping, histopathology, western blot, immunohistochemistry, and qRT-PCR. Abnormalities in ventricular activation and -dV/dt were detected as early as 4 weeks after transgene activation, when the structure and function of the heart remained unaffected. By 8 weeks of ET-1 overexpression, biventricular systolic and diastolic dysfunction, myocardial fibrosis, and cardiomyocyte hypertrophy were observed. Intracardiac and epicardial electrograms revealed prolonged conduction and ventricular activation, reduced -dV/dt, and abnormal atrioventricular nodal function. Within 4 weeks of ET-1 induction, connexin 40 (Cx40) protein and Cx43 mRNA, protein, and phosphorylation levels were reduced by 36, 64, 93, and 69%, respectively; Na(v)1.5 mRNA and protein levels were reduced by 30 and 50%, respectively, as was Na(+) channel conductance. Importantly, the associated electrophysiological abnormalities at this time point were reversible upon suppression of ET-1 overexpression and completely prevented the development of structural and functional remodelling.


CONCLUSIONS
ET-1-mediated electrical remodelling correlates with reduced Cx40, Cx43, and Na(v)1.5 expression and decreased Na(+) channel conductance and precedes HF. The sequence and reversibility of this phenotype suggest that a primary abnormality in electrical remodelling may contribute to the pathogenesis of HF.
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Erin E
EE
Mueller
Abdul
A
Momen
Stéphane
S
Massé
Yu-Qing
YQ
Zhou
Jie
J
Liu
Peter H
PH
Backx
R Mark
RM
Henkelman
Kumaraswamy
K
Nanthakumar
Duncan J
DJ
Stewart
Mansoor
M
Husain
D000818:Animals; D009202:Cardiomyopathies / Q000378:metabolism / Q000503:physiopathology*; D018031:Connexin 43 / Q000235:genetics; D017630:Connexins / Q000235:genetics; D004195:Disease Models, Animal; D022062:Electrophysiologic Techniques, Cardiac; D019332:Endothelin-1 / Q000235:genetics* / Q000378:metabolism*; D015870:Gene Expression / Q000502:physiology; D006329:Heart Conduction System / Q000378:metabolism / Q000503:physiopathology; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000502:physiology; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010641:Phenotype; D015222:Sodium Channels / Q000235:genetics; D020257:Ventricular Remodeling / Q000502:physiology*; D000097003:Gap Junction alpha-5 Protein
D018031:Connexin 43; D017630:Connexins; D019332:Endothelin-1; D062554:NAV1.5 Voltage-Gated Sodium Channel; D015222:Sodium Channels; D000097003:Gap Junction alpha-5 Protein; C568321:Scn5a protein, mouse