From the Departments of Cardiology (M.A.V., S.H.M.d.G., S.C.V., J.v.d.Z.,
H.D.M.L., H.J.J.W.), Physiology (M.v.B., M.A.A.), Anesthesiology (J.J.S.), and
Pathology (J.P.M.C., M.J.A.P.D.), Cardiovascular Research Institute
Maastricht, the Netherlands.
Correspondence to Marc A. Vos, PhD, Department of Cardiology, Cardiovascular Research Institute Maastricht, University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, Netherlands. E-mail m.vos{at}cardio.azm.nl
Background—Chronic, complete AV
block (CAVB) in the dog leads to ventricular
hypertrophy, which has been described as an independent
risk factor for arrhythmias. In this model, we examined (1)
whether the short- and long-term electrical adaptations predispose to
acquired torsade de pointes arrhythmias (TdP) and (2) the
nature of the structural and functional adaptations involved.
Methods and Results—We determined (1) endocardial right (RV) and
left (LV) ventricular APD,
Conclusions—The electrical remodeling occurring after CAVB
predisposes the heart to acquired TdP, whereas the structural changes
(hypertrophy) are successfully aimed at maintaining cardiac
function.
© 1998 American Heart Association, Inc.
Basic Science Reports
Enhanced Susceptibility for Acquired Torsade de Pointes Arrhythmias in the Dog With Chronic, Complete AV Block Is Related to Cardiac Hypertrophy and Electrical Remodeling
APD (LV APD-RV APD),
presence of EADs at 0 weeks (acute: AAVB), and CAVB (6 weeks) and
inducibility of TdP by pacing and d-sotalol (n=10); (2)
steady-state and dynamic LV hemodynamics at 0 and 6
weeks (n=6); (3) plasma neurohumoral levels in time (n=7); (4)
structural parameters of the LV and RV of CAVB dogs (n=6)
compared with sinus rhythm (SR) dogs (n=6); and (5) expression of
ventricular mRNA atrial natriuretic factor
(ANF) in CAVB (n=4) and SR (n=4) dogs. Compared with AAVB, CAVB led to
nonhomogeneous prolongation of LV and RV APD and different
sensitivity for d-sotalol, leading to EADs (4 of 14
versus 9 of 18, P<0.05), increased APD (45±30
versus 125±60 ms, P<0.05), and induction of TdP in
most dogs (0% versus 60%, P<0.05). CAVB led to
biventricular hypertrophy, whereas LV function
was similar in AAVB and CAVB. The neurohumoral levels were transiently
elevated. The LV and RV collagen and the capillary/fiber ratio remained
normal, whereas ventricular ANF mRNA was not detectable.
Key Words: cardiac function • electrophysiology • early after dipolarizations • fibrosis • action potentials
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|
|
|
|
|
|
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|
|
|
 |
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|
|
|
|
|
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|
|
|
|
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|
|
|
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|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
 |
|
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|
|
|
|
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|
|
|
|
|
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|
|
|
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