Abstract 19846: Development of a Murine Pacemaker System for Mechanistic Studies of Dyssynchrony and Resynchronization in Heart Failure
Background: The cellular and molecular effects of dyssynchrony and resynchronization in heart failure (HF) have so far been studied in canines where genetic manipulation is not possible.
Therefore, the objective of this study was to develop a model of dyssynchrony, induced by right ventricular pacing (RVP), and resynchronization (sinus rhythm, SR) in mice with HF.
Methods: Acute pressure-volume loop (PV-loop) studies were performed in muscle LIM protein knockout mice (MLP), with severe HF, during RVP and SR.
A custom built combined pacemaker and ECG-monitoring system was then implanted in: (i) MLP, (ii) wild type (WT) mice with doxorubicin (DOX) induced mild HF and (iii) WT mice with normal cardiac function.
Dyssynchrony was quantified by QRS-duration. MLP (n=7), DOX (n=10) and WT (n=10) were paced chronically for 2 weeks while sham-operated mice served as controls (SHAM). After 2 weeks of RVP, resynchronization (SR) was delivered for additional 2 weeks. Fractional shortening (FS) and end diastolic diameter (EDD) were evaluated with echocardiography.
Results: QRS-duration increased substantially with RVP compared to SR (23±4 vs. 12.1ms, p<0.001).
With RVP at 700 bpm, hemodynamics dramatically deteriorated in the acute PV-loop study in MLP mice but was largely unchanged in WT mice. With chronic RVP, 14-day mortality rate was 71, 10 and 10 % respectively in MLP, DOX and WT mice.
DOX significantly reduced FS (44±4% vs. 54±4%, p<0.001) and increased EDD (2.8±0.2mm vs. 2.6±0.2mm, p<0.001). After 2 weeks of RVP, FS was further reduced (32±6 %) and EDD increased (3.4±0.5mm, p=0.01 for both). Following resynchronization, both FS and LVEDD recovered to pre-RVP level (44±3% and 2.9±0.2mm, p=0.01 for both). FS and LVEDD were unchanged in SHAM operated mice and after 2 weeks pacing in WT mice without HF .
Conclusions: Two weeks of RVP impairs cardiac function and accelerates remodeling in mice with DOX-induced mild HF, while these changes are reversed with reinstitution of SR. These physiological data mimic what is observed with dyssynchrony and resynchronization in human HF subjects. This study suggests that this novel model can be used to study cellular and molecular effects of dyssynchrony and resynchronization in HF in a genetically modifiable animal, for the first time.
Author Disclosures: M. Stahlberg: None. R. Nakagawa: None. D. Bedja: None. D.A. Kass: None.
- © 2016 by American Heart Association, Inc.