The biological mechanisms conveying the salutary effects of
cardiac resynchronization therapy in
heart failure remain elusive. We have recently developed a mouse model of
heart failure with dyssynchrony/resynchronization. The aim of this study was to characterize regional left ventricular heterogeneity in
protein expression comparing early (septum) and late (lateral) activated left ventricular wall segments in synchronous (SHF), dyssynchronous (DHF), and resynchronized
heart failure (RHF).
METHODS AND RESULTS: Mice subjected to ischaemia/reperfusion were divided into three groups: sinus rhythm for 4 weeks (SHF), right ventricular pacing for 4 weeks (DHF), and right ventricular pacing for 2 weeks and 2 weeks of sinus rhythm (RHF). Relative concentrations of 92
proteins from septal and lateral left ventricular wall segments (n = 10 per group) were compared within each group. We also analysed the effect of DHF vs. SHF and RHF vs. DHF on
protein expression pattern comparing the same left ventricular segments between the groups.
Proteins with significantly differential expression between left ventricular segments were analysed for
protein-
protein correlations,
protein-
protein interactions, and biological and signalling pathways. Eight
proteins were significantly down-regulated in the late activated (compared with early activated) lateral wall uniquely in RHF (P < 0.05 adjusted for a 5% false discovery rate): Erbb4, Ntf3,
Pdgfb, Tnf, Notch3, Qdpr, Tpp1, and Itgb6.
Protein correlation matrix showed that six of these were strongly and positively correlated and five had known
protein-
protein interactions. Biological pathways mainly down-regulated in late activated myocardium in RHF were MAPK signalling and
hypertrophic cardiomyopathy. There were no significantly differentially expressed
proteins comparing the same left ventricular segments between the DHF and SHF (range of P-values: 0.05-1.00) and RHF and DHF (range of P-values: 0.32-1.00).
CONCLUSIONS: In a mouse model of
heart failure with dyssynchrony and resynchronization, we observed down-regulation of several
proteins in the late activated lateral wall, compared with the septum, in resynchronized mice. These
proteins display significant
protein-
protein correlation and share biological signalling pathways, including MAPK activation and
hypertrophy signalling.