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Transcriptional Differences in Left Ventricular Extracellular Matrix Remodeling in Primary and Secondary Mitral Regurgitation
Daniella Espiritu, Daisuke Onohara, Muralidhar Padala.
Emory University, Atlanta, GA, USA.

OBJECTIVE: Mitral regurgitation (MR) is a heart valve lesion that imposes low-pressure, volume overload on the left ventricle (LV). LV adapts to this hemodynamic stress, initially with hypertrophy, then with dilatation and extracellular matrix (ECM) degradation. Though these gross changes are known, the underlying biological signaling pathways are vague. In this study we sought quantify expression of genes that regulate ECM synthesis and degradation in two types of clinically relevant MR settings in a rat model.
METHODS: Seventy adult rats (n=70) were assigned to three groups - (G1,n=24) MR only (primary MR); (G2,n=24)MR with myocardial infarction (secondary MR); and (G3,n=22) sham. MR was induced with a 16G needle inserted into mitral anterior leaflet via the LV apex with echocardiography guidance, and moderate-severe MR was created. MI was created by ligating the left coronary artery. All rats were survived, echo was performed at baseline, 2 wk and 20 wks. Some rats in each group were euthanized at 2 wks and at 20 wks and LV tissue was used for ECM gene array studies. RESULTS: At 2 weeks post-surgery, LV function and geometry were equivalent between groups (Fig A1,B1,C1), but gene expression was divergent. In MR, none of the genes were upregulated but MMPs, ADAMTS, integrins and cadherins were significantly downregulated. In MI+MR, genes for collagen 1, MMPs, and ECM adhesion molecules were upregulated, and some MMPs and integrins were downregulated. At 20 weeks, LV function was worse in both groups compared to the control, but was significantly worsened in the MR+MI groups compared to the MR group. In the MR group, cadherins, MMPs, transemembrane receptors and neural adhesion molecules were upregulated, while none of the genes were downregulated . In the MR+MI group, collagens, MMPs, TIMPs, laminins and neural adhesion molecules were upregulated, while none of the genes were downregulated.CONCLUSIONS: LV functional and structural remodeling was more severe in MR+MI than MR at 20 weeks, with a divergent gene expression pattern in each group.


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