Background: Mechanical unloading of the left ventricle may support the recovery of the myocardium after an ischaemic insult, but the mechanisms underlying this reverse remodelling are largely unclear. Here, we used an unbiased transcriptomic approach to identify potentially relevant genetic pathways involved in reverse remodelling.
Hypothesis: We investigated the hypothesis that reverse cardiac remodelling by ventricular unloading normalises expression of genes deregulated by MI.
Methods: MI was induced by coronary artery ligation in syngenic male Lewis rats (12 weeks of age, n=12). In half of the animals, 6 weeks after coronary artery ligation, the infarcted hearts were mechanically unloaded by heterotopic heart transplantation for a period of 2 weeks. Sham-operated animals served as non-infarcted controls (n=6). Myocardial gene expression was investigated by Affymetrix microarray analysis. Coronary artery ligation led to a reduction of ejection fraction (60 ± 3%, n=12, versus 75 ± 2%, n=12, p<0.01) and left ventricular dilatation (7.9 ± 0.1 mm, n=12, versus 7.0 ± 0.1 mm, n=12, p<0.0001) 6 weeks after the intervention. Out of 10,230 genes investigated ~10% were significantly upregulated (n=182) or downregulated (n=874) after MI. Mechanical unloading normalised the expression of 133 of these genes. Out of those, five genes (Ctnna3, LATS1, Cyr61, Nfat5 and ACE2) are associated with the cardiac Hippo pathway, which has recently been shown to regulate adult cardiomyocyte proliferation and regeneration in human ischaemic heart failure.
Conclusion: Mechanical unloading normalises the expression of ~10% of cardiac genes specifically affected by MI. Modulation of the Hippo pathway may contribute to the beneficial effects of left ventricular unloading of ischaemic hearts.