Dr Ehmke outlined that many studies have shown that mechanical unloading of the left ventricle (LV) may support the recovery of myocardium after an ischaemic insult, yet the molecular mechanisms underlying this reverse remodelling are largely unclear.1 His team hypothesised that ventricular unloading leads to the normalisation of genes dysregulated after MI, and this normalised gene expression plays a role in reverse cardiac remodelling. The hypothesis was tested via an unbiased transcriptomic approach aimed at identifying relevant genetic pathways in 12-week-old male Lewis rats. MI was induced by coronary ligation of the left anterior descending artery or sham surgery was performed, followed by an assessment of LV function at 6 weeks. Cardiac gene expression was assessed at 8 weeks using the Affymetrix GeneChip. A subset of the MI-induced and sham rats received mechanical unloading using a syngeneic heterotopic transplanted heart at 6 weeks, followed by assessment of cardiac gene expression at 8 weeks.2
At 6 weeks post-MI, the LV ejection fraction in the MI-induced rats had decreased from 75% to about 25%, along with a significant increase in the LV internal diameter compared to the baseline. The gene expression profiling showed that, in infarcted heart MI, about 1,000 genes were dysregulated, with 874 genes being downregulated and 182 genes being upregulated compared to sham controls. Following unloading, 101 of the 874 downregulated genes and 32 of the 182 upregulated genes were normalised. Further analysis showed that most of the genes normalised by unloading were involved in the Hippo signalling pathway, known to play a key role in cardiac development, cardiomyocyte homeostasis and regeneration.3
In conclusion, MI in rats led to dysregulation of about 1,000 cardiac genes, and mechanical unloading normalised the expression of about 10% of the dysregulated genes. Preliminary analyses suggest that modulation of the Hippo pathway may contribute to the beneficial effects of LV unloading in ischaemic hearts.