Abstract 3256: HAND1 Gene Expression is Down Regulated During Myocardial Recovery from Heart Failure and is Associated with Mitochondrial Energy Pathways.
Background - Altered expression of bHLH transcription factors HAND1 and HAND2 has profound effects on cardiac development but their role in the adult heart remains unclear. Previous reports have suggested expression is altered in heart failure. We hypothesised that HAND1 and HAND2 may be altered during myocardial recovery from heart failure in patients who receive a combination of mechanical unloading using LVAD and pharmacologic therapy.
Methods and results - Real time quantitative PCR analysis was performed on myocardial samples from end-stage HF patients who recovered from heart failure sampled at the time of LVAD implant (implant, n = 12), at the time of LVAD removal following recovery (explant, n = 12) and again at 1 year after removal of the device (1 year, n = 9). Levels of HAND1 showed decreased expression at explant compared to implant and remained low at 1 year. Levels of HAND2 showed a trend to decline with recovery but failed to reach significance. In order to probe the potential functional role of HAND1 we analysed microarray data from a subset of recovery patients (n = 6) sampled at both implant and explant. The HAND1 expression profile associated strongly with genes relating to the mitochondrial compartment (p < 10−9), energy pathways and metabolism (p < 10−4). In order to assess the importance of elevated HAND1 expression in adult heart, we examined the effects of inducible myocardial expression in transgenic mice. Elevated expression resulted in increased mortality and cardiac dysfunction in adult transgenic mice.
Conclusion - Elevated HAND1 expression is associated with heart failure in man and in transgenic mice. Levels normalise following myocardial recovery in man and microarray analysis identified an association between HAND1, mitochondria and energy metabolism revealing novel targets for HAND1 activity and potential therapeutic targets.