Determination of Optimal Duration of Mechanical Unloading for Failing Hearts to Achieve Bridge to Recovery in a Rat Heterotopic Heart Transplantation Model

Background Mechanical unloading (MU) of a failing heart using a left ventricular assist device (LVAD) can lead to “bridge to recovery” in some patients. However, it is still unknown how to determine when to withdraw assistance. We sought to determine the optimal duration of MU by investigating its short- and long-term effects using a rat model of heterotopic heart transplantation. Methods Heart failure (HF) was induced in Lewis rats by ligating the left anterior descending artery. In the MU-HF groups, failing hearts were harvested and heterotopically transplanted. In the non-unloaded HF groups and the control group, hearts were not transplanted. After 2, 4 and 8 weeks, we evaluated papillary muscle function, histologic change and cardiac gene expression. Normal hearts served as the control group. Results In the MU-HF groups, papillary muscle function improved significantly in the early period of unloading. It peaked and normalized at 4 weeks of unloading, but decreased to 50% the level of a normal heart at 8 weeks. In parallel with papillary muscle function, expression of brain natriuretic peptide (BNP) mRNA and SERCA2a mRNA normalized at 2 and 4 weeks of unloading, respectively, but deteriorated after 4 weeks. Cardiomyocyte hypertrophy was normalized at 2 weeks of unloading, but extended unloading induced cardiac atrophy. Myocardial fibrosis increased after unloading. Conclusions Mechanical unloading of the failing heart can help normalize cardiac function, cardiomyocyte hypertrophy and cardiac gene expression for an optimal duration (