Atrophic changes occur in unloaded myocardium and may preclude functional improvement in a time dependent manner
Henriette L. Brinks1, Hendrik Tevaearai2, Christian Muehlfeld3, Daniela Kuklinski2, Thierry P. Carrel2, Marie-Noelle Giraud2; 1Cardiovascular Surgery, Charite University Hospital, Berlin, Berlin, Germany; 2Department of Cardiac and Vascular Surgery, Inselspital University Hospital, Berne, Switzerland; 3Institute of Anatomy, University of Berne, Berne, Switzerland
Comment on this Abstract
Objective: Recent studies have shown that mechanical unloading with ventricular assist devices (LVADs) may result in functional improvement of the myocardium. However, possible benefit might be counterbalanced by myocardial atrophy. Using a model of heterotopic transplantation (HTx), we aimed to characterize, in a time course approach, myocardial atrophy and functional changes induced by long-term unloading.
Methods: HTx was performed in 80 adult Lewis rats and transplants were unloaded for 3, 8, 15, 30, 60 and 90 days (n=12/group). Atrophy and fibrosis of ventricles were assessed stereologically with point counting and disector analysis. mRNA expression of SERCA, TNF-β1, MHC-isoforms and caspase-3 were analyzed by quantitative RT-PCR. Left ventricular developed pressure (LVP) was measured on isolated, perfused transplants.
Results: A decreased ventricular volume of 23.9±5.5% was observed at 3 days, 68.2±3.6% at 90 days, heart weight diminished from 990 +/- 49mg to 769 +/- 59mg and 320 +/-27mg, respectively. Simultaneously, cellular atrophy and rate of fibrosis increased over time, indicated by a decrease in the absolute volume of myocyte nuclei from 7.4+07 +/- 4.7+06 to 2.2+07 +/- 3.7+06 after 30. On the molecular level immediate 3-fold upregulation of the fetal isoform β-MHC occurred while α-MHC remained unchanged. SERCA-2α expression was upregulated after 3 and 8 days of u loading but RNA-levels returned to normal after 15 days of HTx. Atrophic remodeling was associated with a leftward shift of the pressure/volume relationship in the left ventricle after 30 days (Figure) indicating progressive functional impairment. The maximally developed pressure was not significantly changed in the groups after 30 and 60 days.
Conclusion: Our results suggest atrophic changes associated with chronic ventricular unloading may counteract the possibility of functional recovery. Optimizing the unloading timing and/or a partially unloading of the failing heart might improve success rates of “bridge to recovery” programs.
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