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(Circulation. 2009;120:S191-S197.)
© 2009 American Heart Association, Inc.

Cardiac Transplantation and Surgery for Heart Failure

Markers of Autophagy Are Downregulated in Failing Human Heart After Mechanical Unloading

Christos Kassiotis, MD; Kalpana Ballal, PhD; Kari Wellnitz, BS; Deborah Vela, MD; Mei Gong, MD; Rebecca Salazar, BS; O. Howard Frazier, MD; Heinrich Taegtmeyer, MD, DPhil

From The University of Texas Medical School at Houston (C.K., K.B., K.W., D.V., M.G., R.S., H.T.), Department of Internal Medicine, Division of Cardiology, Houston, Tex; Texas Heart Institute at St Luke’s Episcopal Hospital (H.I., D.V., O.H.F.), Houston, Tex.

Correspondence to Heinrich Taegtmeyer, MD, DPhil, University of Texas Houston Medical School, Department of Internal Medicine, Division of Cardiology, 6431 Fannin, MSB 1.246, Houston, TX 77030. E-mail Heinrich.Taegtmeyer{at}uth.tmc.edu

Background— Autophagy is a molecular process that breaks down damaged cellular organelles and yields amino acids for de novo protein synthesis or energy provision. Mechanical unloading with a left ventricular assist device (LVAD) decreases the energy demand of the failing human heart. We tested the hypothesis that LVAD support reverses activation of autophagy.

Methods and Results— Paired biopsy samples of left ventricular myocardium were obtained from 9 patients with idiopathic dilated cardiomyopathy (mean duration of LVAD support, 214 days) at the time of implantation and explantation of the LVAD. Transcript and protein levels of markers and mediators of autophagy and apoptosis were measured by quantitative reverse-transcription polymerase chain reaction and Western blotting. TUNEL assays, C9 immunohistochemistry, and 20S proteasome activity assays were also performed. Mechanical unloading significantly decreased mRNA transcript levels of Beclin-1, autophagy-related gene 5 (Atg5), and microtubule-associated protein-1 light chain-3 (MAP1-LC3 or LC3; P<0.02). Protein levels of Beclin-1, Atg5–Atg12 conjugate, and LC3-II were also significantly reduced after LVAD support (P<0.05). A significant increase in 20S proteasome activity was observed with unloading, in parallel to the decrease in autophagic markers. Although BNIP3 and the ratio of activated caspase 3 to procaspase 3 increased after LVAD support, Bcl-2 and TUNEL-positive nuclei were not significantly different between samples.

Conclusions— Mechanical unloading of the failing human heart decreases markers of autophagy. These findings suggest that autophagy may be an adaptive mechanism in the failing heart, and this phenomenon is attenuated by LVAD support.

Key Words: autophagy • heart failure • left ventricular assist device • mechanical unloading