Visual Abstract - Evidence of Glycolysis Up-Regulation and Pyruvate Mitochondrial Oxidation Mismatch During Mechanical Unloading of the Failing Human Heart: Implications for Cardiac Reloading and Conditioning: 10.1016/j.jacbts.2016.06.009

• LVAD unloading reverses several but not all aspects of myocardial remodeling and usually leads to incomplete cardiac recovery in a subset of patients with advanced HF.

• We performed metabolomic analysis and mitochondrial structural and functional characterization in paired human myocardial tissue procured from 31 patients with advanced HF at LVAD implant and at heart transplant plus tissue from 11 normal donors.

• LVAD unloading induces glycolysis up-regulation without a corresponding increase in glucose oxidation.

• Lack of post-LVAD improvement in mitochondrial function and volume density could explain the glycolysis-glucose oxidation mismatch.

• Therapeutic interventions, such as myocardial conditioning, that are known to improve mitochondrial biogenesis, structure, and function might further improve cardiac metabolism and energy production and thereby enhance cardiac recovery with LVAD-induced unloading.