Evidence of Glycolysis Up-Regulation and Pyruvate Mitochondrial Oxidation Mismatch During Mechanical Unloading of the Failing Human Heart

This study sought to investigate the effects of mechanical unloading on myocardial energetics and the metabolic perturbation of heart failure (HF) in an effort to identify potential new therapeutic targets that could enhance the unloading-induced cardiac recovery. The authors prospectively examined paired human myocardial tissue procured from 31 advanced HF patients at left ventricular assist device (LVAD) implant and at heart transplant plus tissue from 11 normal donors. They identified increased post-LVAD glycolytic metabolites without a coordinate increase in early, tricarboxylic acid (TCA) cycle intermediates. The increased pyruvate was not directed toward the mitochondria and the TCA cycle for complete oxidation, but instead, was mainly converted to cytosolic lactate. Increased nucleotide concentrations were present, potentially indicating increased flux through the pentose phosphate pathway. Evaluation of mitochondrial function and structure revealed a lack of post-LVAD improvement in mitochondrial oxidative functional capacity, mitochondrial volume density, and deoxyribonucleic acid content. Finally, post-LVAD unloading, amino acid levels were found to be increased and could represent a compensatory mechanism and an alternative energy source that could fuel the TCA cycle by anaplerosis. In summary, the authors report evidence that LVAD unloading induces glycolysis in concert with pyruvate mitochondrial oxidation mismatch, most likely as a result of persistent mitochondrial dysfunction. These findings suggest that interventions known to improve mitochondrial biogenesis, structure, and function, such as controlled cardiac reloading and conditioning, warrant further investigation to enhance unloading-induced reverse remodeling and cardiac recovery

Utility of virtual crossmatch in sensitized patients awaiting heart transplantation.

BACKGROUND: Organ transplant candidates with serum antibodies directed against human leukocyte antigens (HLA) face longer waiting times and higher mortality while awaiting transplantation. This study examined the accuracy of virtual crossmatch, in which recipient HLA-specific antibodies, identified by solid-phase assays, are compared to the prospective donor HLA-type in heart transplantation. METHODS: We examined the accuracy of virtual crossmatch in predicting immune compatibility of donors and recipients in heart transplantation and clinical outcomes in immunologically sensitized heart transplant recipients in whom virtual crossmatch was used in allograft allocation. RESULTS: Based on analysis of 257 T-cell antihuman immunoglobulin complement-dependent cytotoxic (AHG-CDC) crossmatch tests, the positive predictive value of virtual crossmatch (the likelihood of an incompatible virtual crossmatch resulting in an incompatible T-cell CDC-AHG crossmatch) was 79%, and the negative predictive value of virtual crossmatch (the likelihood of a compatible virtual crossmatch resulting in a compatible T-cell CDC-AHG crossmatch) was 92%. When used in a cohort of 28 sensitized patients awaiting heart transplantation, 14 received allografts based on a compatible virtual crossmatch alone from donors in geographically distant locations. Compared with the other 14 sensitized patients who underwent transplant after a compatible prospective serologic crossmatch, the rejection rates and survival were similar. CONCLUSION: Our findings are evidence of the accuracy of virtual crossmatch and its utility in augmenting the opportunities for transplantation of sensitized patients