Cristiano Amarelli, Paolo Golino, Gelsomina Mansueto, Michele D'Amico, Ciro Maiello, Claudio Napoli, Salvatore Esposito, Irene Mattucci, Nunzia D'Onofrio, Giuseppe Paolisso, Maria Luisa Balestrieri, Raffaele Marfella, Marisa De Feo, Francesco Cacciatore, Gemma Salerno, Marfella, Raffaele, Amarelli, Cristiano, Cacciatore, Francesco, Balestrieri, Maria Luisa, Mansueto, Gelsomina, D'Onofrio, Nunzia, Esposito, Salvatore, Mattucci, Irene, Salerno, Gemma, De Feo, Marisa, D'Amico, Michele, Golino, Paolo, Maiello, Ciro, Paolisso, Giuseppe, Napoli, Claudio, Marfella, R., Amarelli, C., Cacciatore, F., Balestrieri, M. L., Mansueto, G., D'Onofrio, N., Esposito, S., Mattucci, I., Salerno, G., De Feo, M., D'Amico, M., Golino, P., Maiello, C., Paolisso, G., and Napoli, C.
Background: Early pathogenesis of diabetic cardiomyopathy (DMCM) may involve lipotoxicity of cardiomyocytes in the context of hyperglycemia. There are many preclinical studies of DMCM pathogenesis, but the human evidence is still poorly understood. Objectives: By using a nondiabetic mellitus (non-DM) heart transplanted (HTX) in diabetes mellitus (DM) recipients, this study conducted a serial study of human heart transplant recipients evaluating cardiac effects of diabetic milieu (hyperglycemia and insulin resistance) on lipotoxic-mediated injury. We evaluated cardiomyocyte morpho-pathology by seriated biopsies of healthy implanted hearts in DM recipients during 12-month follow-up from HTX. Because metformin reduces ectopic lipid accumulation, we evaluated the effects of the drug in a nonrandomized subgroup. Methods: The DMCM-AHEAD (Diabetes and Lipid Accumulation and Heart Transplant) prospective ongoing study (NCT03546062) evaluated 158 first HTX recipients (82 non-DM, 76 DM of whom 35 [46%] were receiving metformin). HTX recipients were undergoing clinical standard evaluation (metabolic status, echocardiography, coronary computed tomography angiography, and endomyocardial biopsies). Biopsies evaluated immune response, Oil Red-O staining, ceramide, and triacylglycerol levels. Lipotoxic factors and insulin resistance were evaluated by reverse transcriptase–polymerase chain reaction. Results: There was a significant early and progressive cardiomyocyte lipid accumulation in DM but not in non-DM recipients (p = 0.019). In the subgroup receiving metformin, independently from immunosuppressive therapy that was similar among groups, lipid accumulation was reduced in comparison with DM recipients not receiving the drug (hazard ratio: 6.597; 95% confidence interval: 2.516 to 17.296; p < 0.001). Accordingly, lipotoxic factors were increased in DM versus non-DM recipients, and, relevantly, metformin use was associated with fewer lipotoxic factors. Conclusions: Early pathogenesis of human DMCM started with cardiomyocyte lipid accumulation following HTX in DM recipients. Metformin use was associated with reduced lipid accumulation independently of immunosuppressive therapy. This may constitute a novel target for therapy of DMCM.