Author + information
- Received October 18, 2019
- Revision received December 30, 2019
- Accepted January 7, 2020
- Published online March 16, 2020.
- Raffaele Marfella, MD, PhDa,∗∗ (, )@raffaelemarfell,
- Cristiano Amarelli, MDb,∗,
- Francesco Cacciatore, MD, PhDc,
- Maria Luisa Balestrieri, PhDd,
- Gelsomina Mansueto, MD, PhDe,
- Nunzia D’Onofrio, PhDd,
- Salvatore Esposito, MDf,
- Irene Mattucci, MDg,
- Gemma Salerno, MDg,
- Marisa De Feo, MDh,
- Michele D’Amico, PhDi,
- Paolo Golino, MD, PhDg,
- Ciro Maiello, MDb,
- Giuseppe Paolisso, MDa,† and
- Claudio Napoli, MD, PhDa,j,†
- aDepartment of Advanced Medical and Surgical Sciences (DAMSS), University of Campania “Luigi Vanvitelli,”, Naples, Italy
- bUnit of Cardiac Surgery and Transplants, AORN Ospedali dei Colli-Monaldi Hospital, Naples, Italy
- cDepartment of Translational Medical Sciences, Federico II University of Naples, Naples, Italy
- dDepartment of Precision Medicine, University of Campania “Luigi Vanvitelli,”, Naples, Italy
- eDepartment of Advanced Biomedical Sciences, Federico II University of Naples, Naples, Italy
- fUnit of Pathological Anatomy, Aversa Hospital, Caserta, Italy
- gCardiology Division, University “Luigi Vanvitelli,” Monaldi Hospital, Naples, Italy
- hDepartment of Cardio-Thoracic Sciences, University of Campania “Luigi Vanvitelli,”, Naples, Italy
- iDepartment of Experimental Medicine, University of Campania “Luigi Vanvitelli,”, Naples, Italy
- jIRCCS-SDN, Naples, Italy
- ↵∗Address for correspondence:
Dr. Raffaele Marfella, Department of Advanced Medical and Surgical Sciences (DAMSS), University of Campania “Luigi Vanvitelli”, Piazza Miraglia, 2, 80138 Naples, Italy.
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.
↵∗ Drs. Marfella and Amarelli are co-first authors.
↵† Drs. Paolisso and Napoli are co-senior authors.
This study was funded by Ricerca di Ateneo 2014 from University of Campania “Luigi Vanvitelli,” Naples, Italy. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received October 18, 2019.
- Revision received December 30, 2019.
- Accepted January 7, 2020.
- 2020 The Authors