Original Investigation
Lipid Accumulation in Hearts Transplanted From Nondiabetic Donors to Diabetic Recipients

https://doi.org/10.1016/j.jacc.2020.01.018Get rights and content
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Abstract

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.

Key Words

CVD
diabetes
diabetic cardiomyopathy
heart transplantation

Abbreviations and Acronyms

BMI
body mass index
CHD
coronary heart disease
CT
computed tomography
DM
diabetes mellitus
DMCM
diabetic mellitus cardiomyopathy
EMB
endomyocardial biopsy
HF
heart failure
HOMA-IR
Homeostatic Model Assessment for Insulin Resistance
HR
hazard ratio
HTX
heart transplantation
IRS
insulin receptor substrate
ISHLT
International Society for Heart Lung Transplantation
PPAR
peroxisome proliferator-activated receptor
SREBP-1c
sterol regulatory element-binding transcription factor 1c
TAPSE
tricuspid annular plane systolic excursion

Cited by (0)

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.

Listen to this manuscript's audio summary by Editor-in-Chief Dr. Valentin Fuster on JACC.org.

Drs. Marfella and Amarelli are co-first authors.

Drs. Paolisso and Napoli are co-senior authors.