Lipid Accumulation in Heart Transplant From Non-diabetic Donors to Diabetic Recipients

BACKGROUND Heart failure (HF) is an increasing disease, with a prevalence and incidence of about 1% and 0.15% of the general population respectively, affecting at least 300,000 patients in the USA. However, in cases of advanced heart failure, refractory to maximal medical therapy, and to devices supporting the heart rhythm and cardio-circulatory function, the only valid therapeutic option remains the cardiac transplant. Diabetic patients with advanced heart failure seem to benefit from this therapy not differently as compared to non-diabetics. On other hand, in patients with advanced heart failure and selected for heart transplantation, the diabetes may condition a different degree of structural and molecular pathology that is not present, or present at least in a different way in non-diabetics selected for same HF etiology, clinical features, and HF stage. Therefore, in this study authors will study the anatomical-pathological, cellular, and molecular characteristics, as the pathways of inflammatory, oxidative, apoptotic and epigenetic expression in diabetics vs. non diabetics affected by idiopathic dilated cardiomyopathy (IDCM) and therefore in the absence of ischemic heart disease, and referred to Heart Center for cardiac transplantation. Authors' study hypothesis is that diabetes can condition a different degree of structural, cellular, and molecular pathology in patients with IDCM Vs. non-diabetic patients, due to excessive metabolic activity, with increased synthesis and release of inflammatory, oxidative, and apoptotic molecules. These investigations will be focused on microscopic, histological and functional analysis of the cellular metabolism of cardiac tissue extracted from diabetics vs. non diabetics IDCM patients, and removed during cardiac transplantation. However, in a subsequent ex vivo phase authors will evaluate cellular, molecular, inflammatory and epigenetic effectors related to the different microscopic tissue pattern obtained from myocardial tissue samples. From authors' investigations, these new identified targets of the HF molecular and cellular processes in diabetics vs. non diabetics, may be used in the future as specific therapeutic targets to improve clinical outcomes in IDCM diabetics with advanced heart failure.

MATERIALS AND METHODS Study population Authors will enroll a population of IDCM diabetics and non diabetics selected to receive a heart transplant. This study will be conducted at the Department of Medical Sciences, at the Department of Cardiac Surgery, and at the Department of Biochemistry of the University of Campania "Luigi Vanvitelli". Selection, randomization and enrollment of patients will be carried out at the Department of Medical Sciences, followed by clinical follow up; Cardiac transplantation and cardiac tissue sampling will be performed at the Cardiosurgery Department; Molecular and cellular studies will be conducted at the biochemistry department. The follow-up will be 12 months. The diabetic pathology will be diagnosed according to the international guidelines of the American Heart Association.

Inclusion criteria: patients aged > 18, <75 years, with indication to receive a heart transplant (survival score for accepted heart failure accepted (HFSS) at high risk, peak VO2 <10 ml / kg / min after reaching the anaerobic threshold; arrhythmias recurrent symptomatic ventricles refractory to medical treatment, ICD and surgical), affected by IDCM with heart failure in NYHA class III / IV refractory to maximal medical therapy; diabetic and non-diabetic patients Exclusion criteria: contraindication to receiving cardiac transplantation; non-idiopathic dilated cardiopathy (valvulopathies, ischemic-infarct cardiopathy, etc.), acute myocardial infarction, acute heart failure, neoplastic disease, and chronic diseases that may influence the inflammatory profile both systemic and cardiac (cancer, chronic intestinal inflammation, hepatitis, AIDS) , and a life expectancy <6 months. All patients will be included in the study after signing informed consent to participate in the study. Routine analysis will be performed upon enrollment in the study, before cardiac transplantation and follow-up. During the follow-up (figure 1) clinical examinations, routine ecg and echocardiography will be performed regularly. Molecular study and cell study will be performed on myocardial tissue from explanted hearts. The study will be performed according to the Helsinki declaration.

Intervention In this observational study, authors will evaluate a cohort of consecutive patients (diabetic vs. non-diabetic) affected by IDCM and heart failure in class III / IV NYHA refractory to maximal medical therapy and treated at the Division of Cardiac Surgery of the University of Campania "Luigi Vanvitelli "by cardiac transplantation. The study will be conducted in three different parts: human study, ex vivo cell study, molecular study.

Human study: conducted in the Department of Medical Sciences and Cardiac Surgery, the enrolled patient will be treated by heart transplant, according to the international guidelines governing cardiac transplantation. After cardiac transplantation, a biopsy of myocardial tissue of the removed heart will be performed. The intervention will be conducted at the Cardiosurgery Division of the "Luigi Vanvitelli" University of Campania.