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Diabetes can lead to heart failure independently, but the underlying causes remain incompletely understood. The main aim of this study is to identify differential regulation of mitochondrial substrate utilization and complex activity in heart failure and type 2 diabetes mellitus (T2DM). For this, we will conduct a prospective, observational study to examine myocardial mitochondrial oxidative function and related metabolic parameters, gene expression, histological markers, and inflammation in cardiac tissue from patients with heart failure or patients after heart transplantation. We will further assess cardiac function using cardiac magnetic resonance imaging with and without stress protocols and magnetic resonance spectroscopy. Glycemic control/T2DM will be characterized by oral glucose tolerance tests. The results of this project will help to better understand the cellular mechanisms of the development of diabetic cardiomyopathy and contribute to the development of early diagnostic, as well as therapeutic approaches for the prevention and treatment of diabetic cardiomyopathy.
Full description
Insulin resistance, ectopic lipid accumulation in the liver, and plasma concentrations of free fatty acids are independent predictors of cardiac mortality, the primary cause of death in patients with type 2 diabetes mellitus (T2DM). T2DM predisposes to the development of heart failure independently of other risk factors. Ventricular dysfunction in diabetic patients independent of coronary artery disease or arterial hypertension is termed diabetic cardiomyopathy. Studies suggest that myocardial mitochondrial dysfunction, as well as accumulation of lipids and other metabolites, oxidative stress, and altered insulin signaling, play a significant role in the pathogenesis of diabetic cardiomyopathy. Thus, we also found evidence of impaired mitochondrial function in hyperglycemia and insulin resistance in previous analyses. Nevertheless, it remains unclear, among other things, at which point of mitochondrial metabolism the shown impairments originate, whether the availability of different substrates may influence these effects, what is the temporal sequence of pathomechanistic events, and what are the effect modifiers for the influence of T2DM on the myocardium.
The goal of the present work is to more precisely characterize the underlying pathomechanisms to answer these questions. The focus will be on respirometric analysis of human myocardial tissue samples established by our preliminary work. In previously published studies, we were able to establish its use for the first time in catheter-guided endomyocardial biopsies. By studying further heart failure and heart transplant patients, we will analyze the importance of myocardial mitochondrial function as a prognostic marker of further disease progression and, using larger power, investigate the influence of different effect modifiers.
The results of this project will help to better understand the cellular mechanisms of the development of diabetic cardiomyopathy and contribute to the development of early diagnostic, as well as therapeutic approaches for the prevention and treatment of diabetic cardiomyopathy.
Hypotheses:
Objectives:
WP1:
The aim is to identify altered respiratory chain subcomponents and metabolic pathways associated with the development of manifest diabetic cardiomyopathy in T2DM. For this purpose, patients with and without T2DM (according to the criteria of the "American Diabetes Association" (ADA)) who have an indication for endomyocardial biopsy on clinical grounds will be included. A matched comparison between patients with and without T2DM will provide evidence of diagnostic and therapeutic targets for diabetic cardiomyopathy in newly diagnosed heart failure (with and without left ventricular ejection fraction limitation).
Patients:
WP2:
The aim is to characterize myocardial mitochondrial function and its relevance for clinical phenotypes in heart failure. For this purpose, patients with terminal heart failure from the heart failure program of the Department of Cardiology, Pneumology and Angiology of the University Hospital Düsseldorf who are scheduled for implantation of a left ventricular assist device (LVAD) or are undergoing heart transplantation will be included.
All study examinations of myocardial tissue are performed in an area of the left ventricular apex obtained during surgery (LVAD implantation or cardiac harvest), which is not further clinically analyzed or preserved and which therefore no longer has any direct benefit for the patients.
Patients:
WP3:
The aim is to investigate T2DM as a longitudinal predictor of impaired mitochondrial and clinical cardiac function in heart transplant patients. For this purpose, patients who are included in the heart transplantation follow-up program of the University Hospital Düsseldorf and have the indication for endomyocardial biopsy within this program will be included. Routine myocardial biopsy is necessary in these patients to detect subclinical graft rejection early, as it is associated with increased mortality. Biopsies occur multiple times in the first year after transplantation, and in subsequent years (if there is no evidence of rejection), the goal is to monitor annually.
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200 participants in 3 patient groups
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Central trial contact
Daniel Scheiber, MD; Elric Zweck, MD
Data sourced from clinicaltrials.gov
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