Mitochondrial Substrate Utilization in the Diabetic Human Heart
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 500
- 试验地点
- 1
- 主要终点
- Substrate-specific JVO2 of ventricular myocardial mitochondrial oxidative capacity
研究概览
简要总结
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.
详细描述
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:
- the reduced mitochondrial oxidative capacity of myocardial mitochondria in T2DM is complex- and substrate-specific.
- within patients with heart failure of unclear etiology and indication for myocardial biopsy, there are mitochondrial profiles with different clinical courses and outcomes.
- in T2DM, myocardial oxidative capacity is also longitudinally impaired in heart transplant patients and this impairment is associated with worse clinical outcome.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 20 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥ 20 and ≤ 85 years
- •Male and female patients with manifest heart failure (NYHA II-IV) and clinical indication for myocardial biopsy or after transplantation and clinical indication for myocardial biopsy with or without type II diabetes mellitus or terminal (NYHA IV) heart failure with or without type II diabetes mellitus.
- •Written informed consent
排除标准
- •Acute infectious diseases within the last 2 weeks before the examination
- •Autoimmune diseases or acute immunocompromising diseases (leukocytes < 5000/μl)
- •Pregnancy
- •Use of alcohol or drugs (addiction), psychiatric diseases
- •Suspected or manifest AIDS (HIV); hepatitis B or C.
- •Liver disease not attributed to the presence of nonalcoholic fatty liver hepatitis or congestive hepatopathy in heart failure
- •Malignant cancer
- •Lack of capacity to give informed consent or lack of consent to participate in the study
- •For MRI study with drug stress: contraindications to the use of regadenoson, specifically: a) Hypersensitivity to the active ingredient or any of the other ingredients mentioned. b) Second- or third-degree atrioventricular (AV) block or sinus node dysfunction, unless these patients have a functioning pacemaker. c) Unstable angina that has not been stabilized with medication. d) Severe hypotension. e) Decompensated stages of heart failure.
研究组 & 干预措施
patients with manifest heart failure
patients with manifest heart failure and T2DM or patients with manifest heart failure without T2DM
patients with terminal heart failure
patients with terminal heart failure and T2DM or patients with terminal heart failure without T2DM
patients after heart transplantation
patients after heart transplantation and T2DM or patients after heart transplantation without T2DM
结局指标
主要结局
Substrate-specific JVO2 of ventricular myocardial mitochondrial oxidative capacity
时间窗: at time of the endomyocardial biopsy procedure
measured in (pmol/s\*mg)
次要结局
- Markers of cardiac function and structure(1 day before or after endomyocardial biopsy)
- Cardiac substrate utilization(1 day before or after endomyocardial biopsy)
- Patterns in the myocardial transcriptome and systemic metabolome(at time of the endomyocardial biopsy procedure)
- all-cause mortality(up to 5 years (follow-up in clinical routine))
- Markers of cardiac function(1 day before or after endomyocardial biopsy)
- non-fatal myocardial infarction(up to 5 years (follow-up in clinical routine))
- hospitalization for heart failure(up to 5 years (follow-up in clinical routine))
- allograft rejection(up to 5 years (follow-up in clinical routine))
- non-fatal stroke(up to 5 years (follow-up in clinical routine))
- Longitudinal Substrate-specific JVO2(variable, up to 2 years)