Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT05958706 |
| Other study ID # |
2022-1962 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
December 1, 2021 |
| Est. completion date |
December 2024 |
Study information
| Verified date |
July 2023 |
| Source |
Heinrich-Heine University, Duesseldorf |
| Contact |
Daniel Scheiber, MD |
| Phone |
+492118118800 |
| Email |
daniel.scheiber[@]med.uni-duesseldorf.de |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
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.
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:
1. the reduced mitochondrial oxidative capacity of myocardial mitochondria in T2DM is
complex- and substrate-specific.
2. within patients with heart failure of unclear etiology and indication for myocardial
biopsy, there are mitochondrial profiles with different clinical courses and outcomes.
3. in T2DM, myocardial oxidative capacity is also longitudinally impaired in heart
transplant patients and this impairment is associated with worse clinical outcome.
Objectives:
1. identify specific targets for therapeutic strategies against diabetic cardiomyopathy:
work program (WP) 1.
2. characterization of myocardial mitochondrial function and its relevance to clinical
phenotypes in heart failure: WP 2.
3. investigation of T2DM as a longitudinal predictor of worse mitochondrial and clinical
cardiac function in heart transplant patients: WP 3.
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:
- Group 1: Patients with manifest heart failure (NYHA II-IV) with clinical indication to
perform myocardial biopsy and T2DM according to the "American Diabetes Association"
(ADA) criteria, HbA1c < 9.0%, with/without therapy (insulin, oral/parenteral
antidiabetic drugs).
- Group 2: Patients with manifest heart failure (NYHA II-IV) with clinical indication to
perform myocardial biopsy without T2DM.
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:
- Group 1: Patients with terminal heart failure and diagnosed T2DM according to the
"American Diabetes Association" (ADA) criteria 18, HbA1c < 9.0%, with/without therapy
(insulin, oral/parenteral antidiabetic drugs).
- Group 2: Patients with terminal heart failure (NYHA IV) without T2DM.
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.
Patients:
- Group 1: Patients after heart transplantation with diagnosed T2DM according to the
"American Diabetes Association" (ADA) criteria 18, HbA1c < 9.0%, with/without therapy
(insulin, oral/parenteral antidiabetic drugs).
- Group 2: Patients after heart transplantation without T2DM.
