Brief Summary

It has been suggested that mitochondrial dysfunction might play a role in the development of diabetic cardiomyopathy. From animal studies, it has been suggested that an altered PPAR and PGC1 expression is involved in the reduced cardiac mitochondrial function, however human data on cardiac mitochondrial function and PPAR regulation is scarce. The latter is due to the fact that there is no validated measurement for assessing cardiac mitochondrial function non-invasively in vivo. It has been suggested that measuring PCr/ATP ratio with 31P-MRS in the heart reflects cardiac mitochondrial function. However, so far no direct validation of this method has been performed. The aim of this study will be to validate in vivo 31P-MRS with ex vivo measurements of mitochondrial function. To this end, the hypothesis is that in vivo 31P-MRS is a valid method for measuring cardiac mitochondrial function when compared with ex vivo mitochondrial respirometry.

Trial Health

On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment

participants targeted

Target at P25-P50 for all trials

Timeline

Completed

Started Mar 2017

Typical duration for all trials

Geographic Reach

1 country

1 active site

Status

completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

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Study Timeline

Key milestones and dates

3 years study duration

First Submitted

Initial submission to the registry

January 25, 2017

Completed

16 days until next milestone

First Posted

Study publicly available on registry

February 10, 2017

Completed

1 month until next milestone

Study Start

First participant enrolled

March 21, 2017

Completed

2.9 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

March 1, 2020

Completed

1 day until next milestone

Study Completion

Last participant's last visit for all outcomes

March 2, 2020

Completed

Last Updated

November 4, 2020

Status Verified

November 1, 2020

Enrollment Period

2.9 years

First QC Date

January 25, 2017

Last Update Submit

November 3, 2020

Conditions

Diabetes Mellitus, Type 2 Diabetic Cardiomyopathies

Keywords

Spectrum AnalysisMitochondriaPeroxisome Proliferator-Activated ReceptorsRespirometryHumanHeart

Outcome Measures

Primary Outcomes (2)

Cardiac energy status in vivo
Measured with 31P-MRS to determine ATP/PCr ratio and ex vivo mitochondrial function measured with high-resolution respirometry as a golden standard to validate the in vivo MRS.
1 week before surgery the patient will undergo the MRS scan. That same week the investigators will analyse the ATP/PCr ratio. Data will be presented through study completion, an average of 2 years.
Cellular respiration ex vivo
With the oxygraph the investigators measure how well the muscle is capable of oxidative phosphorylation which reflect the mitochondrial function. This reflects the mitochondrial capacity.
At surgery the investigators obtain tissue samples. Within an hour the investigatorswill use the oxygraph to measure the cellular respiration. Data will be presented through study completion, an average of 2 years.

Secondary Outcomes (8)

Cardiac function
1 week before surgery the patient will undergo the MRI scan. The investigators will analyse this scan within a week. Data will be presented through study completion, an average of 2 years.
Cardiac lipid accumulation
1 week before surgery the patient will undergo the MRS scan. The investigators will analyse this scan within a week. Data will be presented through study completion, an average of 2 years.
Role of PPAR metabolism in the heart on the development of diabetic cardiomyopathy
The investigators will obtain tissue samples from surgery. The investigators will analyse this tissue within a week. Data will be presented through study completion, an average of 2 years.
Glucose Metabolism Status
At inclusion the investigators will take some serum and analyse it the same day. The inclusion will be around 1 week before MRI-scan and 2 weeks before surgery. Data will be presented through study completion, an average of 2 years.
Height in meters
At inclusion the investigators will determine their height, this will be around 1 week before MRI-scan and 2 weeks before surgery. Data will be presented through study completion, an average of 2 years.
+3 more secondary outcomes

Study Arms (3)

Type 2 Diabetic Patients

* Obese (BMI \> 27 kg/m2 \< 35 kg/m2) * Non-insulin dependent; they must be on sulphonylurea(SU)- derivate or metformin therapy for at least six months with a constant dose for at least two months, or on dietary treatment for at least six months * They should have a (moderately) well-controlled diabetes (defined by a HbA1c\<8%)

Diagnostic Test: 31P-MRS scan and cardiac MRI scanDiagnostic Test: Atrial biopsy for high-resolution respirometryDiagnostic Test: Blood analysisDiagnostic Test: Body compositionDiagnostic Test: Indirect Calorimetry

Obese Subjects

* A similar BMI as T2DM patients (BMI \> 27 kg/m2\< 35) * Normo-glycemic with fasting plasma glucose levels lower than 6,1 mmol/L.

Lean subjects

* BMI between 20-25 kg/m2 * Normo-glycemic with fasting plasma glucose levels lower than 6,1 mmol/L.

Interventions

31P-MRS scan and cardiac MRI scanDIAGNOSTIC_TEST

31P-MRS measurement of the heart: Phosphorous magnetic resonance spectroscopy (31P-MRS) will be used for the determination of the energy status of the heart in vivo. The localization of phosphorus energy metabolites in the heart will be performed by one-dimensional spectroscopic imaging, resulting in spectra from slices through the heart of 1 cm thickness. The peaks of PCr and ATP will be fitted in order to calculate the ATP/PCr ratio. The measurement of cardiac function is a standardised protocol. In the 4 chamber view setting a T1 mapping sequence will be performed for the detection of fibrosis. Hereafter patients will receive contrast for T2 mapping and late enhancement studies for determining extracellular volume and ischemia.

Also known as: Spectrum Analysis, MRI