In and ex Vivo Mitochondrial Function of the Heart

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.

Conditions

• Diabetes Mellitus, Type 2
• Diabetic Cardiomyopathies

Interventions

DIAGNOSTIC_TEST

31P-MRS scan and cardiac MRI scan

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.

DIAGNOSTIC_TEST

Atrial biopsy for high-resolution respirometry

Mitochondrial respiration rates are ex vivo measured in tissue homogenates under exposure of different substrates, stimulating different complexes of the electron transport chain of the mitochondria.

DIAGNOSTIC_TEST

Blood analysis

To determine blood glucose metabolism and renal function.

DIAGNOSTIC_TEST

Body composition

This device uses air displacement plethysmography for determining percent fat and fat-free mass in adults and children. The 5-minute test consists of measuring the subject's mass (weight) using a very accurate electronic scale, and volume, which is determined by sitting inside the BOD POD chamber. From these two measurements, the subject's body composition is calculated.

DIAGNOSTIC_TEST

Indirect Calorimetry

As basal energy metabolism might be related to cardiac metabolism and mitochondrial function, and basal metabolic rate shows inter-individual variance, it is an important subject characteristic of the patients. Resting substrate oxidation rates are measured with indirect calorimetry for 30 minutes. A ventilated hood is connected to indirect calorimetry equipment, which measures concentrations of oxygen consumption and CO2 production. From these parameters, the respiratory quotient (RQ), as well as energy expenditure and substrate metabolism will be computed. During this measurement, every 10 minutes (so 4 times) one tube of blood (10ml) will be drawn for the analysis of lipid and glucose metabolites.

Sponsors & Collaborators

• Diabetes Fonds

  collaborator OTHER

• Maastricht University Medical Center

  lead OTHER

Principal Investigators

• Patrick Schrauwen, Prof. · Maastricht University

Eligibility

Min Age

40 Years

Max Age

75 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2017-03-21

Primary Completion

2020-03-01

Completion

2020-03-02

Countries

• Netherlands

Study Locations