Clinical Trial: In and ex Vivo Mitochondrial Function of the Heart

Study Status: Not yet recruiting
Recruit Status: Not yet recruiting
Study Type: Observational [Patient Registry]

Official Title: Cardiac Mitochondrial Function: Comparison of in and ex Vivo Measurements

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.

Detailed Summary:

Cardiovascular diseases remain the main cause of death in type 2 diabetes. Most of this is attributed to atherosclerosis and elevated blood pressure, though even when corrected for these factors, patients with type 2 diabetes are still at increased risk for developing cardiac failure, mainly through diastolic dysfunction. This phenomenon has also been described as diabetic cardiomyopathy. Although not much is known about the aetiology of this disease, there is compelling evidence from animal research that an increased intracellular cardiac fat accumulation and mitochondrial dysfunction, as seen in type 2 diabetes, may play a part in this development.

The reason for a reduced mitochondrial function in diabetic cardiomyopathy is not completely understood, however the gene regulatory pathway of peroxisome proliferator-activated receptor alpha (PPAR-α) has been identified as an important determinant of the shift in substrate metabolism and regulation of oxidative metabolism in type 2 diabetes. In animal studies, the role of PPARα has been tested extensively. In mice with cardiac-restricted overexpression of PPARα (MHC-PPAR), it was found that PPAR-α is involved in the upregulation of CPT-1 in mitochondria, which increases the uptake of long-chain fatty acid into mitochondria and facilitates the fatty acids to undergo beta-oxidation. Chronic exposure to elevated FFAs down regulates PPAR-α in rodent cardiomyocytes, which would further decrease cardiac function by inhibition of FA oxidation and increased intracellular fat accumulation. It is therefore speculated that the increase in fatty acid availability in type 2 diabetes and obesity (due to excessive fat mass) leads to a decrease in cardiac PPAR-α metabolism and thereby a decrease in mitochondrial metabolism, which in turn is paralleled by an increased cardiac fat accumulation and cardiac lipoto
Sponsor: Maastricht University Medical Center

Current Primary Outcome:

• Cardiac energy status in vivo [ Time Frame: 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. ]
  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.
• Cellular respiration ex vivo [ Time Frame: 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. ]
  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.

Original Primary Outcome: Same as current

Current Secondary Outcome:

• Cardiac function [ Time Frame: 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. ]
  With MRI the investigators will determine systolic (ejection fraction) and diastolic function.
• Cardiac lipid accumulation [ Time Frame: 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. ]
  The investigators will measure cardiac lipid accumulation ex vivo from tissue (Elektron Microscopy) and in vivo with MRI.
• Role of PPAR metabolism in the heart on the development of diabetic cardiomyopathy [ Time Frame: 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. ]
  With the use of the tissue the investigators will determine cardiac PPAR expression and possible down-stream targets involved in mitochondrial metabolism ex vivo
• Glucose Metabolism Status [ Time Frame: 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. ]
  At screening the investigators will take blood samples to determine fasting blood glucose so the investigators can divide the participants between normo-glycemic and diabetes.
• Height in meters [ Time Frame: 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. ]
  To be able to determine their BMI (kg/m^2) the investigators have to measure the participants' height in meters at screening.
• Weight in kilograms [ Time Frame: At inclusion the investigators will determine their weight, 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. ]
  To be able to determine their BMI (kg/m^2) the investigators have to measure the participants' weight in kilograms at screening.
• Body composition [ Time Frame: The investigators will measure the body composition right before the MRI-scan, this will be around 1 week before surgery. Data will be presented through study completion, an average of 2 years. ]
  With the Bodpod the investigators will measure the body composition of the participant.
• Basal energy metabolism [ Time Frame: The investigators will measure the basal energy metabolism right before the MRI-scan, this will be 1 week before surgery. Data will be presented through study completion, an average of 2 years. ]
  With the Omnical (Ventilated Hood) the investigators will measure the basal energy metabolism status of the participant.

Original Secondary Outcome: Same as current

Information By: Maastricht University Medical Center

Dates:
Date Received: January 25, 2017
Date Started: April 14, 2017
Date Completion: April 2, 2018
Last Updated: February 7, 2017
Last Verified: February 2017