Clinical Trial Details
— Status: Completed
Administrative data
NCT number |
NCT03049228 |
Other study ID # |
NL.ABR.48376 |
Secondary ID |
|
Status |
Completed |
Phase |
|
First received |
|
Last updated |
|
Start date |
March 21, 2017 |
Est. completion date |
March 2, 2020 |
Study information
Verified date |
November 2020 |
Source |
Maastricht University Medical Center |
Contact |
n/a |
Is FDA regulated |
No |
Health authority |
|
Study type |
Observational [Patient Registry]
|
Clinical Trial 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.
Description:
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 lipotoxicity.
So far, human studies on PPAR expression in the heart are scarce. Marfella et al. found
unaltered expression of PPAR-α in patients with the metabolic syndrome. Conversely, Anderson
et al., showed a slightly reduced PPAR-α protein level and a slightly higher PGC1α level in
diabetic atrial tissue, though these differences did not reach statistical significance in
this cohort of patients. As this study was performed in a small group of subjects and failed
to determine the down-stream targets of the PPAR metabolism or mitochondrial function, it
remains unclear whether like in animal studies also in humans a reduced PPAR-a expression is
related to mitochondrial dysfunction. Therefore there is need for studies exploring the role
of PPAR-a in human heart and the connections with oxidative metabolism and cardiac function.
Mice lacking the cardiac lipase ATGL (ATGL-/- mice) was actually due to a reduction in PPAR
metabolism, and that the cardiomyopathy in these mice could be completely prevented by
treating these animals with synthetic PPAR-a ligands. Very interestingly, patients with a
mutation in the same ATGL gene are also characterized by excessive cardiac and muscle fat
accumulation and reduced mitochondrial function. Treating two patients with such mutations
(which is a very rare mutation) with a PPAR-agonist (bezafibrate) resulted in improved
mitochondrial function and a reduction in muscle and cardiac lipid accumulation. These data
support the notion that a disturbed PPAR metabolism may be involved in the development of
cardiomyopathy, also in humans. However, unfortunately, there is limited data on
PPAR-expression in the failing human diabetic heart. Therefore there is need of studies
validating these mechanisms in humans, as these findings might have great consequences;
prevention and treatment of cardiac lipid accumulation with drugs that improve mitochondrial
function, such as PPAR-agonists, might be of value to patients with type 2 diabetes. Also in
other cardiac diseases, such as chronic heart failure and ischemic heart disease, it has been
suggested that fat accumulation and mitochondrial dysfunction may play a role, which means
that these patients might benefit as well from treatment with drugs that target mitochondrial
function.
Although there is compelling evidence that mitochondrial function plays an important role in
cardiac metabolism, measuring cardiac mitochondrial function non-invasively in vivo remains a
challenge. In vivo mitochondrial function can be estimated non-invasively with 31P-Magnetic
Resonance Spectroscopy (31P-MRS), whereby the ratio Phospho-creatine (PCr) over Adenosine
Triphosphate (ATP) is measured (PCr/ATP-ratio). Several studies have shown that this ratio is
reduced in patients with type 2 diabetes, and that a low PCr/ATP ratio predicts mortality in
patients with cardiac failure15-17. In skeletal muscle it has been shown that PCr-resynthesis
strongly correlates with mitochondrial oxidative capacity18. However, if this method in the
heart truly reflects mitochondrial function in humans has not been revealed.
In 31P-MRS a 2 dimensional measurement method is used, in which multiple slices are planned
over the heart. One slice is planned directly at the base of the heart in the plane just
below the valves and contains both ventricular and septal tissue of both chambers. Here the
signal for acquisition of the spectrum will be derived. This method can be validated against
the golden standard for mitochondrial function: ex vivo respirometry of cardiac tissue19.
Thus, mitochondrial respiration rates are measured in tissue homogenates under exposure of
different substrates, stimulating different complexes of the electron transport chain of the
mitochondria. One issue is that mitochondrial respiration may differ between atrial and
ventricular tissue. However, despite the differences in absolute respiration rates, the
behaviour of the different complexes and relative respiration rates (between complexes) has
been shown to be very strongly related19. Since it is relatively easy to obtain atrial
appendage cardiac tissue during surgery, the investigators propose to use atrial tissue
obtained during surgery to validate 31P-MRS as a tool to determine mitochondrial function.
The investigators will use a broad range of patients to guarantee a range in cardiac
mitochondrial functions, and to examine if cardiac mitochondrial function is indeed reduced
in type 2 diabetic patients.
However, as the 31P-MRS still is a technique in development and the distance to the receiver
coil is crucial for obtaining spectra of good quality, the investigators intend to only
include men at this time (as increased breast mass in women may decrease signal to noise
ratios and hence spectral quality for analysis). Therefore, the validation of this method
will only apply for the male population in this study.