AimsA marked increase in HDL notwithstanding, the cholesterol ester transfer protein (CETP) inhibitor torcetrapib was associated with an increase in all-cause mortality in the ILLUMINATE trial. As underlying mechanisms remain elusive, the present study was designed to delineate potential off-target effects of torcetrapib.
Heart failure after myocardial infarction represents an important and
socio-economic problem. Despite there being actual opportunities for therapy,
heart failure is still characterized by a high morbidity and mortality.
Therefore novel therapeutic targets have to be investigated.
Left ventricular remodeling after myocardial infarction,
which involves changes of structure and form of the left ventricle,
contributes to development and progression of heart failure. Reactive oxygen
species have been implicated in left ventricular remodeling. The NAD(P)H
oxidase is a major source of superoxide anions, which belong to the reactive
oxygen species. Myocardial expression and activity of the NAD(P)H oxidase are
markedly increased in human heart failure. However, the role of the NAD(P)H
oxidase and especially its subunit p47phox remains to be determined for left
ventricular remodeling, dysfunction and survival after myocardial infarction.
Myocardial infarction was induced in wild type and p47phox
deficient mice, lacking the cytosolic NAD(P)H oxidase component p47phox, by
ligating the left coronary artery. Also a sham operation was performed in
each control group of wild type and p47phox deficient mice. Infarct size was
similar among wild type and p47phox deficient animals. Apart from one
exception as mentioned later, the animals were killed four weeks after
myocardial infarction. NAD(P)H oxidase activity detected by electron spin
resonance spectroscopy was markedly increased in remote left ventricular
myocardium of wild type mice after myocardial infarction compared to sham
operated mice, but not in p47phox deficient animals after myocardial
infarction. Similar results could be obtained for xanthine oxidase activity,
suggesting NAD(P)H oxidase dependent xanthine oxidase activation. Reactive
oxygen species production was enhanced in wild type mice, but not in p47phox
deficient mice after myocardial infarction. Left ventricular cavity
dilatation and dysfunction assessed by echocardiography were markedly
attenuated in p47phox deficient mice four weeks after myocardial infarction.
Furthermore, cardiomyocyte hypertrophy, interstitial fibrosis, and cardial
apoptosis were reduced in p47phox deficient mice compared to wild type mice.
In contrast to the other animals wild type mice, killed five days after
myocardial infarction, showed an increased MMP-2 activity in remote and
infarcted myocardium, this was less in p47phox deficient mice. The latter
seems among other things to be partly responsible for the higher survival
rate of p47phox deficient mice in comparison with wild type mice.
The results suggest that the NAD(P)H oxidase and its subunit
p47phox play a pivotal role for left ventricular remodeling, left ventricular
dysfunction and survival after myocardial infarction. They offer a novel
starting point for therapy strategies to reduce left ventricular remodeling
and left ventricular dysfunction after myocardial infarction.
Self-gated dynamic cardiovascular magnetic resonance (CMR) enables non-invasive visualization of the heart and accurate assessment of cardiac function in mouse models of human disease. However, self-gated CMR requires the acquisition of large datasets to ensure accurate and artifact-free reconstruction of cardiac cines and is therefore hampered by long acquisition times putting high demands on the physiological stability of the animal. For this reason, we evaluated the feasibility of accelerating the data collection using the parallel imaging technique SENSE with respect to both anatomical definition and cardiac function quantification.
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