dc.description.abstract | Since 1933, studies have explored the concept of trauma induced secondary cardiac
injury (TISCI), yet till 2012, it had not been defined as the incidence of cardiac
events and rise in cardiac biomarkers following traumatic injury. Despite,
improvements in early outcomes, trauma patients have reduced long-term
mortality with cardiac disease being the major contributor. Although many putative
mechanisms have been suggested for TISCI, the underpinning pathophysiology still
remains unclear.
In this thesis, a prospective study of 290 critically injured patients identifies a 13%
incidence of adverse cardiac events (ACE) with consistently raised serum h-FABP
levels in these patients. H-FABP was found to be a good predictor of ACE through
ROC analysis and a h-FABP of 16.8 ng/ml used to define trauma induced secondary
cardiac injury (TISCI). TISCI was associated with longer hospital stay and higher
mortality. Patients who developed ACE had higher plasma levels of adrenaline and
noradrenaline with a correlating increase in plasma h-FABP. On multivariate
analysis, hypertension was the only independent risk factors for ACE.
The increase in serum cardiac biomarkers was reflected by an increase in serum h-
FABP in our group’s trauma hemorrhage murine models. The hearts of these
models were used in the experiments that form the last experimental chapter of
this thesis. Protein expression studies confirm this increase in serum h-FABP by
evidence of concurrent leaching in the cardiac tissue, along with Troponin I.
Myocardial injury was evident on electron microscopy with evidence of interstitial
and organelle oedema, myofibrillar degeneration, nuclear condensation and
changes in mitochondrial morphology. Immunohistochemistry and western blotting
protein studies demonstrate the translocation of the mitochondrial death-related
protein AIF to the cytosol and nucleus, where it becomes its active pro-apoptotic
form.
This thesis propositions the utility of the cardiac biomarker h-FABP in predicting ACE
and outcomes in critically injured patients. Although increasing serum
noradrenaline and adrenaline levels are associated with higher incidence of ACE
and biochemical evidence of cardiac injury with rising h-FABP levels, multivariate
analysis negates their value as independent predictors of ACE. Leaching out of the
proteins h-FABP and Troponin I in the murine cardiac tissue confirmed the value of
serum measurements of these proteins as markers of cardiac injury. This was
associated with widespread ultrastructural myocardial damage in the TH mice with
changes in mitochondrial morphology. The mitochondrial damage seen is
associated with the translocation of the mitochondrial death-related protein AIF to
the cytosol and the nucleus where I propose its canonical signaling leading to
nuclear degradation and cell death is the driver of cardiac dysfunction. | en_US |