Die akute Lungenarterienembolie stellt eine häufige Erkrankung dar, welche mit einer hohen Letalität einhergeht. Die Risikostratifizierung und Therapieplanung beruht derzeit primär auf klinischen Parametern, Biomarkerbestimmungen und den Ergebnissen der Echokardiographie. Fr¨¹here Untersuchungen zeigten einen möglichen Nutzen von Heart-type Fatty-Acid Binding Protein (H-FABP) als Prognosemarker. Hierbei wurden allerdings unselektierte Patientenkollektive verwendet. Der Nutzen von H-FABP in der Risikostratifizierung normotensiver Patienten mit einer akuten Lungenarterienembolie ist bislang nicht untersucht. H-FABP ist ein Enzym des Myokards, welches eine tragende Bedeutung im Fettstoffwechsel der Myozyten spielt. Es wird bei einer Schädigung des Herzmuskels ins Blutplasma freigesetzt und ist dort innerhalb kurzer Zeit als Marker einer Myokardischämie nachweisbar. Insgesamt wurde in dieser Studie die prognostische Aussagekraft von H-FABP bei 126 normotensiven Patienten mit einer akuten Lungenarterienembolie im Hinblick auf 30-Tages-Komplikationen sowie ihr Langzeit¨¹berleben untersucht. Innerhalb von 30 Tagen kam es bei 9 (7%) Patienten zu Komplikationen. In dieser Subpopulation zeigten sich signifikant (p<0,001) erhöhte H-FABP-Spiegel (median 11,2 ng/ml; IQR 8,0-36,8) im Vergleich zu der Patientengruppe, in der keine Komplikationen auftraten (median 3,4 ng/ml; IQR 82,1-4,9). 29 Patienten zeigten bei Aufnahme einen H-FABP-Wert oberhalb des mittels ROC-Analyse ermittelten cut-offs von 6 ng/ml. Hiervon entwickelten 8 (28%) Patienten Komplikationen. Von 97 Patienten mit einem normwertigen H-FABP-Wert kam es in einem Fall zu Komplikationen (negativer prädiktiver Wert 0,99; p<0,001). Damit lag bei einem erhöhten H-FABP-Spiegel ein 36,6-fach erhöhtes Komplikationsrisiko vor. Die etablierten Marker Troponin T und NT-proBNP waren hingegen nicht mit dem vermehrten Auftreten von Komplikationen assoziiert. Die Kombination von H-FABP mit einer Tachykardie erscheint ein äußerst n¨¹tzlicher und praktikabler Prognosemarker f¨¹r Komplikationen zu sein (OR 33,4; p<0,001). H-FABP zeigte sich außerdem als ein signifikanter Parameter f¨¹r ein verk¨¹rztes Langzeit¨¹berleben (HR 4,5; p<0,001). Die Ergebnisse dieser Studie deuten darauf hin, dass H-FABP ein n¨¹tzlicher Biomarker in der Risikostratifizierung hämodynamisch stabiler Patienten mit einer akuten Lungenarterienembolie ist.

Heart-type Fatty Acid-Binding Protein (H-FABP) is required for high rates of skeletal muscle long chain fatty acid (LCFA) oxidation and esterification. Here we assessed whether H-FABP affects soleus muscle glucose uptake when measured in vitro in the absence of LCFA. Wild type and H-FABP null mice were fed a standard chow or high fat diet before muscle isolation. With the chow, the mutation increased insulin-dependent deoxyglucose uptake by 141% (P<0.01) at 0.02 mU/ml of insulin, but did not cause a significant effect at 2 mU/ml insulin; skeletal muscle triglyceride and long chain acyl-CoA (LCACoA) levels remained normal. With the fat diet, the mutation increased insulin-dependent deoxyglucose uptake by 190% (P<0.01) at 2 mU/ml insulin, thus partially preventing insulin resistance, and completely prevented the threefold (P<0.001) diet-induced increase of muscle triglyceride levels; however, muscle LCACoA levels showed little or no reduction. With both diets, the mutation reduced the basal (insulinindependent) soleus muscle deoxyglucose uptake by 28% (P<0.05). These results establish a close relationship of FABP-dependent lipid pools with insulin sensitivity, and indicate the existence of a non-acute, antagonistic, and H-FABP-dependent fatty acid regulation of basal and insulin-dependent muscle glucose uptake. Liver fatty acid binding protein (L-FABP) has been proposed to limit the availability of chain LCFA for oxidation and for peroxisome proliferator-activated receptor (PPAR-alpha), a fatty acid binding transcription factor that determines the capacity of hepatic fatty acid oxidation. Here, we used L-FABP null mice to test this hypothesis. Under fasting conditions, this mutation reduced &#946;-hydroxybutyrate (BHB) plasma levels as well as BHB release and palmitic acid oxidation by isolated hepatocytes. However, the capacity for ketogenesis was not reduced: BHB plasma levels were restored by octanoate injection; BHB production and palmitic acid oxidation were normal in liver homogenates; and hepatic expression of key PPAR-alpha target (MCAD, mitochondrial HMG CoA synthase, ACO, CYP4A3) and other (CPT1, LCAD) genes of mitochondrial and extramitochondrial LCFA oxidation and ketogenesis remained at wild-type levels. These results suggest that under fasting conditions, hepatic L-FABP contributes to hepatic LCFA oxidation and ketogenesis by a nontranscriptional mechanism.

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.

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