## 4 Discussion
Similar to H-FABP, GDF-15 remained predictive for sepsis after correction for potential confounders. [PERSON] et al. observed similar findings when they compared GDF-15 levels of ICU patients with and without sepsis. They were able to show a strong association of high GDF-15 values with multi-organ dysfunction and mortality [15]. Of note is the significant elevation of GDF-15 observed in STEMI patients, compared to HF and controls, which indicated a proinflammatory state of the vascular system in acute coronary events. An elevation in cytokines IL-6/-10/-12 and TNF-\(\alpha\), as well as a lowered concentration of dendritic cells in peripheral blood due to recruitment and cell migration in infarcted myocardium, was already proposed as a potential explanation by former studies [16]. Levels of sST2 were significantly elevated in both sepsis- and STEMI-patients compared to controls and heart-failure patients, while a trend towards higher levels in sepsis patients was observed compared to STEMI-patients. There are two isoforms of ST2, a soluble (sST2) and a membrane-bound (ST2L) form. IL-33 acts as a ligand to both isoforms, inducing cardioprotective effects through the ST2L pathway [17]. sST2, acting as a decoy receptor for IL-33, counteracts these cardioprotective effects and consequently leads to myocardial hypertrophy and cardiac remodeling [18]. Therefore, elevated levels of sST2 can be found in states of hemodynamic stress and cardiomyocyte strain. ST2L also activates the MyD88/NF-\(\kappa\)B-pathway and enhances functions of T-cells, mast cells and cells of the innate lymphoid type, emphasizing the involvement of sST2 in inflammatory processes [19]. Given the combination of a systemic inflammatory state as well as a significant increase in cardiac stress as part of the multi-organ involvement and systemic hypoperfusion in the context of sepsis, an additive effect of ischemia and inflammation has to be considered as the most probable explanation for the high levels of sST2 observed in sepsis [16]. Similar to our findings, [PERSON] et al. also were able to show significantly elevated sST2-levels in patients with septic shock, compared to individuals with cardiogenic shock or STEMI. Additionally, a significant difference between cardiogenic shock and STEMI could be observed, underlining the generalized immunologic state of emergency in shock [20]. The greater systemic immunological escalation in a shock event compared to other disease entities is also reflected by suPAR counts in our study. suPAR is a proinflammatory marker, indicative of an activation of the immune system, and plays an important role in chemotaxis, cell adhesion and cell migration [21]. Studies reported a correlation of suPAR and outcomes in critically ill and sepsis patients [22]. Another study on the application of suPAR in intensive care medicine showed a correlation with disease severity, readmission and mortality [23]. suPAR probably also reflects the role of the immune system in cardiac remodeling in heart failure or incipient scarring in acute ischemia [24]. Again, the high suPAR levels observed for sepsis patients might be based on a combination of myocardial and inflammatory processes. Our results emphasize the myocardial involvement in sepsis patients. While inflammatory processes account for a great part of the myocardial involvement, according to our results ischemic processes also seem to be of utmost importance in this regard. Interestingly, H-FABP and GDF-15 remained predictive for sepsis even after correction for potential confounders, including CRP. Thus, it can be assumed, that H-FABP and GDF-15 are less influenced by inflammatory activity compared to sST2 and suPAR, which seemed more suited to reflect the inflammatory burden in sepsis. The usefulness of a given test in the clinical application depends on the availability of reliable references or cut-off values, and our data show that for patients with sepsis the proposed cut-off values could be applied in future sepsis studies for external validation.