Complex dynamics in systemic inflammation : quantification of coupling and targeting of the nitric oxide-soluble guanylate cyclase axis

Sepsis and septic shock are associated with high mortality rates and the majority of sepsis patients die due to complications of multiple organ dysfunction. The nitric oxide (NO) – soluble guanylate cyclase (sGC) axis is centrally involved in the homeodynamics of the (micro)circulation and cardiac function. Malfunctioning of this pathway can lead to failure of end-organ perfusion and cytopathic hypoxia, culminating in progressive multiple organ dysfunction and death. Although the pathway has been linked to detrimental effects in the pathogenesis of sepsis, the emerging consensus is that functional NO/sGC signaling is a prerequisite for microcirculatory and cardiac function, and thus stabilization of end-organ function during sepsis-induced systemic inflammation. Therefore we examined the feasibility of pharmacological targeting of sGC in a murine endotoxic shock model. The sGC activator BAY 58-2667 (cinaciguat) will specifically reactivate sGC that was exposed to oxidative stress and can prevent morbidity, cardiomyocyte apoptosis, and mortality when administered as a late therapeutic treatment. However, treatment was restricted to an optimal time window: administration of BAY 58-2667 too early after the sepsis-inducing challenge exacerbated mortality, indicating that the dynamics of the redox status of sGC were changing as a function of oxidative stress during the progression of endotoxic shock, and emphasizing the highly bivalent function of the pathway. We hypothesize that treatment with BAY 58-2667 in this optimal window specifically reestablished microcirculatory flow in hypoxic capillary beds by vasodilation, anti-platelet aggregation, anti-leukocyte adhesion, and cardioprotective effects. Together, these effects should lead to improved perfusion, decreased (cytopathic) hypoxia, and subsequently, improved organ function and survival. In addition, the effect of BAY 58-2667 on inter-organ coupling was quantified via variability of beat-to-beat dynamics. We identified improvements in unifractal dynamics and increased spectral power in the low frequency band acutely post-treatment. The latter is indicative for increased sympathetic input to the sinus node of the heart. Furthermore, a large number of measures of beat-to-beat variability were examined in a murine tumor necrosis factor (TNF) and endotoxic shock model. Our results indicate that analysis of beat-to-beat dynamics at high temporal resolution via multiscale entropy (MSE), a measure of complex dynamics, can predict outcome very early after the initial challenge, in contrast to other variability parameters, absolute heart rate, or blood pressure. Because the output of the MSE algorithm is a complex aggregate of multiscalar information, we developed a more clinically relevant MSE scoring method that amplifies the relevant features of an MSE profile, and summarizes that information in simple scoring components that can be easily followed as a function of time. Thus, quantification of multiscale complexity in physiological time series appears to be representative for the underlying complex regulation of the organism, the degree of loss of inter-organ coupling, and can be highly sensitive and specific for detecting state changes linked to disease, as demonstrated in these murine models. Preliminary results indicate that this is also possible in more complex sepsis models, as well as intensive care patients. Finally, we also showed that the hypersensitivity of MK2-deficient mice to TNF is likely caused by defects in the stress fiber response and/or failure of certain granulocytes to extravasate