Mechanisms for Reduced Beat to Beat Variability in Sepsis

Sepsis refers to a spectrum of illness ranging from systemic infection to multiple organ dysfunction syndrome and death. Mortality rates are high, amounting to 30% for sepsis and 80% for septic shock. Early recognition of sepsis allows fast therapeutic intervention but remains difficult because antecedent symptoms are subtle and hardly recognizable. Especially in intensive care units, patients are at risk of infection with multidrug-resistant pathogens through invasive, life-sustaining measures. In recent years, a reduction in heart rate variability (HRV) has been suggested as prognostic marker for severe infection and has been shown to correlate with a worse outcome for the patient. The HRV originates from dynamic changes of autonomic inputs on the ion channel activity in the sinoatrial node. But a certain degree of beat to beat variability (BBV) is inherently present at the level of sinoatrial cells due to the intrinsic properties of the underlying pacemaking mechanisms. This implies, that the HRV reduction in sepsis could to some extent originate from alterations in the pacemaking process and/or from altered responsiveness of sinoatrial cells to autonomic input. Elucidating the molecular mechanisms leading to HRV reduction is essential to validate this diagnostic marker for the detection of early-stage sepsis. In this project we aim to investigate basic mechanisms that could contribute to the observed HRV reduction in sepsis. We assume that the responsible mechanisms involve modifications in the pacemaking process in the sinoatrial node cells. A comprehensive analysis of the pacemaking process will be performed in sinoatrial node cells, isolated from the mouse heart. Experimental methods comprise patch clamp, microelectrode and extracellular potential recordings, Ca2+ imaging, molecular biology, and FRET. Understanding the causative mechanisms contributing to the sepsis-induced HRV reduction opens new avenues to initiate appropriate therapeutic intervention at the earliest possible time point. The responsible researchers in this proposal are Susanne Scherübel, Brigitte Pelzmann, and Klaus Zorn-Pauly, all from the Gottfried Schatz Research Center, Biophysics, Medical University.

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