Decreased communication leads to diminished physiologic variability in a multiscale model of inflammation

Abstract

was used to assess parasympathetic influences on the heart. The present study expanded our prior work in an attempt to include systemic level interactions associatedwith the effect onheart rate of the dynamic interplay between sympathetic and parasympathetic branches of autonomic nervous system. Physicochemical interactions related to the release and binding of cardiac neurotransmitters in the synapses between neural fibers and the sinoatrial nodal cells were explicitly incorporated. Furthermore, the 2 major autonomic control systems were considered to act antagonistically giving rise to changes in heart rate. Finally, quantifiable relationships among these complex physiologic signals were established using the principles of indirect response modeling. Thus, this study links inflammation and clinical outcomes via a multiscale host response model. Results: This modeling effort describes cardiovascular responses to acute endotoxin injury, phenotypically expressed as tachycardia, because of autonomic imbalance that reflects sympathetic activity excess and parasympathetic attenuation. Such dysregulation is mediated by an acute neuroendocrine stress response evoked by inflammation, making it a critical enabler for assessing the cardiovascular effects of antecedent stresses upon the systemic inflammatory manifestations of human endotoxemia. For instance, the proposed model captures the vagolytic influence of exogenously induced catecholamine excess as observed in relevant human experimental studies. Furthermore, a series of nonlinear but relevant inflammatory scenariosaresimulatedthatexplorestheimpactofanti-inflammationon compromisingoutcomeduringthecourseofunremittinginflammation. Such scenarios associate adverse stress outcomes with severe cardiovascular complications simulated as persistent tachycardia. Conclusions: The major conclusion of this work was to demonstrate the feasibility of a multiscale, physiology-based human inflammation model that links inflammation and autonomic control of cardiovascular function. Such a relationship is disturbed in actual acute illnesses and, therefore, the proposed model lays the foundation for a translational, computational model that could potentially clarify the clinical contexts in which autonomic dysregulation contributes to morbidity in acutely stressed patients.