A multiscale computational model provides a conceptual framework linking systemic inflammation and physiological complexity in autonomic heart rate regulation.
May guide modeling of autonomic responses in sepsis; leaves open clinical validation before any practice implications.
The systemic inflammatory response syndrome often accompanies critical illnesses and can be an important cause of morbidity and mortality. Marked abnormalities in cardiovascular function accompany acute illnesses manifested as sustained tachyarrhythmias, which are but one component of systemic dysregulation. The realization that cardiac pacemaker activity is under control of the autonomic nervous system has promoted the analysis of heart rate (HR) variation for assessing autonomic activities. In acute illnesses, autonomic imbalance manifesting in part as parasympathetic attenuation is associated with increased morbidity in patients who manifest systemic inflammatory response syndrome phenotype. Driven by the premise that biological phenotypes emerge as the outcome of the coordinated action of network elements across the host, a multiscale model of human endotoxemia, as a prototype model of systemic inflammation in humans, is developed that quantifies critical aspects of the complex relationship between inflammation and autonomic HR regulation. In the present study, changes in HR response to acute injury, phenotypically expressed as tachycardia, are simulated as a result of autonomic imbalance that reflects sympathetic activity excess and parasympathetic attenuation. The proposed model assesses both the anti-inflammatory and cardiovascular effects of antecedent stresses upon the systemic inflammatory manifestations of human endotoxemia as well as a series of nonlinear inflammatory relevant scenarios. Such a modeling approach provides a comprehensive conceptual framework linking inflammation and physiological complexity via a multiscale model that may advance the translational potential of systems modeling in clinical research. ABBREVIATIONS-LPS-lipopolysaccharide, endotoxin; R-endotoxin signaling receptor (TLR4); LPSR-endotoxin-TLR4 complex; mRNA,R-gene transcript of endotoxin receptor (TLR4); IKK-kinase activity; NFκBn-nuclear concentration of NF-κB; mRNAIκBa-gene transcript of NF-κB inhibitor (IκBa); IκBa-protein inhibitor IκBa; P-transcriptional proinflammatory response; A-transcriptional anti-inflammatory response; E-transcriptional energetic response; F-cortisol; Rm-gene transcript of glucocorticoid receptor; RF-free cytosolic glucocorticoid receptor; FR -cytosolic steroid-receptor complex; FR(N)-nuclear steroid-receptor complex; EPI-epinephrine; REPI-β-adrenergic receptor; EPIR-epinephrine-adrenergic receptor complex; fP-efferent (cardiac) nerve activity; Sf-cardiac active signal; HRV-heart rate variability; A1-catecholamines at the SNS nerve ending; A2-catecholamines at the sinus node (SA); B-chemical substance at the SA of the heart; Tsym-efferent sympathetic activity; Tpar-efferent parasympathetic activity; HR-heart rate
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Foteinou et al. (2010) studied this question.
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