Computational modelling of cardiac control following myocardial infarction using an in silico patient cohort.

Abstract

Loss of cardiac physiological function following myocardial infarction (MI) is accompanied by neural adaptations in the baroreflex that are compensatory in the short term, but then become associated with long-term disease progression. One marker of these adaptations is decreased baroreflex sensitivity, a strong predictor of post-MI mortality. The relative contributions of cardiac remodelling and neural adaptation in the sensory, central brainstem and peripheral ganglionic loci to baroreflex sensitivity changes remain underexplored. We used a computational model-based approach that accounts for the short-term dynamics of closed-loop human cardiac control to integrate disparate experimental studies on neural adaptation following MI into a unified quantitative framework. We developed an ensemble of 59 distinct model parameterizations that account for the clinically observed heterogeneity of cardiac control in healthy individuals. We simulated an in silico cohort of 35,400 patients with MI, corresponding to six scenarios of one or more loci of neural adaptation coupled with cardiac remodelling. We evaluated the range of MI-induced shifts in arterial pressure, heart rate and baroreflex curve responses. Our results show that adaptation in any single neural locus coupled with cardiac remodelling is sufficient to account for the MI-induced haemodynamic and autonomic changes observed experimentally. Of the adaptation pathways, we found that individuals with central or peripheral vagal efferent adaptation and preserved baroreceptor gain could maintain high baroreflex sensitivity after ischaemic injury. These results suggest that there are a multitude of adaptive pathways for tuning the baroreflex circuit to shift cardiac control physiology, potentially explaining patient heterogeneity post-MI. KEY POINTS: Baroreflex sensitivity is a strong indicator of post-myocardial ischaemia survival and is variable among individuals. We fine-tuned a computational model ensemble based on physiological observations to develop an in silico patient cohort consistent with the range of baroreflex responses observed experimentally. Simulation and analysis of the in silico cohort show that individuals with a functional afferent pathway and the ability to adapt along the vagal efferent pathway can maintain baroreflex sensitivity post-cardiac ischaemia.