Abstract

Objectives: Cardiac wound healing post-myocardial infarction represents a complex balance between inflammation and fibrosis (Richardson 2017). A biphasic immune response post-infarction (Kologrivova 2021) regulates the repair process to produce a scar in the infarcted area. Inter-individual variability has shown various clinical outcomes, from relatively stable individuals to those subject to insufficient repair and heart failure (Cahill 2017). A quantitative, mechanistic model of cardiac pathophysiology was developed to provide insight into individual differences and in predicting post-infarction efficacy of potential therapies.

Methods: We utilize a quantitative systems pharmacology (QSP) approach to develop a mechanistic model of a left ventricle myocardial infarction with inflammatory and fibrotic responses. The model represents cardiomyocytes, innate immune cells (macrophages, neutrophils), fibroblasts, collagenproduction, and regulatory mediators. The model represents an infarct proximal region, including cardiomyocytes susceptible to further injury, inflammation, and fibrotic wound healing. It also represents a distal region, with lesser inflammation and fibrosis.

Results: Simulated cardiomyocytes post-infarction undergo necrosis in proportion to the simulated infarct size, releasing danger signals (Kohno 2009, Andrassy 2011). These signals induce an acute inflammatory response, where simulated macrophages and neutrophils increase orders of magnitude then shift to a chronic, reparative/fibrotic phase in accordance with human data (Lee 2012, van der Laan 2014, Czepluch 2013). Corresponding increased levels of inflammatory and fibrotic mediators (TNFα, IL-10, TGFβ, PDGF, MMP-9) were calibrated to data (Gruzdeva 2017, Chen 2014, Wallace 1998, Tan 2012) and regulate the timing of fibroblast activation to myofibroblasts (Fishbein 1978) and level of collagen deposition (Marijianowski 1997). A sensitivity analysis was conducted on mechanistic pathways impacting therapeutic outcomes and on individual variability in the inflammation/fibrosis balance with subsequent impact on infarct scar formation and susceptibility to heart failure.

Conclusions: The mechanistic QSP model CARDIOsym describes the inflammatory and fibrotic responses post-myocardial infarction, consistent with the expected range of patient responses. This model is well-suited to study the effects of therapeutic interventions in modifying the balance between inflammation and fibrosis and determining effects on cardiac remodeling.

By Zackary R. Kenz, Christina Battista, Lisl K.M. Shoda, Yeshitila Gebremichael, Scott Siler, Lyn Powell, Limei Cheng

Presented at American Conference of Pharmacometrics (ACoP), November 8-12, 2021