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Introduction: After myocardial infarction (MI), the heart undergoes necrosis, inflammation, scar formation, and remodeling. While restoring blood flow is crucial, it can cause ischemia-reperfusion (IR) injury, driven by reactive oxygen species (ROSs), which exacerbate cell death and tissue damage. This study introduces a mathematical model capturing key post-MI dynamics, including inflammatory responses, IR injury, cardiac remodeling, and stem cell therapy. The model uses nonlinear ordinary differential equations to simulate these processes under varying conditions, offering a predictive tool to understand MI pathophysiology better and optimize treatments. Methods: After myocardial infarction (MI), left ventricular remodeling progresses through three distinct yet interconnected phases. The first phase captures the immediate dynamics following MI, prior to any medical intervention. This stage is mathematically modeled using the system of ordinary differential equations: The second and third stages of the remodeling process account for the system dynamics of medical treatments, including oxygen restoration and subsequent stem cell injection at the injury site. Results: We simulate heart tissue and immune cell dynamics over 30 days for mild and severe MI using the novel mathematical model under medical treatment. The treatment involves no intervention until 2 h post-MI, followed by oxygen restoration and stem cell injection at day 7, which is shown experimentallyand numerically to be optimal. The simulation incorporates a baseline ROS threshold (Rc) where subcritical ROS levels do not cause cell damage. Conclusion: This study presents a novel mathematical model that extends a previously published framework by incorporating three clinically relevant parameters: oxygen restoration rate (ω), patient risk factors (γ), and neutrophil recruitment profile (δ). The model accounts for post-MI inflammatory dynamics, ROS-mediated ischemia-reperfusion (IR) injury, cardiac remodeling, and stem cell therapy. The model’s sensitivity highlights critical clinical insights: while oxygen restoration is vital, excessive rates may exacerbate ROS-driven IR injury. Additionally, heightened patient risk factors (e.g., smoking, obesity) and immunodeficiency significantly impact tissue damage and recovery. This predictive tool offers valuable insights into MI pathology and aids in optimizing treatment strategies to mitigate IR injury and improve post-MI outcomes.
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Don’t go breakin’ my heart: cardioprotective alterations to the mechanical and structural properties of reperfused myocardium during post-infarction inflammation
Myocardial infarctions (MIs) kickstart an intense inflammatory response resulting in extracellular matrix (ECM) degradation, wall thinning, and chamber dilation that leaves the heart susceptible to rupture. Reperfusion therapy is one of the most effective strategies for limiting adverse effects of MIs, but is a challenge to administer in a timely manner. Late reperfusion therapy (LRT; 3 + hours post-MI) does not limit infarct size, but does reduce incidences of post-MI rupture and improves long-term patient outcomes. Foundational studies employing LRT in the mid-twentieth century revealed beneficial reductions in infarct expansion, aneurysm formation, and left ventricle dysfunction. The mechanism by which LRT acts, however, is undefined. Structural analyses, relying largely on one-dimensional estimates of ECM composition, have found few differences in collagen content between LRT and permanently occluded animal models when using homogeneous samples from infarct cores. Uniaxial testing, on the other hand, revealed slight reductions in stiffness early in inflammation, followed soon after by an enhanced resistance to failure for cases of LRT. The use of one-dimensional estimates of ECM organization and gross mechanical function have resulted in a poor understanding of the infarct’s spatially variable mechanical and structural anisotropy. To resolve these gaps in literature, future work employing full-field mechanical, structural, and cellular analyses is needed to better define the spatiotemporal post-MI alterations occurring during the inflammatory phase of healing and how they are impacted following reperfusion therapy. In turn, these studies may reveal how LRT affects the likelihood of rupture and inspire novel approaches to guide scar formation.
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- Award ID(s):
- 2030173
- PAR ID:
- 10480532
- Publisher / Repository:
- Springer Nature
- Date Published:
- Journal Name:
- Biophysical Reviews
- Volume:
- 15
- Issue:
- 3
- ISSN:
- 1867-2450
- Page Range / eLocation ID:
- 329 to 353
- Subject(s) / Keyword(s):
- Myocardial infarction Reperfusion therapy Inflammation Extracellular matrix Collagen Biomechanics
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1007/s12551-023-01068-3
