Clinical phenotypes in acute and chronic infarction explained through human ventricular electromechanical modelling and simulations

Reviewer #1 (Public Review):

Summary:
In this study by Zhou, Wang, and colleagues, the authors utilize biventricular electromechanical simulations to illustrate how different degrees of ionic remodeling can contribute to different ECG morphologies that are observed in either acute or chronic post-myocardial infarction (MI) patients. Interestingly, the simulations show that abnormal ECG phenotypes - associated with a higher risk of sudden cardiac death - are predicted to have almost no correspondence with left ventricular ejection fraction, which is conventionally used as a risk factor for arrhythmia.

Strengths:
The numerical simulations are state-of-the-art, integrating detailed electrophysiology and mechanical contraction predictions, which are often modeled separately. The simulation provides mechanistic interpretation, down to the level of single-cell ionic current remodeling, for different types of ECG morphologies observed in post-MI patients. Collectively, these results demonstrate compelling and significant evidence for the need to incorporate additional risk factors for assessing post-MI patients.

Weaknesses:
The study is rigorous and well-performed. However, some aspects of the methodology could be clearer, and the authors could also address some aspects of the robustness of the results. Specifically, does variability in ionic currents inherent in different patients, or the location/size of the infarct and surrounding remodeled tissue impact the presentation of these ECG morphologies?

Reviewer #2 (Public Review):

Summary:
The authors constructed multi-scale modeling and simulation methods to investigate the electrical and mechanical properties of acute and chronic myocardial infarction (MI). They simulated three acute MI conditions and two chronic MI conditions. They showed that these conditions gave rise to distinct ECG characteristics that have been seen in clinical settings. They showed that the post-MI remodeling reduced ejection fraction up to 10% due to weaker calcium current or SR calcium uptake, but the reduction of ejection fraction is not sensitive to remodeling of the repolarization heterogeneities.

Strengths:
The major strength of this study is the construction of computer modeling that simulates both electrical behavior and mechanical behavior for post-MI remodeling. The links of different heterogeneities due to MI remodeling to different ECG characteristics provide some useful information for understanding complex clinical problems.

Weaknesses:
The rationale (e.g., physiological or medical bases) for choosing the 3 acute MI and 2 chronic MI settings is not clear. Although the authors presented a huge number of simulation data, in particular in the supplemental materials, it is not clearly stated what novel findings or mechanistic insights this study gained beyond the current understanding of the problem.