Background:
About 30% of acute myocardial infarction (AMI) patients develop long-term heart failure (HF), primarily due to irreversible left ventricular (LV) cardiomyocyte loss and interstitial fibrosis during cardiac remodeling. Preserving the function of cardiomyocytes and mitigating the adverse effects of fibrosis is therefore critical to prevent LV dysfunction and progression to HF.
Recent single-cell transcriptomics analysis have identified distinct subpopulations of LV cardiomyocytes after myocardial infarction, depending on the degree of cellular stress arising from changes in perfusion, metabolic supply, and the microenvironment. These subpopulations appear to differentially impact post-infarction healing and ventricular remodeling, yet their specific roles remain unclear. A further understanding of these cardiomyocyte subpopulations in the reperfused myocardial infarction (repAMI) is essential to elucidate the mechanisms regulating fibrosis formation and cardiac remodeling.
Methods:
We identified stressed cardiomyocyte subpopulations on a protein level in an in vivo mouse model of repAMI. Immunofluorescence and confocal microscopy were used to localize these cardiomyocytes in heart tissue samples collected at various time points following infarction.
To analyze spatial distribution, we employed 3D imaging techniques using light sheet microscopy. Fibrotic regions were visualized using Picrosirius red staining. Temporal dynamics and localization patterns were assessed throughout a 28-day reperfusion period.
Results:
Stressed cardiomyocytes were consistently localized in the border zone of the infarcted area in the left ventricle. While their number varied over time, their presence in this region remained stable throughout the healing process and was observed up to 28 days in reperfusion.
Picrosirius red staining revealed a spatial association between the stressed cardiomyocyte subpopulation and fibrotic regions. These findings suggest that stressed cardiomyocytes may influence fibroblast activation and the progression of fibrosis during cardiac remodeling.
Conclusions:
This study demonstrates the consistent presence of stressed cardiomyocyte subpopulations in the infarct border zone and their spatial association with fibrosis during cardiac remodeling following repAMI.
We aim to further characterize the temporal and spatial dynamics of these cardiomyocytes, their interactions with fibroblasts, and their role in fibrosis development. Future experiments will provide mechanistic insight into how cardiomyocyte subpopulations influence fibroblast activity and fibrosis, potentially identifying novel therapeutic targets to modulate adverse cardiac remodeling.
