Global fibroblast activation throughout the left ventricle but localized fibrosis after myocardial infarction

Area of Science:

• Cardiovascular Biology
• Cardiac Pathophysiology
• Fibrosis Research

Background:

• Fibroblast differentiation and fibrosis are key drivers of cardiac remodeling and dysfunction post-myocardial infarction (MI).
• Understanding the regional differences in fibrosis regulation after MI is crucial for developing targeted therapies.

Purpose of the Study:

• To investigate the regional distribution and regulatory mechanisms of fibrosis in a pig model of myocardial infarction.
• To differentiate between scar, adjacent, and remote myocardial regions based on function, perfusion, and fibrotic markers.

Main Methods:

• In vivo analysis of regional cardiac function and perfusion.
• Histological assessment of interstitial and perivascular fibrosis, and collagen type I.
• Measurement of fibroblast-activated protein-alpha (FAP-α), TGF-β1, lysyl oxidase, decorin, and biglycan.
• Isolation and culture of fibroblasts for characterization, gene expression profiling (RNA sequencing), and functional assays.

Main Results:

• Interstitial and perivascular fibrosis, along with increased collagen type I, were localized to the myocardium adjacent to the scar (MI_adjacent).
• Fibroblast-activated protein-alpha (FAP-α) was enriched in MI_adjacent compared to remote regions.
• While TGF-β1 was upregulated in both adjacent and remote areas, lysyl oxidase and specific proteoglycans were increased only in the MI_adjacent region.
• Cultured fibroblasts showed similar characteristics, but scar-derived fibroblasts were more effective in collagen matrix contraction.

Conclusions:

• Myocardial infarction triggers fibroblast activation throughout the left ventricle, likely via TGF-β1 signaling influenced by mechanical load.
• Regional signaling pathways dictate the subsequent maturation of fibroblasts and extracellular matrix remodeling, leading to localized fibrosis in the MI_adjacent zone.