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Myocardial matrix was injected into infarcted myocardium 1 week post-ischemia-reperfusion in Sprague-Dawley rats, with promising results, according to research published in the Journal of the American College of Cardiology.
The study was conceived out of an increasing need for more effective therapies to prevent heart failure development after myocardial infarction (MI). As the authors pointed out, while the heart has been recognized as an organ capable of self-regeneration, its efforts are insufficient to compensate for the many cardiomyocytes lost after an MI.
“After an infarct, cardiomyocyte death peaks 24 hours after the injury then decreases, but continues to be increased above baseline levels for at least 12 weeks,” researchers noted. “Therefore, delivery of the myocardial matrix could play an important role in salvaging cardiomyoctyes that are pre-apoptotic.”
Researchers examined several key pathways, including inflammatory response, cardiomyocyte apoptosis, infarct neovascularization, cardiac hypertrophy and fibrosis, metabolic enzyme expression, cardiac transcription factor expression, progenitor cells, and general cardiac function and hemodynamics.
Myocardial matrix injection significantly reduced the percent change in ejection fraction (P=.028) and end-systolic volume (P=.004) from 6 days after MI (1 day before injection) to 6 weeks after MI (5 weeks after injection).
In terms of immune response pathways, including migration and infiltration of various cell types, a substantial number of genes were –26.6% at day 3 and 9.8% at 1 week, indicating an increase of macrophage infiltration as a result of the matrix injection. However, an immunohistochemistry analysis revealed no differences in macrophage infiltration between saline- and matrix-injected infarcts at 3 days.
While increased blood vessel development was not directly predicted at the 1 week mark after injection, many growth factors associated with angiogenesis and neovascularization were identified, including a decrease in angioproietin-2, increases in acidic fibroblast growth factor, and vascular endothelial growth factors A and B.
Cardiomyocyte apoptosis decreases were predicted at both 3 days and 1 week. Caspase-3-expressing cardiomyocytes within the infarct wall demonstrated a trend toward decreased apoptotic cardiomyocytes at the 3-day mark. And after 1 week from injection, oxidative metabolism and mitochondrial biogensis genes were upregulated and predicted to be activated by Ingenuity Pathway Analysis (Qiagen; Redwood City, CA).
Gene ontology analysis categorized 53% of the differentially expressed transcripts to be involved in the metabolic processes. Several upregulated nuclear receptors were discovered to be involved in cardiac metabolism and mitochondrial biogensis.
Cardiac hypertrophy was highly represented in the pathways predicted to be downregulated by Ingenuity Pathway Analysis, at 1 week after injection. Negative regulators of hypertrophy were increased in expression and the positive regulator NUPR1 was decreased.
“Similar analyses have also been applied to other experimental therapies for MI including cell transplantation and injection of cell-derived products,” researchers wrote. “However, to our knowledge, no other biologic-based therapy has been reported to induce a distinct transcription signature at a global level.”
These results provide both transcriptional and histologic evidence that myocardial matrix may become an effective therapy in the prevention of HF after MI.
Reference
Wassenaar JW, Gaetani R, Garcia JJ, et al. Evidence for mechanisms underlying the functional benefits of a myocardial matrix hydrogel for post-MI treatment. JACC. 2016;67(9):1074-1086. doi: 10.1016/j.jacc.2015.12.035.
