Rescue PCI, previously shown to be superior in the short term to both repeat thrombolysis and conservative therapy, maintains benefit in terms of long-term mortality. This strategy for failed lysis should be mandated as part of thrombolytic-based ST-segment elevation myocardial infarction protocols.
Alterations in the accumulation and composition of the extracellular matrix are part of the normal tissue repair process. During fibrosis, this process becomes dysregulated and excessive extracellular matrix alters the biomechanical properties and function of tissues involved. Historically fibrosis was thought to be progressive and irreversible; however, studies suggest that fibrosis is a dynamic process whose progression can be stopped and even reversed. This realization has led to an enhanced pursuit of therapeutic agents targeting fibrosis and extracellular matrix-producing cells. In many organs, fibroblasts are the primary cells that produce the extracellular matrix. In response to diverse mechanical and biochemical stimuli, these cells are activated or transdifferentiate into specialized cells termed myofibroblasts that have an enhanced capacity to produce extracellular matrix. It is clear that interactions between diverse cells of the heart are able to modulate fibroblast activation and fibrosis. Exosomes are a form of extracellular vesicle that play an important role in intercellular communication via the cargo that they deliver to target cells. While relatively recently discovered, exosomes have been demonstrated to play important positive and negative roles in the regulation of fibroblast activation and tissue fibrosis. These roles as well as efforts to engineer exosomes as therapeutic tools will be discussed.
Mast cells are bone marrow‐derived effector cells that have been described historically for their role in mediating allergic reactions. More recently, they have received considerable attention due to their involvement in innate defense, tissue remodeling and other processes. Several studies have illustrated roles for mast cells in cardiovascular diseases including ventricular remodeling associated with myocardial infarction, hypertension and volume overload. Mast cells produce a variety of secretory components including cytokines, proteases, growth factors and fatty acid metabolites. The compliment of components synthesized by a given mast cell appears to be dictated by the tissue microenvironment giving these cells diverse roles in tissue homeostasis and disease. Mast cell proteases including tryptase and chymase are some of the most abundant proteins produced by mast cells. Several studies have illustrated that mast cell chymase plays a significant role in the formation of angiotensin II in the heart and thus this protease may indirectly promote a fibrotic response via angiotensin II‐induced TGF‐beta production. However, the direct effect of this protease on cardiac fibroblast function has not been evaluated. The present studies were performed to elucidate the effects of chymase on isolated cardiac fibroblasts. Fibroblasts were treated for 24 hours with varying doses of chymase (0 to 1000 ng/ml) and the effects on proliferation, collagen scaffold remodeling, myofibroblast formation and expression of extracellular matrix components assayed. Treatment of cardiac fibroblasts with chymase significantly reduced the conversion of quiescent fibroblasts to a myofibroblast phenotype. Chymase also impaired contraction of three‐dimensional collagen gels and the expression of specific extracellular matrix components by fibroblasts. These studies illustrate that treatment of isolated cardiac fibroblasts with mast cell chymase elicits an anti‐fibrotic effect, which may contribute to the transition to heart failure in vivo.
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