Implications of scar structure and mechanics for post-infarction cardiac repair and regeneration

Regenerating cardiac muscle lost during a heart attack is a topic of broad interest and enormous potential impact. One promising approach is to regenerate or re-engineer new myocardium in situ, at the site of damage, by injecting cells, growth factors, and other materials, or by reprogramming aspects of the normal wound healing process. A wide variety of strategies have been explored, from promoting angiogenesis to injection of a variety of different progenitor cell types, to re-engineering resident cells to produce key growth factors or even transdifferentiate into myocytes. Despite substantial progress and continued promise, clinical impact of this work has fallen short of expectations. One contributing factor may be that many efforts focus primarily on generating cardiomyocytes, with less attention to re-engineering the extracellular matrix (ECM). Yet the role of the ECM is particularly crucial to consider following myocardial infarction, which leads to rapid formation of a collagen-rich scar. This review combines a brief summary of current efforts to regenerate cardiomyocytes with what is currently known about the structure and mechanics of post-infarction scar, with the goal of identifying principles that can guide efforts to produce new myocytes embedded in an extracellular environment that facilitates their differentiation, maintenance, and function.