Review articleModifying the mechanics of healing infarcts: Is better the enemy of good?
Introduction
The articles in this special issue attest to the wealth of knowledge now available regarding the biology of cardiac extracellular matrix synthesis, degradation, and remodeling, as well as the complex inflammatory and wound healing processes that occur in response to cardiac injury. Building on this knowledge, it may soon be possible to selectively manipulate the composition, structure, and mechanical properties of healing post-infarction scar tissue. Yet such therapies must be designed with particular care, because post-infarction scar plays the essential role of maintaining the mechanical integrity of the heart. Prior interventions that intentionally or accidentally modified scar structure frequently produced unexpected, even counterintuitive results, illustrating the difficulty of intervening in the complex, evolving network of biological, chemical, and mechanical interactions that govern scar structure. The goal of this review is to first outline what is known about the structure and mechanical properties of healing post-infarction scar; then to discuss how those properties affect likelihood of rupture, depression of pump function, and long-term remodeling leading to heart failure; and finally to formulate principles that could help guide the design of future interventions.
Section snippets
Mechanical properties of healing myocardial infarcts
Following occlusion of a coronary artery, the affected myocardium stops contracting within minutes [1] and myocytes begin to die within hours [2]. Over the next several weeks, dead myocytes are gradually removed through an inflammatory response and replaced by collagenous scar tissue generated by fibroblasts. The evolving mechanical properties of the healing infarct are an important determinant of several of the most important complications of myocardial infarction, including infarct rupture,
Functional impact of infarct mechanical properties
There are many different mechanisms by which a myocardial infarction can impair the pump function of the heart either directly or indirectly [24]: 1) if post-infarction necrosis weakens the infarct too much before sufficient new collagen is deposited, the heart can rupture, leading to sudden death. 2) In the first few days after infarction, the damaged region stretches passively as the rest of the heart contracts, reducing pressure generation and ejection from the LV and wasting mechanical
Modifying infarct mechanical properties
For conditions discussed elsewhere in this special issue – such as heart failure with preserved ejection fraction (HFpEF) – current efforts appropriately focus on therapies to reduce fibrosis [60]. Yet the history of therapeutic interventions intended to target inflammation or fibrosis in post-infarction scar provides stark reminders that infarct scar performs an essential mechanical function, maintaining integrity of the heart wall against enormous mechanical forces. As novel, exciting ideas
Summary and conclusions
In conclusion, the data reviewed here highlight two striking facts about healing infarcts. First, collagen fiber structure (Fig. 1), mechanical properties (Fig. 2), and geometric remodeling (expansion/compaction and thinning, Fig. 3) vary widely among different animal models, and in some cases even between different studies employing the same animal model. Unfortunately, this variability suggests that it will be extremely difficult to predict the effect of a therapy in one species based on
Disclosures
None.
Acknowledgments
The authors acknowledge funding from the National Institutes of Health (R01 HL116449 to JWH), the American Heart Association (14POST20460271 to WJR), and the National Science Foundation (NSF Graduate Research Fellowship to SAC).
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