Why Is Infarct Expansion Such an Elusive Therapeutic Target?

Abstract

Myocardial infarct expansion has been associated with an increased risk of infarct rupture and progression to heart failure, motivating therapies such as infarct restraint and polymer injection that aim to limit infarct expansion. However, an exhaustive review of quantitative studies of infarct remodeling reveals that only half found chronic in-plane expansion, and many reported in-plane compaction. Using a finite element model, we demonstrate that the balance between scar stiffening due to collagen accumulation and increased wall stresses due to infarct thinning can produce either expansion or compaction in the pressurized heart-potentially explaining variability in the literature-and that loaded dimensions are much more sensitive to changes in thickness than in stiffness. Our analysis challenges the concept that in-plane expansion is a central feature of post-infarction remodeling; rather, available data suggest that radial thinning is the dominant process during infarct healing and may be an attractive therapeutic target.

Keywords: Expansion; Fibroblast; Infarction; Mechanics; Remodeling; Wound healing.

Fig. 1. Infarct dimension studies report both expansion and compaction

Studies that made quantitative measurements of in-plane (circumferential or longitudinal) dimensions at multiple healing time-points consistently showed expansion over the first 24 hours (A), but a mix of expansion (increased in-plane dimension), compaction (decreased), or insignificant change at later times (B). The balance of reported dimension changes differed when measurements were made in an unloaded (zero cavity pressure) or loaded state. [,,,,,–,–64,85]

Fig. 2. Healing infarcts thin, sometimes expand, and sometimes compact

Infarct dimensions from studies of rat, dog, pig, sheep, baboon, and patient infarcts were compared by calculating remodeled dimension ratios (thickness and in-plane) as the scar dimension at a given time relative to that dimension at the initial measurement at least 24h post-infarction [,,,,,,,–,,,–91]. Analysis shows that infarcts (1) consistently thin (A), (2) typically compact when measured in the unloaded state (B), and (3) sometimes expand and sometimes compact when measured in the pressurized LV (B).

Fig. 3. Infarct stiffening and thinning can lead to compaction or expansion

A finite-element model of an infarcted rat ventricle (A) and infarcted dog ventricle (D) were developed from gadolinium-enhanced MR images, and used to predict the changes in end-diastolic (loaded) infarct circumferential segment length resulting from changes in unloaded infarct stiffness or thickness (B, C, &E). End-diastolic circumferential dimension ratios increase (ratio>1, usually interpreted as in-plane infarct expansion) as the infarct thins, but decrease (ratio<1, in-plane compaction) as the infarct stiffens.