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.

Modifying the mechanics of healing infarcts: Is better the enemy of good?

“…Yet as discussed in Section 4.4 below, therapies intended to limit infarct expansion have produced mixed results in animal studies. Seeking to explain this finding, Richardson and Holmes recently reviewed quantitative studies of changes in infarct dimensions during infarct healing and found that while nearly all studies documented infarct thinning, only half found infarct expansion (an increase in circumferential or longitudinal dimensions) after the first 24 hours; many actually showed substantial circumferential and/or longitudinal compaction (Figure 3) [59]. Here again, variability among animal models and even between studies in the same animal model has potentially important consequences for the development of post-infarction therapies: the authors noted that therapies designed to prevent expansion may be effective only in the subset of cases where expansion would normally occur, potentially explaining variability in the efficacy of such therapies in animal trials.…”

“…Using a similar logic, a number of studies explored the hypothesis that preventing infarct expansion would improve outcomes; yet these studies produced mixed results (see recent reviews by Gorman [95] and Clarke [45]). Richardson et al proposed that the surprising variability in reported infarct dimension changes during healing in different animal models (Figure 3) may explain why: if only half of all infarcts normally expand, even an effective therapy would appear to work in only half of cases [59]. On the other hand, the fact that some infarcts spontaneously compact – significantly reducing their circumferential or longitudinal dimensions over time – suggests that existing mechanisms could be harnessed to reduce infarct size even after the extent of myocardial damage is determined [59].…”

“…Richardson et al proposed that the surprising variability in reported infarct dimension changes during healing in different animal models (Figure 3) may explain why: if only half of all infarcts normally expand, even an effective therapy would appear to work in only half of cases [59]. On the other hand, the fact that some infarcts spontaneously compact – significantly reducing their circumferential or longitudinal dimensions over time – suggests that existing mechanisms could be harnessed to reduce infarct size even after the extent of myocardial damage is determined [59]. As a promising example of this approach, Laeremanns et al showed that a peptide blocker of the Frizzled receptors Fzd-1 and Fzd-2 increased myofibroblast density and wall thickness while decreasing in-plane infarct dimensions following infarction in mice [96].…”

“…Geometric remodeling of post-infarction scars across a range of species (data replotted from Richardson et al [59]). A Quantitative studies of chronic changes in infarct thickness almost always find significant thinning, regardless of animal model or time point (box plots show range, 25%ile, mean, and 75%ile of values reported at least 1 week after MI, normalized to dimensions 3±2 days post-MI).…”

Making better scar: Emerging approaches for modifying mechanical and electrical properties following infarction and ablation

“…Richardson and Holmes recently compiled data from more than 50 studies that reported quantitative data on changes in infarct dimensions over time. (Richardson and Holmes, 2015) They found while all reports showed infarct expansion over the first 24 hours, over the ensuing weeks only 50% documented further increase in circumferential or longitudinal dimensions consistent with infarct expansion, while 23% reported compaction (reduced dimensions) and the rest observed no significant change. Furthermore, measurements in unloaded hearts were less likely to show expansion, suggesting that in some cases increased dimensions are simply due to increased stretching under load rather than geometric rearrangement or remodeling.…”