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

Abstract

Following myocardial infarction (MI), damaged myocytes are replaced by collagenous scar tissue, which serves an important mechanical function – maintaining integrity of the heart wall against enormous mechanical forces – but also disrupts electrical function as structural and electrical remodeling in the infarct and borderzone predispose to re-entry and ventricular tachycardia. Novel emerging regenerative approaches aim to replace this scar tissue with viable myocytes. Yet an alternative strategy of therapeutically modifying selected scar properties may also prove important, and in some cases may offer similar benefits with lower risk or regulatory complexity. Here, we review potential goals for such modifications as well as recent proof-of-concept studies employing specific modifications, including gene therapy to locally increase conduction velocity or prolong the refractory period in and around the infarct scar, and modification of scar anisotropy to improve regional mechanics and pump function. Another advantage of scar modification techniques is that they have applications well beyond MI. In particular, ablation treats electrical abnormalities of the heart by intentionally generating scar to block aberrant conduction pathways. Yet in diseases such as atrial fibrillation (AF) where ablation can be extensive, treating the electrical disorder can significantly impair mechanical function. Creating smaller, denser scars that more effectively block conduction, and choosing the location of those lesions by balancing their electrical and mechanical impacts, could significantly improve outcomes for AF patients. We review some recent advances in this area, including the use of computational models to predict the mechanical effects of specific lesion sets and gene therapy for functional ablation. Overall, emerging techniques for modifying scar properties represents a potentially important important set of tools for improving patient outcomes across a range of heart diseases, whether used in place of or as an adjunct to regenerative approaches.

Effect of ablation pattern on mechanical function in the atrium

“…In modeling postablation scar tissue, we were forced to approximate passive mechanical properties based on published infarct scar mechanics, given a lack of information on how material properties change postablation; however, since the loss of active function turned out to be much more important in our simulations than the change in passive function, we expect any error in the assumed scar material properties to have minimal impact on the conclusions of the study. Our model geometry intentionally omitted the left atrial appendage (LAA) due to its heterogeneity among patients .…”

Submillimeter diffusion tensor imaging and late gadolinium enhancement cardiovascular magnetic resonance of chronic myocardial infarction

“…Our observations in porcine and human ventricles suggest that the existing ECM might play a significant role in the alignment of collagen fibers, as the general transmural patterns of primary diffusion eigenvector angles are preserved inside the scar. This information could be important to therapeutic approaches in the treatment of the infarct, such as tissue engineering and regenerative medicine, as ECM orientation is likely to determine the orientation of regenerated myocytes [31]. …”

“…In addition, the 3D information regarding the collagen fiber orientation in the intact scar as provided here could improve the accuracy of the modeling approaches aimed at understanding the mechanical role of the passive scar on post-MI ventricular function [38–40]. This could ultimately lead to optimal design of therapies aimed at modifying the electromechanical properties of the infarct [31, 41, 42]. Furthermore, patient-specific models are being constructed from clinical images with clinical applications such as patient arrhythmia risk stratification and optimal treatment planning for rhythm disorders [43, 44].…”

Remodeling by fibroblasts alters the rate-dependent mechanical properties of collagen

“…The structural aspects of remodeling are central to the mechanics of ETCs [13, 31], and are particularly important for promising new therapies to improve cardiac function after myocardial infarction through guiding scar development [41]. They are also key to understanding how myofibroblasts invade an infarct region [42, 43].…”