Hypertrophic scars occur following cutaneous wounding and result in severe functional and esthetic defects. The pathophysiology of this process remains unknown. Here, we demonstrate for the first time that mechanical stress applied to a healing wound is sufficient to produce hypertrophic scars in mice. The resulting scars are histopathologically identical to human hypertrophic scars and persist for more than six months following a brief (one-week) period of augmented mechanical stress during the proliferative phase of wound healing. Resulting scars are structurally identical to human hypertrophic scars and showed dramatic increases in volume (20-fold) and cellular density (20-fold). The increased cellularity is accompanied by a four-fold decrease in cellular apoptosis and increased activation of the prosurvival marker Akt. To clarify the importance of apoptosis in hypertrophic scar formation, we examine the effects of mechanical loading on cutaneous wounds of animals with altered pathways of cellular apoptosis. In p53-null mice, with down-regulated cellular apoptosis, we observe significantly greater scar hypertrophy and cellular density. Conversely, scar hypertrophy and cellular density are significantly reduced in proapoptotic BclII-null mice. We conclude that mechanical loading early in the proliferative phase of wound healing produces hypertrophic scars by inhibiting cellular apoptosis through an Akt-dependent mechanism.

Myocardial infarction is a prevalent major cardiovascular event that arises from myocardial ischemia with or without reperfusion, and basic and translational research is needed to better understand its underlying mechanisms and consequences for cardiac structure and function. Ischemia underlies a broad range of clinical scenarios ranging from angina to hibernation to permanent occlusion, and while reperfusion is mandatory for salvage from ischemic injury, reperfusion also inflicts injury on its own. In this consensus statement, we present recommendations for animal models of myocardial ischemia and infarction. With increasing awareness of the need for rigor and reproducibility in designing and performing scientific research to ensure validation of results, the goal of this review is to provide best practice information regarding myocardial ischemia-reperfusion and infarction models.Listen to this article’s corresponding podcast at ajpheart.podbean.com/e/guidelines-for-experimental-models-of-myocardial-ischemia-and-infarction/.

Therapies for myocardial infarction have historically been developed by trial and error, rather than from an understanding of the structure and function of the healing infarct. With exciting new bioengineering therapies for myocardial infarction on the horizon, we have reviewed the time course of structural and mechanical changes in the healing infarct in an attempt to identify key structural determinants of mechanics at several stages of healing. Based on temporal correlation, we hypothesize that normal passive material properties dominate the mechanics during acute ischemia, edema during the subsequent necrotic phase, large collagen fiber structure during the fibrotic phase, and cross-linking of collagen during the long-term remodeling phase. We hope these hypotheses will stimulate further research on infarct mechanics, particularly studies that integrate material testing, in vivo mechanics, and quantitative structural analysis.

The mechanical properties of the healing scar are an important determinant of heart function following myocardial infarction. Yet the relationship between scar structure, scar mechanics, and ventricular function remains poorly understood, in part because no published study has tracked all of these factors simultaneously in any animal model. We therefore studied the temporal evolution of scar structure, scar mechanics, and left ventricular (LV) function in large anterior myocardial infarcts in rats. At 1, 2, 3, and 6 wk after left anterior descending coronary ligation, we examined LV function using sonomicrometry, infarct mechanical properties using biaxial mechanical testing, infarct structure using polarized light microscopy, and scar collagen content and cross-linking using biochemical assays. Healing infarcts in the rat were structurally and mechanically isotropic at all time points. Collagen content increased with time and was the primary determinant of scar mechanical properties. The presence of healing infarcts influenced systolic LV function through a rightward shift of the end-systolic pressure-volume relationship (ESPVR) that depended on infarct size, infarct collagen content, and LV dilation. We conclude that in sharp contrast to previous reports in large animal models, healing infarcts are structurally and mechanically isotropic in the standard rat model of myocardial infarction. On the basis of the regional strain patterns we observed in healing rat infarcts in this study and in healing pig infarcts in previous studies, we hypothesize that the local pattern of stretching determines collagen alignment in healing myocardial infarct scars.

Once myocardium dies during a heart attack, it is replaced by scar tissue over the course of several weeks. The size, location, composition, structure and mechanical properties of the healing scar are all critical determinants of the fate of patients who survive the initial infarction. While the central importance of scar structure in determining pump function and remodeling has long been recognized, it has proven remarkably difficult to design therapies that improve heart function or limit remodeling by modifying scar structure. Many exciting new therapies are under development, but predicting their long-term effects requires a detailed understanding of how infarct scar forms, how its properties impact left ventricular function and remodeling, and how changes in scar structure and properties feed back to affect not only heart mechanics but also electrical conduction, reflex hemodynamic compensations, and the ongoing process of scar formation itself. In this article, we outline the scar formation process following an MI, discuss interpretation of standard measures of heart function in the setting of a healing infarct, then present implications of infarct scar geometry and structure for both mechanical and electrical function of the heart and summarize experiences to date with therapeutic interventions that aim to modify scar geometry and structure. One important conclusion that emerges from the studies reviewed here is that computational modeling is an essential tool for integrating the wealth of information required to understand this complex system and predict the impact of novel therapies on scar healing, heart function, and remodeling following myocardial infarction.