Longitudinal Reinforcement of Acute Myocardial Infarcts Improves Function by Transmurally Redistributing Stretch and Stress.

A wide range of emerging therapies, from surgical restraint to biomaterial injection to tissue engineering, aim to improve heart function and limit adverse remodeling following myocardial infarction (MI). We previously showed that longitudinal surgical reinforcement of large anterior infarcts in dogs could significantly enhance systolic function without restricting diastolic function, but the underlying mechanisms for this improvement are poorly understood. The goal of this study was to construct a finite element model that could match our previously published data on changes in regional strains and left ventricular function following longitudinal surgical reinforcement, then use the model to explore potential mechanisms for the improvement in systolic function we observed. The model presented here, implemented in febio, matches all the key features of our experiments, including diastolic remodeling strains in the ischemic region, small shifts in the end-diastolic pressure-volume relationship (EDPVR), and large changes in the end-systolic pressure-volume relationship (ESPVR) in response to ischemia and to patch application. Detailed examination of model strains and stresses suggests that longitudinal reinforcement reduces peak diastolic fiber stretch and systolic fiber stress in the remote myocardium and shifts those peaks away from the endocardial surface by reshaping the left ventricle (LV). These findings could help to guide the development of novel therapies to improve post-MI function by providing specific design objectives.

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

Myocardial infarction (MI) is a major source of morbidity and mortality worldwide, with over 7 million people suffering infarctions each year. Heart muscle damaged during MI is replaced by a collagenous scar over a period of several weeks, and the mechanical properties of that scar tissue are a key determinant of serious post-MI complications such as infarct rupture, depression of heart function, and progression to heart failure. Thus, there is increasing interest in developing therapies that modify the structure and mechanics of healing infarct scar. Yet most prior attempts at therapeutic scar modification have failed, some catastrophically. This article reviews available information about the mechanics of healing infarct scar and the functional impact of scar mechanical properties, and attempts to infer principles that can better guide future attempts to modify scar. One important conclusion is that collagen structure, mechanics, and remodeling of healing infarct scar vary so widely among experimental models that any novel therapy should be tested across a range of species, infarct locations, and reperfusion protocols. Another lesson from past work is that the biology and mechanics of healing infarcts are sufficiently complex that the effects of interventions are often counterintuitive; for example, increasing infarct stiffness has little effect on heart function, and inhibition of matrix metalloproteases (MMPs) has little effect on scar collagen content. Computational models can help explain such counterintuitive results, and are becoming an increasingly important tool for integrating known information to better identify promising therapies and design experiments to test them. Moving forward, potentially exciting new opportunities for therapeutic modification of infarct mechanics include modulating anisotropy and promoting scar compaction.

Postprocedure mapping of cardiac resynchronization lead position using standard fluoroscopy systems: implications for the nonresponder with scar.

BACKGROUND: The relationship between cardiac resynchronization therapy (CRT), left ventricular (LV) lead position, scar, and regional mechanical function influences CRT response. OBJECTIVE: To determine LV lead position relative to LV structural characteristics in standard clinical practice, we developed and validated a practical yet mathematically rigorous method to register procedural fluoroscopic LV lead position with pre-CRT cardiac magnetic resonance (CMR). METHODS: After one-time calibration of the standard fluoroscopic suite, we identified the projected CMR LV lead position using three reference landmarks on both CMR and fluoroscopy. This predicted lead position was validated in a canine model by histology and in eight "validation group" patients based on postoperative computed tomography scans (n = 7) or CMR coronary sinus venography (n = 1). The methodology was applied in an additional eight patients with CRT nonresponse and infarction-related myocardial scar. RESULTS: The projected and actual lead positions were within 1.2 mm in the canine model. The median distance between projected and actual lead positions for the validation group (n = 8) and animal validation case was 11.3 mm (interquartile range 9.2-14.6 mm). In the application (nonresponder) group (n = 8), the lead mapped to the scar periphery in three patients, the core of the scar in one patient, and more than 3 cm from scar in four patients. CONCLUSIONS: This methodology projects procedural fluoroscopic LV lead position onto pre-CRT CMR using standard fluoroscopic equipment and a one-time calibration, enabling assessment of LV lead position with sufficient accuracy to identify the lead position relative to regional function and infarction-related scar in CRT nonresponders.

Effect of Scar Compaction on the Therapeutic Efficacy of Anisotropic Reinforcement Following Myocardial Infarction in the Dog.

Cardiac restraint devices have been used following myocardial infarction (MI) to limit left ventricular (LV) dilation, although isotropic restraints have not been shown to improve post-MI LV function. We have previously shown that anisotropic reinforcement of acute infarcts dramatically improves LV function. This study examined the effects of chronic, anisotropic infarct restraint on LV function and remodeling. Hemodynamics, infarct scar structure, and LV volumes were measured in 28 infarcted dogs (14 reinforced, 14 control). Longitudinal restraint reduced 48-h LV volumes, but no differences in LV volume, function, or infarct scar structure were observed after 8 weeks of healing. All scars underwent substantial compaction during healing; we hypothesize that compaction negated the effects of restraint therapy by mechanically unloading the restraint device. Our results lend support to the concept of adjustable restraint devices and suggest that scar compaction may explain some of the variability in published studies of local infarct restraint.

Physiological Implications of Myocardial Scar Structure.

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 a myocardial infarction, 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.

Impact of mechanical activation, scar, and electrical timing on cardiac resynchronization therapy response and clinical outcomes.

OBJECTIVES: Using cardiac magnetic resonance (CMR), we sought to evaluate the relative influences of mechanical, electrical, and scar properties at the left ventricular lead position (LVLP) on cardiac resynchronization therapy (CRT) response and clinical events. BACKGROUND: CMR cine displacement encoding with stimulated echoes (DENSE) provides high-quality strain for overall dyssynchrony (circumferential uniformity ratio estimate [CURE] 0 to 1) and timing of onset of circumferential contraction at the LVLP. CMR DENSE, late gadolinium enhancement, and electrical timing together could improve upon other imaging modalities for evaluating the optimal LVLP. METHODS: Patients had complete CMR studies and echocardiography before CRT. CRT response was defined as a 15% reduction in left ventricular end-systolic volume. Electrical activation was assessed as the time from QRS onset to LVLP electrogram (QLV). Patients were then followed for clinical events. RESULTS: In 75 patients, multivariable logistic modeling accurately identified the 40 patients (53%) with CRT response (area under the curve: 0.95 [p < 0.0001]) based on CURE (odds ratio [OR]: 2.59/0.1 decrease), delayed circumferential contraction onset at LVLP (OR: 6.55), absent LVLP scar (OR: 14.9), and QLV (OR: 1.31/10 ms increase). The 33% of patients with CURE <0.70, absence of LVLP scar, and delayed LVLP contraction onset had a 100% response rate, whereas those with CURE ≥0.70 had a 0% CRT response rate and a 12-fold increased risk of death; the remaining patients had a mixed response profile. CONCLUSIONS: Mechanical, electrical, and scar properties at the LVLP together with CMR mechanical dyssynchrony are strongly associated with echocardiographic CRT response and clinical events after CRT. Modeling these findings holds promise for improving CRT outcomes.