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

doi:10.1016/j.yjmcc.2015.11.028

Journal of Molecular and Cellular Cardiology

Volume 93, April 2016, Pages 115-124

https://doi.org/10.1016/j.yjmcc.2015.11.028 Get rights and content

Highlights

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Mechanics of post-infarction scar help determine risk of serious complications.
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Scar properties vary across experimental models, complicating testing of therapies.
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Prior attempts to therapeutically modify scar have produce unexpected results.
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Computational models can help guide intervention in this complex healing process.

Abstract

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.

Introduction

The articles in this special issue attest to the wealth of knowledge now available regarding the biology of cardiac extracellular matrix synthesis, degradation, and remodeling, as well as the complex inflammatory and wound healing processes that occur in response to cardiac injury. Building on this knowledge, it may soon be possible to selectively manipulate the composition, structure, and mechanical properties of healing post-infarction scar tissue. Yet such therapies must be designed with particular care, because post-infarction scar plays the essential role of maintaining the mechanical integrity of the heart. Prior interventions that intentionally or accidentally modified scar structure frequently produced unexpected, even counterintuitive results, illustrating the difficulty of intervening in the complex, evolving network of biological, chemical, and mechanical interactions that govern scar structure. The goal of this review is to first outline what is known about the structure and mechanical properties of healing post-infarction scar; then to discuss how those properties affect likelihood of rupture, depression of pump function, and long-term remodeling leading to heart failure; and finally to formulate principles that could help guide the design of future interventions.

Section snippets

Mechanical properties of healing myocardial infarcts

Following occlusion of a coronary artery, the affected myocardium stops contracting within minutes [1] and myocytes begin to die within hours [2]. Over the next several weeks, dead myocytes are gradually removed through an inflammatory response and replaced by collagenous scar tissue generated by fibroblasts. The evolving mechanical properties of the healing infarct are an important determinant of several of the most important complications of myocardial infarction, including infarct rupture,

Functional impact of infarct mechanical properties

There are many different mechanisms by which a myocardial infarction can impair the pump function of the heart either directly or indirectly [24]: 1) if post-infarction necrosis weakens the infarct too much before sufficient new collagen is deposited, the heart can rupture, leading to sudden death. 2) In the first few days after infarction, the damaged region stretches passively as the rest of the heart contracts, reducing pressure generation and ejection from the LV and wasting mechanical

Modifying infarct mechanical properties

For conditions discussed elsewhere in this special issue – such as heart failure with preserved ejection fraction (HFpEF) – current efforts appropriately focus on therapies to reduce fibrosis [60]. Yet the history of therapeutic interventions intended to target inflammation or fibrosis in post-infarction scar provides stark reminders that infarct scar performs an essential mechanical function, maintaining integrity of the heart wall against enormous mechanical forces. As novel, exciting ideas

Summary and conclusions

In conclusion, the data reviewed here highlight two striking facts about healing infarcts. First, collagen fiber structure (Fig. 1), mechanical properties (Fig. 2), and geometric remodeling (expansion/compaction and thinning, Fig. 3) vary widely among different animal models, and in some cases even between different studies employing the same animal model. Unfortunately, this variability suggests that it will be extremely difficult to predict the effect of a therapy in one species based on

Disclosures

None.

Acknowledgments

The authors acknowledge funding from the National Institutes of Health (R01 HL116449 to JWH), the American Heart Association (14POST20460271 to WJR), and the National Science Foundation (NSF Graduate Research Fellowship to SAC).

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Myocardial infarction (MI) is accompanied by the formation of a fibrotic scar in the left ventricle (LV) and initiates significant alterations in the architecture and constituents of the LV free wall (LVFW). Previous studies have shown that LV adaptation is highly individual, indicating that the identification of remodeling mechanisms post-MI demands a fully subject-specific approach that can integrate a host of structural alterations at the fiber-level to changes in bulk biomechanical adaptation at the tissue-level. We present an image-driven micromechanical approach to characterize remodeling, assimilating new biaxial mechanical data, histological studies, and digital image correlation data within an in-silico framework to elucidate the fiber-level remodeling mechanisms that drive tissue-level adaptation for each subject. We found that a progressively diffused collagen fiber structure combined with similarly disorganized myofiber architecture in the healthy region leads to the loss of LVFW anisotropy post-MI, offering an important tissue-level hallmark for LV maladaptation. In contrast, our results suggest that reductions in collagen undulation are an adaptive mechanism competing against LVFW thinning. Additionally, we show that the inclusion of subject-specific geometry when modeling myocardial tissue is essential for accurate prediction of tissue kinematics. Our approach serves as an essential step toward identifying fiber-level remodeling indices that govern the transition of MI to systolic heart failure. These indices complement the traditional, organ-level measures of LV anatomy and function that often fall short of early prognostication of heart failure in MI. In addition, our approach offers an integrated methodology to advance the design of personalized interventions, such as hydrogel injection, to reinforce and suppress native adaptive and maladaptive mechanisms, respectively, to prevent the transition of MI to heart failure.
Biomechanical and architectural adaptation of the LVFW remains a central, yet overlooked, remodeling process post-MI. Our study indicates the biomechanical adaptation of the LVFW post-MI is highly individual and driven by altered fiber network architecture and collective changes in collagen fiber content, undulation, and stiffness. Our findings demonstrate the possibility of using cardiac strains to infer such fiber-level remodeling events through in-silico modeling, paving the way for in-vivo characterization of multiscale biomechanical indices in humans. Such indices will complement the traditional, organ-level measures of LV anatomy and function that often fall short of early prognostication of heart failure in MI.
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After myocardial infarction (MI), fibroblasts progress from proliferative to myofibroblast states, resulting in fibrosis. Platelet-derived growth factors (PDGFs) are reported to induce fibroblast proliferation, myofibroblast differentiation, and fibrosis. However, we have previously shown that PDGFs improve heart function post-MI without increasing fibrosis. We treated human cardiac fibroblasts with PDGF isoforms then performed RNA sequencing to show that PDGFs reduced cardiac fibroblasts myofibroblast differentiation and downregulated cell cycle pathways. Using mouse/pig MI models, we reveal that PDGF-AB infusion increases cell-cell interactions, reduces myofibroblast differentiation, does not affect proliferation, and accelerates scar formation. RNA sequencing of pig hearts after MI showed that PDGF-AB reduces inflammatory cytokines and alters both transcript variants and long noncoding RNA expression in cell cycle pathways. We propose that PDGF-AB could be used therapeutically to manipulate post-MI scar maturation with subsequent beneficial effects on cardiac function.
Fabrication and characterization methods for investigating cell-matrix interactions in environments possessing spatial orientation heterogeneity
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Fibrillar collagen is a ubiquitous structural protein that plays a significant role in determining the mechanical properties of various tissues. The constituent collagen architecture can give direct insight into the respective functional role of the tissue due to the strong structure-function relationship that is exhibited. In such tissues, matrix structure can vary across local subregions contributing to mechanical heterogeneity which can be implicated in tissue function or failure. The post-myocardial infarction scar environment is an example of note where mechanically insufficient collagen can result in impaired cardiac function and possibly tissue rupture due to post-MI cellular response and matrix interactions. In order to further develop the understanding of cell-matrix interactions within heterogeneous environments, we developed a method of heterogeneous collagen gel fabrication which produces a region of randomly oriented fibers directly adjacent to an interconnected region of anisotropic alignment. To fully capture and evaluate the degree of alignment and spatial orientation heterogeneity, several image processing and automated analysis methods were employed. Our analysis revealed the successful fabrication of an interconnected spatially heterogeneous collagen gel possessing distinct regions of random or preferential alignment. Additionally, embedded cell populations were observed to recognize and reorient with their underlying and surrounding architectures through our cell-centric analysis techniques.
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Cardiovascular diseases are one of the leading causes of death worldwide and cardiac fibrosis is a common pathological process for cardiac remodeling in cardiovascular diseases. Cardiac fibrosis not only accelerates the deterioration progress of diseases but also becomes a pivotal contributor for futile treatment in clinical cardiovascular trials. Although cardiac fibrosis is common and prevalent, effective medicines to provide sufficient clinical intervention for cardiac fibrosis are still unavailable. Traditional Chinese medicine (TCM) is the natural essence experienced boiling, fry, and other processing methods, including active ingredients, extracts, and herbal formulas, which have been applied to treat human diseases for a long history. Recently, research has increasingly focused on the great potential of TCM for the prevention and treatment of cardiac fibrosis. Here, we aim to clarify the identified pro-fibrotic mechanisms and intensively summarize the application of TCM in improving cardiac fibrosis by working on these mechanisms. Through comprehensively analyzing, TCM mainly regulates the following pathways during ameliorating cardiac fibrosis: attenuation of inflammation and oxidative stress, inhibition of cardiac fibroblasts activation, reduction of extracellular matrix accumulation, modulation of the renin-angiotensin-aldosterone system, modulation of autophagy, regulation of metabolic-dependent mechanisms, and targeting microRNAs. We also discussed the deficiencies and the development direction of anti-fibrotic therapies on cardiac fibrosis. The data reviewed here demonstrates that TCM shows a robust effect on alleviating cardiac fibrosis, which provides us a rich source of new drugs or drug candidates. Besides, we also hope this review may give some enlightenment for treating cardiac fibrosis in clinical practice.
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In addition, fibroblasts and myofibroblasts also secrete matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) which are the crucial regulators of ECM (Ma et al., 2017). The fine balance between matrix synthesis and degradation is a prerequisite for optimal infarct healing (Clarke et al., 2016). Excessive matrix degradation by MMPs is profoundly associated with LV chamber dilation and rupture (Nielsen et al., 2019).
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Review articleModifying the mechanics of healing infarcts: Is better the enemy of good?

Highlights

Abstract

Introduction

Section snippets

Mechanical properties of healing myocardial infarcts

Functional impact of infarct mechanical properties

Modifying infarct mechanical properties

Summary and conclusions

Disclosures

Acknowledgments

J. Am. Coll. Cardiol.

Am. J. Cardiol.

J. Mol. Cell. Cardiol.

J. Mol. Cell. Cardiol.

J. Am. Coll. Cardiol.

Am. J. Cardiol.

Am. Heart J.

J. Am. Coll. Cardiol.

Ann. Thorac. Surg.

J. Mol. Cell. Cardiol.

Pharmacol. Ther.

Int. J. Cardiol.

Ann. Thorac. Surg.

JACC Heart Fail.

J. Am. Coll. Cardiol.

Ann. Thorac. Surg.

J. Card. Fail.

Am. J. Cardiol.

J. Am. Coll. Cardiol.

Am. J. Cardiol.

J. Am. Coll. Cardiol.

J. Mol. Cell. Cardiol.

J. Thorac. Cardiovasc. Surg.

Am. J. Pathol.

J. Mol. Cell. Cardiol.

J. Mol. Cell. Cardiol.

Life Sci.

J. Mol. Cell. Cardiol.

Med. Image Anal.

J. Mol. Cell. Cardiol.

Lancet

The effect of coronary occlusion on myocardial contraction

Am. J. Physiol.

Movement of necrotic wavefront after coronary artery occlusion in rabbit

Am. J. Physiol.

Evolution of scar structure, mechanics, and ventricular function after myocardial infarction in the rat

Am. J. Physiol. Heart Circ. Physiol.

Functional implications of myocardial scar structure

Am. J. Physiol.

Effect of scar compaction on the therapeutic efficacy of anisotropic reinforcement following myocardial infarction in the dog

J. Cardiovasc. Transl. Res.

Regional differences in LV collagen accumulation and mature cross-linking after myocardial infarction in rats

Am. J. Physiol.

Changes in passive mechanical stiffness of myocardial tissue with aneurysm formation

Circulation

Time course of collagen and decorin changes in rat cardiac and skeletal muscle post-MI

Am. J. Physiol. Heart Circ. Physiol.

Analysis of healing after myocardial infarction using polarized light microscopy

Am. J. Pathol.

An analysis of segmental ischemic dysfunction utilizing the pressure–length loop

Circulation

Regional myocardial function and dimensions early and late after myocardial infarction in the unanesthetized dog

Circ. Res.

Physiological implications of myocardial scar structure

Compr. Physiol.

Scar remodeling and transmural deformation after infarction in the pig

Circulation

Functional recovery of subepicardial myocardial tissue in transmural myocardial infarction after successful reperfusion: an important contribution to the improvement of regional and global left ventricular function

Circulation

Relationship between myocardial edema and regional myocardial function after reperfused acute myocardial infarction: an MR imaging study

Radiology

Effects of reperfusion after coronary artery occlusion on post-infarction scar tissue

Circ. Res.

Structure and mechanics of healing myocardial infarcts

Annu. Rev. Biomed. Eng.

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