Intracoronary Injection of In Situ Forming Alginate Hydrogel Reverses Left Ventricular Remodeling After Myocardial Infarction in Swine

Leor, Jonathan; Tuvia, Shmuel; Guetta, Victor; Manczur, Ferenc; Castel, David; Willenz, Udi; Petneházy, Örs; Landa, Natali; Feinberg, Micha S.; Konen, Eli; Goitein, Orly; Tsur-Gang, Orna; Shaul, Mazal; Klapper, Lea; Cohen, Smadar

doi:10.1016/j.jacc.2009.06.010

Cited by 304 publications

(286 citation statements)

References 36 publications

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“…These alterations increase the mechanical burden on the injured heart and initiate maladaptive biological processes that act together to produce heart failure (11,12). Although recent data have demonstrated that injectable materials can affect the post-MI LV remodeling (17-24, 26, 28), only a few groups (23,25,26) have evaluated the impact of acellular intramyocardial injections in large-animal models of MI (e.g., swine or ovine). Furthermore, the influence of specific material properties on the associated LV remodeling response has not been explored experimentally and is not well understood.…”

Section: Discussionmentioning

confidence: 99%

“…Future work will evaluate the impact of MeHA treatment time and infarct reperfusion status on LV remodeling. This MI model involves a permanent occlusion, which generally is associated with a more profound remodeling stimulus (34,35) than in reperfused infarct models that have been used to evaluate the impact of other injectable materials with reperfusion (17,25,36).…”

Section: Discussionmentioning

confidence: 99%

“…To circumvent the surgical placement of restraining devices early post-MI, our group and others have begun to explore the use of injectable materials to limit infarct expansion and normalize the regional stress distribution (17)(18)(19)(20)(21)(22)(23)(24)(25)(26). Such an approach offers the potential for a noninvasive, catheter-based treatment that could be administered early post-MI to attenuate the remodeling process and prevent the development of heart failure.…”

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confidence: 99%

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Injectable hydrogel properties influence infarct expansion and extent of postinfarction left ventricular remodeling in an ovine model

Ifkovits

Tous

Minakawa

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

269

273

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A recent trend has emerged that involves myocardial injection of biomaterials, containing cells or acellular, following myocardial infarction (MI) to influence the remodeling response through both biological and mechanical effects. Despite the number of different materials injected in these approaches, there has been little investigation into the importance of material properties on therapeutic outcomes. This work focuses on the investigation of injectable hyaluronic acid (MeHA) hydrogels that have tunable mechanics and gelation behavior. Specifically, two MeHA formulations that exhibit similar degradation and tissue distribution upon injection but have differential moduli (∼8 versus ∼43 kPa) were injected into a clinically relevant ovine MI model to evaluate the associated salutary effect of intramyocardial hydrogel injection on the remodeling response based on hydrogel mechanics. Treatment with both hydrogels significantly increased the wall thickness in the apex and basilar infarct regions compared with the control infarct. However, only the higher-modulus (MeHA High) treatment group had a statistically smaller infarct area compared with the control infarct group. Moreover, reductions in normalized end-diastolic and end-systolic volumes were observed for the MeHA High group. This group also tended to have better functional outcomes (cardiac output and ejection fraction) than the low-modulus (MeHA Low) and control infarct groups. This study provides fundamental information that can be used in the rational design of therapeutic materials for treatment of MI.L eft ventricular (LV) remodeling caused by a myocardial infarction (MI) is responsible for almost 70% of the 5 million cases of heart failure that have occurred in the United States in recent years (1). Early infarct expansion or stretching has been associated with poor long-term prognosis (2-4) and has been identified as the mechanical phenomenon that initiates and sustains the process of adverse post-MI LV remodeling that leads to heart failure (5-10). Infarct expansion causes abnormal stress distribution in myocardial regions outside the infarction, especially in the adjacent borderzone region, putting this region at a mechanical disadvantage. With time, increased regional stress is the impetus for several maladaptive biologic processes, such as myocyte apoptosis and matrix metalloproteinase activation, that inherently alter the contractile properties of normally perfused myocardium (11,12). Once initiated, these maladaptive processes lead to a heart failure phenotype that is difficult to reverse by medical or surgical means.We have demonstrated that ventricular restraint early after MI reduces infarct expansion and limits long-term global LV remodeling in large-animal infarction models (10, 13-16). To circumvent the surgical placement of restraining devices early post-MI, our group and others have begun to explore the use of injectable materials to limit infarct expansion and normalize the regional stress distribution (17-26). Such an approach offers th...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Injectable hydrogel properties influence infarct expansion and extent of postinfarction left ventricular remodeling in an ovine model

Ifkovits

Tous

Minakawa

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

269

273

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“…Unlike fibrin, alginate must be modified with adhesive peptides to facilitate cell binding. Both non-modified alginate and alginate modified with adhesive peptides such as Arg-Gly-Asp (RGD) or Tyr-Ile-Gly-Ser-Arg (YIGSR) have been explored as bulking agents [26,31,34,50,51], and comparisons have been performed between the two [31,51]. Yu et al compared modified alginate to non-modified alginate using a rat reperfusion-MI model with injections 5 weeks post-MI, more indicative of a chronic response [51].…”

Section: Natural Hydrogelsmentioning

confidence: 99%

“…A review of injectable materials illustrates that a wide range of volumes have been injected as bulking agents ( Table 1). As a single example of differences in injected volumes, Leor et al injected an alginate-calcium solution into the LAD 4 days post-MI via a coronary catheter in swine [50]. During this time post-MI, the vasculature of the infarcted myocardium is leaky, allowing the alginate mixture to be delivered to the infarct site.…”

Section: Materials Optimization: Comparing Properties and Introducing mentioning

confidence: 99%

Injectable Acellular Hydrogels for Cardiac Repair

Tous

Purcell

Ifkovits

et al. 2011

J. of Cardiovasc. Trans. Res.

147

136

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Injectable hydrogels are being developed as potential translatable materials to influence the cascade of events that occur after myocardial infarction. These hydrogels, consisting of both synthetic and natural materials, form through numerous chemical crosslinking and assembly mechanisms and can be used as bulking agents or for the delivery of biological molecules. Specifically, a range of materials are being applied that alter the resulting mechanical and biological signals after infarction and have shown success in reducing stresses in the myocardium and limiting the resulting adverse left ventricular (LV) remodeling. Additionally, the delivery of molecules from injectable hydrogels can influence cellular processes such as apoptosis and angiogenesis in cardiac tissue or can be used to recruit stem cells for repair. There is still considerable work to be performed to elucidate the mechanisms of these injectable hydrogels and to optimize their various properties (e.g., mechanics and degradation profiles). Furthermore, although the experimental findings completed to date in small animals are promising, future work needs to focus on the use of large animal models in clinically relevant scenarios. Interest in this therapeutic approach is high due to the potential for developing percutaneous therapies to limit LV remodeling and to prevent the onset of congestive heart failure that occurs with loss of global LV function. This review focuses on recent efforts to develop these injectable and acellular hydrogels to aid in cardiac repair.

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Carbohydrate‐Derived Hydrogels and Microgels

Ebara

2010

Engineered Carbohydrate‐Based Materials for Biomedical Applications

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Intracoronary Injection of In Situ Forming Alginate Hydrogel Reverses Left Ventricular Remodeling After Myocardial Infarction in Swine

Abstract: Intracoronary injection of alginate biomaterial is feasible, safe, and effective. Our findings suggest a new percutaneous intervention to improve infarct repair and prevent adverse remodeling after reperfused MI.

Cited by 304 publications

References 36 publications

Injectable hydrogel properties influence infarct expansion and extent of postinfarction left ventricular remodeling in an ovine model

Injectable hydrogel properties influence infarct expansion and extent of postinfarction left ventricular remodeling in an ovine model

Injectable Acellular Hydrogels for Cardiac Repair

Carbohydrate‐Derived Hydrogels and Microgels

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