Myocardial infarct expansion, infarct extension, and reinfarction: Pathophysiologic concepts

Weisman, Harlan F.; Healy, Bernadine

doi:10.1016/0033-0620(87)90004-1

Cited by 193 publications

(86 citation statements)

References 164 publications

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“…37 Patients with myocardial infarct expansion have poorer exercise tolerance, more symptoms of congestive heart failure, and greater early and late mortality than those without expansion. 38,39 Excitingly, using a chronic MI model, we found that MEKK3 deficiency significantly impaired microthrombosis at the edge of the infarct area, alleviated infarct expansion from the ischemic region, and improved heart function post-MI. The above data indicated that platelet MEKK3 serves as an effective target to prevent infarct expansion in MI patients.…”

Section: Discussionmentioning

confidence: 94%

Platelet MEKK3 regulates arterial thrombosis and myocardial infarct expansion in mice

et al. 2018

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Key Points• MEKK3 regulates platelet activation through ERK1/2 and JNK2.• MEKK3 2/2 mice are protected from microthrombosis and myocardial infarct expansion post-MI.MAPKs play important roles in platelet activation. However, the molecular mechanisms by which MAPKs are regulated in platelets remain largely unknown. Real-time polymerase chain reaction and western blot data showed that MEKK3, a key MAP3K family member, was expressed in human and mouse platelets. Then, megakaryocyte/platelet-specific MEKK3-deletion (MEKK3 2/2 ) mice were developed to elucidate the platelet-related function(s) of MEKK3. We found that agonist-induced aggregation and degranulation were reduced in MEKK3 2/2 platelets in vitro. MEKK3 deficiency significantly impaired integrin aIIbb3-mediated inside-out signaling but did not affect the outside-in signaling.At the molecular level, MEKK3 deficiency led to severely impaired activation of extracellular signal-regulated kinases 1/2 (ERK1/2) and c-Jun NH 2 -terminal kinase 2 but not p38 or ERK5. In vivo, MEKK3 2/2 mice showed delayed thrombus formation following FeCl 3 -induced carotid artery injury. Interestingly, the tail bleeding time was normal in MEKK3 2/2 mice. Moreover, MEKK3 2/2 mice had fewer microthrombi, reduced myocardial infarction (MI) size, and improved post-MI heart function in a mouse model of MI.These results suggest that MEKK3 plays important roles in platelet MAPK activation and may be used as a new effective target for antithrombosis and prevention of MI expansion.

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Section: Discussionmentioning

confidence: 94%

Platelet MEKK3 regulates arterial thrombosis and myocardial infarct expansion in mice

et al. 2018

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“…Early infarct expansion or stretching has been associated with poor long-term prognosis [2][3][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][6][7][8][9][10]. Infarct expansion causes abnormal stress distributions in myocardial regions outside the infarction, especially in the adjacent border zone (BZ) region, putting this region at a mechanical disadvantage.…”

Section: Introductionmentioning

confidence: 99%

Injectable Acellular Hydrogels for Cardiac Repair

Tous

Purcell

Ifkovits

et al. 2011

J. of Cardiovasc. Trans. Res.

153

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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“…Early infarct expansion or stretching has been associated with poor long-term prognosis (2)(3)(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.…”

mentioning

confidence: 99%

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.

276

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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Myocardial infarct expansion, infarct extension, and reinfarction: Pathophysiologic concepts

Cited by 193 publications

References 164 publications

Platelet MEKK3 regulates arterial thrombosis and myocardial infarct expansion in mice

Platelet MEKK3 regulates arterial thrombosis and myocardial infarct expansion in mice

Injectable Acellular Hydrogels for Cardiac Repair

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

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