Shaina R. Eckhouse

Local Hydrogel Release of Recombinant TIMP-3 Attenuates Adverse Left Ventricular Remodeling After Experimental Myocardial Infarction

Delivery of a hydrogel providing sustained release of recombinant TIMP-3 attenuated adverse ventricular remodeling after myocardial infarction in pigs. Hydrogel-Inhibitor Combo Stops Heart Damage After a heart attack, or myocardial infarction (MI), the heart tries to repair itself. This natural process is well intentioned but results in infarct expansion, scar formation, and, in turn, reduced heart function. To prevent such adverse remodeling, Eckhouse and colleagues designed an injectable hydrogel that inhibits the activity of enzymes directly involved in tissue repair. Matrix metalloproteinases (MMPs) are enzymes that are activated in heart tissue after MI. The authors encapsulated TIMP-3 (tissue inhibitor of metalloproteinase 3) in hyaluronic acid hydrogels. The gel/TIMP-3 combo or a control gel without the inhibitor was injected into the hearts of pigs after a heart attack. Weeks later, heart function, inflammation, and remodeling were evaluated. Animals administered the hydrogel with TIMP-3 had improved heart function [as determined by the left ventricular ejection fraction (LVEF)], improved LV geometry, and reduced infarct size. This local delivery mechanism could be used in the context of surgery, such as during coronary revascularization after a heart attack. Because it has been tested in pigs—which have similar heart anatomy to humans—and because other hydrogels, like alginate, have been tested in the human heart before, it is possible that this gel-inhibitor combination therapy could advance to clinical trials in the near future. An imbalance between matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) contributes to the left ventricle (LV) remodeling that occurs after myocardial infarction (MI). However, translation of these observations into a clinically relevant, therapeutic strategy remains to be established. The present study investigated targeted TIMP augmentation through regional injection of a degradable hyaluronic acid hydrogel containing recombinant TIMP-3 (rTIMP-3) in a large animal model. MI was induced in pigs by coronary ligation. Animals were then randomized to receive targeted hydrogel/rTIMP-3, hydrogel alone, or saline injection and followed for 14 days. Instrumented pigs with no MI induction served as referent controls. Multimodal imaging (fluoroscopy/echocardiography/magnetic resonance imaging) revealed that LV ejection fraction was improved, LV dilation was reduced, and MI expansion was attenuated in the animals treated with rTIMP-3 compared to all other controls. A marked reduction in proinflammatory cytokines and increased smooth muscle actin content indicative of myofibroblast proliferation occurred in the MI region with hydrogel/rTIMP-3 injections. These results provide the first proof of concept that regional sustained delivery of an MMP inhibitor can effectively interrupt adverse post-MI remodeling.

Changes in the myocardial interstitium and contribution to the progression of heart failure.

The myocardial interstitium is highly organized and orchestrated, whereby small disruptions in composition, spatial relationships, or content lead to altered myocardial systolic and/or diastolic performance. These changes in extracellular matrix structure and function are important in the progression to heart failure in pressure overload hypertrophy, dilated cardiomyopathy, and ischemic heart disease. The myocardial interstitium is not a passive entity, but rather a complex and dynamic microenvironment that represents an important structural and signaling system within the myocardium.

GENE TARGETING IN ISCHEMIC HEART DISEASE AND FAILURE: TRANSLATIONAL AND CLINICAL STUDIES

Alternative and innovative targeted strategies hold relevance in improving the current treatments for ischemic heart disease (IHD). One potential treatment modality, gene targeting, may provide a unique alternative to current IHD therapies. The principal function of gene targeting in IHD is to augment the expression of an endogenous gene through amplification of an exogenous gene, delivered by a plasmid or a viral vector to enhance myocardial perfusion, and limit the long-term sequelae. The initial clinical studies of gene targeting in IHD were focused upon induction of angiogenic factors and the outcomes were equivocal. Nevertheless, significant advancements have been made in viral vectors, mode of delivery, and potentially relevant targets for IHD. Several of these advancements, particularly with a focus on translational large animal studies, are the focus of this review. The development of novel vectors with prolonged transduction efficiency and minimal inflammation, coupled with hybrid perfusion-mapping delivery devices, and improving the safety of vector use and efficacy of gene systems are but a few of the exciting progresses that are likely to proceed to clinical studies in the near future.

Reproducible Porcine Model of Thoracic Aortic Aneurysm

Background— Thoracic aortic aneurysms (TAAs) develop secondary to abnormal aortic extracellular matrix remodeling, resulting in a weakened and dilated aortic wall that progressed to rupture if left unattended. Currently, no diagnostic/prognostic tests are available for the detection of TAA disease. This is largely driven by the lack of a large animal model, which would permit longitudinal/mechanistic studies. Accordingly, the objective of the present study was to establish a reproducible porcine model of aortic dilatation, which recapitulates the structural and biochemical changes observed during human TAA development. Methods and Results— Descending TAAs were induced in Yorkshire pigs (20–25 kg; n=7) through intra-adventitial injections of collagenase (5 mL, 0.35 mg/mL) and periadventitial application of crystalline CaCl2 (0.5 g). Three weeks after TAA induction, aortas were harvested and tissue was collected for biochemical and histological measurements. A subset of animals underwent MRI preoperatively and at terminal surgery. Results were compared with sham-operated controls (n=6). Three weeks after TAA induction, aortic luminal area increased by 38±13% (P=0.018 versus control). Aortic structural changes included elastic lamellar degradation and decreased collagen content. The protein abundance of matrix metalloproteinases 3, 8, 9, and 12 increased in TAA tissue homogenates, whereas tissue inhibitors of metalloproteinases 1 and 4 decreased. Conclusions— These data demonstrate aortic dilatation, aortic medial degeneration, and alterations in matrix metalloproteinase/tissue inhibitors of metalloproteinase abundance, consistent with TAA formation. This study establishes for the first time a large animal model of TAA that recapitulates the hallmarks of human disease and provides a reproducible test bed for examining diagnostic, prognostic, and therapeutic strategies.

Sternoclavicular joint infection necessitating through skin and lung parenchyma.

Infections of the sternoclavicular joint associated with extensive local soft tissue involvement or abscess formation often require surgical debridement and drainage. This condition typically presents with joint pain, local erythema, and swelling. This case demonstrates the simultaneous extension of a sternoclavicular joint infection into the left upper pulmonary lobe and through the overlying skin.