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PRE-CLINICAL RESEARCH

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

Jonathan Leor, MD^_*,1, Shmuel Tuvia, PhD, Victor Guetta, MD^_*, Ferenc Manczur, PhD, DVM, David Castel, DVM^_*, Udi Willenz, DVM^_*, Örs Petneházy, DVM, Natali Landa, PhD^_*, Micha S. Feinberg, MD^_*, Eli Konen, MD^||, Orly Goitein, MD^||, Orna Tsur-Gang, PhD^¶, Mazal Shaul, PhD, Lea Klapper, PhD and Smadar Cohen, PhD^¶,2

^_* Neufeld Cardiac Research Institute, Sheba Medical Center, Tel-Aviv University, Tel-Hashomer, Israel
BiolineRx, Jerusalem, Israel
Department of Internal Medicine Faculty of Veterinary Science Szent István University, Budapest, Hungary
Institute of Diagnostic Imaging and Radiation Oncology Kaposvár University, Kaposvár, Hungary
^|| Department of Diagnostic Imaging, Sheba Medical Center, Tel-Hashomer, Israel
^¶ Department of Biotechnology Engineering, Ben-Gurion University of the Negev, Beer-Sheva, Israel

Manuscript received October 24, 2008; revised manuscript received April 17, 2009, accepted June 2, 2009.

¹ Reprint requests and correspondence: Dr. Jonathan Leor, Neufeld Cardiac Research Institute, Sheba Medical Center, Tel-Hashomer 52621, Israel (Email: leorj{at}post.tau.ac.il).

² Dr. Smadar Cohen, Department of Biotechnology Engineering, Ben-Gurion University of the Negev, Beer-Sheva, Israel (Email: scohen{at}bgu.ac.il).

Objectives: This study sought to determine whether alginate biomaterial can be delivered effectively into the infarcted myocardium by intracoronary injection to prevent left ventricular (LV) remodeling early after myocardial infarction (MI).

Background: Although injectable biomaterials can improve infarct healing and repair, the feasibility and effectiveness of intracoronary injection have not been studied.

Methods: We prepared a calcium cross-linked alginate solution that undergoes liquid to gel phase transition after deposition in infarcted myocardium. Anterior MI was induced in swine by transient balloon occlusion of left anterior descending coronary artery. At 4 days after MI, either alginate solution (2 or 4 ml) or saline was injected selectively into the infarct-related coronary artery. An additional group (n = 19) was treated with incremental volumes of biomaterial (1, 2, and 4 ml) or 2 ml saline and underwent serial echocardiography studies.

Results: Examination of hearts harvested after injection showed that the alginate crossed the infarcted leaky vessels and was deposited as hydrogel in the infarcted tissue. At 60 days, control swine experienced an increase in left ventricular (LV) diastolic area by 44%, LV systolic area by 45%, and LV mass by 35%. In contrast, intracoronary injection of alginate (2 and 4 ml) prevented and even reversed LV enlargement (p < 0.01). Post-mortem analysis showed that the biomaterial (2 ml) increased scar thickness by 53% compared with control (2.9 ± 0.1 mm vs. 1.9 ± 0.3 mm; p < 0.01) and was replaced by myofibroblasts and collagen.

Conclusions: 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.

Key Words: biomaterials • heart failure • myocardial infarction • remodeling

Abbreviations and Acronyms   CT = computed tomography   ECG = electrocardiogram/electrocardiographic   ECM = extracellular matrix   LAD = left anterior descending   LV = left ventricle/ventricular   MI = myocardial infarction   MPG = myocardial perfusion grade   MR = mitral regurgitation   TFG = Thrombolysis In Myocardial Infarction flow grade   TIMI = Thrombolysis In Myocardial Infarction

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