Catheter-based Intramyocardial Injection of FGF1 or NRG1-loaded MPs Improves Cardiac Function in a Preclinical Model of Ischemia-Reperfusion

Cardiovascular protein therapeutics such as neuregulin (NRG1) and acidic-fibroblast growth factor (FGF1) requires new formulation strategies that allow for sustained bioavailability of the drug in the infarcted myocardium. However, there is no FDA-approved injectable protein delivery platform due to translational concerns about biomaterial administration through cardiac catheters. We therefore sought to evaluate the efficacy of percutaneous intramyocardial injection of poly(lactic-co-glycolic acid) microparticles (MPs) loaded with NRG1 and FGF1 using the NOGA MYOSTAR injection catheter in a porcine model of ischemia-reperfusion. NRG1- and FGF1-loaded MPs were prepared using a multiple emulsion solvent-evaporation technique. Infarcted pigs were treated one week after ischemia-reperfusion with MPs containing NRG1, FGF1 or non-loaded MPs delivered via clinically-translatable percutaneous transendocardial-injection. Three months post-treatment, echocardiography indicated a significant improvement in systolic and diastolic cardiac function. Moreover, improvement in bipolar voltage and decrease in transmural infarct progression was demonstrated by electromechanical NOGA-mapping. Functional benefit was associated with an increase in myocardial vascularization and remodeling. These findings in a large animal model of ischemia-reperfusion demonstrate the feasibility and efficacy of using MPs as a delivery system for growth factors and provide strong evidence to move forward with clinical studies using therapeutic proteins combined with catheter-compatible biomaterials.

[1]  Douglas Losordo,et al.  Rebuilding the damaged heart: the potential of cytokines and growth factors in the treatment of ischemic heart disease. , 2010, Journal of the American College of Cardiology.

[2]  A. Abizaid,et al.  New Drug-Eluting Stents: An Overview on Biodegradable and Polymer-Free Next-Generation Stent Systems , 2010, Circulation. Cardiovascular interventions.

[3]  V. Dilsizian,et al.  Therapeutic Angiogenesis With Recombinant Fibroblast Growth Factor-2 Improves Stress and Rest Myocardial Perfusion Abnormalities in Patients With Severe Symptomatic Chronic Coronary Artery Disease , 2000, Circulation.

[4]  M. Gyöngyösi,et al.  Diagnostic and prognostic value of 3D NOGA mapping in ischemic heart disease , 2011, Nature Reviews Cardiology.

[5]  Brian H Annex,et al.  The VIVA Trial Vascular Endothelial Growth Factor in Ischemia for Vascular Angiogenesis , 2003 .

[6]  T. Henry,et al.  Pharmacological Treatment of Coronary Artery Disease With Recombinant Fibroblast Growth Factor-2: Double-Blind, Randomized, Controlled Clinical Trial , 2002, Circulation.

[7]  P. Stayton,et al.  Delivery of basic fibroblast growth factor with a pH-responsive, injectable hydrogel to improve angiogenesis in infarcted myocardium. , 2011, Biomaterials.

[8]  H. Ohta,et al.  Pathophysiological roles of FGF signaling in the heart , 2013, Front. Physiol..

[9]  P. Delafontaine,et al.  Technique and Imaging for Transthoracic Echocardiography of the Laboratory Pig , 2004, Echocardiography.

[10]  Hua-Lin Wu,et al.  Intramyocardial Peptide Nanofiber Injection Improves Postinfarction Ventricular Remodeling and Efficacy of Bone Marrow Cell Therapy in Pigs , 2010, Circulation.

[11]  F. Prósper,et al.  Heart regeneration after myocardial infarction using synthetic biomaterials. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[12]  J. Gorman,et al.  Local Hydrogel Release of Recombinant TIMP-3 Attenuates Adverse Left Ventricular Remodeling After Experimental Myocardial Infarction , 2014, Science Translational Medicine.

[13]  F. Prósper,et al.  Biodegradation and heart retention of polymeric microparticles in a rat model of myocardial ischemia. , 2013, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[14]  A. DeMaria,et al.  Catheter-deliverable hydrogel derived from decellularized ventricular extracellular matrix increases endogenous cardiomyocytes and preserves cardiac function post-myocardial infarction. , 2012, Journal of the American College of Cardiology.

[15]  H. Alkadhi,et al.  Transcatheter based electromechanical mapping guided intramyocardial transplantation and in vivo tracking of human stem cell based three dimensional microtissues in the porcine heart. , 2013, Biomaterials.

[16]  D. Sawyer,et al.  Neuregulin in Cardiovascular Development and Disease , 2012, Circulation research.

[17]  F. Prósper,et al.  Repeated implantation of skeletal myoblast in a swine model of chronic myocardial infarction. , 2010, European heart journal.

[18]  Richard T. Lee,et al.  FGF1/p38 MAP kinase inhibitor therapy induces cardiomyocyte mitosis, reduces scarring, and rescues function after myocardial infarction , 2006, Proceedings of the National Academy of Sciences.

[19]  F. Prósper,et al.  Functional benefits of PLGA particulates carrying VEGF and CoQ10 in an animal of myocardial ischemia. , 2013, International journal of pharmaceutics.

[20]  E. Garbayo,et al.  Tracking the in vivo release of bioactive NRG from PLGA and PEG-PLGA microparticles in infarcted hearts. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[21]  A. DeMaria,et al.  Safety and Efficacy of an Injectable Extracellular Matrix Hydrogel for Treating Myocardial Infarction , 2013, Science Translational Medicine.

[22]  F. Rademakers,et al.  Myocardial function defined by strain rate and strain during alterations in inotropic states and heart rate. , 2002, American journal of physiology. Heart and circulatory physiology.

[23]  F. Prósper,et al.  Controlled delivery of fibroblast growth factor-1 and neuregulin-1 from biodegradable microparticles promotes cardiac repair in a rat myocardial infarction model through activation of endogenous regeneration. , 2014, Journal of controlled release : official journal of the Controlled Release Society.

[24]  K. Yutzey.  Regenerative biology: Neuregulin 1 makes heart muscle , 2015, Nature.

[25]  P. Macdonald,et al.  Parenteral administration of recombinant human neuregulin‐1 to patients with stable chronic heart failure produces favourable acute and chronic haemodynamic responses , 2011, European journal of heart failure.

[26]  K. Christman,et al.  Biomaterials for the treatment of myocardial infarction: a 5-year update. , 2011, Journal of the American College of Cardiology.

[27]  K. Sunagawa,et al.  A New Therapeutic Modality for Acute Myocardial Infarction: Nanoparticle-Mediated Delivery of Pitavastatin Induces Cardioprotection from Ischemia-Reperfusion Injury via Activation of PI3K/Akt Pathway and Anti-Inflammation in a Rat Model , 2015, PloS one.

[28]  R. Graham,et al.  Neuregulin-1/erbB-activation improves cardiac function and survival in models of ischemic, dilated, and viral cardiomyopathy. , 2006, Journal of the American College of Cardiology.

[29]  Yi-Dong Lin,et al.  Instructive Nanofiber Scaffolds with VEGF Create a Microenvironment for Arteriogenesis and Cardiac Repair , 2012, Science Translational Medicine.

[30]  F. Harrell,et al.  Anti‐Remodeling and Anti‐Fibrotic Effects of the Neuregulin‐1β Glial Growth Factor 2 in a Large Animal Model of Heart Failure , 2014, Journal of the American Heart Association.

[31]  H. Johnsen,et al.  Stem Cell Mobilization Induced by Subcutaneous Granulocyte-Colony Stimulating Factor to Improve Cardiac Regeneration After Acute ST-Elevation Myocardial Infarction: Result of the Double-Blind, Randomized, Placebo-Controlled Stem Cells in Myocardial Infarction (STEMMI) Trial , 2006, Circulation.

[32]  Richard T. Lee,et al.  Injectable Self-Assembling Peptide Nanofibers Create Intramyocardial Microenvironments for Endothelial Cells , 2005, Circulation.

[33]  R. A. Jain,et al.  The manufacturing techniques of various drug loaded biodegradable poly(lactide-co-glycolide) (PLGA) devices. , 2000, Biomaterials.

[34]  K. Coulombe,et al.  The Roles of Neuregulin-1 in Cardiac Development, Homeostasis, and Disease , 2015, Biomarker insights.

[35]  Hai-dong Guo,et al.  Sustained delivery of VEGF from designer self-assembling peptides improves cardiac function after myocardial infarction. , 2012, Biochemical and biophysical research communications.

[36]  Joseph C. Wu,et al.  Biomaterial applications in cardiovascular tissue repair and regeneration , 2012, Expert review of cardiovascular therapy.

[37]  D. Berman,et al.  The VIVA Trial: Vascular Endothelial Growth Factor in Ischemia for Vascular Angiogenesis , 2003, Circulation.

[38]  Conor J. Walsh,et al.  Drug and cell delivery for cardiac regeneration. , 2015, Advanced drug delivery reviews.

[39]  S. Anker,et al.  A single dose of erythropoietin in ST-elevation myocardial infarction. , 2010, European heart journal.

[40]  Carlos Ortiz-de-Solorzano,et al.  Sustained release of VEGF through PLGA microparticles improves vasculogenesis and tissue remodeling in an acute myocardial ischemia-reperfusion model. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[41]  A. Kastrati,et al.  Stem cell mobilization by granulocyte-colony-stimulating factor in acute myocardial infarction: lessons from the REVIVAL-2 trial , 2007, Nature Clinical Practice Cardiovascular Medicine.

[42]  James J. Lai,et al.  Functionalized nanoparticles provide early cardioprotection after acute myocardial infarction. , 2013, Journal of controlled release : official journal of the Controlled Release Society.

[43]  Gregory M. Barker,et al.  Novel bioresorbable stent coating for drug release in congenital heart disease applications. , 2015, Journal of biomedical materials research. Part A.

[44]  Mark D. Huffman,et al.  AHA Statistical Update Heart Disease and Stroke Statistics — 2012 Update A Report From the American Heart Association WRITING GROUP MEMBERS , 2010 .

[45]  L. Ling,et al.  An autologous platelet-rich plasma hydrogel compound restores left ventricular structure, function and ameliorates adverse remodeling in a minimally invasive large animal myocardial restoration model: a translational approach: Vu and Pal "Myocardial Repair: PRP, Hydrogel and Supplements". , 2015, Biomaterials.

[46]  F. Prósper,et al.  Treatment of Reperfused Ischemia with Adipose-Derived Stem Cells in a Preclinical Swine Model of Myocardial Infarction , 2012, Cell transplantation.

[47]  Richard T. Lee,et al.  Biomaterials to enhance stem cell function in the heart. , 2011, Circulation research.

[48]  Patrick W Serruys,et al.  Catheter-based intramyocardial injection of autologous skeletal myoblasts as a primary treatment of ischemic heart failure: clinical experience with six-month follow-up. , 2003, Journal of the American College of Cardiology.

[49]  S M Dillon,et al.  Electroanatomic left ventricular mapping in the porcine model of healed anterior myocardial infarction. Correlation with intracardiac echocardiography and pathological analysis. , 1999, Circulation.

[50]  B. Gersh.  Stem Cell Mobilization Induced by Subcutaneous Granulocyte-Colony Stimulating Factor to Improve Cardiac Regeneration After Acute ST-Elevation Myocardial Infarction: Result of the Double-Blind, Randomized, Placebo-Controlled Stem Cells in Myocardial Infarction (STEMMI) Trial , 2007 .

[51]  Huajun Zhang,et al.  Blood vessel repair and regeneration in the ischaemic heart , 2014, Open Heart.

[52]  P. Serruys,et al.  Bioresorbable scaffold technologies. , 2011, Circulation journal : official journal of the Japanese Circulation Society.

[53]  F. von Knobelsdorff-Brenkenhoff,et al.  A pilot study of chronic, low‐dose epoetin‐β following percutaneous coronary intervention suggests safety, feasibility, and efficacy in patients with symptomatic ischaemic heart failure , 2011, European journal of heart failure.

[54]  M. Doblaré,et al.  Epicardial delivery of collagen patches with adipose-derived stem cells in rat and minipig models of chronic myocardial infarction. , 2014, Biomaterials.

[55]  P. Doevendans,et al.  Fibroblast growth factor-1 improves cardiac functional recovery and enhances cell survival after ischemia and reperfusion: a fibroblast growth factor receptor, protein kinase C, and tyrosine kinase-dependent mechanism. , 2004, Journal of the American College of Cardiology.

[56]  R Shofti,et al.  Detailed endocardial mapping accurately predicts the transmural extent of myocardial infarction. , 2001, Journal of the American College of Cardiology.

[57]  X. Rabasseda,et al.  A report from the American Heart Association Scientific Sessions 2012 (November 3-7 - Los Angeles, California, USA). , 2013, Drugs of today.

[58]  S. Hoerstrup,et al.  Comparison of NOGA Endocardial Mapping and Cardiac Magnetic Resonance Imaging for Determining Infarct Size and Infarct Transmurality for Intramyocardial Injection Therapy Using Experimental Data , 2014, PloS one.

[59]  K. Kuck,et al.  Percutaneous intramyocardial stem cell injection in patients with acute myocardial infarction: first-in-man study , 2009, Heart.

[60]  Yadong Wang,et al.  Towards comprehensive cardiac repair and regeneration after myocardial infarction: Aspects to consider and proteins to deliver. , 2016, Biomaterials.

[61]  P. Menasché.  Stem cell therapy for heart failure: are arrhythmias a real safety concern? , 2009, Circulation.

[62]  J. Minguell,et al.  Myocardial implantation of a combination stem cell product by using a transendocardial MYOSTAR injection catheter: A technical assessment , 2011, Acute cardiac care.