title: Intracoronary Delivery of Mitochondria to the Ischemic Heart for Cardioprotection.
abstract: We have previously shown that transplantation of autologously derived, respiration-competent mitochondria by direct injection into the heart following transient ischemia and reperfusion enhances cell viability and contractile function. To increase the therapeutic potential of this approach, we investigated whether exogenous mitochondria can be effectively delivered through the coronary vasculature to protect the ischemic myocardium and studied the fate of these transplanted organelles in the heart. Langendorff-perfused rabbit hearts were subjected to 30 minutes of ischemia and then reperfused for 10 minutes. Mitochondria were labeled with 18F-rhodamine 6G and iron oxide nanoparticles. The labeled mitochondria were either directly injected into the ischemic region or delivered by vascular perfusion through the coronary arteries at the onset of reperfusion. These hearts were used for positron emission tomography, microcomputed tomography, and magnetic resonance imaging with subsequent microscopic analyses of tissue sections to confirm the uptake and distribution of exogenous mitochondria. Injected mitochondria were localized near the site of delivery; while, vascular perfusion of mitochondria resulted in rapid and extensive dispersal throughout the heart. Both injected and perfused mitochondria were observed in interstitial spaces and were associated with blood vessels and cardiomyocytes. To determine the efficacy of vascular perfusion of mitochondria, an additional group of rabbit hearts were subjected to 30 minutes of regional ischemia and reperfused for 120 minutes. Immediately following regional ischemia, the hearts received unlabeled, autologous mitochondria delivered through the coronary arteries. Autologous mitochondria perfused through the coronary vasculature significantly decreased infarct size and significantly enhanced post-ischemic myocardial function. In conclusion, the delivery of mitochondria through the coronary arteries resulted in their rapid integration and widespread distribution throughout the heart and provided cardioprotection from ischemia-reperfusion injury.
authors: Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA, United States of America.
authors: Douglas B
authors: DB
authors: Cowan
authors: Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA, United States of America.
authors: Rouan
authors: R
authors: Yao
authors: Department of Radiology, Boston Children's Hospital and Harvard Medical School, Boston, MA, United States of America.
authors: Vamsidhar
authors: V
authors: Akurathi
authors: Department of Radiology, Boston Children's Hospital and Harvard Medical School, Boston, MA, United States of America.
authors: Erin R
authors: ER
authors: Snay
authors: Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA, United States of America.
authors: Jerusha K
authors: JK
authors: Thedsanamoorthy
authors: Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA, United States of America.|Department of Cardiac Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA, United States of America.
authors: David
authors: D
authors: Zurakowski
authors: Department of Cell Biology, Harvard Medical School, Boston, MA, United States of America.
authors: Maria
authors: M
authors: Ericsson
authors: Department of Cardiac Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA, United States of America.
authors: Ingeborg
authors: I
authors: Friehs
authors: Department of Radiology, Boston Children's Hospital and Harvard Medical School, Boston, MA, United States of America.
authors: Yaotang
authors: Y
authors: Wu
authors: Department of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States of America.
authors: Sidney
authors: S
authors: Levitsky
authors: Department of Cardiac Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA, United States of America.
authors: Pedro J
authors: PJ
authors: Del Nido
authors: Department of Radiology, Boston Children's Hospital and Harvard Medical School, Boston, MA, United States of America.
authors: Alan B
authors: AB
authors: Packard
authors: Department of Cardiac Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA, United States of America.
authors: James D
authors: http://orcid.org/0000-0003-1058-6976
authors: JD
authors: McCully
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000008:administration & dosage*; D003331:Coronary Vessels; D005260:Female; D006801:Humans; D008928:Mitochondria / Q000378:metabolism / Q000637:transplantation*; D009200:Myocardial Contraction; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D011817:Rabbits
chemical_list: D002316:Cardiotonic Agents