A Translational Study of a New Therapeutic Approach for Acute Myocardial Infarction: Nanoparticle-Mediated Delivery of Pitavastatin into Reperfused Myocardium Reduces Ischemia-Reperfusion Injury in a Preclinical Porcine Model.
BACKGROUND
There is an unmet need to develop an innovative cardioprotective modality for acute myocardial infarction, for which interventional reperfusion therapy is hampered by ischemia-reperfusion (IR) injury. We recently reported that bioabsorbable poly(lactic acid/glycolic acid) (PLGA) nanoparticle-mediated treatment with pitavastatin (pitavastatin-NP) exerts a cardioprotective effect in a rat IR injury model by activating the PI3K-Akt pathway and inhibiting inflammation. To obtain preclinical proof-of-concept evidence, in this study, we examined the effect of pitavastatin-NP on myocardial IR injury in conscious and anesthetized pig models.


RESULTS
Eighty-four Bama mini-pigs were surgically implanted with a pneumatic cuff occluder at the left circumflex coronary artery (LCx) and telemetry transmitters to continuously monitor electrocardiogram as well as to monitor arterial blood pressure and heart rate. The LCx was occluded for 60 minutes, followed by 24 hours of reperfusion under conscious conditions. Intravenous administration of pitavastatin-NP containing ≥ 8 mg/body of pitavastatin 5 minutes before reperfusion significantly reduced infarct size; by contrast, pitavastatin alone (8 mg/body) showed no therapeutic effects. Pitavastatin-NP produced anti-apoptotic effects on cultured cardiomyocytes in vitro. Cardiac magnetic resonance imaging performed 4 weeks after IR injury revealed that pitavastatin-NP reduced the extent of left ventricle remodeling. Importantly, pitavastatin-NP exerted no significant effects on blood pressure, heart rate, or serum biochemistry. Exploratory examinations in anesthetized pigs showed pharmacokinetic analysis and the effects of pitavastatin-NP on no-reflow phenomenon.


CONCLUSIONS
NP-mediated delivery of pitavastatin to IR-injured myocardium exerts cardioprotective effects on IR injury without apparent adverse side effects in a preclinical conscious pig model. Thus, pitavastatin-NP represents a novel therapeutic modality for IR injury in acute myocardial infarction.
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Kenzo
K
Ichimura
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Tetsuya
T
Matoba
Department of Cardiovascular Research, Development, and Translational Medicine, Center for Cardiovascular Disruptive Innovation, Kyushu University, Fukuoka, Japan.
Kaku
K
Nakano
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Masaki
M
Tokutome
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Katsuya
K
Honda
Department of Cardiovascular Research, Development, and Translational Medicine, Center for Cardiovascular Disruptive Innovation, Kyushu University, Fukuoka, Japan.
Jun-Ichiro
J
Koga
Department of Cardiovascular Research, Development, and Translational Medicine, Center for Cardiovascular Disruptive Innovation, Kyushu University, Fukuoka, Japan.
Kensuke
K
Egashira
D000758:Anesthesia; D000818:Animals; D001794:Blood Pressure; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D016923:Cell Death; D002478:Cells, Cultured; D003243:Consciousness; D004195:Disease Models, Animal; D006339:Heart Rate; D007677:Kidney Function Tests; D019344:Lactic Acid / Q000737:chemistry; D008111:Liver Function Tests; D008279:Magnetic Resonance Imaging; D009203:Myocardial Infarction / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D015425:Myocardial Reperfusion; D015428:Myocardial Reperfusion Injury / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D009206:Myocardium / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000473:pathology; D053758:Nanoparticles / Q000737:chemistry*; D054318:No-Reflow Phenomenon; D010766:Phosphorylation; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011804:Quinolines / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013318:Stroke Volume; D013552:Swine; D013556:Swine, Miniature; D057170:Translational Research, Biomedical; D020257:Ventricular Remodeling
D002316:Cardiotonic Agents; D011804:Quinolines; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D051057:Proto-Oncogene Proteins c-akt; C108475:pitavastatin