Key result
Administration of NAP9 in a porcine model of ischemia/reperfusion reduced cardiac necrosis (14.1 vs 35.5) and improved left ventricle ejection fraction (64.0 vs 47.3) at 21 days.
Why the study?
Rapid screening and diagnosis of acute myocardial infarction are critical to reduce myocardial necrosis, and previous mouse studies demonstrated that targeting EMMPRIN with conjugated nanoparticles improved cardiac function after ischemia/reperfusion.
Does administration of NAP9 nanoparticles reduce cardiac necrosis and improve ventricular function in a porcine model of coronary ischemia/reperfusion?
Does administration of NAP9 nanoparticles reduce cardiac necrosis and improve ventricular function in a porcine model of coronary ischemia/reperfusion?
Absolute Event Rate: 14.1% vs 35.5%
Targeting EMMPRIN with NAP9 nanoparticles reduces myocardial injury, preserves left ventricular function, and allows noninvasive imaging of cardiac necrosis in a porcine model of acute myocardial infarction.
Hypothesis-generating for EMMPRIN-targeted nanoparticles in porcine AMI; leaves open translation to human therapy.
BACKGROUND: Rapid screening and accurate diagnosis of acute myocardial infarction are critical to reduce the progression of myocardial necrosis, in which proteolytic degradation of myocardial extracellular matrix plays a major role. In previous studies, we found that targeting the extracellular matrix metalloprotease inducer (EMMPRIN) by injecting nanoparticles conjugated with the specific EMMPRIN-binding peptide AP9 significantly improved cardiac function in mice subjected to ischemia/reperfusion. METHODS: In a porcine model of coronary ischemia/reperfusion, we tested the theragnostic effects of administering 0.1 mg/kg gadolinium-containing nanoparticles conjugated with AP9 (NAP9), a synthetic peptide that targets EMMPRIN or a control nanoparticle (NAPSC). Cardiac magnetic resonance assessment of the infarct progression, ventricular function, and nanoparticle distribution was performed the next 7 days. We also measured the infarcted area of the heart and cardiac remodeling at 7 or 21 days after ischemia/reperfusion. RESULTS: After 21 days of ischemia/reperfusion, NAP9 reduced the extension of cardiac necrosis (14.1±9.7 versus 35.5±1.8) and the levels of collagenolytic activity of MMPs (matrix metalloproteases), along with a significant reduction in collagen deposition (7.5±4.5 versus 41.3±20); including the ratio of type I versus III collagen fibers in the necrotic myocardium. In terms of cardiac function, the response to NAP9 administration resulted in a significant improvement of cardiac performance overtime, as evidenced by the left ventricle ejection fraction (64.0±7.8), when compared with those present in the NAPSC group (47.3±4.7). As shown by magnetic resonance imaging, noninvasive molecular imaging of NAP9 enabled us to find a significant reduction in cardiac necrosis, myocardial edema, hemorrhage, and microvascular obstruction, suggesting that NAP9 may reduce myocardial injury and preserve left ventricular function, at least, by preventing the effect of EMMPRIN on extracellular matrix degradation. CONCLUSIONS: Our data point towards NAP9 as a promising theragnostic tool in managing acute myocardial infarction, by inhibiting EMMPRIN-induced extracellular matrix degradation and allowing noninvasive visualization of cardiac necrosis progression over time.
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Ramírez-Carracedo et al. (2022) studied acute myocardial infarction. gadolinium-containing nanoparticles conjugated with AP9 (NAP9) vs. control nanoparticle (NAPSC) was evaluated on extension of cardiac necrosis. Administration of NAP9 in a porcine model of ischemia/reperfusion reduced cardiac necrosis (14.1 vs 35.5) and improved left ventricle ejection fraction (64.0 vs 47.3) at 21 days.
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