Abstract 3833: P2X7 Inhibition: A Novel Strategy to Prevent Adverse Cardiac Remodeling Following AMI
Background. Necrosis during acute myocardial infarction (AMI) stimulates an intense inflammatory response elicited by the release of intracellular content, including ATP. Extracellular ATP is a powerful agonist for the P2X7 receptor which leads to caspase-1 activation and generation of IL-1beta, which itself promotes apoptosis and cardiac remodeling after acute myocardial infarction (AMI), and also promotes further IL-1beta release in an autocrine and paracrine fashion. This study evaluates blockade of the P2X7 receptor as a treatment strategy for the prevention of adverse cardiac remodeling after experimental AMI in the mouse.
Methods. ICR mice (male, n=9) were randomized to daily intraperitoneal injections with PPADS, a P2X7 inhibitor (25 mg/kg, n=3), or NaCl 0.9% (n=6) for 7 days following permanent coronary artery ligation. Echocardiography was performed at baseline and 7 days after surgery to measure left ventricle (LV) end-diastolic and end-systolic dimensions, systolic function, and extent of the infarct scar at pathology. Four mice underwent sham operations including every step of the procedure except ligation of the coronary artery.
Results When compared to sham-operated animals, mice from both groups experienced significant left ventricular dilatation and dysfunction after surgery. Mice treated with PPADS had more favorable cardiac remodeling with significantly smaller increase in LV end-diastolic diameter (−53%) and end-systolic diameter (−33%) at 7 days when compared to NaCl 0.9% (p<0.01 for both comparisons). PPADS lead also to a significant reduction in infarct size (17±1% vs 32±2%, P<0.001).
Conclusions P2X7 blockade reduced infarct size and prevents pathologic cardiac enlargement following AMI. This represents a completely novel treatment strategy for ischemic cardiomyopathy and the prevention of heart failure by inhibiting the inflammatory response secondary to myocardial necrosis.
This research has received full or partial funding support from the American Heart Association, Mid-Atlantic Affiliate (Maryland, North Carolina, South Carolina, Virginia & Washington, DC).