Sodium-hydrogen exchange inhibition: novel strategy to prevent myocardial injury following ischemia and reperfusion.
Activation of Na+/H+ exchange and subsequent calcium overload in cardiac myocytes appear to play an important role in myocardial tissue injury following ischemia and reperfusion. Results of several in vitro studies in isolated myocytes and heart preparations and in vivo studies in pigs and rats have suggested that inhibition of Na+/H+ exchange is an effective means to prevent lethal reperfusion injury, arrhythmia, and improve myocardial contractile dysfunction. In patients with acute myocardial infarction (MI), any preventive agent is administered immediately before or shortly after reperfusion, rather than before the occurrence of coronary occlusion. The direct interventional approach to treating acute MI provides the opportunity to see if reperfusion has already occurred; if not, a protective agent prior to mechanical reperfusion by percutaneous transluminal coronary angioplasty (PTCA) can be administered to limit reperfusion injury. In a multicenter, randomized, placebo-controlled clinical trial, we tested the hypothesis that inhibition of Na+/H+ exchange with cariporide (HOE 642) could limit infarct size and improve myocardial function in patients with acute transmural MI treated with direct PTCA. Patients were randomized to receive placebo or cariporide given as a 40-mg intravenous bolus prior to reperfusion. Global and regional left ventricular function were analyzed via paired contrast left ventriculograms performed before direct PTCA and after 21 days. Myocardial enzymes (i.e., creatine kinase [CK], CK-MB, and lactate dehydrogenase) as markers for myocardial tissue injury were evaluated as well. The results of this pilot study suggested that the Na+/H+ exchange inhibition could be of benefit to prevent reperfusion injury in patients with acute anterior MI treated with direct angioplasty.
Buerke
M
M
II. Department of Internal Medicine, Johannes Gutenberg University, Mainz, Germany.
Rupprecht
H J
HJ
vom Dahl
J
J
Terres
W
W
Seyfarth
M
M
Schultheiss
H P
HP
Richardt
G
G
Sheehan
F H
FH
Drexler
H
H
D015906:Angioplasty, Balloon, Coronary; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects / Q000627:therapeutic use*; D006146:Guanidines / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D007262:Infusions, Intravenous; D009203:Myocardial Infarction / Q000188:drug therapy*; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy*; D010865:Pilot Projects; D011292:Premedication; D051381:Rats; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013450:Sulfones / Q000009:adverse effects / Q000627:therapeutic use*
D000889:Anti-Arrhythmia Agents; D006146:Guanidines; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C093373:cariporide