Dexrazoxane Shows No Protective Effect in the Acute Phase of Reperfusion during Myocardial Infarction in Pigs

Abstract

Calcium and iron overload participate in the mechanisms of ischemia/reperfusion (I/R) injury during myocardial infarction (MI). Calcium overload induces cardiomyocyte death by hypercontraction, while iron catalyses generation of reactive oxygen species (ROS). We therefore hypothesized that dexrazoxane, an intracellular metal chelator, would attenuate I/R injury. MI was induced in pigs by occlusion of the left anterior descending artery for 1 hour followed by 2 hours reperfusion. Thirty minutes before reperfusion either 5 mg/ml dexrazoxane (n = 5) or saline (n = 5) was infused intravenously. Myocardial necrosis as percentage of the area at ischemic risk was found to be similar in both groups (77.2 ± 18% for dexrazoxane and 76.4 ± 14% for saline group) as determined by triphenyl tetrazolium chloride staining of the ischemic myocardium. Also, serum levels of troponin-I were similar in both groups. A conductance catheter was used to measure left ventricular pressure and volume at all times. Markers for tissue damage due to ROS (HNE), endothelial cell activation (CD31) and inflammation (IgG, C3b/c, C5b9, MCP-1) were assessed on tissue and/or in serum. No significant differences were observed between the groups for the parameters analyzed. To conclude, in this clinically relevant model of early reperfusion after acute myocardial ischemia, dexrazoxane lacked attenuating effects on I/R injury as shown by the measured parameters.

Targeting Ferroptosis as a Promising Therapeutic Strategy for Ischemia-Reperfusion Injury

“…Similarly, other well-recognized ferroptosis inhibitors, such as Fer-1 [ 59 ], DFO [ 63 ] and dexrazoxane (DXZ) [ 64 ], have been shown to provide effective protection against MIRI by attenuating ferroptosis. However, it should be noted that even some common ferroptosis inhibitors, such as DXZ, an intracellular metal chelator, have previously been reported to have no protective effect on MIRI in pigs [ 148 ]. Thus, the different pharmacodynamics, bioavailability and subcellular localization of ferroptosis inhibitors should be considered in future studies on I/R injuries.…”

Pathological Roles of Iron in Cardiovascular Disease

“…Chelation therapy using EDTA (ethylene diamine tetraacetic acid) with acute MI patients showed attenuated adverse cardiovascular outcomes [103]. Dexrazoxane, a mitochondria-permeable intracellular metal chelator, also decreased free radicals and improved the ex vivo hemodynamics of I/R injuries in rat hearts [104], while showing no protective effect on I/R injuries in pigs [105]. Further studies could take advantage of the different bioavailibilities, pharmacodynamics, and subcellular localization of chelators to select the right chelator in combination with other therapies that target the effect of iron in cardiovascular disease.…”

Effects of prostaglandin E1 on reperfusion injury patients

“…However, several clinical and animal studies have found that, when low tissue perfusion after ischemia is addressed, not only does ischemic tissue damage fail to resolve but also the injury is aggravated. [ 2 – 8 ] This phenomenon, first described by Jennings et al [ 9 ] in 1960, is defined as ischemic reperfusion injury (IRI). Myocardial IRI is often found in patients undergoing procedures involving ischemia reperfusion such as percutaneous coronary intervention (PCI), thrombolysis, coronary artery bypass grafting (CABG), and valve replacement, and its primary clinical manifestations are ventricular arrhythmia, lack of reflow phenomenon, and distal embolization.…”