Why Do We Still Not Have Cardioprotective Drugs?

Abstract

Despite thousands of publications describing agents that limit infarct size in animals, all we have available today is reperfusion therapy. In this review, we examine why these drugs have not been translated into clinical practice.Many of the first interventions tested in clinical trials were very controversial in animal trials and their actual efficacy is still in question. Interventions based on the preconditioning mechanism have been very reproducible in animals, but clinical testing of them has just begun. Only approximately 25% of reperfused patients have infarcts large enough to put them at risk of heart failure and would require additional treatment. Inclusion of the 75% of patients with small infarcts in treatment groups has greatly diluted the significance of data in past clinical trials. Size of the risk zone has emerged as a reliable way to identify the vulnerable 25%. Recent small-scale clinical trials using risk stratification algorithms have shown clear infarct size limitation using ischemic and pharmacological postconditioning, confirming that the human heart responds like hearts of animal models. Most cardioprotectants have been studied in healthy animals, but recent studies indicate that aging and diabetes, common in coronary patients, do interfere with preconditioning-based interventions in animals. Clearly more study is needed to identify which interventions are adversely affected by comorbidities. (Circ J 2009; 73: 1171 -1177

CGP-37157 Inhibits the Sarcoplasmic Reticulum Ca2+ATPase and Activates Ryanodine Receptor Channels in Striated Muscle

“…Reports in the literature suggest that mitochondrial Ca 2ϩ efflux may play a deleterious role during cardiac ischemia, which can be prevented by CGP or clonazepam (Liu and O'Rourke, 2008;Csordá s and Hajnóczky, 2009;Bonazzola and Takara, 2010). A cardioprotective action has been reported for benzothiazepine derivatives (Farber and Gross, 1989;Wehrens et al, 2005) and for many other drug classes and processes such as preconditioning (Downey and Cohen, 2009). Although there is large heterogeneity in the mechanisms of action for cardioprotective agents, many of them seem to produce, directly or indirectly, a decrease in the use of Ca 2ϩ sources/sinks (mitochondria, SR stores, and/or plasmalemma) during excitation-contraction coupling.…”

Single-Dose Intravenous Administration of Recombinant Human Erythropoietin Is a Promising Treatment for Patients With Acute Myocardial Infarction

“…2, 3 Despite previous intensive research, no drug has exceeded the effect of reperfusion by PCI to reduce infarct size in patients with AMI. 4 In addition to hematopoietic activity, erythropoietin (EPO) has been found to have anti-apoptotic and tissue-protective effects on the myocardium in animal models. Independent of hematopoietic activity, administration of EPO improved cardiac contractility in post-hypoxic mice, 5 repressed cell death of the myocardium in a rabbit AMI model, 6 expressed an acute cardioprotective effect in rat ischemia -reperfusion injuries, 7 showed a preventive effect on cardiac dysfunction in doxorubicin-induced cardiomyopathy in mice, 8 and protected the myocardium in rats with experimental autoimmune OZAWA T et al myocarditis 9,10 via protein kinase C and phosphatidylinositol 3-kinase signaling directly 11 and neovascularization by EPO indirectly.…”

Cell-Based Therapies for Ischemic Heart Disease "Trick and Treat"

“…Classical pharmacological reagents of myocardial preconditioning strategies, such as adenosine, which provides tissue protection during ischemia and induces anti-inflammatory responses as well as bradykinin that acts through the release of nitric oxide, 38,39 might as well elicit their therapeutic effects by modifying trafficking properties of transplanted cells in ex vivo protocols. The precise mechanism would have to be tested.…”