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Interventions that reduce infarct size in animal models have largely failed to improve outcome in patients suffering acute myocardial infarction (MI) or ‘heart attack.’ Our group recently reported a reduction of infarct size by chloramphenicol treatment in a porcine in vivo model of acute MI, through a mechanism involving the induction of autophagy. Since 2005 several studies have implicated autophagy as a target for cardioprotection.
Our previous work had established a requirement for autophagy for cardioprotection in rodent models mediated by a variety of agents including the adenosine A1 receptor agonist chlorocyclopentyladenosine, sulfaphenazole and ischemic preconditioning. The requirement was established with the use of Tat-Atg5K130R, a cell-penetrating protein we have used to block autophagy selectively. In the rodent model, administration of this protein also blocks chloramphenicol succinate (CAPS)-induced cardioprotection. In the recent publication, we used the open-chest swine model to determine whether pharmacological upregulation of autophagy could reduce infarct size in a clinically relevant model of myocardial ischemia/reperfusion injury. Pigs were treated with CAPS or placebo and were subjected to 45 min left anterior descending coronary artery occlusion followed by 3 h reperfusion. Autophagy markers LC3-II and Beclin 1 were upregulated within 10 min after IV administration of CAPS. Considering that CAPS is a pro-drug that is metabolized to the active form by blood or liver esterases within 5–15 min, this is a remarkably rapid activation of autophagy. Pretreatment with CAPS 10 min before ischemia yields a ~50% reduction in infarct size compared to placebo controls. More importantly, from the perspective of a potential therapeutic, CAPS administered 15 min before reperfusion (i.e., 30 min into the ischemic period) is able to reduce infarct size by ~27%, demonstrating the feasibility of reperfusion therapy with an agent whose mechanism of action is the induction of autophagy.
The development of a pharmacological agent to salvage myocardium after an ischemic insult has been regarded as the “Holy Grail” of cardioprotection, and a number of promising agents have been explored, but none has been sufficiently successful to become commercialized. There is a consensus that many clinical trials have failed in the past because the preceding animal studies were incomplete and not sufficiently representative of the clinical setting, for instance lacking the presence of co-morbidities such as diabetes. Since CAPS is already approved for use in humans, it could be advanced to clinical trial fairly quickly. However, there are some open questions and concerns.
Chloramphenicol is an antibiotic that has been in clinical use for >30 years. Although it has a known risk of aplastic anemia (incidence of 2–4 per 100,000, idiosyncratic and not dose-related), it is still considered an effective antimicrobial, although many other antibiotics have a better safety profile. However, its risk profile in comparison to other cardiovascular therapeutics is acceptable. For comparison, the incidence of fatal intracranial hemorrhage with TPA is 2%; of fatal bleeding with clopidogrel, 0.2%; and of fatal rhabdomyolysis with statins, 3 per 100,000 person-years. Thus, CAPS has a safety profile that falls within the norms for drugs already employed to treat serious cardiovascular conditions.
While we demonstrated infarct size reduction after a 4 h reperfusion period, it will be important to assess effects on cardiac function and remodeling days to weeks after the ischemic insult. A second question is whether this drug will be effective in aged animals or in those with metabolic syndrome. It has been previously reported that ischemic preconditioning is impaired in aged animals or in those with diabetes or metabolic syndrome. Since autophagy is also attenuated in those conditions, it will be important to establish whether treatment with CAPS can elicit the cardioprotective response in the face of such co-morbid conditions. Finally, the signal transduction mechanism by which CAPS induces autophagy and a cardio-protected state remains to be established.
The cardioprotective activity of CAPS raises the possibility that it should be considered as a candidate for clinical use to attenuate myocardial ischemia-reper-fusion injury through the induction of autophagy.
Punctum to: Sala-Mercado JA, Wider J, Undyala VVR, Jahania S, Yoo W, Mentzer RM, et al. Profound cardioprotection with chloramphenicol succinate in the swine model of ischemia-reperfusion injuryCirculation2010122179184 doi: 10.1161/CIRCULATIONAHA.109.928242.