Acute myocardial infarction (AMI) is a leading cause of heart failure and premature death worldwide [1]. Both immediate medical treatment and rapid reperfusion to limit myocardial damage are strongly recommended [2, 3]. However, reperfusion has the potential to initiate additional lethal injury, known as ‘ischemia–reperfusion (IR) injury,’ and could result in increased cardiac cell death [4]. New therapeutic strategies that directly target the reperfusion-mediated damage have been proved to reduce infarct size (IS) in experimental animal models. These approaches include (1) ischemic postconditioning [5, 6] and even remote postconditioning [7]; (2) pharmacological postconditioning including cyclosporine A [8] or normalization of intracellular calcium homeostasis [9, 10]; and (3) genetic perturbation in animal models of critical proapoptotic pathways involved in reperfusion injury [11, 12]. These new approaches have been shown to improve ventricular remodeling and clinical outcomes after AMI [13–17].

IR lesions are partly mediated and worsened by oxidative stress [18]. One of the most known anti-oxidative agents is N-acetylcysteine (NAC), but results in clinical translation have been most often disappointing as regards cardiovascular disease [19] as well as nephrology [20]. Nevertheless, NAC is currently under study in various fields of medical research, as briefly presented in the Table 1, noticeably in psychiatry disorders. This venerable drug had been already proposed as an interesting candidate for cardioprotection for decades [21–24], but controversial results have been obtained.

Table 1 Incomplete trials evaluating N-acetylcysteine that are currently registered on the clinicaltrials.gov registry
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In this issue of the Journal, Talasaz et al. [25] once again address the efficacy of NAC to control post-MI remodeling. They suggest that NAC could improve the myocardial remodeling following AMI in a proof-of-concept clinical trial. In this prospective, double-blinded, randomized clinical trial, 98 patients were allocated to placebo or NAC at the dose of 600 mg orally twice daily during three days upon hospital arrival. The authors showed that serum levels of metalloproteinase (MMP)-9 and MMP-2 after 72 h and major adverse cardiac events including re-infarction during the 1-year follow-up were significantly lower in the treated group than in the placebo group. However, several limitations have to be underlined, and this proof-of-concept trial has to be confirmed in larger trials. Among the limitations, mainly biochemical and baseline echographic parameters have been considered, so it is difficult to conclude on echocardiographic evolution, IS (whether this was accurately measured) or specific clinical outcomes. Reperfusion is not always obtained (only 40 % of the patients received primary coronary intervention), collateral flow or area at risk are not taken into consideration, and, importantly, the sample is small. Whether the design of the study, especially the timing (as soon as possible to treat the IR lesions), the route (would intravenous/intracoronary route, if safe, be more efficient?), and the very drug under study, including the dose (dose-effect? high dosage?), the formulation, or even the chemical modifications [26] could be improved remains to be explored.

Beyond oxidative stress, several drugs have been recently evaluated in the clinic (recent reviews are available, see, for instance, [27–30]) or are presently under study in the cardioprotection field, as briefly presented in the Table 2. Detailed descriptions of included trials can be accessed from the clinicaltrials.gov site. The focus of the trials included in Table 2 is on reduction of IS. Despite our efforts to present an exhaustive list, trials that could not be identified by the keywords used here (e.g., cardioprotection, myocardial infarction) would have been missed.

Table 2 Ongoing clinical trials evaluating pharmacological conditioning
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The largest trials currently underway are evaluating the interest of cyclosporine A (a well-known immunomodulator) (see Table 2). All the drugs presented in Table 2 aim at one or several specific targets involved in IR lesions. Antiplatelet effect or correction of microcirculation, cooling, controlled reperfusion, and blood pressure control represent other powerful cardioprotective strategies described elsewhere. Some distinct families are schematically depicted in Table 2: inflammation, metabolism, immunomodulation, vasodilators, etc. Obviously, there are numerous cross-talk and redundant pathways. For instance, although cyclosporine A is mainly used as an immunomodulator, its putative interest as regards cardioprotection is its impact on the mitochondrial permeability transition pore (mPTP). Research is particularly intense on molecules targeting metabolism and immune response, as well as on anti-inflammatory agents, as depicted in Table 2. Some of these studies precisely target the IR lesions, whereas others target cardiac remodeling more specifically (e.g., spironolactone) or other phenomena, depending on the design of the study.

Whether NAC or other pharmacological agents can deliver on their promise is currently being investigated in clinical trials. This is a highly active field, both in basic research and in clinical translation. A combination of various strategies could also be considered in the future: optimal medical treatment including ACE inhibitors, high-dose statins, mineralocorticoid receptor antagonists, anti-platelet agents, pharmacological/remote/post-conditioning, but also cooling or other physical stimuli. Furthermore, the ideal timing is difficult to determine, as are the ideal patients. Treatments and/or comorbidities could affect the efficiency of treatment modalities. Combining inexpensive and relatively nontoxic drugs such as NAC could then be an interesting option in the future.