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Both immediate medical treatment and rapid reperfusion to limit myocardial damage are strongly recommended for the treatment of acute myocardial infarction (AMI) [1, 2]. However, beside obvious beneficial effects, reperfusion initiates additional lethal injury, known as ‘ischaemia-reperfusion (IR) injury’ and results in increased cardiac cells death through both necrosis and apoptosis [3] (see Fig. 1 for schematic presentation). Genetic perturbation in animal models of critical proapoptotic pathways involved in IR injury has been demonstrated to be beneficial [4, 5] and underline the involvement of apoptosis in IR lesions. To reduce this phenomenon, various cardioprotective strategies including post-, remote or pharmacological conditioning target specifically IR injury.

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Figure 1. A cellular network in the heart of ischaemia-reperfusion injury. Ischaemia-reperfusion (IR) triggers necrosis (ischaemia) and apoptosis of several cell populations mainly cardiomyocytes, but also endothelial cells (EC). Cardiomyocytes cell death activates in turn inflammatory cells including macrophages, leading to the activation of the profibrotic process and remodelling. EC play a crucial role, not only regarding cell arrival but also because they are involved in many cross-talks. Progenitors cells either systemic or local are involved in endothelial and cardiomyocytes repair. (IR)EC: endothelial cells; ECM: extracellular matrix; ROS: reactive oxygen species.

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The ‘noble cell’ to rescue appears often to be the cardiomyocyte. However, other cellular populations are of importance. Nearly 75% of the cells in the healthy heart are not cardiomyocytes [6], representing one-third of the mass or 10% of the volume. Most of these cells are fibroblasts [7], and endothelial cells could represent 10–15% of the volume of the heart [7]. The noncardiomyocytes cells play also critical roles, especially regulating fibrosis and extracellular matrix as regards fibroblasts (see recent review [8]). Inflammatory cells play a major role in local inflammation during IR injury. The importance of endothelial cells (EC) should not be underestimated: they are not only deeply involved in ischaemic disease but also could participate in paracrine regulation, proinflammatory and profibrotic pathways. The pathophysiology of IR injury could then be considered as a cross-talk between various cellular populations and different biological pathways could be logically intricate (see Fig. 1 for a schematic presentation). ECs should be an interesting therapeutic target as they are easy to identify, especially after acute coronary syndromes [9] and linked with treatments [10].

Here, Forteza et al. explore in vitro the dynamics of EC viability, apoptosis and necrosis when treated with sera drawn in patients with acute STEMI after primary angioplasty. This study although small and in vitro provides important data on the subject. First, the authors establish that both EC viability nadir and EC apoptosis peak occur relatively late after the onset of reperfusion, that is at 96 h, which challenges the usually admitted narrow window for cardioprotection after AMI [11, 12]. Indeed, cardioprotective therapies could be of interest even after the early minute following reperfusion because the development of biological events triggered by reperfusion occurs during a wider time window. This consideration is reinforced by the fact that EC apoptosis assessed in vitro remains active even at day 30, whereas EC necrosis appears as a rare event. Secondly, the kinetics of this phenomenon and the important role played by EC deserve to be underlined: these data illustrate that apoptotic phenomena triggered by IR are involved not only in myocytes, but likely in all cell types present or migrating on site (see for schematic presentation the Fig. 1). Among them, EC represent a promising target for immediate and delayed therapeutic intervention.

Clinical translation in the field of cardioprotection is deeply mutating as recently reviewed [13]. Presently, due to new tools such as magnetic resonance imaging, infarct size is not the single point of interest in AMI, but myocardial oedema or microvascular obstruction could be accurately evaluated [14]. In a near future, among the numerous trials on cardioprotection in patients with AMI, new parameters and endpoints could be proposed such as distinguishing various pathophysiologies. For instance, beyond infarct size, apoptotic events, activation of progenitor cells, specific proinflammatory or profibrotic pathways need to be explored, to better understand the impact of specific drugs and perhaps to better tailor individual treatments.

Consistently, EC appear as an important target both in basic [15, 16] and clinical approaches [17], especially to correct myocardial oedema [18] and because they can be easily and promptly targeted by a drug. The further step could even be to modulate the cross-talks between various players.

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Cardiology Department, University hospital of Montpellier, Université de Montpellier 1, 371 Avenue du doyen Gaston Giraud, 34295 Montpellier Cedex 5, France (F. Roubille); Montreal Heart Institute, Université de Montréal, 5000 Belanger Street, Montreal, PQ H1T 1C8, Canada (F. Roubille); Institute for Functional Genomics; CNRS UMR5203, Inserm U661, University Montpellier 1 and 2, Montpellier, France (S. Barrere-Lemaire).

References

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