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.


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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  3. References

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).


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  2. Address
  3. References
  • 1
    Antman EM, Anbe DT, Armstrong PW, Bates ER, Green LA, Hand M et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients with Acute Myocardial Infarction). Circulation 2004;110:e82292.
  • 2
    Taylor J. 2012 ESC Guidelines on acute myocardial infarction (STEMI). Eur Heart J 2012;33:25012.
  • 3
    Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med 2007;357:112135.
  • 4
    Roubille F, Combes S, Leal-Sanchez J, Barrere C, Cransac F, Sportouch-Dukhan C et al. Myocardial expression of a dominant-negative form of Daxx decreases infarct size and attenuates apoptosis in an in vivo mouse model of ischemia/reperfusion injury. Circulation 2007;116:270917.
  • 5
    Vincent A, Gahide G, Sportouch-Dukhan C, Covinhes A, Franck-Miclo A, Roubille F et al. Down-regulation of the transcription factor ZAC1 upon pre- and postconditioning protects against I/R injury in the mouse myocardium. Cardiovasc Res 2012;94:3518.
  • 6
    Zak R. Development and proliferative capacity of cardiac muscle cells. Circ Res 1974;35(Suppl. 2):1726.
  • 7
    Jugdutt BI. Ventricular remodeling after infarction and the extracellular collagen matrix: when is enough enough? Circulation 2003;108:1395403.
  • 8
    Roubille F, Busseuil D, Merlet N, Kritikou E, Rhéaume E, Tardif J-C. Investigational drugs targeting cardiac fibrosis. Expert Rev Cardiovasc Ther 2013 In press.
  • 9
    Dignat-George F, Blann A, Sampol J. Circulating endothelial cells in acute coronary syndromes. Blood 2000;95:728.
  • 10
    Bonello L, Laine M, Baumstarck K, Fernandez J, Maillard L, Peyrol M et al. A randomized trial of platelet reactivity monitoring-adjusted clopidogrel therapy versus prasugrel therapy to reduce high on-treatment platelet reactivity. Int J Cardiol 2013;168:42448.
  • 11
    Kin H, Zhao ZQ, Sun HY, Wang NP, Corvera JS, Halkos ME et al. Postconditioning attenuates myocardial ischemia-reperfusion injury by inhibiting events in the early minutes of reperfusion. Cardiovasc Res 2004;62:7485.
  • 12
    Roubille F, Franck-Miclo A, Covinhes A, Lafont C, Cransac F, Combes S et al. Delayed postconditioning in the mouse heart in vivo. Circulation 2011;124:13306.
  • 13
    Heusch G. Cardioprotection: chances and challenges of its translation to the clinic. Lancet 2013;381:16675.
  • 14
    Mewton N, Liu CY, Croisille P, Bluemke D, Lima JA. Assessment of myocardial fibrosis with cardiovascular magnetic resonance. J Am Coll Cardiol 2011;57:891903.
  • 15
    Kang KT, Coggins M, Xiao C, Rosenzweig A, Bischoff J. Human vasculogenic cells form functional blood vessels and mitigate adverse remodeling after ischemia reperfusion injury in rats. Angiogenesis 2013;16:77384.
  • 16
    Galaup A, Gomez E, Souktani R, Durand M, Cazes A, Monnot C et al. Protection against myocardial infarction and no-reflow through preservation of vascular integrity by angiopoietin-like 4. Circulation 2012;125:1409.
  • 17
    Tardif JC, Tanguay JF, Wright SS, Duchatelle V, Petroni T, Gregoire JC et al. Effects of the P-selectin antagonist inclacumab on myocardial damage after percutaneous coronary intervention for non-ST-segment elevation myocardial infarction: results of the SELECT-ACS trial. J Am Coll Cardiol 2013;61:204855.
  • 18
    Garcia-Dorado D, Andres-Villarreal M, Ruiz-Meana M, Inserte J, Barba I. Myocardial edema: a translational view. J Mol Cell Cardiol 2012;52:9319.