Basic Research in Cardiology (2021) 116:37 https://doi.org/10.1007/s00395-021-00876-6 EDITORIAL The platelet paradox of injury versus protection in myocardial infarction—has it been overlooked? Petra Kleinbongard1 · Ioanna Andreadou2 · Gemma Vilahur3,4 Received: 26 April 2021 / Accepted: 26 April 2021 © The Author(s) 2021 The rupture of an atherosclerotic plaque triggers platelet and deflating a pneumatic cuff placed on the upper arm or activation and thrombus formation, often resulting in coro- thigh has facilitated the translation of RIC into the clini- nary occlusion and acute myocardial infarction (MI) [3]. cal setting [17, 21, 26]. In the CONDI-2/ERIC-PPCI trial, Accordingly, the use of antiplatelet therapy has become the the primary endpoint was a combination of cardiac death or standard of care in acute coronary syndromes to attenuate hospitalization for heart failure at 12 months post-randomi- and reduce recurrent thrombotic events. However, the clini- zation. Secondary endpoints included major cardiovascular cal benefit of P­ 2Y12 receptor antagonists is not limited to and cerebral adverse events at 30 days and 12 months and their ability to inhibit platelet function and prevent arterial myocardial damage in a subset of 2662 patients estimated thrombus formation but they have been shown to also pro- from biomarker release over 48 h after PPCI [19]. However, vide direct cardioprotective effects [37, 56]. and unfortunately, this trial failed to confirm prior single In the study by Dr. Hjortbak and collaborators [23], the center studies [11, 20, 22]. There was no difference between authors retrospectively examined data from the CONDI-2/ the control group and the RIC group in the combined pri- ERIC-PPCI trial. The CONDI-2/ERIC-PPCI trial was an mary endpoint of cardiac death or heart failure or in major international, multicentre, single-blinded, randomized con- cardiovascular and cerebral adverse events or myocardial trolled trial comprising 5401 ST-segment elevation myo- damage [19]. cardial infarction (STEMI) patients [19]. Patients were Now, the group by Dr. Botker has taken advantage of randomly assigned to receive either standard treatment or these neutral findings to retrospectively investigate the remote ischemic conditioning (RIC), initiated prior to pri- potential protective effects of the most commonly prescribed mary percutaneous coronary intervention (PPCI). RIC, brief ­P2Y12 receptor antagonists—clopidogrel, prasugrel and tica- cycles of ischemia and reperfusion applied to an organ or grelor—on cardiac damage post-MI and clinical outcome tissue remote from the heart, has been shown to reduce myo- [23]. Undoubtedly, this retrospective analysis touches upon cardial damage after myocardial ischemia/reperfusion (IR) a topic of high clinical interest. On one hand, novel and in animal models but also in humans [21]. The ability to innovative treatment strategies are needed to limit the infarct deliver the cardioprotective RIC stimulus by simply inflating size, preserve left ventricular function and improve clinical outcomes in STEMI patients undergoing PPCI [2, 10, 18, 33–35]. On the other hand, this multicentre study expands This comment refers to the article available at https://​doi.​org/​10.​ 1007/​s00395-​021-​00870-y. on the reported existence of potential differences in cardio- protection achieved with the most widely prescribed ­P2Y12 * Petra Kleinbongard receptor antagonists and demonstrates a benefit of ticagre- petra.kleinbongard@uk-essen.de lor over clopidogrel and prasugrel in clinical outcomes. As 1 Institute for Pathophysiology, West German Heart such, as compared to clopidogrel, the composite endpoint of and Vascular Center, University of Essen Medical School, cardiac death or hospitalization for heart failure was reduced University of Duisburg-Essen, Hufelandstr. 55, 45122 Essen, in STEMI patients treated with ticagrelor, but not prasu- Germany grel [23]. Platelet ­P2Y12 receptor antagonists are thought 2 Laboratory of Pharmacology, Faculty of Pharmacy, National to induce cardioprotection through conditioning mimetic and Kapodistrian University of Athens, Athens, Greece effects [45, 56] and thus to potentially limit further protec- 3 CIBERCV, Instituto Salud Carlos III, Madrid, Spain tion from additional ischemic conditioning [8, 25]. Yet, an 4 Cardiovascular Research Chair Autonomous University increasing number of experimental and small clinical studies of Barcelona (UAB), Barcelona, Spain 13 Vol.:(0123456789) 37 Page 2 of 5 Basic Research in Cardiology (2021) 116:37 have suggested, that ticagrelor exerts cardioprotection and attenuates adverse cardiac remodelling post-MI to a larger extent than clopidogrel through its platelet-independent platelet-leukocyte interaction (inflammation, effects [1, 38, 51]. In this regard, ticagrelor has been shown no-reflow) thromboxane A2 to increase the circulating levels of adenosine, an endog- microvesicles (vasoconstriction) exosomes apoptotic enous cardioprotective substance, by inhibiting its uptake bodies chemerin (cardiomyocyte through the equilibrative nucleoside transporter 1 receptor apoptosis) serotonin [6]. Furthermore, ticagrelor administration has been associ- (cardiac sympathetic stimulation) microRNA199a ated in a pig model of MI with enhanced expression and microthrombi (cardiac regeneration) activation of adenosine monophosphate-activated (AMPK) (cardiac damage) microRNA22 microRNA185 microRNA320b and reduced aquaporine-4 levels in the ischemic myocar- TGFβ1 (regulation of oxidation-, platelet-activating adenine nucleotides SDF1α inflammation- and adhesion- factor serotonin (cardioprotection) related gene expression in the (cardioprotection) (cardioprotection) dium as compared to clopidogrel-treated animals [52, 53]. endothelium) In the study by Dr. Hjortbak [23], the authors reproduced παράδοξοσ - parádoxos the clinical data in an in vivo rat model of IR—ticagrelor reduced infarct size, clopidogrel and prasugrel did not. Doses and timing of the P ­ 2Y12 receptor antagonists were Fig. 1  The platelet paradox. Paradox—from the ancient Greek adjec- chosen from the literature. However, as discussed by the tive παράδοξος parádoxos [29], “i.e., contrary to expectation, unex- pected, incredible”: platelets contribute to cardiac damage during authors, potential differences in their pharmacokinetic (drug myocardial infarction, but also carry and release multiple cardiopro- concentrations) or pharmacodynamic (degree of platelet tective factors. Our understanding of platelets in the setting of acute inhibition) profile at reperfusion, that could partly explain myocardial infarction is not complete—it only appears to be a closed ticagrelor’s superiority over prasugrel and clopidogrel, were structure—as with the "Penrose triangle". The British Nobel Prize- winning mathematician Sir Roger Penrose popularized this triangle, not excluded. Yet, ticagrelor’s superiority was evidenced in which gives the appearance of a closed three-dimensional structure of both the preclinical and clinical data. Future studies should three right angles, but in the Euclidean geometry it cannot exist as a aim to determine the cellular targets and signaling pathways solid object [40]. SDF1α: stromal cell-derived factor-1α, and TGFβ1: by which ticagrelor contributes to such beneficial effects. transforming growth factor β1 This paper, however, overlooks one crucial aspect: the paradoxical role of platelets in the setting of MI. Activated and to delay the rate of cardiomyocyte death by activating platelets, beyond promoting arterial thrombus formation, the RISK and SAFE pathways [46, 55]. Platelets also carry may contribute to cardiac damage via different mecha- microRNAs, known to exert beneficial effects on cardiac nisms, including the formation of coronary microvascular IR, regulate endothelial gene expression and promote car- microthrombi, induction of platelet-leukocyte interactions, diac regeneration (Fig. 1) [9]. An in-depth understanding of release of vasoconstrictor molecules (e.g., thromboxane the role of platelet-derived components on infarct size and A2), and (microRNA-containing) microvesicles [4, 9]. How- cardioprotection in the setting of MI will allow to properly ever, increasing evidence supports the notion that platelets tackle the potential of ­P2Y12 receptor antagonists to limit also carry and release multiple factors with the potential cardiac damage beyond arterial thrombus formation and to reduce rather than promote IR injury (Fig. 1) [9, 13]! growth. It is conceivable that the administration of ­P2Y12 Whereas the injurious role of platelets is mainly attributed receptor antagonists may interfere with the protective role to its (intra-)vascular actions, platelet protective effects are of platelets during MI [36], making things more complex. mainly mediated through their secreted factors on cardio- This paper also makes us wonder what the potential myocytes. Platelets contain sphingosine kinase, which, upon impact of RIC on platelet function is. In a recent substudy activation, can transform membrane sphingosine into sphin- of the CONDI-2/ERIC-PPCI trial that included 53 patients gosine-1 phosphate (S1P), a pivotal mediator of cardiopro- with RIC versus 47 without, RIC was associated with a tection [24, 49, 54]. Multiple studies have demonstrated the reduction in platelet reactivity within the first 48 h post- ability of platelet-derived S1P to protect against IR injury STEMI [15], confirming a prior single-center trial, where by activating the survivor activating factor enhancement RIC was associated with a reduction in the exercise-related (SAFE), reperfusion injury salvage kinase (RISK), and pro- increase of platelet reactivity in patients with obstructive tein kinase B (Akt)/endothelial nitric oxide synthase cardio- coronary artery disease [5]. RIC has also been shown to protective signaling pathways [32, 50]. Furthermore, adeno- prevent systemic platelet activation associated with IR injury sine nucleotides and serotonin released from dense granules in humans [39], to decrease the conformation changes of have demonstrated tissue-protective effects, and stromal cell- platelet GPIIb/IIIa (a marker of platelet activation) [28] derived factor 1α (SDF1α) and transforming growth factor and platelet–monocyte aggregate formation [27, 28, 48] in β1 (TGFβ1) released from alpha granules have been shown patients with suspected stable angina undergoing coronary to reduce IR injury in rodent and human myocardium [12], angiography [27, 28] and in those undergoing ablation for 13 Basic Research in Cardiology (2021) 116:37 Page 3 of 5 37 atrial fibrillation [48]. These clinical data support previous References experimental findings in animal models of myocardial IR injury in which ischemic conditioning approaches attenu- 1. 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