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Therapeutic hypothermia to protect the heart against acute myocardial infarction
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Archives of Cardiovascular Disease (2016) xxx, xxx—xxx
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REVIEW
Therapeutic hypothermia to protect the heart against acute myocardial infarction L’hypothermie thérapeutique : une stratégie cardioprotectrice contre l’infarctus du myocarde Matthias Kohlhauer a,b,c, Alain Berdeaux a,b,c, Bijan Ghaleh a,b,c, Renaud Tissier a,b,c,∗ a
Inserm, U955, Équipe 3, 94000 Créteil, France UMR S955, DHU A-TVB, UPEC, université Paris Est, 94000 Créteil, France c Université Paris Est, École nationale vétérinaire d’Alfort, 94700 Maisons-Alfort, France b
Received 18 March 2016; received in revised form 29 April 2016; accepted 3 May 2016
KEYWORDS Acute myocardial infarction; STEMI; Hypothermia; Temperature; Cardioprotection
Summary The cardioprotective effect of therapeutic hypothermia (32—34 ◦ C) has been well demonstrated in animal models of acute myocardial infarction. Beyond infarct size reduction, this protection was associated with prevention of the no-reflow phenomenon and long-term improvement in terms of left ventricular remodelling and performance. However, all these events were observed when hypothermia was induced during the ischaemic episode, and most benefits virtually vanished after reperfusion. This is consistent with clinical findings showing a lack of benefit from hypothermia in patients presenting acute myocardial infarction in most trials. In these studies, hypothermia was most often achieved too far into the reperfusion phase (i.e. possibly too late to reduce infarct size); this is supported by meta-analyses and subgroup analyses suggesting that the benefits of hypothermia could still be observed in patients with a large infarction and more rapid cooling before reperfusion. Novel strategies for ultra-fast induction of hypothermia and/or prehospital cooling might therefore be more beneficial. © 2016 Elsevier Masson SAS. All rights reserved.
Abbreviations: AMI, acute myocardial infarction; ATP, adenosine triphosphate; ERK, extracellular signal-regulated kinase; mPTP, mitochondrial permeability transition pore; RCT, randomized controlled trial. ∗ Corresponding author. Équipe 3, Inserm unité 955, université Paris Est, École nationale vétérinaire d’Alfort, 7, avenue du Général-deGaulle, 94704 Maisons-Alfort cedex, France. E-mail address: [email protected] (R. Tissier). http://dx.doi.org/10.1016/j.acvd.2016.05.005 1875-2136/© 2016 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Kohlhauer M, et al. Therapeutic hypothermia to protect the heart against acute myocardial infarction. Arch Cardiovasc Dis (2016), http://dx.doi.org/10.1016/j.acvd.2016.05.005
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MOTS CLÉS Infarctus du myocarde ; STEMI ; Hypothermie ; Température ; Cardioprotection
Résumé L’effet cardioprotecteur de l’hypothermie thérapeutique (32—34 ◦ C) a été largement démontré dans des modèles animaux d’infarctus du myocarde. En complément de la réduction de la taille de l’infarctus, l’hypothermie est capable de limiter le phénomène de « no-reflow » et d’améliorer la récupération fonctionnelle cardiaque à long terme. Ces effets sont puissants lorsque l’hypothermie est induite au cours de l’épisode ischémique, mais ils disparaissent lorsqu’elle n’est induite qu’après la reperfusion. Cela permet d’expliquer l’absence de bénéfice dans les essais cliniques évaluant l’effet cardioprotecteur de l’hypothermie. Dans ces études, l’hypothermie était en effet probablement atteinte trop tardivement (i.e. après la reperfusion). Néanmoins, des analyses en sous-groupes et des méta-analyses ont montré un effet bénéfique chez les patients refroidis plus rapidement avant la reperfusion. De nouvelles approches thérapeutiques permettant une hypothermie plus rapide ou une induction précoce en milieu préhospitalier pourrait permettre de renforcer ces bénéfices. © 2016 Elsevier Masson SAS. Tous droits r´ eserv´ es.
Background Despite the well-established beneficial effects of reperfusion therapies in patients presenting acute myocardial infarction (AMI), morbidity and mortality remain high in this situation. Consequently, seeking new cardioprotective strategies to improve myocardial salvage and cardiac function remains a priority in this field. Therapeutic hypothermia could be one of those promising strategies, and it has been tested in many experimental settings of ischaemic injury, such as cardiac arrest [1,2], stroke [3], myocardial ischaemia [4] and organ preservation [5]; it has also been shown to be well tolerated in humans, when induced with an average target temperature of 32—34 ◦ C (‘‘mild hypothermia’’). However, the clinical benefit of therapeutic hypothermia remains questionable in AMI patients in terms of infarct size reduction [6—10]. Importantly, this apparent discrepancy between experimental and clinical data could be related to different schedules of application. Indeed, animal studies showed that the benefit of cooling was mostly observed when achieved early during ischaemia, while patients are usually cooled just before — or even after — reperfusion. The purpose of this article is to present a state-of-the-art review of the research on hypothermia for cardioprotection.
Experimental evidence of hypothermia-induced cardioprotection Infarct size reduction In animal models of coronary artery occlusion, infarct size has been widely demonstrated to depend upon myocardial temperature, even for very mild temperature variations within ‘‘the normothermic range’’ [11,12]. For instance, Chien et al. compared infarct sizes at different cardiac temperatures (35—42 ◦ C) in rabbits submitted to 30 minutes of coronary artery occlusion [11]; they demonstrated that any decrease in myocardial temperature was linearly correlated to infarct size (—8% of the risk zone for each ◦ C decrement), showing that mild temperature reduction
Figure 1. Pooled analysis of several studies performed in rabbits submitted to 30 minutes of coronary artery occlusion and 3 hours of reperfusion with different temperatures during the ischaemic episode. Each open circle represents the mean infarct size obtained at a different cardiac temperature in these studies. A correlation could be drawn from the pooled analysis of all values, emphasizing that infarct size was virtually abolished at 32 ◦ C. These data are extracted from the following studies: a [14], b [26], c [29], d [27], e [1], f [28], g [4].
could be protective, while hyperthermia was detrimental [11]. A considerable amount of data further support the cardioprotective benefit of mild hypothermia (32—34 ◦ C) during coronary artery occlusion (e.g. in rabbits [13—16], dogs [12,17,18], sheep [19,20], swine [21—24] and rats [25]). All of these studies were performed by independent investigators in different laboratories and species, providing a high level of evidence. For instance, Fig. 1 illustrates the infarct sizes observed at different temperatures in rabbits submitted to 30 mins of coronary artery occlusion in independent studies [1,4,14,26—29]. As illustrated by the regression slope, infarct size was linearly correlated to cardiac temperature (R2 = 0.87). This regression analysis also shows that every 1 ◦ C decrement reduces infarct size by
Please cite this article in press as: Kohlhauer M, et al. Therapeutic hypothermia to protect the heart against acute myocardial infarction. Arch Cardiovasc Dis (2016), http://dx.doi.org/10.1016/j.acvd.2016.05.005
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Hypothermia and cardioprotection approximately 6% of the risk zone, leading to ‘‘maximal’’ cardioprotection at 32 ◦ C in these conditions. Interestingly, earlier studies also tested the effect of deeper hypothermia (e.g. in dogs submitted to 5—10 hours of coronary artery occlusion at 26 ◦ C) [30]. In this model, hypothermia was still efficient at reducing ischaemic injury (−20 and −25%, respectively). However, such profound levels of cooling raise safety issues, and seem very challenging for clinical translation. Most studies were therefore conducted in the mild hypothermia range (32—34 ◦ C).
Functional benefits Beyond infarct size reduction, the beneficial effect of therapeutic hypothermia on left ventricular post-ischaemic dysfunction has also been demonstrated. For example, cardiac output was not altered with hypothermia in pigs submitted to 60 minutes of coronary artery occlusion [31]. In rabbits, intraischaemic hypothermia also significantly increased left ventricular wall motion after reperfusion compared with normothermic animals [15]. This functional benefit was not just related to infarct size reduction, as left ventricular recovery was more rapid with intraischaemic cooling than with ischaemic preconditioning, which similarly reduced infarct size [32,33]. Such a functional benefit was also observed in rabbits concomitantly submitted to 40 minutes of coronary artery occlusion and cardiac arrest [1]. In this model, ultra-fast cooling dramatically improved cardiac output and left ventricular contractility after resuscitation. These benefits were further associated with reduced mortality from cardiovascular origin in this model [1]. Interestingly, similar benefits were also observed in a pure model of cardiac arrest treated with therapeutic hypothermia in rabbits [34]. Longer term, hypothermia-induced cardioprotection leads to reduced left ventricular remodelling and improved contractility; for example, in rats, left ventricular function and remodelling were improved 6 weeks after coronary artery occlusion when it was combined with mild hypothermia [35]. Similar results were obtained in sheep after 8 weeks following myocardial ischaemia [20].
3 with hypothermia after 10 minutes of coronary occlusion in pigs [22] or isolated heart [37]. Conversely, vascular relaxation was not influenced by hypothermia in vitro in rabbit aorta rings [38]. The exact role played by hypothermia in vascular reactivity therefore needs to be further investigated.
Importance of the window of application of hypothermia The above-mentioned cardioprotective effects of hypothermia have been widely described, with myocardial cooling maintained throughout the ischaemic period [11]. However, this schedule of application is of poor clinical relevance, as patients cannot be cooled from the onset of symptoms. Several studies have therefore tested cooling with different timings for its institution during ischaemia or reperfusion. For example, Fig. 2 pools the results of different studies in rabbits submitted to 30 mins of myocardial ischaemia and hypothermia started at different time points [4,15,29,36]. Interestingly, the cardioprotective effects of hypothermia decreased exponentially, along with any delay in the institution of cooling during ischaemia. Therefore, cooling seems to be poorly protective regarding infarct size when induced after the onset of reperfusion [13,22,23]. In other words, therapeutic hypothermia should be initiated as soon as possible, with a high cooling rate, in order to maximize infarct size reduction (‘‘the sooner, the better’’). However, in large animals, little benefit was observed with cooling started at the end of the ischaemic period (i.e. just before reperfusion). For instance, Götberg et al. performed an elegant study evaluating the proper effect of hypothermic reperfusion compared with normothermic reperfusion
Effect of hypothermia on no-reflow and microvascular alteration In addition to infarct size reduction and functional improvement, therapeutic hypothermia has also been shown to prevent microvascular obstruction and no-reflow after myocardial ischaemia. For example, cooling the myocardium to 32 ◦ C potently decreased the no-reflow area after 30 minutes of coronary artery occlusion in rabbits (noreflow: 11 ± 3% and 37 ± 3% of the risk zone in hypothermic versus normothermic animals, respectively) [36]. Interestingly, regression analyses suggested that no-reflow reduction was not explained solely by infarct size reduction; this was further confirmed with cooling started after reperfusion, which only reduced no-reflow area, but not infarct size [13,22]. These findings suggest that intraischaemic hypothermia protects not only cardiomyocytes, but also microvessels against ischaemic injury. This is consistent with decreased post-ischaemic coronary reactive hyperaemia
Figure 2. Pooled analysis of several studies performed in rabbits submitted to 30 minutes of coronary artery occlusion and 3 hours of reperfusion, with hypothermia started after different delays during the ischaemic episode. Each open circle represents the cardioprotective effect observed with cooling started at different time points. Cardioprotection was assessed by infarct size reduction (compared with the corresponding control groups). A correlation could be drawn between the different values. These data are extracted from the following studies: a [29], b [4], c [36], d [15].
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[39]. Pigs were submitted to 40 mins of normothermic ischaemia versus 45 minutes of ischaemia with cooling started 5 mins before reperfusion (40 minutes of normothermic ischaemia plus 5 minutes to achieve cooling before reperfusion). In these conditions, hypothermic reperfusion significantly decreased infarct size by 18% compared with normothermia, despite a longer ischaemic period [39]. Interestingly, this very mild beneficial effect of hypothermic reperfusion on infarct size was combined with a more potent effect on no-reflow and microvascular obstruction [13]. Overall, it is clear that hypothermia must be instituted as soon as possible to afford significant benefit during the ischaemic process. Therefore, different cooling strategies have been tested, to increase the cooling rate and to reduce the normothermic ischaemic time [33,40]. In patients, cooling is typically induced using external approaches [41], eventually combined with endovascular cooling [8]. Some other strategies have also been proposed to improve cooling efficiency, such as cold peritoneal lavage [42] or intranasal evaporative cooling [43]. New invasive approaches are tested benchside in order to provide ultra-fast cooling through total liquid ventilation [44] or extracorporeal life support [2].
Mechanisms of cardioprotection by therapeutic hypothermia Energy preservation For a long time, the mechanism underlying the cardioprotective effect of hypothermia was considered to be a direct consequence of reduced metabolism and energy preservation. For example, cold cardioplegia (< 20 ◦ C) is associated with a reduction in cardiac metabolism and preservation of adenosine triphosphate (ATP) concentration [45]. Using mild hypothermia (32—34 ◦ C), a reduction in ATP consumption was also observed in ischaemic isolated heart [46] or after in vivo regional ischaemia [47], although to a lesser extent than deeper hypothermia (< 31 ◦ C) [46]. Interestingly, in vitro studies have shown that energy preservation is not linearly correlated to temperature decrease, and that ATP and glucose consumption are almost unaltered when the temperature remains above 35 ◦ C [48]. Yet, cooling at 35 ◦ C remains effective for infarct size reduction, which could suggest that therapeutic hypothermia acts through mechanisms other than metabolism reduction [29,49]. This is also supported by other mechanistic studies showing, for example, that inhibition of the extracellular signal-regulated kinase (ERK) survival pathway does not alter the ATP-sparing properties of hypothermia, while abolishing its infarct-size reducing properties in isolated rabbit heart [16]. All these results suggest that metabolic adaptation probably does not entirely explain all the cardioprotective effects of hypothermia (Fig. 3). Beyond its direct effect on cell metabolism, it was also speculated that hypothermia-induced bradycardia could preserve energy in vivo and improve tolerance to ischaemia. This hypothesis has been disproven, as cardiac pacing at
‘‘high’’ heart rate did not abolish the cardioprotective effect of hypothermia [11].
Role of mitochondria and generation of reactive oxygen species For a long time, mitochondria have been highlighted as a potential target for the cardioprotective effect of hypothermia, beyond the above-mentioned metabolic adaptation. Indeed, mitochondrial electron transfers and respiratory function are well known to be directly influenced by temperature [50]. For instance, the respiratory control ratio is significantly better in isolated rabbit cardiac mitochondria at 32 ◦ C compared with 38 ◦ C (+22 ± 3%) in normoxic conditions. Concomitantly, generation of reactive oxygen species was also much lower (−41 ± 1%) at 32 ◦ C vs 38 ◦ C in similar conditions. In isolated rat cardiomyocytes, reactive oxygen species generation is also dramatically decreased during hypoxia at 32 ◦ C vs 38 ◦ C (−55 ± 8% after 140 minutes of hypoxia). In addition, hypothermia attenuates mitochondrial complex I, II and III dysfunction in rabbits submitted to 30 mins of coronary artery occlusion [50]. This effect was accompanied by a limitation in mitochondrial reactive oxygen species production and subsequent oxidative stress assessed by lipid peroxidation. In addition, hypothermia has also been shown to modulate the mitochondrial permeability transition pore (mPTP), which is a well-established target of cardioprotective strategies. For example, this was investigated in rabbits submitted to 30 mins of coronary artery occlusion, with myocardial mitochondria sampled just before reperfusion (ischaemic mitochondria) or 5 minutes after reperfusion (reperfused mitochondria). The authors demonstrated that hypothermia increased mitochondrial calcium restrain capacity at the end of the ischaemic period, but did not prevent the increased sensitivity induced by reperfusion [15]. Therefore, it seems that hypothermia potently protects against mPTP opening during ischaemia, but does not mitigate the reperfusion injury [15]. Again, this is consistent with physiological data showing that hypothermia does not potently reduce infarct size at reperfusion [13,22,23]. This is a main difference compared with ischaemic preconditioning, which is well known to inhibit mPTP opening during reperfusion, through activation of reperfusion-induced salvaged kinase [51].
Effect of hypothermia on signalling pathways Many experimental studies have also attempted to decipher the action mechanism of hypothermia and the potential involvement of a signalling pathway. Importantly, this could open promising perspectives, if part of the benefit afforded by hypothermia could be mimicked pharmacologically. These mechanistic studies have been summarized in detail in a review [33]. Briefly, temperature reduction was, for example, shown to activate the Akt pathways and heat-shock proteins 27 or 70 in isolated mice cardiomyocytes exposed to simulated ischaemia [49]. The role of ERKs was also well demonstrated in isolated rabbit heart submitted to regional ischaemia, in which the protection afforded by mild hypothermia (35 ◦ C) was completely eliminated by two different ERK inhibitors [15]. Interestingly,
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Figure 3. Potential targets of the cardioprotective effect of mild hypothermia (non-exhaustive). TRPV: transient receptor potential cation channel subfamily V.
ERK inhibition did not directly affect ATP concentration, suggesting that energy preservation was unrelated to hypothermia cardioprotection. Therefore, additional investigations are still needed to better understand the anti-ischaemic effect of hypothermia, and to provide new targets, allowing mimicking of its cardioprotective effect.
Clinical trials with hypothermia in the catheterization laboratory In the two last decades, several randomized controlled trials (RCTs) have been performed to evaluate the cardioprotective effect of therapeutic hypothermia in AMI patients [6—9,52,53]. While analysing those findings, one should keep in mind that the benefit was well demonstrated in animal studies when hypothermia was achieved during ischaemia, but not after reperfusion. One of the first feasibility trials was conducted by Dixon et al., in patients submitted to endovascular cooling before percutaneous coronary intervention in the catheterization laboratory. This study showed that the mean core temperature could reach 34.7 ± 0.9 ◦ C before the first balloon inflation, while cooling could be safely maintained at 33 ◦ C for 3 hours after reperfusion [7]. In 2003, the COOL-MI trial investigated the same cooling protocol in a larger population of 357 patients [6]. Unfortunately, this study failed to demonstrate a significant reduction in infarct size with
cooling. The ICE-IT trial was then conducted to investigate the same procedure in 228 patients with 6 hours of hypothermia after reperfusion [52]; again, this failed to demonstrate any significant benefit with a longer duration of therapeutic hypothermia [52]. However, a pooled analysis of both COOLMI and ICE-IT trials demonstrated that a majority of patients failed to effectively reach the target temperature of 33 ◦ C at the onset of reperfusion [6]. Further trials were therefore conducted with a more aggressive protocol, combining rapid infusion of cold saline and concomitant endovascular cooling [8,9]. The RAPID MI-ICE trial demonstrated that this protocol was feasible and safe in 20 patients, but the body core temperature reached only 34.7 ± 0.3 ◦ C at the onset of reperfusion [9]. Interestingly, this was sufficient here to obtain a significant decrease in infarct size (—38%) with hypothermia, despite a slight increase (+3 minutes) in door-to-balloon time. The further large-scale CHILL-MI trial in 120 patients failed to confirm this significant benefit, with just a trend towards infarct-size reduction (−13%; P = 0.15) [8]. However, the post-hoc pooled analysis of both the RAPID MI-ICE and CHILL-MI trials showed a significant infarct-size reduction with cooling, and a significant decrease in heart failure occurrence [54]. Maximal benefits were observed in the subgroups of patients with the most rapid cooling and/or larger risk zone. Overall, these clinical data confirm that hypothermia apparently needs to be induced during ischaemia (i.e. before reperfusion) to provide benefits in the clinical arena, as shown previously in the experimental studies.
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Overall, the meta-analysis of all the above-mentioned RCTs did not show any significant beneficial effect of therapeutic hypothermia on cardiovascular events, mortality, heart failure or infarct size [10]. However, subgroup analysis showed a significant infarct-size reduction in patients presenting anterior AMI [10]. This trend needs to be properly confirmed in a specific trial. Several RCTs are currently ongoing with cooling for AMI treatment, such as the STATIM trial, which is investigating out-of-hospital cooling through external pads (NCT01777750); this should help us to better understand the consequences of very early cooling in AMI patients. The SHOCK-COOL trial will also determine the functional consequences of therapeutic hypothermia in patients presenting AMI complicated by cardiogenic shock (NCT01890317). Recently, another strategy was also tested; namely, to achieve more rapid cooling through cold peritoneal lavage [53]. This strategy seemed to be safe, but the mean temperature at reperfusion was similar to that in the previous studies (34.7 ◦ C [34.0—34.9 ◦ C] at first balloon inflation). The implementation of this procedure led to prolongation of door-to-balloon time, and did not provide any infarct-size reduction.
Conclusions In conclusion, therapeutic hypothermia provides potent and universally acknowledged benefits regarding infarct size, cardiac function and no-reflow phenomenon when achieved during ischaemia in experimental models. However, no clinical evidence strongly supports the use of mild therapeutic hypothermia in AMI patients at present. This discrepancy is largely explained by different schedules for institution of cooling at the bench and the bedside, with different cooling rates and timings of institution. In the clinical setting, hypothermia can only be instituted after incompressible delay following the onset of ischaemia. Novel strategies for ultra-fast induction of hypothermia and/or prehospital cooling might provide better benefits in patients in whom cooling could be achieved during the ischaemic phase (e.g. when revascularization could not be instituted rapidly for any reason).
Sources of funding This study was supported by ‘‘Region Île-de-France’’ (CORDDIM) and the ‘‘Fondation pour la Recherche Médicale’’ (Grant DBS20140930781). M. Kohlhauer received a grant from ‘‘Region Île-de-France’’ (CORDDIM).
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Disclosure of interest
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The authors declare that they have no competing interest. [17]
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7 [37] Ning XH, Chi EY, Buroker NE, et al. Moderate hypothermia (30 degrees C) maintains myocardial integrity and modifies response of cell survival proteins after reperfusion. Am J Physiol Heart Circ Physiol 2007;293:H2119—28. [38] Kohlhauer M, Darbera L, Lidouren F, et al. Comparative effect of hypothermia and adrenaline during cardiopulmonary resuscitation in rabbits. Shock 2014;41:154—8. [39] Gotberg M, van der Pals J, Gotberg M, et al. Optimal timing of hypothermia in relation to myocardial reperfusion. Basic Res Cardiol 2011;106:697—708. [40] Tissier R, Chenoune M, Ghaleh B, Cohen MV, Downey JM, Berdeaux A. The small chill: mild hypothermia for cardioprotection? Cardiovasc Res 2010;88:406—14. [41] Koreny M, Sterz F, Uray T, et al. Effect of cooling after human cardiac arrest on myocardial infarct size. Resuscitation 2009;80:56—60. [42] Polderman KH, Noc M, Beishuizen A, et al. Ultrarapid induction of hypothermia using continuous automated peritoneal lavage with ice-cold fluids: final results of the cooling for cardiac arrest or acute ST-elevation myocardial infarction trial. Crit Care Med 2015;43:2191—201. [43] Lyon RM, Van Antwerp J, Henderson C, Weaver A, Davies G, Lockey D. Prehospital intranasal evaporative cooling for outof-hospital cardiac arrest: a pilot, feasibility study. Eur J Emerg Med 2014;21:368—70. [44] Hutin A, Lidouren F, Kohlhauer M, et al. Total liquid ventilation offers ultra-fast and whole-body cooling in large animals in physiological conditions and during cardiac arrest. Resuscitation 2015;93:69—73. [45] Caputo M, Ascione R, Angelini GD, Suleiman MS, Bryan AJ. The end of the cold era: from intermittent cold to intermittent warm blood cardioplegia. Eur J Cardiothorac Surg 1998;14:467—75. [46] Jones RN, Reimer KA, Hill ML, Jennings RB. Effect of hypothermia on changes in high-energy phosphate production and utilization in total ischemia. J Mol Cell Cardiol 1982;14(Suppl 3):123—30. [47] Simkhovich BZ, Hale SL, Kloner RA. Metabolic mechanism by which mild regional hypothermia preserves ischemic tissue. J Cardiovasc Pharmacol Ther 2004;9:83—90. [48] Ning XH, Xu CS, Song YC, et al. Temperature threshold and modulation of energy metabolism in the cardioplegic arrested rabbit heart. Cryobiology 1998;36:2—11. [49] Shao ZH, Sharp WW, Wojcik KR, et al. Therapeutic hypothermia cardioprotection via Akt- and nitric oxide-mediated attenuation of mitochondrial oxidants. Am J Physiol Heart Circ Physiol 2010;298:H2164—73. [50] Tissier R, Chenoune M, Pons S, et al. Mild hypothermia reduces per-ischemic reactive oxygen species production and preserves mitochondrial respiratory complexes. Resuscitation 2013;84:249—55. [51] Ong SB, Samangouei P, Kalkhoran SB, Hausenloy DJ. The mitochondrial permeability transition pore and its role in myocardial ischemia reperfusion injury. J Mol Cell Cardiol 2015;78:23—34. [52] Grines CL. Intravascular cooling adjunctive to percutaneous coronary intervention for acute myocardial infarction (ICE-IT). Washington DC, USA: Presented at the Annual Scientific Session of the Transcatheter Therapeutics Meeting; 2004. [53] Nichol G, Strickland W, Shavelle D, et al. Prospective, multicenter, randomized, controlled pilot trial of peritoneal hypothermia in patients with ST-segment- elevation myocardial infarction. Circ Cardiovasc Interv 2015;8:e001965. [54] Erlinge D, Gotberg M, Noc M, et al. Therapeutic hypothermia for the treatment of acute myocardial infarction-combined analysis of the RAPID MI-ICE and the CHILL-MI trials. Ther Hypothermia Temp Manag 2015;5:77—84.
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Therapeutic hypothermia to protect the heart against acute myocardial infarction L’hypothermie thérapeutique : une stratégie cardioprotectrice contre l’infarctus du myocarde Matthias Kohlhauer a,b,c, Alain Berdeaux a,b,c, Bijan Ghaleh a,b,c, Renaud Tissier a,b,c,∗ a
Inserm, U955, Équipe 3, 94000 Créteil, France UMR S955, DHU A-TVB, UPEC, université Paris Est, 94000 Créteil, France c Université Paris Est, École nationale vétérinaire d’Alfort, 94700 Maisons-Alfort, France b
Received 18 March 2016; received in revised form 29 April 2016; accepted 3 May 2016
KEYWORDS Acute myocardial infarction; STEMI; Hypothermia; Temperature; Cardioprotection
Summary The cardioprotective effect of therapeutic hypothermia (32—34 ◦ C) has been well demonstrated in animal models of acute myocardial infarction. Beyond infarct size reduction, this protection was associated with prevention of the no-reflow phenomenon and long-term improvement in terms of left ventricular remodelling and performance. However, all these events were observed when hypothermia was induced during the ischaemic episode, and most benefits virtually vanished after reperfusion. This is consistent with clinical findings showing a lack of benefit from hypothermia in patients presenting acute myocardial infarction in most trials. In these studies, hypothermia was most often achieved too far into the reperfusion phase (i.e. possibly too late to reduce infarct size); this is supported by meta-analyses and subgroup analyses suggesting that the benefits of hypothermia could still be observed in patients with a large infarction and more rapid cooling before reperfusion. Novel strategies for ultra-fast induction of hypothermia and/or prehospital cooling might therefore be more beneficial. © 2016 Elsevier Masson SAS. All rights reserved.
Abbreviations: AMI, acute myocardial infarction; ATP, adenosine triphosphate; ERK, extracellular signal-regulated kinase; mPTP, mitochondrial permeability transition pore; RCT, randomized controlled trial. ∗ Corresponding author. Équipe 3, Inserm unité 955, université Paris Est, École nationale vétérinaire d’Alfort, 7, avenue du Général-deGaulle, 94704 Maisons-Alfort cedex, France. E-mail address: [email protected] (R. Tissier). http://dx.doi.org/10.1016/j.acvd.2016.05.005 1875-2136/© 2016 Elsevier Masson SAS. All rights reserved.
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MOTS CLÉS Infarctus du myocarde ; STEMI ; Hypothermie ; Température ; Cardioprotection
Résumé L’effet cardioprotecteur de l’hypothermie thérapeutique (32—34 ◦ C) a été largement démontré dans des modèles animaux d’infarctus du myocarde. En complément de la réduction de la taille de l’infarctus, l’hypothermie est capable de limiter le phénomène de « no-reflow » et d’améliorer la récupération fonctionnelle cardiaque à long terme. Ces effets sont puissants lorsque l’hypothermie est induite au cours de l’épisode ischémique, mais ils disparaissent lorsqu’elle n’est induite qu’après la reperfusion. Cela permet d’expliquer l’absence de bénéfice dans les essais cliniques évaluant l’effet cardioprotecteur de l’hypothermie. Dans ces études, l’hypothermie était en effet probablement atteinte trop tardivement (i.e. après la reperfusion). Néanmoins, des analyses en sous-groupes et des méta-analyses ont montré un effet bénéfique chez les patients refroidis plus rapidement avant la reperfusion. De nouvelles approches thérapeutiques permettant une hypothermie plus rapide ou une induction précoce en milieu préhospitalier pourrait permettre de renforcer ces bénéfices. © 2016 Elsevier Masson SAS. Tous droits r´ eserv´ es.
Background Despite the well-established beneficial effects of reperfusion therapies in patients presenting acute myocardial infarction (AMI), morbidity and mortality remain high in this situation. Consequently, seeking new cardioprotective strategies to improve myocardial salvage and cardiac function remains a priority in this field. Therapeutic hypothermia could be one of those promising strategies, and it has been tested in many experimental settings of ischaemic injury, such as cardiac arrest [1,2], stroke [3], myocardial ischaemia [4] and organ preservation [5]; it has also been shown to be well tolerated in humans, when induced with an average target temperature of 32—34 ◦ C (‘‘mild hypothermia’’). However, the clinical benefit of therapeutic hypothermia remains questionable in AMI patients in terms of infarct size reduction [6—10]. Importantly, this apparent discrepancy between experimental and clinical data could be related to different schedules of application. Indeed, animal studies showed that the benefit of cooling was mostly observed when achieved early during ischaemia, while patients are usually cooled just before — or even after — reperfusion. The purpose of this article is to present a state-of-the-art review of the research on hypothermia for cardioprotection.
Experimental evidence of hypothermia-induced cardioprotection Infarct size reduction In animal models of coronary artery occlusion, infarct size has been widely demonstrated to depend upon myocardial temperature, even for very mild temperature variations within ‘‘the normothermic range’’ [11,12]. For instance, Chien et al. compared infarct sizes at different cardiac temperatures (35—42 ◦ C) in rabbits submitted to 30 minutes of coronary artery occlusion [11]; they demonstrated that any decrease in myocardial temperature was linearly correlated to infarct size (—8% of the risk zone for each ◦ C decrement), showing that mild temperature reduction
Figure 1. Pooled analysis of several studies performed in rabbits submitted to 30 minutes of coronary artery occlusion and 3 hours of reperfusion with different temperatures during the ischaemic episode. Each open circle represents the mean infarct size obtained at a different cardiac temperature in these studies. A correlation could be drawn from the pooled analysis of all values, emphasizing that infarct size was virtually abolished at 32 ◦ C. These data are extracted from the following studies: a [14], b [26], c [29], d [27], e [1], f [28], g [4].
could be protective, while hyperthermia was detrimental [11]. A considerable amount of data further support the cardioprotective benefit of mild hypothermia (32—34 ◦ C) during coronary artery occlusion (e.g. in rabbits [13—16], dogs [12,17,18], sheep [19,20], swine [21—24] and rats [25]). All of these studies were performed by independent investigators in different laboratories and species, providing a high level of evidence. For instance, Fig. 1 illustrates the infarct sizes observed at different temperatures in rabbits submitted to 30 mins of coronary artery occlusion in independent studies [1,4,14,26—29]. As illustrated by the regression slope, infarct size was linearly correlated to cardiac temperature (R2 = 0.87). This regression analysis also shows that every 1 ◦ C decrement reduces infarct size by
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Hypothermia and cardioprotection approximately 6% of the risk zone, leading to ‘‘maximal’’ cardioprotection at 32 ◦ C in these conditions. Interestingly, earlier studies also tested the effect of deeper hypothermia (e.g. in dogs submitted to 5—10 hours of coronary artery occlusion at 26 ◦ C) [30]. In this model, hypothermia was still efficient at reducing ischaemic injury (−20 and −25%, respectively). However, such profound levels of cooling raise safety issues, and seem very challenging for clinical translation. Most studies were therefore conducted in the mild hypothermia range (32—34 ◦ C).
Functional benefits Beyond infarct size reduction, the beneficial effect of therapeutic hypothermia on left ventricular post-ischaemic dysfunction has also been demonstrated. For example, cardiac output was not altered with hypothermia in pigs submitted to 60 minutes of coronary artery occlusion [31]. In rabbits, intraischaemic hypothermia also significantly increased left ventricular wall motion after reperfusion compared with normothermic animals [15]. This functional benefit was not just related to infarct size reduction, as left ventricular recovery was more rapid with intraischaemic cooling than with ischaemic preconditioning, which similarly reduced infarct size [32,33]. Such a functional benefit was also observed in rabbits concomitantly submitted to 40 minutes of coronary artery occlusion and cardiac arrest [1]. In this model, ultra-fast cooling dramatically improved cardiac output and left ventricular contractility after resuscitation. These benefits were further associated with reduced mortality from cardiovascular origin in this model [1]. Interestingly, similar benefits were also observed in a pure model of cardiac arrest treated with therapeutic hypothermia in rabbits [34]. Longer term, hypothermia-induced cardioprotection leads to reduced left ventricular remodelling and improved contractility; for example, in rats, left ventricular function and remodelling were improved 6 weeks after coronary artery occlusion when it was combined with mild hypothermia [35]. Similar results were obtained in sheep after 8 weeks following myocardial ischaemia [20].
3 with hypothermia after 10 minutes of coronary occlusion in pigs [22] or isolated heart [37]. Conversely, vascular relaxation was not influenced by hypothermia in vitro in rabbit aorta rings [38]. The exact role played by hypothermia in vascular reactivity therefore needs to be further investigated.
Importance of the window of application of hypothermia The above-mentioned cardioprotective effects of hypothermia have been widely described, with myocardial cooling maintained throughout the ischaemic period [11]. However, this schedule of application is of poor clinical relevance, as patients cannot be cooled from the onset of symptoms. Several studies have therefore tested cooling with different timings for its institution during ischaemia or reperfusion. For example, Fig. 2 pools the results of different studies in rabbits submitted to 30 mins of myocardial ischaemia and hypothermia started at different time points [4,15,29,36]. Interestingly, the cardioprotective effects of hypothermia decreased exponentially, along with any delay in the institution of cooling during ischaemia. Therefore, cooling seems to be poorly protective regarding infarct size when induced after the onset of reperfusion [13,22,23]. In other words, therapeutic hypothermia should be initiated as soon as possible, with a high cooling rate, in order to maximize infarct size reduction (‘‘the sooner, the better’’). However, in large animals, little benefit was observed with cooling started at the end of the ischaemic period (i.e. just before reperfusion). For instance, Götberg et al. performed an elegant study evaluating the proper effect of hypothermic reperfusion compared with normothermic reperfusion
Effect of hypothermia on no-reflow and microvascular alteration In addition to infarct size reduction and functional improvement, therapeutic hypothermia has also been shown to prevent microvascular obstruction and no-reflow after myocardial ischaemia. For example, cooling the myocardium to 32 ◦ C potently decreased the no-reflow area after 30 minutes of coronary artery occlusion in rabbits (noreflow: 11 ± 3% and 37 ± 3% of the risk zone in hypothermic versus normothermic animals, respectively) [36]. Interestingly, regression analyses suggested that no-reflow reduction was not explained solely by infarct size reduction; this was further confirmed with cooling started after reperfusion, which only reduced no-reflow area, but not infarct size [13,22]. These findings suggest that intraischaemic hypothermia protects not only cardiomyocytes, but also microvessels against ischaemic injury. This is consistent with decreased post-ischaemic coronary reactive hyperaemia
Figure 2. Pooled analysis of several studies performed in rabbits submitted to 30 minutes of coronary artery occlusion and 3 hours of reperfusion, with hypothermia started after different delays during the ischaemic episode. Each open circle represents the cardioprotective effect observed with cooling started at different time points. Cardioprotection was assessed by infarct size reduction (compared with the corresponding control groups). A correlation could be drawn between the different values. These data are extracted from the following studies: a [29], b [4], c [36], d [15].
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[39]. Pigs were submitted to 40 mins of normothermic ischaemia versus 45 minutes of ischaemia with cooling started 5 mins before reperfusion (40 minutes of normothermic ischaemia plus 5 minutes to achieve cooling before reperfusion). In these conditions, hypothermic reperfusion significantly decreased infarct size by 18% compared with normothermia, despite a longer ischaemic period [39]. Interestingly, this very mild beneficial effect of hypothermic reperfusion on infarct size was combined with a more potent effect on no-reflow and microvascular obstruction [13]. Overall, it is clear that hypothermia must be instituted as soon as possible to afford significant benefit during the ischaemic process. Therefore, different cooling strategies have been tested, to increase the cooling rate and to reduce the normothermic ischaemic time [33,40]. In patients, cooling is typically induced using external approaches [41], eventually combined with endovascular cooling [8]. Some other strategies have also been proposed to improve cooling efficiency, such as cold peritoneal lavage [42] or intranasal evaporative cooling [43]. New invasive approaches are tested benchside in order to provide ultra-fast cooling through total liquid ventilation [44] or extracorporeal life support [2].
Mechanisms of cardioprotection by therapeutic hypothermia Energy preservation For a long time, the mechanism underlying the cardioprotective effect of hypothermia was considered to be a direct consequence of reduced metabolism and energy preservation. For example, cold cardioplegia (< 20 ◦ C) is associated with a reduction in cardiac metabolism and preservation of adenosine triphosphate (ATP) concentration [45]. Using mild hypothermia (32—34 ◦ C), a reduction in ATP consumption was also observed in ischaemic isolated heart [46] or after in vivo regional ischaemia [47], although to a lesser extent than deeper hypothermia (< 31 ◦ C) [46]. Interestingly, in vitro studies have shown that energy preservation is not linearly correlated to temperature decrease, and that ATP and glucose consumption are almost unaltered when the temperature remains above 35 ◦ C [48]. Yet, cooling at 35 ◦ C remains effective for infarct size reduction, which could suggest that therapeutic hypothermia acts through mechanisms other than metabolism reduction [29,49]. This is also supported by other mechanistic studies showing, for example, that inhibition of the extracellular signal-regulated kinase (ERK) survival pathway does not alter the ATP-sparing properties of hypothermia, while abolishing its infarct-size reducing properties in isolated rabbit heart [16]. All these results suggest that metabolic adaptation probably does not entirely explain all the cardioprotective effects of hypothermia (Fig. 3). Beyond its direct effect on cell metabolism, it was also speculated that hypothermia-induced bradycardia could preserve energy in vivo and improve tolerance to ischaemia. This hypothesis has been disproven, as cardiac pacing at
‘‘high’’ heart rate did not abolish the cardioprotective effect of hypothermia [11].
Role of mitochondria and generation of reactive oxygen species For a long time, mitochondria have been highlighted as a potential target for the cardioprotective effect of hypothermia, beyond the above-mentioned metabolic adaptation. Indeed, mitochondrial electron transfers and respiratory function are well known to be directly influenced by temperature [50]. For instance, the respiratory control ratio is significantly better in isolated rabbit cardiac mitochondria at 32 ◦ C compared with 38 ◦ C (+22 ± 3%) in normoxic conditions. Concomitantly, generation of reactive oxygen species was also much lower (−41 ± 1%) at 32 ◦ C vs 38 ◦ C in similar conditions. In isolated rat cardiomyocytes, reactive oxygen species generation is also dramatically decreased during hypoxia at 32 ◦ C vs 38 ◦ C (−55 ± 8% after 140 minutes of hypoxia). In addition, hypothermia attenuates mitochondrial complex I, II and III dysfunction in rabbits submitted to 30 mins of coronary artery occlusion [50]. This effect was accompanied by a limitation in mitochondrial reactive oxygen species production and subsequent oxidative stress assessed by lipid peroxidation. In addition, hypothermia has also been shown to modulate the mitochondrial permeability transition pore (mPTP), which is a well-established target of cardioprotective strategies. For example, this was investigated in rabbits submitted to 30 mins of coronary artery occlusion, with myocardial mitochondria sampled just before reperfusion (ischaemic mitochondria) or 5 minutes after reperfusion (reperfused mitochondria). The authors demonstrated that hypothermia increased mitochondrial calcium restrain capacity at the end of the ischaemic period, but did not prevent the increased sensitivity induced by reperfusion [15]. Therefore, it seems that hypothermia potently protects against mPTP opening during ischaemia, but does not mitigate the reperfusion injury [15]. Again, this is consistent with physiological data showing that hypothermia does not potently reduce infarct size at reperfusion [13,22,23]. This is a main difference compared with ischaemic preconditioning, which is well known to inhibit mPTP opening during reperfusion, through activation of reperfusion-induced salvaged kinase [51].
Effect of hypothermia on signalling pathways Many experimental studies have also attempted to decipher the action mechanism of hypothermia and the potential involvement of a signalling pathway. Importantly, this could open promising perspectives, if part of the benefit afforded by hypothermia could be mimicked pharmacologically. These mechanistic studies have been summarized in detail in a review [33]. Briefly, temperature reduction was, for example, shown to activate the Akt pathways and heat-shock proteins 27 or 70 in isolated mice cardiomyocytes exposed to simulated ischaemia [49]. The role of ERKs was also well demonstrated in isolated rabbit heart submitted to regional ischaemia, in which the protection afforded by mild hypothermia (35 ◦ C) was completely eliminated by two different ERK inhibitors [15]. Interestingly,
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Figure 3. Potential targets of the cardioprotective effect of mild hypothermia (non-exhaustive). TRPV: transient receptor potential cation channel subfamily V.
ERK inhibition did not directly affect ATP concentration, suggesting that energy preservation was unrelated to hypothermia cardioprotection. Therefore, additional investigations are still needed to better understand the anti-ischaemic effect of hypothermia, and to provide new targets, allowing mimicking of its cardioprotective effect.
Clinical trials with hypothermia in the catheterization laboratory In the two last decades, several randomized controlled trials (RCTs) have been performed to evaluate the cardioprotective effect of therapeutic hypothermia in AMI patients [6—9,52,53]. While analysing those findings, one should keep in mind that the benefit was well demonstrated in animal studies when hypothermia was achieved during ischaemia, but not after reperfusion. One of the first feasibility trials was conducted by Dixon et al., in patients submitted to endovascular cooling before percutaneous coronary intervention in the catheterization laboratory. This study showed that the mean core temperature could reach 34.7 ± 0.9 ◦ C before the first balloon inflation, while cooling could be safely maintained at 33 ◦ C for 3 hours after reperfusion [7]. In 2003, the COOL-MI trial investigated the same cooling protocol in a larger population of 357 patients [6]. Unfortunately, this study failed to demonstrate a significant reduction in infarct size with
cooling. The ICE-IT trial was then conducted to investigate the same procedure in 228 patients with 6 hours of hypothermia after reperfusion [52]; again, this failed to demonstrate any significant benefit with a longer duration of therapeutic hypothermia [52]. However, a pooled analysis of both COOLMI and ICE-IT trials demonstrated that a majority of patients failed to effectively reach the target temperature of 33 ◦ C at the onset of reperfusion [6]. Further trials were therefore conducted with a more aggressive protocol, combining rapid infusion of cold saline and concomitant endovascular cooling [8,9]. The RAPID MI-ICE trial demonstrated that this protocol was feasible and safe in 20 patients, but the body core temperature reached only 34.7 ± 0.3 ◦ C at the onset of reperfusion [9]. Interestingly, this was sufficient here to obtain a significant decrease in infarct size (—38%) with hypothermia, despite a slight increase (+3 minutes) in door-to-balloon time. The further large-scale CHILL-MI trial in 120 patients failed to confirm this significant benefit, with just a trend towards infarct-size reduction (−13%; P = 0.15) [8]. However, the post-hoc pooled analysis of both the RAPID MI-ICE and CHILL-MI trials showed a significant infarct-size reduction with cooling, and a significant decrease in heart failure occurrence [54]. Maximal benefits were observed in the subgroups of patients with the most rapid cooling and/or larger risk zone. Overall, these clinical data confirm that hypothermia apparently needs to be induced during ischaemia (i.e. before reperfusion) to provide benefits in the clinical arena, as shown previously in the experimental studies.
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Overall, the meta-analysis of all the above-mentioned RCTs did not show any significant beneficial effect of therapeutic hypothermia on cardiovascular events, mortality, heart failure or infarct size [10]. However, subgroup analysis showed a significant infarct-size reduction in patients presenting anterior AMI [10]. This trend needs to be properly confirmed in a specific trial. Several RCTs are currently ongoing with cooling for AMI treatment, such as the STATIM trial, which is investigating out-of-hospital cooling through external pads (NCT01777750); this should help us to better understand the consequences of very early cooling in AMI patients. The SHOCK-COOL trial will also determine the functional consequences of therapeutic hypothermia in patients presenting AMI complicated by cardiogenic shock (NCT01890317). Recently, another strategy was also tested; namely, to achieve more rapid cooling through cold peritoneal lavage [53]. This strategy seemed to be safe, but the mean temperature at reperfusion was similar to that in the previous studies (34.7 ◦ C [34.0—34.9 ◦ C] at first balloon inflation). The implementation of this procedure led to prolongation of door-to-balloon time, and did not provide any infarct-size reduction.
Conclusions In conclusion, therapeutic hypothermia provides potent and universally acknowledged benefits regarding infarct size, cardiac function and no-reflow phenomenon when achieved during ischaemia in experimental models. However, no clinical evidence strongly supports the use of mild therapeutic hypothermia in AMI patients at present. This discrepancy is largely explained by different schedules for institution of cooling at the bench and the bedside, with different cooling rates and timings of institution. In the clinical setting, hypothermia can only be instituted after incompressible delay following the onset of ischaemia. Novel strategies for ultra-fast induction of hypothermia and/or prehospital cooling might provide better benefits in patients in whom cooling could be achieved during the ischaemic phase (e.g. when revascularization could not be instituted rapidly for any reason).
Sources of funding This study was supported by ‘‘Region Île-de-France’’ (CORDDIM) and the ‘‘Fondation pour la Recherche Médicale’’ (Grant DBS20140930781). M. Kohlhauer received a grant from ‘‘Region Île-de-France’’ (CORDDIM).
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Disclosure of interest
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The authors declare that they have no competing interest. [17]
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