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.
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.
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 , stroke , myocardial ischaemia and organ preservation ; 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 . 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” . 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 ; 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 could be protective, while hyperthermia was detrimental . A considerable amount of data further support the cardioprotective benefit of mild hypothermia (32–34 °C) during coronary artery occlusion (e.g. in rabbits , dogs , sheep , swine and rats ). 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 . As illustrated by the regression slope, infarct size was linearly correlated to cardiac temperature ( R 2 = 0.87). This regression analysis also shows that every 1 °C decrement reduces infarct size by 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) . 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 . In rabbits, intraischaemic hypothermia also significantly increased left ventricular wall motion after reperfusion compared with normothermic animals . 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 . Such a functional benefit was also observed in rabbits concomitantly submitted to 40 minutes of coronary artery occlusion and cardiac arrest . 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 . Interestingly, similar benefits were also observed in a pure model of cardiac arrest treated with therapeutic hypothermia in rabbits .
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 . Similar results were obtained in sheep after 8 weeks following myocardial ischaemia .
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 (no-reflow: 11 ± 3% and 37 ± 3% of the risk zone in hypothermic versus normothermic animals, respectively) . 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 . 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 with hypothermia after 10 minutes of coronary occlusion in pigs or isolated heart . Conversely, vascular relaxation was not influenced by hypothermia in vitro in rabbit aorta rings . 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 . 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 . 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 . 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 . 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 . 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 .
