Author + information
- William Wijns, MD, PhD, FESC⁎ ( and )
- Guy R. Heyndrickx, MD, PhD
- ↵⁎Reprint requests and correspondence:
Dr. William Wijns, OLV-Clinic, Cardiovascular Center Aalst, Cardiovascular Center, Moorselbaan, 164, B-9300 Aalst, Belgium.
Since antiquity, the myth of being able to freeze the course of time and perpetuate life has haunted human minds. The idea does make sense because life is biochemistry, and biochemical reactions are exquisitely sensitive to temperature: slowing down when temperature declines and the opposite when temperature increases. Nature itself has successfully taken advantage of the conservative capabilities of cooling, the most advanced and sophisticated protective mechanisms being found in hibernating animals. In contrast with non-hibernating animals, where hypothermia is associated with severe arrhythmias and contractile arrest, hibernating animals exhibit remarkable tolerance and resistance to these environmental stresses. Hibernation induces adaptive changes in Ca2+handling of myocytes whereby the contractile force remains preserved (1). In the late 1970s, Rahimtoola (2) used the metaphor of hibernation to explain the adaptive contractile mechanisms operating during chronic myocardial ischemia. Whether or not these chronic changes, including structural abnormalities, which at best are only partially reversible upon revascularization (3), truly represent some form of hibernation remains elusive. However, during acute conditions, cooling already has received many applications in clinical medicine among which are organ preservation for transplantation, myocardial protection during cardiac surgery, or neuroprotection during ischemic stroke or cardiac arrest. The present study by Otake et al. (4) in this issue of the Journalexamines again the possibility that controlled regional hypothermia might be a useful adjunct to reperfusion therapy for ST-segment elevation myocardial infarction (STEMI).
Is There An Unmet Need?
Yes, there is. Although reperfusion therapy has considerably improved patient outcome after STEMI, the optimal modalities of reperfusion remain under investigation. Even though there is evidence that mechanical reperfusion by direct percutaneous intervention is superior to pharmacologically induced fibrinolysis, treatment delays or unavailability with either therapy continues to prevent significant myocardial salvage (“infarct size reduction”) to occur, and reperfusion in itself causes additional damage, largely through oxidative stress. In the future, depending on available resources, the most promising scenario may involve pre-hospital care of STEMI, perhaps using a combined pharmacomechanical approach. Thus, there remains a need for adjunctive therapy both prior to reperfusion in order to increase the tolerance to ischemia and during reperfusion in order to limit reperfusion damage. However, any adjunctive therapy of value will have to be compatible with each of these possible reperfusion scenarios.
Catheter-Based Transcoronary Hypothermia
In the first part of this pre-clinical study, which was performed in open-chested pigs, Otake et al. (4) have studied the effect of reducing the local intramyocardial temperature by some 3°C while coronary artery occlusion was maintained. As compared with a control group receiving the same volume (2.5 ml/min) of normothermic saline, infarct sizes were significantly reduced by an impressive 75%, as clearly shown by the Reimer (5) plot of necrotic versus risk area (Fig. 7 of their study). Other indexes were significantly improved, including reduced rate of arrhythmias, increased left ventricular dP/dt max, maintained coronary flow velocity reserve, and reduced biomarker release.
In the second part of the study, hypothermic saline (8 ml/min) was delivered at the time of reperfusion. As compared with a control group receiving no intracoronary infusion, no significant changes were observed in the indexes related to infarct size. The flow velocity reserve was improved at 60 min (but no longer at 180 min), and the release of isoprostans was decreased, as a marker of reduced oxidative stress.
A detailed analysis of Figure 1 in the study by Otake et al. (4) reveals that the time required to reach the desired myocardial hypothermia varies from 20 to 40 min after starting the infusion, presumably depending on the interplay between flow rates of the infusion and the coronary flow. Most interestingly, when reperfusion was restored in Study 1, the myocardial temperature returned to baseline values despite continued infusion of hypothermic saline at the rate of 2.5 ml/min. This finding has prompted the use of higher flow rates in Study 2, allowing for a faster achievement and maintenance of the desired temperature decrease, despite ongoing reperfusion.
Because intracoronary flow rates had to be increased up to at least twice the normal baseline coronary flow, as can be estimated from the size of the risk area of the left ventricle, the authors have verified that no excessive edema resulted. Although this represents a worthwhile finding, the authors have introduced a flaw in the design of Study 2. Indeed, the control group of animals did not receive any coronary infusion. Strictly speaking, one cannot exclude that the intracoronary infusion of normothermic saline could have similar beneficial effects on indexes of microcirculatory function than those observed with hypothermia. Indeed, in the presence of angiographic no-reflow, increasing coronary flow by infusion of adenosine or other vasoactive agents was shown beneficial (6).
Potential Clinical Relevance
Prior clinical studies on the effect of cooling during reperfusion treatment of STEMI have failed to show significant benefit (7). Limitations of the therapy were related to shivering and systemic effects of reducing total body temperature. Targeted approaches to the myocardium have only been tested in animal models and require access to the pericardium (8). Although feasible, this approach entails an additional invasive procedure that exposes the already acutely ill patient to incremental treatment-related risks. Therefore, the use of a catheter-based transcoronary approach would seem extremely appealing, in particular in patients already submitted to mechanical reperfusion in whom invasive procedures are performed on a routine basis. Also, the current approach was demonstrated not to cause any changes in core body temperature. Thus, from an instrumental viewpoint, catheter-based transcoronary hypothermia as proposed by Otake et al. (4) seems like a potentially useful adjunct to reperfusion therapy for STEMI.
However, the key question remains whether the current pre-clinical data are robust enough to support early translation in the clinic. The most impressive results were obtained in Study protocol 1, which provides strong proof of concept but unfortunately is not relevant to clinical practice. Catheter-based transcoronary hypothermia obviously requires invasive access to the coronaries, under which circumstances coronary occlusion will not be maintained for 60 min (Fig. 1 in Otake et al. ). Study protocol 2 is more relevant to the practice of direct percutaneous coronary intervention, but paradoxically, the observed results of hypothermic coronary perfusion are modest, limited to minor microcirculatory changes, and perhaps obtainable with infusion of normothermic saline (not tested). As to the large number of patients treated either with systemic fibrinolysis or in the future during the pre-hospital phase of STEMI, catheter access will not be available, and other approaches than the currently proposed transcoronary delivery of cold saline will be required.
Summary and Future Investigations
The current study by Otake et al. (4) adds further evidence to the available data that support the strong cardioprotective effect of myocardial cooling, when applied during coronary occlusion and evolving myocardial infarction. The issue remains whether cardioprotection will be maintained with reperfusion and, if so, by which means selective myocardial cooling will be achievable in the various possible reperfusion scenarios. Of paramount importance and not addressed in the study by Otake et al. (4) is the understanding of the underlying mechanisms. As indirectly demonstrated, one of the protective actions of cooling is probably mediated by a reduction in the oxidative stress. To what extent hypothermia also suppresses the inflammatory response during reperfusion, as was shown in models of ischemia-reperfusion in other organs (9), remains to be investigated.
The current approach could easily be combined with direct percutaneous coronary intervention. However, further positive pre-clinical studies will be required before the potential role of the proposed catheter-based transcoronary hypothermia can be formally tested as an adjunctive therapy to reperfusion in patients with STEMI. It is highly desirable that these future studies are designed as to mimic as closely as possible the clinical scene.
↵⁎ Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
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