Therapeutic hypothermia to protect the heart against acute myocardial infarction

Kohlhauer, Matthias; Berdeaux, Alain; Ghaleh, Bijan; Tissier, Renaud

doi:10.1016/j.acvd.2016.05.005

Cited by 22 publications

(30 citation statements)

References 51 publications

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“…For example, although cold cardioplegia at 4 °C has been shown to preserve energy, mild hypothermia to 32 °C has been shown to be insufficient to promote energy preservation as compared to the extent of the cardioprotective benefit [17]. Even if a clear linear relationship has been demonstrated between myocardial temperature and infarct size in experimental models, the metabolic reduction does not seem to correlate linearly with temperature [18]. Metabolic inhibition by mild hypothermia is poor even if cardioprotection seem to be maximal at 32 °C, suggesting that metabolic reduction only partially explains the benefit of mild hypothermia.…”

Section: Discussionmentioning

confidence: 99%

Protection against cardiac ischemia-reperfusion injury by hypothermia and by inhibition of succinate accumulation and oxidation is additive

et al. 2019

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Hypothermia induced at the onset of ischemia is a potent experimental cardioprotective strategy for myocardial infarction. The aim of our study was to determine whether the beneficial effects of hypothermia may be due to decreasing mitochondria-mediated mechanisms of damage that contribute to the pathophysiology of ischemia/reperfusion injury. New Zealand male rabbits were submitted to 30 min of myocardial ischemia with hypothermia (32 °C) induced by total liquid ventilation (TLV). Hypothermia was applied during ischemia alone (TLV group), during ischemia and reperfusion (TLV-IR group) and normothermia (Control group). In all the cases, ischemia was performed by surgical ligation of the left anterior descending coronary artery and was followed by 3 h of reperfusion before assessment of infarct size. In a parallel study, male C57BL6/J mice underwent 30 min myocardial ischemia followed by reperfusion under either normothermia (37 °C) or conventionally induced hypothermia (32 °C). In both the models, the levels of the citric acid cycle intermediate succinate, mitochondrial complex I activity were assessed at various times. The benefit of hypothermia during ischemia on infarct size was compared to inhibition of succinate accumulation and oxidation by the complex II inhibitor malonate, applied as the pro-drug dimethyl malonate under either normothermic or hypothermic conditions. Hypothermia during ischemia was cardioprotective, even when followed by normothermic reperfusion. Hypothermia during ischemia only, or during both, ischemia and reperfusion, significantly reduced infarct size (2.8 ± 0.6%, 24.2 ± 3.0% and 49.6 ± 2.6% of the area at risk, for TLV-IR, TLV and Control groups, respectively). The significant reduction of infarct size by hypothermia was neither associated with a decrease in ischemic myocardial succinate accumulation, nor with a change in its rate of oxidation at reperfusion. Similarly, dimethyl malonate infusion and hypothermia during ischemia additively reduced infarct size (4.8 ± 2.2% of risk zone) as compared to either strategy alone. Hypothermic cardioprotection is neither dependent on the inhibition of succinate accumulation during ischemia, nor of its rapid oxidation at reperfusion. The additive effect of hypothermia and dimethyl malonate on infarct size shows that they are protective by distinct mechanisms and also suggests that combining these different therapeutic approaches could further protect against ischemia/reperfusion injury during acute myocardial infarction.

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Section: Discussionmentioning

confidence: 99%

Protection against cardiac ischemia-reperfusion injury by hypothermia and by inhibition of succinate accumulation and oxidation is additive

et al. 2019

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“…In a pooled analysis of whole-body or whole-heart TH applied to rabbits from seven independent studies, researchers found a linear correlation between IS and myocardial temperature during ischemia. 3 For every 1 C reduction in temperature, IS/AAR was reduced by 6% of the risk zone with the maximum reduction observed at the coldest temperature studied at 32 C. Their pooled regression analysis also investigated TH benefit with respect to timing. They observed an exponential decrease in IS reduction as TH was delayed with little benefit observed if initiated at reperfusion.…”

Section: Discussionmentioning

confidence: 99%

“…Similar target temperatures have been reported in both animals and humans. 3,19,20,25 In fact, a recent patient-level pooled analysis of six randomized trials using wholebody endovascular cooling used during primary PCI for ST-segment elevation myocardial infarction (STEMI) showed a 30% relative reduction in IS when whole-body temperatures were <35 C. No other study to our knowledge has linked discrete dynamic heart tissue temperature behavior in human-sized swine following localized cooling to IS reduction using clinically relevant conditions and devices. However,…”

Section: Discussionmentioning

confidence: 99%

“…Therapeutic hypothermia (TH) is a powerful protective strategy proven to reduce RI pre-clinically. 3,4 Critical reviews report the need for reaching target temperatures rapidly and before reperfusion occurs to achieve a clinically viable outcome. 5 Current clinical practice primarily entails whole-body cooling, making rapid cooling more difficult and limiting the depth of cooling.…”

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confidence: 99%

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Myocardial tissue salvage is correlated with ischemic border region temperature at reperfusion

Merrill

Mitchell

Merrill

et al. 2019

Cathet Cardio Intervent

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Objectives: Our pilot study investigated the association between region-specific myocardial tissue temperature and tissue salvage using a novel tri-lumen cooling catheter to provide rapid localized cooling directly to the heart in an open-chest porcine model of ischemia-reperfusion. Background: Therapeutic hypothermia remains a promising strategy to limit reperfusion injury following myocardial ischemia. Methods: Large swine underwent 60 min of coronary occlusion followed by 3 hr of reperfusion. Prior to inducing ischemia, six temperature probes were placed directly on the heart, monitoring myocardial temperatures in different locations. Hemodynamic parameters and core temperature were also collected. Approximately 15 min prior to reperfusion, the cooling catheter was inserted via femoral artery and the distal tip advanced proximal to the occluded coronary vessel under fluoroscopic guidance. Autologous blood was pulled from the animal via femoral sheath and delivered through the central lumen of the cooling catheter, delivering at 50 ml/min, 27 C at the distal tip. Cooling was continued for an additional 25 min after reperfusion followed by a 5-min controlled rewarming. Hearts were excised and assessed for infarct size per area at risk. Results: Although cooling catheter performance was consistent throughout the study (38 W), the resulting tissue cooling was not. Our results show a correlation between myocardial tissue salvage and ischemic border region (IBR) temperature at the time of reperfusion (R 2 = 0.59, p = 0.027). IBR tissue is the tissue located at the boundary between healthy and ischemic tissues. Conclusions: Our findings suggest that localized, rapid, short-term myocardial tissue cooling has the potential to limit reperfusion injury in humans.

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“…In addition to the benefits of PPCI, the reperfusion process itself, pathophysiologically involving the mechanisms of ischemia and reperfusion injury, may contribute to secondary damage to the myocardium . Induction of therapeutic hypothermia (TH), by cooling the jeopardized myocardium to 33°C, may attenuate this reperfusion injury . Numerous experimental studies have reported that TH reduces IS in different animal models of STEMI.…”

Section: Introductionmentioning

confidence: 99%

A pilot clinical study of adjunctive therapy with selective intracoronary hypothermia in patients with ST‐segment elevation myocardial infarction

Wang

Zhang

et al. 2018

Cathet Cardio Intervent

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Objectives: We aimed to assess the effect of selective intracoronary hypothermia on outcomes in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI).Background: Intracoronary hypothermia, the feasibility and safety of which has been validated in humans, induced by selective trans-coronary infusion of saline at different temperatures can reduce infarct size (IS) prior to reperfusion in animal models of STEMI.Methods: Sixty STEMI patients presenting with thrombolysis in myocardial infarction (TIMI) flow grade 0/1 were randomized after coronary artery angiography. Intracoronary hypothermia was induced by selective trans-coronary infusion of saline at 4 C to the endangered myocardium in the 30 patients. The primary endpoint, absolute IS expressed as IS/myocardium at risk (MaR), was assessed by cardiac magnetic resonance imaging at day 7 post-PPCI in 50 patients.Clinical follow-up was undertaken at day 30 after procedure.Results: Intracoronary hypothermia was successfully performed in hypothermia group, without increase in arrhythmia or hemodynamic instability. The mean temperature reduction of 5.8 AE 1.1 C in distal coronary artery was achieved before reperfusion. Mean IS/MaR was predominantly reduced in the hypothermia group (44.85 AE 5.89% vs. 50.69 AE 10.75%, P = 0.022), especially in the anterior STEMI subgroup (46.12 AE 7.54% vs. 55.27 AE 11.175%, P = 0.023). The clinical events appeared no statistical difference between the two groups at the 30-day follow-up.Conclusion: The statistical difference in IS/MaR by intracoronary hypothermia as adjunctive therapy to PPCI is an important observation and warrants a larger pivotal trial fully powered for efficacy. K E Y W O R D S intracoronary hypothermia, primary percutaneous coronary intervention, ST-segment elevation myocardial infarction

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Therapeutic hypothermia to protect the heart against acute myocardial infarction

Cited by 22 publications

References 51 publications

Protection against cardiac ischemia-reperfusion injury by hypothermia and by inhibition of succinate accumulation and oxidation is additive

Protection against cardiac ischemia-reperfusion injury by hypothermia and by inhibition of succinate accumulation and oxidation is additive

Myocardial tissue salvage is correlated with ischemic border region temperature at reperfusion

A pilot clinical study of adjunctive therapy with selective intracoronary hypothermia in patients with ST‐segment elevation myocardial infarction

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