Targeted temperature management has been originally used to reduce neurological injury and improve outcome in patients after out-of-hospital cardiac arrest. Myocardial infarction remains a major cause of death in the world and several investigators are studying the effect of mild therapeutic hypothermia during an acute cardiac ischemic injury. A search on MEDLINE, Scopus and EMBASE databases was conducted to obtain data regarding the cardioprotective properties of therapeutic hypothermia. Preclinical studies have shown that therapeutic hypothermia provides a cardioprotective effect in animals. The proposed pathways for the cardioprotective effects of therapeutic hypothermia include stabilization of mitochondrial permeability, production of nitric oxide, equilibration of reactive oxygen species, and calcium channels homeostasis. Clinical trials in humans have yielded controversial results. Current trials are therefore seeking to combine therapeutic hypothermia with other treatment modalities in order to improve the outcomes of patients with acute ischemic injury. This article provides a review of the hypothermia effects on the cardiovascular system, from the basic science of physiological changes in the human body and molecular mechanisms of cardioprotection to the bench of clinical trials with therapeutic hypothermia in patients with acute ischemic injury.
Bernard S: Hypothermia after cardiac arrest: expanding the therapeutic scope. Crit Care Med2009; 37: S227–S233.
2.
ZobelCAdlerCKranzA. Mild therapeutic hypothermia in cardiogenic shock syndrome. Crit Care Med2012; 40: 1715–1723.
3.
TestoriCHolzerMSterzF. Rapid induction of mild therapeutic hypothermia by extracorporeal veno-venous blood cooling in humans. Resuscitation2013; 84: 1051–1055.
4.
PoldermanKHVaronJ. We should not abandon therapeutic cooling after cardiac arrest. Crit Care2014; 18: 130.
5.
HolzerMCerchiariEMartensP. Mild therapeutic hypothermia to improve the neurological outcome after cardiac arrest. N Engl J Med2002; 346: 549–556.
6.
PoldermanKH. Mechanisms of action, physiological effects, and complications of hypothermia. Crit Care Med2009; 37: S186-S202.
7.
MooreEMNicholADBernardSA. Therapeutic hypothermia: benefits, mechanisms and potential clinical applications in neurological, cardiac and kidney injury. Injury2011; 42: 843–854.
8.
NielsenNWetterslevJCronbergT. Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med2013; 369: 2197–2206.
9.
WolfrumSPierauCRadkePW. Mild therapeutic hypothermia in patients after out-of-hospital cardiac arrest due to acute ST-segment elevation myocardial infarction undergoing immediate percutaneous coronary intervention. Crit Care Med2008; 36: 1780–1786.
10.
FinegoldJAAsariaPFrancisDP. Mortality from ischaemic heart disease by country, region, an age: Statistics from World Health Organisation and United Nations. Int J Cardiol2013; 168: 934–945.
11.
ErlingeDGötbergMLangI. Rapid endovascular catheter core cooling combined with cold saline as an adjunct to percutaneous coronary intervention for the treatment of acute myocardial infarction. The CHILL-MI trial: A randomized controlled study of the use of central venous catheter core cooling combined with cold saline as an adjunct to percutaneous coronary intervention for the treatment of acute myocardial infarction. J Am Coll Cardiol2014; 63: 1857–1865.
12.
SchwartzBGKlonerRAThomasJL. Therapeutic hypothermia for acute myocardial infarction and cardiac arrest. Am J Cardiol2012; 110: 461–466.
13.
DaeMWGaoDWSesslerDI. Effect of endovascular cooling on myocardial temperature, infarct size, and cardiac output in human-sized pigs. Am J Physiol Heart Circ Physiol2002; 282: H1585–H1591.
14.
TissierRGhalehBCohenMV. Myocardial protection with mild hypothermia. Cardiovasc Res2012; 94: 217–225.
15.
StegmanBMNewbyLKHochmanJS. Post-myocardial infarction cardiogenic shock is a systemic illness in neat of systemic treatment: Is therapeutic hypothermia one possibility?J Am Coll Cardiol2012; 59: 644–647.
16.
GötbergMOlivecronaGKKoulS. A pilot study of rapid cooling by cold saline and endovascular cooling before reperfusion in patients with ST-elevation myocardial infarction. Circ Cardiovasc Interv2010; 3: 400–407.
17.
BigelowWGLindsayWKGreenwoodWF. Hypothermia; its possible role in cardiac surgery: An investigation of factors governing survival in dogs at low body temperatures. Ann Surg1950; 132: 849–866.
18.
BigelowWGCallaghanJCHoppsJA. General hypothermia for experimental intracardiac surgery; the use of electrophrenic respirations, an artificial pacemaker for cardiac standstill and radio-frequency rewarming in general hypothermia. Ann Surg1950; 132: 531–539.
19.
SwanHZeavinI. Cessation of circulation in general hypothermia. III. Technics of intracardiac surgery under direct vision. Ann Surg1954; 139: 385–396.
20.
ShumwayNELewisFJ. Induced ventricular fibrillation for experimental intracardiac surgery under hypothermia. Ann Surg1956; 143: 230–234.
21.
VaronJAcostaP. Therapeutic hypothermia: Past, present, and future. Chest2008; 133: 1267–1274.
22.
BigelowWGMcBirnieJE. Further experiences with hypothermia for intracardiac surgery in monkeys and groundhogs. Ann Surg1953; 137: 361–365.
23.
HaleSLKlonerRA. Mild hypothermia as a cardioprotective approach for acute myocardial infarction: Laboratory to clinical application. J Cardiovasc Pharmacol Ther2011; 16: 131–139.
24.
AbendscheinDRTackerWAJrBabbsCF. Protection of ischemic myocardium b whole-body hypothermia after coronary artery occlusion in dogs. Am Heart J1978; 96: 772–780.
25.
VoorheesWDAbendcheinDRTackerWAJr.Effect of whole-body hypothermia on myocardial blood flow and infarct salvage during coronary artery occlusion in dogs. Am Heart J1984; 107: 945–949.
26.
SchwarzlMHuberSMaechlerH. Left ventricular diastolic dysfunction during acute myocardial infarction: Effect of mild hypothermia. Resuscitation2012; 83: 1503–1510.
27.
SchwarzlMSteendijkPHuberS. The induction of mild hypothermia improves systolic function of the resuscitated porcine heart at no further sympathetic activation. Acta Physiol (Oxf) 2011; 203: 409–418.
28.
YangXLiuYYangXM. Cardioprotection by mild hypothermia during ischemia involves preservation of ERK activity. Basic Res Cardiol2011; 106: 421–430.
29.
OtakeHShiteJParedesOL. Catheter-based transcoronary myocardia hypothermia attenuates arrhythmia and myocardial necrosis in pigs with acute myocardial infarction. J Am Coll Cardiol2007; 49: 250–260.
30.
WeissAJPawaleAGrieppRB. Deep versus mild hypothermia during thoracoabdominal aortic surgery. Ann Cardiothorac Surg2012; 1: 329–333.
31.
PoldermanKH. Application of therapeutic hypothermia in the ICU: Opportunities and pitfalls of a promising treatment modality. Part 1: Indications and evidence. Intensive Care Med2004; 30: 556–575.
32.
WangHOliveroWWangD. Cold as a therapeutic agent. Acta Neurochir (Wien)2006; 148: 565–570.
33.
AlzagaAGSalazarGAVaronJ. Resuscitation great: Breaking the thermal barrier; Dr. Temple Fay. Resuscitation2006; 69: 359–364.
34.
FayT. Early experiences with local and generalized refrigeration of the human brain. J Neurosurg1959; 16: 239–259
35.
BensonDWWilliamsGRJrSpencerFC. The use of hypothermia after cardiac arrest. Anesth Analg1959; 38: 423–428.
36.
PoolJLKesslerLA. Mechanism and control of centrally induced cardiac irregularities during hypothermia: I. Clinical observations. J Neurosurg1958; 15: 52–64.
37.
WebbWRDeguzmanVCGroganJB. Hypothermia: Its effects upon hematologic clearance in experimentally induced staphylococcal bacteremia. Surgery1962; 52: 643–647.
38.
BernardSAGrayTWBuistMD. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med2002; 346: 557–563.
39.
NolanJPMorleyPTHoekTL. Therapeutic hypothermia after cardiac arrest: An advisory statement by the Advancement Life Support Task Force of the International Liaison Committee on Resuscitation. Resuscitation2003; 57: 231–235.
40.
ZvimanMMRoguinAJacobsA. A new method for inducing hypothermia during cardiac arrest. Crit Care Med2004; 32: S369–S373.
41.
RinconFMayerSA. Therapeutic hypothermia for brain injury after cardiac arrest. Semin Neurol2006; 26: 387–395.
42.
HaugkMSterzFGrassbergerM. Feasibility and efficacy of a new non-invasive surface cooling device in post-resuscitation intensive care medicine. Resuscitation2007; 75: 76–81.
43.
GulyH. History of accidental hypothermia. Resuscitation2011; 82: 122–125.
44.
GilbertMBusundRSkagsethA. Resuscitation from accidental hypothermia of 13.7 degrees C with circulatory arrest. Lancet2000; 355: 375–376.
45.
DaVeeTSReinbergEJ. Extreme hypothermia and ventricular fibrillation. Ann Emerg Med1980; 9: 100–102.
46.
NiaziSALewisFJ. Profound hypothermia in man: Report of case. Ann Surg1958; 147: 254–266.
47.
VaronJSadovnikoffNSternbachGL.Hypothermia. Saving patients from the big chill. Postgrad Med1992; 92: 47–54, 59.
48.
ZeinerAHolzerMSterzF. Mild resuscitative hypothermia to improve neurological outcome after cardiac arrest. A clinical feasibility trial. Hypothermia after cardiac arrest (HACA) study group. Stroke2000; 31: 86–94.
49.
XuBJacquirSLaurentG. In vitro arrhythmia generation by mild hypothermia: A pitchfork bifurcation type process. Physiol Meas2015; 36: 579–594.
50.
MalletML. Pathophysiology of accidental hypothermia. QJM2002; 95: 775–785.
51.
JacobshagenCPelsterTPaxA. Effects of mild hypothermia on hemodynamics in cardiac arrest survivors and isolated failing human myocardium. Clin Res Cardiol2010; 99: 267–276.
52.
HeXSuFTacconeFS. Cardiovascular and microvascular responses to mild hypothermia in an ovine model. Resuscitation2012; 83: 760–766.
53.
PoldermanKHVaronJ. Cool hemodynamics—the intricate interplay between therapeutic hypothermia and the post-cardiac arrest syndrome. Resuscitation2014; 85: 975–976.
54.
FillipiSGizziACherubiniC. Mechanistic insights into hypothermic ventricular fibrillation: The role of temperature and tissue size. Europace2014; 16: 424–434.
55.
TiainenMParikkaHJMakijarviM. Arrhythmias and heart rate variability during and after therapeutic hypothermia for cardiac arrest. Crit Care Med2009; 37: 403–409.
56.
KudlickaJMlcekMBelohlavekJ. Inducibility of ventricular fibrillation during mild therapeutic hypothermia: Electrophysiological study in a swine model. J Transl Med2015; 13: 72.
57.
LebiedzPMeinersJSamolA. Electrocardiographic changes during therapeutic hypothermia. Resuscitation2012; 83: 602–606.
58.
KarnatovskaiaLVWartenbergKEFreemanWD. Therapeutic hypothermia for neuroprotection history, mechanisms, risks, and clinical applications. Neurohospitalist2014; 4: 153–163.
59.
Staer-JensenHSundeKOlasveengenTM. Bradycardia during therapeutic hypothermia is associated with good neurologic outcome in comatose survivors of out-of-hospital cardiac arrest. Crit Care Med2014; 42: 2401–2408.
60.
ThomsenJHHassagerCBro-JeppesenJ. Sinus bradycardia during hypothermia in comatose survivors of out-of-hospital cardiac arrest – a new early marker of favorable outcome?Resuscitation2015; 89: 36–42.
61.
KiyosueTAritaMMutamatsuH. Ionic mechanisms of action potential prolongation at low temperature in guinea-pig ventricular myocytes. J Physiol1993; 468: 85–106.
62.
MattuABradyWJPerronAD. Electrocardiographic manifestations of hypothermia. Am J Emerg Med2002; 20: 314–326.
63.
VasalloSUDelaneyKAHoffmanRS. A prospective evaluation of the electrocardiographic manifestations of hypothermia. Acad Emerg Med1999; 6: 1121–1126.
64.
Benezet-MazuecosJIbanezBFarreJ. Severe hypothermia showing Osborn waves associated with transient atrial fibrillation and ST segment depression. Heart2006; 92: 1666.
65.
LiGLYangLCuiCC. J wave syndromes: A decade of progress. Chin Med J (Engl)2015; 128: 969.
66.
KeransVEspinozaASkulstadH. Systolic left ventricular function is preserved during therapeutic hypothermia, also during increases in heart rate with impaired diastolic filling. Intensive Care Med Exp2015; 3: 6.
67.
FischerUMCoxCSJrLaineGA. Mild hypothermia impairs left ventricular diastolic but not systolic function.J Invest Surg2005; 18: 291–296.
68.
WeisserJMartinJBispingE. Influence of mild hypothermia on myocardial contractility and circulatory function. Basic Res Cardiol2001; 96: 198–205.
69.
LewisMEAl-KhalidiAHTownendJN. The effect of hypothermia on human left ventricular contractile function during cardiac surgery. J Am Coll Cardiol2002; 39: 102–108.
70.
NishimuraYNaitoYNishiokaT. The effects of cardiac cooling under surface-induced hypothermia on the cardiac function in the in situ heart. Interact Cardiovasc Thorac Surg2005; 4: 101–105.
71.
AndrzejowskiJCLuscombeM. Clinical applications of induced hypothermia. Contin Educ Anaesth Crit Care Pain2006; 6: 23–27.
72.
GötbergMvan der PalsJOlivercronaGK. Mild hypothermia reduces acute mortality and improves hemodynamic outcome in a cardiogenic shock pig model. Resuscitation2010; 81: 1190–1196.
73.
FrankSMSatitpunwaychaPBruceSR. Increased myocardial perfusion and sympathoadrenal activation during mild core hypothermia in awake humans. Clin Sci (Lond)2003; 104: 503–508.
74.
BoyerNHGersteinMM. Induced hypothermia in dogs with acute myocardial infarction and shock. J Thorac Cardiovasc Surg1977; 74: 286–294.
75.
BergmanRBraberAAdriaanseMA. Haemodynamic consequences of mild therapeutic hypothermia after cardiac arrest. Eur J Anaesthesiol2010; 27: 383–387.
76.
SchmidFXPhilippAFoltanM. Adequacy of perfusion during hypothermia: Regional distribution of cardiopulmonary bypass flow, mixed venous and regional venous oxygen saturation-hypothermia and distribution of flow and oxygen. Thorac Cardiovasc Surg2003; 51: 306–311.
77.
GiraudRSiegenthalerNBendjelidK. Cardiac index during therapeutic hypothermia: Which target value is optimal?Crit Care2013; 17: 214.
78.
KlonerRABolliRMarbanE. Medical and cellular implications of stunning, hibernation, and preconditioning: An NHLBI workshop. Circulation1998; 97: 1848–1867.
79.
ItoH. No-reflow phenomenon and prognosis in patients with acute myocardial infarction. Nat Clin Pract Cardiovasc Med2006; 3: 499–506.
80.
LuoAKWuKC. Imaging microvascular obstruction and its clinical significance following acute myocardial infarction. Heart Fail Rev2006; 11: 305–312.
81.
HeuschGKleinbongardPBoseD. Coronary microembolization: From bedside to bench and back to bedside. Circulation2009; 120: 1822–1836.
82.
YellonDMHausenloyDJ. Myocardial reperfusion injury. N Engl J Med2007; 357: 1121–1135.
83.
VermaSFedakPWWeiselRD. Fundamentals of reperfusion injury for the clinical cardiologist. Circulation2002; 105: 2332–2336.
84.
CardenDLGrangerDN. Pathophysiology of ischaemia-reperfusion injury. J Pathol2000; 190: 255–266.
85.
HuangCHChiangCYPenRH. Hypothermia treatment preserves mitochondrial integrity and viability of cardiomyocytes after ischaemic reperfusion injury. Injury2015; 46: 233–239.
86.
GrangerDN. Ischemia-reperfusion: Mechanisms of microvascular dysfunction and the influence of risk factors for cardiovascular disease. Microcirculation1999; 6: 167–178.
87.
Ruiz-MeanaMGarcia-DoradoD. Translational cardiovascular medicine (II). Pathophysiology of ischemia-reperfusion injury: New therapeutic options for acute myocardial infarction. Rev Esp Cardiol2009; 62: 199–209.
ShaoZHSharpWWWojcikKR. Therapeutic hypothermia cardioprotection via AKT-and nitric oxide mediated attenuation of mitochondria oxidants. Am J Physiol Heart Circ Physiol2010; 298: H2164-H2173.
90.
ShaoZHChangWTChanKC. Hypothermia-induced cardioprotection using extended ischemia and early reperfusion cooling. Am J Physiol Heart Circ Physiol2007; 292: H1995–H2003.
91.
HaleSLKlonerRA. Myocardial temperature reduction attenuates necrosis after prolonged ischemia in rabbits. Cardiovasc Res1998; 40: 502–507.
92.
MikiTLiuGSCohenMV. Mild hypothermia reduces infarct size in the beating rabbit heart; a practical intervention for acute myocardial infarction?Basic Res Cardiol1998; 93: 372–383.
93.
NingXHXuCSSonYC. Hypothermia preserves function and signaling for mitochondrial biogenesis during subsequent ischemia. Am J Physiol1998; 274: H786–H793.
94.
SimkhovichBZHaleSLKonerRA. Metabolic mechanism by which mild regional hypothermia preserves ischemic tissue. J Cardiovasc Pharmacol Ther2004; 9: 83–90.
95.
MochizukiTYuSKatohT. Cardioprotective effect of therapeutic hypothermia at 34°C against ischaemia/reperfusion injury mediated by PI3K and nitric oxide in a rat isolated heart model. Resuscitation2012; 83: 238–242.
96.
NingXHChiEYBurokerNE. Moderate hypothermia (30 degrees C) maintains myocardial integrity and modifies response of cell survival proteins after reperfusion. Am J Physiol Heart Circ Physiol2007; 293: H2119–H2128.
97.
KanekoTKibayashiK. Mild hypothermia facilitates the expression of cold-inducible RNA binding protein and heat shock protein 70.1 in mouse brain. Brain Res2012; 1466:128–136.
NicholGStricklandWShavelleD. Prospective, multicenter, randomized, controlled pilot trial of peritoneal hypothermia in patients with ST-segment-elevation myocardial infarction. Circ Cardiovas Interv2015; 8: e001965.
100.
MaengMKristiansenSBMortensenUM. Myocardial cooling for reperfusion injury protection achieved by organ specific hypothermic autologous perfusion. Scand Cardiovasc J2003; 37: 297–303.
101.
OrbanMMayerKMorathT. The impact of therapeutic hypothermia on on-treatment platelet reactivity and clinical outcome in cardiogenic shock patients undergoing primary PCI for acute myocardial infarction: Results from the ISAR-SHOCK registry. Thromb Res2015; 136: 87-93.
102.
SchwartzDSBremnerRMBakerCJ. Regional topical hypothermia of the beating heart: Preservation of function and tissue. Ann Thorac Surg2001; 72: 804–809.
103.
HaleSLKlonerRA. Myocardial temperature in acute myocardial infarction: Protection with mild regional hypothermia. Am J Physiol1997; 273: H220–H227.
104.
HaleSLDaveRHKlonerRA. Regional hypothermia reduces myocardial necrosis even when instituted after the onset of ischemia. Basic Res Cardiol1997; 92: 351–357.
105.
van den DoelMAGhoBCDuvalSY. Hypothermia extends the cardioprotection by ischaemic preconditioning to coronary artery occlusions of longer duration. Cardiovasc Res1998; 37: 76–81.
106.
SchwartzLMVerbinskiSGVander HeideRS. Epicardial temperature is a major predictor of myocardial infarct size in dogs. J Mol Cell Cardiol1997; 29: 1577–1583.
107.
HamamotoHSakamotoHLeshnowerBG. Very mild hypothermia during ischemia and reperfusion improves postinfarction ventricular remodeling. Ann Thorac Surg2009; 87: 172–177.
108.
HaleSLHerringMJKlonerRA. Delayed treatment with hypothermia protects against the no-reflow phenomenon despite failure to reduce infarct size. J Am Heart Assoc2013; 2: e004234.
109.
DaveRHHaleSLKlonerRA. Hypothermic, closed circuit pericardioperfusion: A potential cardioprotective technique in acute regional ischemia. J Am Coll Cardiol1998; 31: 1667–1671.
110.
GrinesC. Intravascular cooling adjunctive to PCI for acute myocardial infarction. Presented at: Transcatheter cardiovascular therapeutics, September 2004; Washington DC.
111.
O’NeillW. Cooling as an adjunct to primary PCI for myocardial infarction. Presented at: Transcatheter cardiovascular therapies, September 2003, Washington DC.
112.
O’NeillWWDixonSRGrinesCL. The year in interventional cardiology. J Am Coll Cardiol2005; 45: 1117–1134.
113.
ErlingeDGötbergMGrinesC. A pooled analysis of the effect of endovascular cooling on infarct size in patients with ST-elevation myocardial infarction. Eurointervention2013; 8: 1435–1440.
114.
TestoriCSterzFDelle-KarthG. Strategic target temperature management in myocardial infarction – a feasibility trial. Heart2013; 99: 1663–1667.
115.
ErlingeDGötbergMNocM. Therapeutic hypothermia for the treatment of acute myocardial infarction combined analysis of the RAPID MI-ICE and the CHILL-MI Trials. Ther Hypothermia Temp Manag2015; 5: 77–84.
