Heart attack is the leading cause of death in the United States. Despite advances in angioplasty procedures and thrombolytics, within the first year after an attack, about 30% of all patients die as a result of lingering heart damage. 1 Therefore, therapeutic strategies that will reduce the overall damage sustained during a heart attack are critical to improving heart attack patient outcomes.
Reperfusion Injury
The main treatment goal for myocardial infarction is to restore blood flow to oxygen-deprived tissue as quickly as possible. Blood reperfusion, however, can cause significant damage, accounting for up to 50% of the damaged tissue. 2 This reperfusion injury is a cascade of complex and interdependent mechanisms including: formation of oxygen free radicals, increased cytokine activity, calcium overload, neutrophil-mediated myocardial and endothelial injury, reduced microvascular flow, and depletion of high energy phosphate stores.
With the success rate of thrombolysis drugs and percutaneous coronary intervention to reperfuse ischemic tissue, cardioprotective strategies to address reperfusion injury are now a necessity.
Benefits of Hypothermia
The following are benefits of therapeutic hypothermia in the setting of acute myocardial infarction:
Reduces metabolic demand in risk region 4,5
Decreases oxygen consumption 6,7
Maintains ion hemostasis 7
Reduces myocyte apoptosis 8
Reduces levels of cytotoxins and free radical (oxygen) production 9
Reduces reperfusion injury (creatine kinase) 10
Reduces mycrovascular obstruction, no reflow 11,12
Reduces inflammatory response 8
Reduces post-ischemic reactive hyperemia 13
Induces mitochondrial biogenesis 14
Maintains myocardial integrity and modifies response of cell survival proteins after reperfusion 15
Inhibits platelet aggregation 16
Preserves ATP and glycogen stores and reduced creatine phosphate 17
Reduces intracellular Ca overload (via inhibition of Na+/Ca2+ exchanger) and decreases homeostasis proteins (heat shock proteins) during reperfusion 18
FocalCool Technology
FocalCool seeks to develop products that fully harness the protective power of hypothermia. Unlike existing devices, our emphasis is not whole-body or systemic cooling. Instead, we are developing devices that cool individual organs rapidly – reaching target temperatures at least four times faster. Faster cooling will save more organ tissue – reducing treatment costs and improving patient outcomes. Our initial focus is myocardial infarction (heart attack). Future products will also address stroke, spinal cord and kidney injury and epilepsy.
Research References
(1) Lloyd-Jones D, Adams R, Carnethon M, De Simone G, Ferguson TB, Flegal K, et al. Heart disease and stroke statistics--2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2009 Jan 27;119(3):e21-181.
(3) Holzer M, Behringer W. Therapeutic hypothermia after cardiac arrest and myocardial infarction. Best Pract.Res.Clin.Anaesthesiol. 2008 Dec;22(4):711-728.
(4) Maeng M, Kristiansen SB, Mortensen UM, Andersen HR. Myocardial cooling for reperfusion injury protection achieved by organ specific hypothermic autologous perfusion. Scand.Cardiovasc.J. 2003 Sep;37(5):297-303.
(5) Dae MW, Gao DW, Ursell PC, Stillson CA, Sessler DI. Safety and efficacy of endovascular cooling and rewarming for induction and reversal of hypothermia in human-sized pigs. Stroke 2003 Mar;34(3):734-738.
(6) Miki T, Liu GS, Cohen MV, Downey JM. Mild hypothermia reduces infarct size in the beating rabbit heart: a practical intervention for acute myocardial infarction? Basic Res.Cardiol. 1998 Oct;93(5):372-383.
(7) Schwartz DS, Bremner RM, Baker CJ, Uppal KM, Barr ML, Cohen RG, et al. Regional topical hypothermia of the beating heart: preservation of function and tissue. Ann.Thorac.Surg. 2001 Sep;72(3):804-809.
(9) Maeng M, Mortensen UM, Kristensen J, Kristiansen SB, Andersen HR. Hypothermia during reperfusion does not reduce myocardial infarct size in pigs. Basic Res.Cardiol. 2006 Jan;101(1):61-68.
(10) Otake H, Shite J, Paredes OL, Shinke T, Yoshikawa R, Tanino Y, et al. Catheter-based transcoronary myocardial hypothermia attenuates arrhythmia and myocardial necrosis in pigs with acute myocardial infarction. J.Am.Coll.Cardiol. 2007 Jan 16;49(2):250-260.
(11) Hale SL, Dae MW, Kloner RA. Hypothermia during reperfusion limits 'no-reflow' injury in a rabbit model of acute myocardial infarction. Cardiovasc.Res. 2003 Sep 1;59(3):715-722.
(12) Gotberg M, Olivecrona GK, Engblom H, Ugander M, van der Pals J, Heiberg E, et al. Rapid short-duration hypothermia with cold saline and endovascular cooling before reperfusion reduces microvascular obstruction and myocardial infarct size. BMC Cardiovasc.Disord. 2008 Apr 10;8:7.
(13) Olivecrona GK, Gotberg M, Harnek J, Van der Pals J, Erlinge D. Mild hypothermia reduces cardiac post-ischemic reactive hyperemia. BMC Cardiovasc.Disord. 2007 Feb 26;7:5.
(14) Ning XH, Xu CS, Song YC, Xiao Y, Hu YJ, Lupinetti FM, et al. Hypothermia preserves function and signaling for mitochondrial biogenesis during subsequent ischemia. Am.J.Physiol. 1998 Mar;274(3 Pt 2):H786-93.
(15) Ning XH, Chi EY, Buroker NE, Chen SH, Xu CS, Tien YT, 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 Oct;293(4):H2119-28.
(16) Frelinger AL,3rd, Furman MI, Barnard MR, Krueger LA, Dae MW, Michelson AD. Combined effects of mild hypothermia and glycoprotein IIb/IIIa antagonists on platelet-platelet and leukocyte-platelet aggregation. Am.J.Cardiol. 2003 Nov 1;92(9):1099-1101.
(17) Simkhovich BZ, Hale SL, Kloner RA. Metabolic mechanism by which mild regional hypothermia preserves ischemic tissue. J.Cardiovasc.Pharmacol.Ther. 2004 Jun;9(2):83-90.
(18) Inoue K, Ando S, Gyuan F, Takaba T. A study of the myocardial protective effect of rapid cooling based on intracellular Ca, intracellular pH, and HSP70. Ann.Thorac.Cardiovasc.Surg. 2003 Oct;9(5):301-306.
