title: Cardioprotection and myocardial reperfusion: pitfalls to clinical application.
abstract: With the advent of thrombolytic therapy and angioplasty, it has become possible to reduce myocardial infarct size through early reperfusion. Enormous effort has been expended to find therapies that can further reduce infarct size after early intervention. Animal studies have identified many cardioprotective pathways that have the potential to reduce infarct size if activated before the onset of ischemia. More recently, interventions effective at the onset of reperfusion have been described. Although basic research has identified many targets, most has been conducted in rodent models which may not be directly applicable to human disease and even promising agents have been disappointing in large-scale clinical trials. There are many potential explanations for this failure which is the subject of this review. Potential factors include (1) the variability inherent in the patient population, whereas animal studies usually use single sex homogeneous groups maintained on standard diets in carefully controlled environments; (2) the duration of ischemia is generally shorter in animal studies, resulting in potentially more salvageable myocardium than is often the case in patients; (3) that the animals are usually young without comorbidities, whereas the patient population is generally older and has significant comorbidities; (4) animals are not treated with medications a priori, whereas the patient population is often taking medications that may affect ischemic injury; and (5) animal studies may not involve thorough assessment of effects on organs other than the heart, whereas patients can experience adverse effects of treatment in other organs that can preclude clinical use.
authors.affiliation: Department of Pathology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA. rvand3@lsuhsc.edu
authors.forename: Richard S
authors.initials: RS
authors.lastname: Vander Heide
authors.forename: Charles
authors.initials: C
authors.lastname: Steenbergen
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D004195:Disease Models, Animal; D006801:Humans; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D012720:Severity of Illness Index; D013997:Time Factors; D057170:Translational Research, Biomedical
chemical_list: D002316:Cardiotonic Agents
keywords: clinical trial; myocardial infarction; reperfusion injury
references.citation: Nutrition. 2011 Jul-Aug;27(7-8):733-44
references.pmid: 21454053
references.citation: J Mol Cell Cardiol. 1978 Jul;10(7):641-68
references.pmid: 691070
references.citation: Circulation. 2001 Dec 4;104(23):2778-83
references.pmid: 11733394
references.citation: J Pharmacol Sci. 2007 Feb;103(2):222-33
references.pmid: 17299242
references.citation: Cardiovasc Res. 2004 Feb 15;61(3):448-60
references.pmid: 14962476
references.citation: Circulation. 1987 Nov;76(5):1135-45
references.pmid: 3664998
references.citation: Cardiovasc Res. 2006 May 1;70(2):191-9
references.pmid: 16497286
references.citation: Eur Heart J. 2010 Feb;31(4):430-8
references.pmid: 19903682
references.citation: Am J Physiol. 1984 Jun;246(6 Pt 2):H776-83
references.pmid: 6331179
references.citation: Proc Natl Acad Sci U S A. 2007 Nov 27;104(48):19144-9
references.pmid: 18025468
references.citation: Am J Pathol. 1974 Mar;74(3):399-422
references.pmid: 4814895
references.citation: Circulation. 2008 Jun 10;117(23):2986-94
references.pmid: 18519850
references.citation: Ann N Y Acad Sci. 1969 Jan 31;156(1):61-78
references.pmid: 5291154
references.citation: Circulation. 1986 Nov;74(5):1124-36
references.pmid: 3769170
references.citation: J Am Coll Surg. 2013 Apr;216(4):719-26; discussion 726-9
references.pmid: 23415552
references.citation: J Clin Invest. 2005 May;115(5):1232-40
references.pmid: 15841216
references.citation: J Clin Invest. 1988 Feb;81(2):624-9
references.pmid: 3339135
references.citation: Circulation. 2005 Oct 4;112(14):2143-8
references.pmid: 16186417
references.citation: Circ Res. 1989 Sep;65(3):607-22
references.pmid: 2548761
references.citation: Eur Heart J. 2006 Oct;27(20):2400-5
references.pmid: 16782719
references.citation: Basic Res Cardiol. 2013 May;108(3):343
references.pmid: 23525499
references.citation: Antioxid Redox Signal. 2011 Mar 1;14(5):923-39
references.pmid: 20578958
references.citation: Circ Res. 2005 Oct 28;97(9):916-21
references.pmid: 16179590
references.citation: J Cardiovasc Transl Res. 2011 Feb;4(1):92-8
references.pmid: 21136310
references.citation: Am J Pathol. 1987 Nov;129(2):327-44
references.pmid: 3314531
references.citation: Circ Res. 1987 Apr;60(4):478-86
references.pmid: 2439227
references.citation: Am J Physiol. 1990 Mar;258(3 Pt 2):H821-8
references.pmid: 2316696
references.citation: Am J Physiol Heart Circ Physiol. 2003 Aug;285(2):H579-88
references.pmid: 12860564
references.citation: Circulation. 1994 Apr;89(4):1792-801
references.pmid: 8149545
references.citation: Nat Rev Drug Discov. 2012 Dec;11(12):937-57
references.pmid: 23197040
references.citation: N Engl J Med. 2008 Jul 31;359(5):473-81
references.pmid: 18669426
references.citation: J Am Coll Cardiol. 2012 Mar 13;59(11):969-78
references.pmid: 22402067
references.citation: Interact Cardiovasc Thorac Surg. 2012 May;14(5):634-9
references.pmid: 22286602
references.citation: J Am Coll Cardiol. 1999 Nov 15;34(6):1711-20
references.pmid: 10577561
references.citation: J Cardiovasc Pharmacol Ther. 2011 Sep-Dec;16(3-4):223-32
references.pmid: 21821520
references.citation: Cardiovasc Res. 1976 Jan;10(1):81-90
references.pmid: 1253198
references.citation: Circ Res. 2000 Nov 24;87(11):972-83
references.pmid: 11090541
references.citation: Basic Res Cardiol. 1999 Jun;94(3):180-7
references.pmid: 10424236
references.citation: Crit Care Med. 2002 May;30(5 Suppl):S214-9
references.pmid: 12004238
references.citation: J Cardiovasc Pharmacol. 2010 Mar;55(3):227-33
references.pmid: 20010437
references.citation: Circulation. 1991 Jan;83(1):237-47
references.pmid: 1984882
references.citation: J Mol Cell Cardiol. 1987 Nov;19(11):1085-103
references.pmid: 3437460
references.citation: Circ Res. 2012 Jan 6;110(1):105-10
references.pmid: 22095727
references.citation: Am J Physiol Heart Circ Physiol. 2006 Mar;290(3):H1011-8
references.pmid: 16214840
references.citation: Circulation. 2006 Oct 3;114(14):1531-44
references.pmid: 17015805
references.citation: Circulation. 1985 May;71(5):1069-75
references.pmid: 3838707
references.citation: Am J Cardiol. 1985 Oct 1;56(10):672-7
references.pmid: 4050705
references.citation: Circulation. 2001 Jun 19;103(24):2935-41
references.pmid: 11413083
references.citation: N Engl J Med. 2010 Jun 10;362(23):2155-65
references.pmid: 20558366
references.citation: JAMA. 2007 Jan 3;297(1):43-51
references.pmid: 17200474
references.citation: J Clin Invest. 1975 Oct;56(4):978-85
references.pmid: 1159098
references.citation: J Am Coll Cardiol. 1991 Sep;18(3):868-75
references.pmid: 1869751
references.citation: Cardiovasc Res. 1996 May;31(5):711-8
references.pmid: 8763400
references.citation: JACC Cardiovasc Imaging. 2011 Sep;4(9):1014-21
references.pmid: 21920341
references.citation: Cardiovasc Res. 2004 Feb 15;61(3):481-97
references.pmid: 14962479
references.citation: Circ Res. 1985 Dec;57(6):864-75
references.pmid: 4064260
references.citation: Lancet. 2007 Oct 27;370(9597):1483-93
references.pmid: 17964349
references.citation: J Am Coll Cardiol. 2002 Oct 2;40(7):1199-204
references.pmid: 12383565
references.citation: Ann Thorac Surg. 2008 Apr;85(4):1261-70
references.pmid: 18355507
references.citation: PLoS One. 2012;7(12):e48513
references.pmid: 23272043
references.citation: Circulation. 2008 Feb 26;117(8):1037-44
references.pmid: 18268150
references.citation: Heart. 2010 Nov;96(21):1710-5
references.pmid: 20956486
references.citation: Lancet. 2010 Feb 27;375(9716):727-34
references.pmid: 20189026
references.citation: Heart. 2009 Oct;95(19):1567-71
references.pmid: 19508973
references.citation: Circulation. 2007 Apr 10;115(14):1895-903
references.pmid: 17389262
references.citation: Circulation. 1990 Aug;82(2):595-608
references.pmid: 2372906
references.citation: Lancet. 2007 Aug 18;370(9587):575-9
references.pmid: 17707752
references.citation: Circ Res. 2010 Feb 19;106(3):546-50
references.pmid: 20007913
references.citation: J Am Coll Cardiol. 2001 Nov 15;38(6):1644-50
references.pmid: 11704395
references.citation: Am J Pathol. 1986 Oct;125(1):55-68
references.pmid: 3777140
references.citation: J Thorac Cardiovasc Surg. 2003 Aug;126(2):420-7
references.pmid: 12928639
references.citation: J Am Coll Cardiol. 2003 Apr 16;41(8):1404-7
references.pmid: 12706939
references.citation: Radiology. 2012 Oct;265(1):12-22
references.pmid: 22993217
references.citation: J Mol Cell Cardiol. 1989 Nov;21(11):1187-93
references.pmid: 2481748
references.citation: Eur Heart J. 2012 Jan;33(1):103-12
references.pmid: 21846677
references.citation: Circ Res. 2003 Oct 17;93(8):776-82
references.pmid: 12970112
references.citation: J Am Coll Cardiol. 2005 Jun 7;45(11):1775-80
references.pmid: 15936605
references.citation: Circulation. 1992 Mar;85(3):1160-74
references.pmid: 1537114
references.citation: Cardiovasc Res. 1994 Oct;28(10):1526-32
references.pmid: 8001041
references.citation: Basic Res Cardiol. 2002 Jul;97(4):268-75
references.pmid: 12111036
references.citation: Lab Invest. 1979 Jun;40(6):633-44
references.pmid: 449273
references.citation: Eur Heart J. 1983 Dec;4 Suppl H:63-71
references.pmid: 6662135
references.citation: J Clin Invest. 1987 Dec;80(6):1728-34
references.pmid: 3680525
references.citation: Am J Physiol. 1988 Sep;255(3 Pt 2):H608-15
references.pmid: 2843057