Pharmacological Agents in the Clinic: Trial and Error
DOI:
https://doi.org/10.17140/HROJ-2-122Abstract
Following an explosion of molecular and cellular research in the last 50 years, the
study of specific molecular targets in the context of heart failure has generated much excitement.
With the incidence of heart failure rising worldwide, new pharmacological agents are
eagerly anticipated as a key tool with the potential for significant impact. In this regard, the
results of the keenly awaited Does Cyclosporine Improve Clinical Outcome in ST Elevation
Myocardial Infarction Patients (CIRCUS) trial have just been made available. Despite a substantial
programme of supporting experimental and preclinical evidence however, the results
have proved negative. This is of great disappointment to the clinical and scientific community.
Here, this is discussed in the context of previous studies and future directions explored.
References
Fiedler LR. Cardiovascular research: past, present and future. Heart Res Open J. 2015; 2(2): 70-81. doi: 10.17140/HROJ-2-
White HD, Chew DP. Acute myocardial infarction. Lancet, 2008; 372(9638): 570-584.
Heidenreich PA, Albert NM, Allen LA, et al. Forecasting the impact of heart failure in the United States: a policy statement from the American Heart Association. Circ. Heart Fail, 2013; 6(3): 606-619. doi: 10.1161/HHF.0b013e318291329a
Miller TD, Christian TF, Hopfenspirger RN, Hodge DO, Gersh BJ, Gibbons RJ. Infarct size after acute myocardial in-farction measured by quantitativetomographic 99mTc sestamibi imaging predicts subsequent mortality. Circ. 1995; 92(3): 334- 341. doi: 10.1161/01.CIR.92.3.334
Simoons ML, Serruys PW, van den Brand M, et al. Early thrombolysis in acute myocardial infarction: Limitation of in-farct sizeand improved survival. J Am Coll Cardiol. 1986; 7(4): 717-728. doi: 10.1016/S0735-1097(86)80329-1
Brener SJ, Maehara A, Dizon JM, et al. Relationship be-tween myocardial reperfusion, infarct size, and mortality: The INFUSEAMI (intracoronary abciximab and aspiration throm-bectomy in patients with large anteriormyocardial Infarction) trial. JACC: Cardiovasc Intervent. 2013; 6(7): 718-724. doi: 10.1016/j.jcin.2013.03.013
Murphy E, Steenbergen C. Mechanisms underlying acute pro-tection from cardiac ischemia-reperfusion injury. Physiol Rev. 2008; 88: 581-609. doi: 10.1152/physrev.00024.2007
Baines CP, Kaiser RA, Purcell NH, et al. Loss of cyclophilin D reveals a critical role for mitochondrial permeability transi-tion in cell death. Nature. 2005; 434: 658-662. doi: 10.1038/ nature03434
Duchen MR, McGuinness O, Brown LA, Crompton M. On the involvement of a cyclosporin A sensitive mitochondrial pore in myocardial reperfusion injury. Cardiovasc Res. 1993; 27: 1790-1794. doi: 10.1093/cvr/27.10.1790
Ibáñez B, Heusch G, Ovize M, Van de Werf F. Evolving therapies for myocardial ischemia/reperfusion injury. J Am Coll Cardiol. 2015; 65: 1454-1471. doi: 10.1016/j.jacc.2015.02.032
Ong SB, Samangouei P, Kalkhoran SB, Hausenloy DJ. The mitochondrial permeability transition pore and its role in myo-cardial ischemia reperfusion injury. J Mol Cell Cardiol. 2015; 78: 23-34. doi: 10.1016/j.yjmcc.2014.11.005
Oie E, Bjornerheim R, Clausen OP, Attramadal H. Cyclo-sporin A inhibits cardiac hypertrophy and enhances cardiac dys-function during postinfarction failure in rats. Am J Physiol Heart Circ Physiol. 2000; 278: 2115-2123.
Youn TJ, Piao H, Kwon JS, et al. Effects of the calcineu-rin dependent signaling pathway inhibition by cyclosporin A on early and late cardiac remodeling following myocardial infarc-tion. Eur J Heart Fail. 2002; 4: 713-718. doi: 10.1016/S1388- 9842(02)00120-4
Mewton N, Croisille P, Gahide G, et al. Effect of cyclospo-rine on left ventricular remodeling after reperfused myocardial infarction. J Am Coll Cardiol. 2010; 55(12): 1200-1205. doi: 10.1016/j.jacc.2009.10.052
Piot C, Croisille P, Staat P, et al. Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N Engl J Med 2008; 359: 473-481. doi: 10.1056/NEJMoa071142
Ghaffari, B. Kazemi, M. Toluey, et al. The effect of pre-thrombolytic cyclosporine-A injection on clinical outcome of acute anterior ST-elevation myocardial infarction. Cardiovasc Ther. 2013; 31(4): e34-e39. doi: 10.1111/1755-5922.12010
Cung TT, Morel O, Cayla G, et al. Cyclosporine before PCI in patients with acute myocardial infarction. N Engl J Med. 2015; 373(11): 1021-1031. doi: 10.1056/NEJMoa1505489
Mewton N, Cung TT, Morel O, et al. (Rationale and design of the Cyclosporine to Improve clinical outcome in ST-elevation myocardial infarction patients (the CIRCUS trial). Am Heart J. 2015; 169: 758. doi: 10.1016/j.ahj.2015.02.020
Sanchez H, Zoll J, Bigard X, et al. Effect of cyclosporin A and its vehicle on cardiac and skeletal muscle mitochondria: relationship to efficacy of the respiratory chain. Br J Pharmacol. 2001; 133: 781-788. doi: 10.1038/sj.bjp.0704129
Karlsson LO, Zhou AX, Larsson E, et al. Cyclosporine does not reduce myocardial infarct size in a porcine ischemia-reper-fusion model. J Cardiovasc Pharmacol Ther. 2010; 15: 182-189. doi: 10.1177/1074248410362074
Krolikowski JG, Bienengraeber M, Weihrauch D, Warltier DC, Kersten JR, Pagel PS. Inhibition of mitochondrial perme-ability transition enhances isoflurane-induced cardioprotection during early reperfusion: role of mitochondrial KATP chan-nels.Anesth Analg. 2005; 101: 1590-1596. doi: 10.1213/01. ANE.0000181288.13549.28
Li J, Iorga A, Sharma S, et al. Intralipid, a clinically safe compound, protects the heart against ischemia-reperfusion inju-ry more efficiently than cyclosporine-A. Anesthesiology. 2012; 117: 836-846. doi: 10.1097/ALN.0b013e3182655e73
Pagel PS, Krolikowski JG. Transient metabolic alkalo-sis during early reperfusion abolishes helium preconditioning against myocardial infarction: restoration of cardioprotection by cyclosporin A in rabbits. Anesth Analg. 2009; 108: 1076-1082. doi: 10.1213/ane.0b013e318193e934
Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG. Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol. 2010; 8(6): e1000412. doi: 10.1371/journal.pbio.1000412
Robertson C, Tran DD, George SC. Concise review: matura-tion phases of human pluripotent stem cell-derived cardiomyo-cytes. Stem Cells. 2013; 31(5): 829-837. doi: 10.1002/stem.1331
Schwan J, Campbell SG. Prospects for in vitro myofilament maturation in stem cell-derived cardiac myocytes. Biomark In-sights. 2015; 10(Suppl 1): 91-103. doi: 10.4137/BMI.S23912
Lefer DJ, Bolli R. Development of an NIH consor-tium for preclinical assessment of cardioprotective therapies (CAESAR): a paradigm shift in studies of infarct size limita-tion. J Cardiovasc Pharmacol Ther 2011; 16: 332-339. doi: 10.1177/1074248411414155
Lecour S, Bøtker HE, Condorelli G, et al. ESC working group cellular biology of the heart: position paper: improving the preclinical assessment of novel cardioprotective therapies. Car-diovasc Res. 2014; 104(3): 399-411. doi: 10.1093/cvr/cvu225
Hausenloy DJ, Yellon DM. Targeting myocardial reperfu-sion injury-the search continues. N Engl J Med. 2015; 373(11): 1073-1075. doi: 10.1056/NEJMe1509718
Bing OHL. Hypothesis: apoptosis may be a mechanism for the transition to heart failure with chronic pressure over-load. J Mol Cell Cardiol. 1994; 26(8): 943-948. doi: 10.1006/ jmcc.1994.1115
Narula J, Haider N, Virmani R, et al. Apoptosis in myocytes in end-stage heart failure. N Engl J Med. 1996; 335(16): 1182- 1189. doi: 10.1056/NEJM199610173351603
Olivetti G, Abbi R, Quaini F, et al. Apoptosis in the fail-ing human heart. N Engl J Med. 1997; 336(16): 1131-1141. doi: 10.1056/NEJM199704173361603
Kytö V, Saraste A, Saukko P, et al. Apoptotic cardiomyocyte death in fatal myocarditis. Am J Cardiol. 2004; 94(6): 746-750. doi: 10.1016/j.amjcard.2004.05.056
Nadal-Ginard B, Kajstura J, Anversa P, Leri A. A matter of life and death: Cardiac myocyte apoptosis and regenera-tion. J Clin Invest. 2003; 111(10): 1457-1459. doi: 10.1172/ JCI200318611
Wencker D, Chandra M, Nguyen K, et al. A mechanistic role for cardiac myocyte apoptosis in heart failure. J Clin Invest. 2003; 111(10): 1497-1504. doi: 10.1172/JCI200317664
Fiedler LR, Maifoshie E, Schneider MD. Mouse models of heart failure: cell signaling and cell survival. Curr Top Dev Biol. 2014; 109: 171-247. doi: 10.1016/B978-0-12-397920-9.00002-0
Nakagawa T, Shimizu S, Watanabe T, et al. Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature. 2005; 434: 652- 658. doi: 10.1038/nature03317
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