Correspondence
Cyclosporine in Acute Myocardial Infarction
N Engl J Med 2008; 359:2286-2289November 20, 2008
- Article
To the Editor:
In the article by Piot et al. (July 31 issue),1 cyclosporine, an inhibitor of the mitochondrial permeability transition, decreased infarct size after percutaneous coronary intervention (PCI) when administered just before the procedure. Although promising, cyclosporine has drawbacks, including immunosuppression, nephrotoxicity, and variable bioavailability. Cyclosporine is effective at lower concentrations (0.5 to 2 μM), but protection is lost at higher concentrations (≥5 μM); thus the drug has a narrow therapeutic window.2 Nonimmunosuppressive analogues of cyclosporine, such as NIM811, seem not to lose efficacy at high doses and might be more suitable for PCI.3 Other drugs block the mitochondrial permeability transition, prevent reperfusion injury, and are promising drug candidates. One such drug is minocycline, a tetracycline derivative that blocks the calcium-dependent mitochondrial permeability transition by inhibiting mitochondrial calcium uptake.4
The mitochondrial permeability transition is also emerging as a pathogenic mechanism in many chronic diseases (e.g., neurodegeneration and heart failure).5 For such diseases, long-term immunosuppression is undesirable, and nonimmunosuppressive mitochondrial permeability-transition inhibitors therefore show better promise as therapeutic agents.
Tom P. Theruvath, M.D., Ph.D.
John J. Lemasters, M.D., Ph.D.
Medical University of South Carolina, Charleston, SC 29425
jjlemasters@musc.edu Dr. Lemasters reports receiving speaking fees and travel expenses from Novartis and Scynexis. No other potential conflict of interest relevant to this letter was reported.
5 References1
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
Full Text | Web of Science | Medline2
Nazareth W ,Yafei N ,Crompton M . Inhibition of anoxia-induced injury in heart myocytes by cyclosporin A. J Mol Cell Cardiol 1991;23:1351-1354
CrossRef | Web of Science | Medline3
Waldmeier PC ,Feldtrauer JJ ,Qian T ,Lemasters JJ . Inhibition of the mitochondrial permeability transition by the nonimmunosuppressive cyclosporin derivative NIM811. Mol Pharmacol 2002;62:22-29
CrossRef | Web of Science | Medline4
Theruvath TP ,Zhong Z ,Pediaditakis P , et al. Minocycline and N-methyl-4-isoleucine cyclosporin (NIM811) mitigate storage/reperfusion injury after rat liver transplantation through suppression of the mitochondrial permeability transition. Hepatology 2008;47:236-246
CrossRef | Web of Science | Medline5
Lemasters JJ . The mitochondrial permeability transition and the calcium, oxygen and pH paradoxes: one paradox after another. Cardiovasc Res 1999;44:470-473
CrossRef | Web of Science | Medline
To the Editor:
Piot and colleagues report the results of a well-designed pilot study of cyclosporine infusion for myocardial infarction with ST-segment elevation. We are concerned that a single outlier in the control group may have resulted in a type I error. The omission of a single patient in the control group who had a very large myocardial infarction (area of hyperenhancement on magnetic resonance imaging [MRI], approximately 115 g, which was more than twice the median value) would decrease the mean infarct mass in the control group by more than 10%, and the difference between the two groups would be decreased and would probably not meet the 0.05 threshold for significance chosen by the authors. Similar effects would be likely in the analysis of the area under the curve for troponin I and creatine kinase MB. In addition, there were more patients with failed thrombolysis in the control group than in the cyclosporine group (eight vs. five), which may have had similar effects. Traditional values of alpha and beta may not be appropriate, since the goal of most pilot studies is not to suggest clinical efficacy but rather safety and feasibility.1 Cyclosporine infusion seems reasonably safe, and any trend toward a positive effect suggests that further evaluation is warranted.
1 ReferencesJoseph S. Rossi, M.D.
Ross J. Simpson, Jr., M.D., Ph.D.
University of North Carolina, Chapel Hill, NC 27599
jrossi@med.unc. edu To the Editor:
Piot et al. report reduced myocardial infarct size after angioplasty supplemented by single doses of cyclosporine, a drug with well-documented clinical and experimental adverse effects on microvascular function.1-3 Any future studies of cyclosporine in combination with angioplasty should include observations reflecting possible microvascular dysfunction, such as the Thrombolysis in Myocardial Infarction (TIMI) frame count and blush grade, contrast echocardiography, or serial MRI with the administration of contrast material.4 Perhaps the authors could review their angiographic data to determine whether cyclosporine had any detectable microvascular effect suggesting an increased incidence of the “no-reflow” phenomenon.
4 ReferencesIrwin Hoffman, M.D.
Lovelace Medical Center, Albuquerque, NM 87102
irw.hoffman@stvin. org 1
Zoja C ,Furci L ,Ghilardi F ,Zilio P ,Benigni A ,Remuzzi G . Cyclosporin-induced endothelial cell injury. Lab Invest 1986;55:455-462
Web of Science | Medline2
Wilasrusmee C ,Da Silva M ,Siddiqui J , et al. Role of endothelin-1 in microvascular dysfunction caused by cyclosporin A. J Am Coll Surg 2003;196:584-591
CrossRef | Medline3
Petrakopoulou P ,Anthopoulou L ,Muscholl M , et al. Coronary endothelial vasomotor function and vascular remodeling in heart transplant recipients randomized for tacrolimus or cyclosporine immunosuppression. J Am Coll Cardiol 2006;47:1622-1629
CrossRef | Web of Science | Medline4
Nijveldt R ,Beek AM ,Hirsch A , et al. Functional recovery after acute myocardial infarction: comparison between angiography, electrocardiography, and cardiovascular magnetic resonance measures of microvascular injury. J Am Coll Cardiol 2008;52:181-189
CrossRef | Web of Science | Medline
To the Editor:
Myocardial reperfusion injury is a complex phenomenon encompassing various interconnected mechanisms. The opening of the mitochondrial permeability-transition pore is one of these mechanisms, but there are other processes that are equally important. Neutrophil infiltration of ischemic tissue early after reperfusion, apoptotic cell death, activation of salvage kinases, and other processes are clearly involved in this type of cell death.1 Cyclosporine inhibits the mitochondrial permeability transition through cyclophilin D, but it has other actions that could explain its cardioprotective effect. Besides its effects on T cells, cyclosporine has been shown to inhibit neutrophil activation2; the activation of neutrophils is a well-known modulator of reperfusion injury.3 The clear beneficial effects of cyclosporine, shown by Piot and colleagues, could be the result not only of inhibition of the mitochondrial permeability-transition pore opening but also of its effects on neutrophil activation and infiltration into the ischemic area at reperfusion. It would be of great interest if the authors could report the neutrophil myeloperoxidase activity in plasma from the patients included in their study.
3 ReferencesBorja Ibanez, M.D.
Fundación Jiménez Díaz-Capio, 28040 Madrid, Spain
ibanez.borja@gmail. com Juan J. Badimon, Ph.D.
Mount Sinai School of Medicine, New York, NY 100291
Yellon DM ,Hausenloy DJ . Myocardial reperfusion injury. N Engl J Med 2007;357:1121-1135
Full Text | Web of Science | Medline2
Spisani S ,Fabbri E ,Muccinelli M , et al. Inhibition of neutrophil responses by cyclosporin A: an insight into molecular mechanisms. Rheumatology (Oxford) 2001;40:794-800
CrossRef | Web of Science | Medline3
Frangogiannis NG ,Smith CW ,Entman ML . The inflammatory response in myocardial infarction. Cardiovasc Res 2002;53:31-47
CrossRef | Web of Science | Medline
To the Editor:
The article by Piot et al. raises a number of issues about the potential benefit of cyclosporine in the treatment of myocardial infarction and the use of a surrogate end point. Calcineurin inhibition by cyclosporine has myriad effects other than inhibition of mitochondrial permeability-transition pore opening. Cyclosporine is known to attenuate cardiomyocyte hypertrophy, alter the expression of voltage-gated potassium channels,1 and modify cardiac energy metabolism.2 It has also been shown to augment mobilization of endothelial progenitor cells in response to ischemia.3 The net effect of these actions is likely to be complex and unpredictable. Indeed, studies in a rat model of ischemia reperfusion have shown that short-term cyclosporine treatment actually leads to a dose-dependent reduction in left ventricular function in the long term, despite an initial reduction in infarct size.4 The failure of Piot et al. to demonstrate an improvement in left ventricular function is therefore a cause for concern, and I would question whether infarct size can adequately assess the overall clinical effect of cyclosporine treatment.
4 ReferencesAlisdair D. Ryding, Ph.D.
Westmead Hospital, Sydney, NSW 2415, Australia
aryding@doctors.org. uk 1
Deng L ,Huang B ,Qin D ,Ganguly K ,El-Sherif N . Calcineurin inhibition ameliorates structural, contractile, and electrophysiologic consequences of postinfarction remodeling. J Cardiovasc Electrophysiol 2001;12:1055-1061
CrossRef | Web of Science | Medline2
Niemann CU ,Saeed M ,Akbari H , et al. Close association between the reduction in myocardial energy metabolism and infarct size: dose-response assessment of cyclosporine. J Pharmacol Exp Ther 2002;302:1123-1128
CrossRef | Web of Science | Medline3
Wang CH ,Cherng WJ ,Yang NI , et al. Cyclosporine increases ischemia-induced endothelial progenitor cell mobilization through manipulation of the CD26 system. Am J Physiol Regul Integr Comp Physiol 2008;294:R811-R818
CrossRef | Web of Science | Medline4
Laudi S ,Weimann J ,Haschke M , et al. Worsening of long-term myocardial function after successful pharmacological pretreatment with cyclosporine. J Physiol Pharmacol 2007;58:19-32
Web of Science | Medline
Author/Editor Response
One may question whether the effects of cyclosporine on neutrophil activation, as suggested by Ibanez and Badimon, or on microvascular function, as suggested by Hoffman, might have influenced our results. In fact, reperfusion injury is present (and prevented by cyclosporine) in isolated heart or isolated cardiomyocyte preparations that are devoid of neutrophils, and specific inhibitors of mitochondrial permeability-transition pore opening (e.g., NIM811), which do not influence neutrophil activation, prevent lethal reperfusion injury in animal models of acute myocardial infarction.1,2 The undesirable vascular effects of cyclosporine have been observed mainly in cases of long-term exposure to the drug (i.e., in transplant recipients).3 In contrast, we administered cyclosporine as a single intravenous injection. We did not observe any reduction of TIMI flow or attenuation of ST-segment resolution on the electrocardiogram in cyclosporine-treated patients, as might have been expected if coronary vasoconstriction had occurred.
Experimental studies that have addressed the potential influence of cyclosporine on the postinfarction remodeling process, as cited by Ryding, often raise methodologic concerns (high mortality rates, long-term administration of high doses, and lack of evaluation of major cofactors of left ventricular remodeling). Our study was not powered to address this issue; it is therefore not surprising that the exploratory analysis of the left ventricular ejection fraction 3 months after infarction showed a nonsignificant difference between patients in the control group and those in the cyclosporine group.
As suggested by Rossi and Simpson, we did consider whether one outlier data point for infarct size measurements or any imbalance between the two study groups might have biased our results. Statistical analyses performed with and without these patients confirmed that in both cases cyclosporine did reduce infarct size.
As noted by Theruvath and Lemasters, more specific and nonimmunosuppressive drugs are currently being developed for direct inhibition or indirect inhibition (e.g., through inhibition of the calcium uniporter) of the opening of the mitochondrial permeability-transition pore in acute conditions or even chronic diseases. These newer agents will probably provide valuable tools for future large-scale trials.4 Despite the lack of specificity of cyclosporine, our small study suggests that prevention of lethal reperfusion injury represents an important new therapeutic option and that the mitochondrial permeability transition may be an interesting new molecular target for the treatment of acute myocardial infarction.
4 ReferencesChristophe Piot, M.D., Ph.D.
Université de Montpellier I et II, F-34295 Montpellier, FranceEric Bonnefoy-Cudraz, M.D., Ph.D.
Michel Ovize, M.D., Ph.D.
Université de Lyon, F-69009 Lyon, France
michel.ovize@recherche. univ-lyon1. fr 1
Nazareth W ,Yafei N ,Crompton M . Inhibition of anoxia-induced injury in heart myocytes by cyclosporin A. J Mol Cell Cardiol 1991;23:1351-1354
CrossRef | Web of Science | Medline2
Argaud L ,Gateau-Roesch O ,Muntean D , et al. Specific inhibition of the mitochondrial permeability transition prevents lethal reperfusion injury. J Mol Cell Cardiol 2005;38:367-374
CrossRef | Medline3
Petrakoupolou P ,Anthopoulou L ,Muscholl M , et al. Coronary endothelial vasomotor function and vascular remodeling in heart transplant recipients randomized for tacrolimus or cyclosporine immunosuppression. J Am Coll Cardiol 2006;47:1622-1629
CrossRef | Web of Science | Medline4
Merlini L ,Angelin A ,Tiepolo T , et al. Cyclosporin A corrects mitochondrial dysfunction and muscle apoptosis in patients with collagen VI myopathies. Proc Natl Acad Sci U S A 2008;105:5225-5229
CrossRef | Web of Science | Medline
- Citing Articles (1)
Citing Articles
1
Eric Lawitz, Eliot Godofsky, Regine Rouzier, Thomas Marbury, Tuan Nguyen, June Ke, MeiMei Huang, Jens Praestgaard, Denise Serra, Thomas G. Evans. (2011) Safety, pharmacokinetics, and antiviral activity of the cyclophilin inhibitor NIM811 alone or in combination with pegylated interferon in HCV-infected patients receiving 14 days of therapy. Antiviral Research 89:3, 238-245
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