Cyclosporine A in Reperfused Myocardial Infarction

Ottani, Filippo; Latini, Roberto; Staszewsky, Lidia; Vecchia, Luigi La; Locuratolo, Nicola; Sicuro, Marco; Masson, Serge; Barlera, Simona; Milani, Valentina; Lombardi, Mario; Costalunga, Alessandra; Mollichelli, Nadia; Santarelli, Andrea; Cesare, Nicoletta De; Sganzerla, Paolo; Boi, Alberto; Maggioni, Aldo P.; Limbruno, Ugo; Investigators, Cycle

doi:10.1016/j.jacc.2015.10.081

Cited by 159 publications

(77 citation statements)

References 39 publications

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“…17,18 Therefore, rat IRI results may not directly extrapolate to human IRI. However, previous experimental studies strongly suggest the usefulness of CysA for IRI.…”

Section: Discussionmentioning

confidence: 99%

Imaging of Myocardial Ischemia–Reperfusion Injury Using Sodium [¹⁸F]Fluoride Positron Emission Tomography/Computed Tomography in Rats and Humans

et al. 2017

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Positron emission tomography (PET)/computed tomography (CT) using sodium [18F]fluoride (Na[18F]F) has been proven to be a promising hot-spot imaging modality for myocardial infarction (MI). We investigated Na[18F]F uptake in ischemia–reperfusion injury (IRI) of rats and humans. Sodium [18F]fluoride PET/CT was performed in Sprague-Dawley rats that had IRI surgery, and it readily demonstrated prominent Na[18F]F uptake in the infarct area post-IRI. Sodium [18F]fluoride uptake was matched with negative 2,3,5-triphenyl-2H-tetrazolium chloride staining results, accompanied by myocardial apoptosis and associated with positive calcium staining results. Furthermore, area at risk was negative for Na[18F]F uptake. Cyclosporine A (CysA) treatment reduced standardized uptake value of 18F over the infarct area, and a significant decrease in infarct size was also observed by the CysA treatment. In humans, Na[18F]F PET/CT readily demonstrated increased Na[18F]F uptake in the 2 patients with MI post-percutaneous coronary intervention. In conclusion, this study sheds light on the potential utility of Na[18F]F PET/CT as a hot-spot imaging modality for myocardial IRI.

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“…17,18 Therefore, rat IRI results may not directly extrapolate to human IRI. However, previous experimental studies strongly suggest the usefulness of CysA for IRI.…”

Section: Discussionmentioning

confidence: 99%

Imaging of Myocardial Ischemia–Reperfusion Injury Using Sodium [¹⁸F]Fluoride Positron Emission Tomography/Computed Tomography in Rats and Humans

et al. 2017

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“…More recently, also the cardioprotection by cyclosporine A which had been shown in a small-scale proof-of-concept trial 223 was not confirmed in another smaller study with prethrombolytic cyclosporine A 224 and, importantly, not in 2 larger-scale phase III trials, Does Cyclosporine Improve Clinical Outcome in ST Elevation Myocardial Infarction Patients (CIRCUS) and CyclosporinE A in Reperfused Myocardial Infarct (CYCLE). 225,226 Many potential reasons for this discrepancy have been discussed, such as lack of direct stenting and greater use of P2Y 12 antagonists, and also the use of a different vehicle in CIRCUS, but not in CYCLE. 227 In some of these studies, not only infarct size but also parameters reflecting coronary microvascular function were reported, and the effects of cardioprotective drugs on infarct size and coronary microvascular function were mostly concordant (Figures 5-8).…”

Section: Clinical Studiesmentioning

confidence: 99%

The Coronary Circulation as a Target of Cardioprotection

Heusch

2016

Circulation Research

209

160

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Abstract:The atherosclerotic coronary vasculature is not only the culprit but also a victim of myocardial ischemia/ reperfusion injury. Manifestations of such injury are increased vascular permeability and edema, endothelial dysfunction and impaired vasomotion, microembolization of atherothrombotic debris, stasis with intravascular cell aggregates, and finally, in its most severe form, capillary destruction with hemorrhage. In animal experiments, local and remote ischemic pre-and postconditioning not only reduce infarct size but also these manifestations of coronary vascular injury, as do drugs which recruit signal transduction steps of conditioning. Clinically, no-reflow is frequently seen after interventional reperfusion, and it carries an adverse prognosis. The translation of cardioprotective interventions to clinical practice has been difficult to date. Only 4 drugs (brain natriuretic peptide, exenatide, metoprolol, and esmolol) stand unchallenged to date in reducing infarct size in patients with reperfused acute myocardial infarction; unfortunately, for these drugs, no information on their impact on the ischemic/reperfused coronary circulation is available. (Circ Res.

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“…[13][14][15][16][17][18][19] Although there are several positive proof-of-concept studies for each of the conditioning phenomena, no phase III study has yet reported a better clinical outcome as the primary end point. With the neutral results of 2 recent phase III trial in cardiosurgical patients, that is, ERICCA (Effect of Remote Ischemic Preconditioning on Clinical Outcomes in CAGB Surgery) 37 and RIPHeart (Remote Ischemic Preconditioning in Heart Surgery), 38 and also a number of recent neutral trials which used drugs to recruit signaling steps of the conditioning phenomena in patients with AMI, that is, CIRCUS (Does Cyclosporine Improve Clinical Outcome in ST Elevation Myocardial Infarction Patients) 39 and CYCLE (Cyclosporine A in Reperfused Myocardial Infarction), 40 disappointment and frustration prevail.…”

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confidence: 99%

Time to Give Up on Cardioprotection?

Heusch

Rassaf

2016

Circulation Research

176

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Abstract:The mortality from acute myocardial infarction (AMI) remains significant, and the prevalence of postmyocardial infarction heart failure is increasing. Therefore, cardioprotection beyond timely reperfusion is needed. Conditioning procedures are the most powerful cardioprotective interventions in animal experiments. However, ischemic preconditioning cannot be used to reduce infarct size in patients with AMI because its occurrence is not predictable; several studies in patients undergoing surgical coronary revascularization report reduced release of creatine kinase and troponin. Ischemic postconditioning reduces infarct size in most, but not all, studies in patients undergoing interventional reperfusion of AMI, but may require direct stenting and exclusion of patients with >6 hours of symptom onset to protect. Remote ischemic conditioning reduces infarct size in patients undergoing interventional reperfusion of AMI, elective percutaneous or surgical coronary revascularization, and other cardiovascular surgery in many, but not in all, studies. Adequate dose-finding phase II studies do not exist. There are only 2 phase III trials, both on remote ischemic conditioning in patients undergoing cardiovascular surgery, both with neutral results in terms of infarct size and clinical outcome, but also both with major problems in trial design. We discuss the difficulties in translation of cardioprotection from animal experiments and proof-ofconcept trials to clinical practice. Given that most studies on ischemic postconditioning and all studies on remote ischemic preconditioning in patients with AMI reported reduced infarct size, it would be premature to give up on cardioprotection. (Circ Res. 2016;119:676-695.

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Cyclosporine A in Reperfused Myocardial Infarction

Cited by 159 publications

References 39 publications

Imaging of Myocardial Ischemia–Reperfusion Injury Using Sodium [¹⁸F]Fluoride Positron Emission Tomography/Computed Tomography in Rats and Humans

Imaging of Myocardial Ischemia–Reperfusion Injury Using Sodium [¹⁸F]Fluoride Positron Emission Tomography/Computed Tomography in Rats and Humans

The Coronary Circulation as a Target of Cardioprotection

Time to Give Up on Cardioprotection?

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Cyclosporine A in Reperfused Myocardial Infarction

Cited by 159 publications

References 39 publications

Imaging of Myocardial Ischemia–Reperfusion Injury Using Sodium [18F]Fluoride Positron Emission Tomography/Computed Tomography in Rats and Humans

Imaging of Myocardial Ischemia–Reperfusion Injury Using Sodium [18F]Fluoride Positron Emission Tomography/Computed Tomography in Rats and Humans

The Coronary Circulation as a Target of Cardioprotection

Time to Give Up on Cardioprotection?

Contact Info

Product

Resources

About

Imaging of Myocardial Ischemia–Reperfusion Injury Using Sodium [¹⁸F]Fluoride Positron Emission Tomography/Computed Tomography in Rats and Humans

Imaging of Myocardial Ischemia–Reperfusion Injury Using Sodium [¹⁸F]Fluoride Positron Emission Tomography/Computed Tomography in Rats and Humans