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‘Gaps’ in targeted ischaemic injury therapies in ST-elevation myocardial infarction
  1. Scott R Johnstone1,
  2. Brant E Isakson1,2
  1. 1 Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, Virginia, USA
  2. 2 Department of Molecular Physiology and Biophysics, University of Virginia School of Medicine, Charlottesville, Virginia, USA
  1. Correspondence to Dr Brant E Isakson, Robert M Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; brant{at}virginia.edu

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ST-elevation myocardial infarction (STEMI) is a medical emergency, resulting from blockade of one or several conduit arteries supplying the myocardium. Early and rapid intervention limits ischaemic time, tissue damage and infarct size and is a major determinant of patient prognosis. In principle, restoration of oxygenated blood flow via percutaneous coronary intervention (PCI) and stent placement should limit the damage to the affected myocardium. However, ischaemia-reperfusion injury after restoration of flow can account for 50% of infarct size.

Multiple factors reportedly affect the extent of injury including types of occlusion, failed reperfusion of tissues resulting from haemorrhage, thrombosis, microvascular obstruction (MVO) and cellular generation of free radicals. Recently, a number of proposed therapeutic modalities have been the subject of clinical trials. These include ischaemic preconditioning/postconditioning therapies, cooling strategies and pharmacological interventions. While some studies have reported patient benefits and improved outcomes, these are controversial, with larger studies generally reflecting no overall patient benefit.1 Thus, at present, there are currently no clinically available tools that are specifically indicated to reduce ischaemic-reperfusion injury in patients.

In their recent phase 2 clinical trial, Engstrom et al report on the outcomes of the trial of a novel peptide therapeutic, danegaptide, aimed at limiting ischaemia-reperfusion injury in patients with STEMI.2 Danegaptide (ZP1609) is an analogue of rotigaptide (ZP123), Gap-134 and of the antiarrhythmic peptide (AAP10) first identified as a naturally occurring peptide in bovine serum.3 The various iterations of this peptide (AAP10→rotagaptide→danegaptide) have increased in vivo peptide stability and efficacy. Both AAP10 and rotigaptide have been demonstrated in multiple preclinical studies to limit ischaemia-induced cardiac damage and arrhythmias. Similar studies have demonstrated effects for danegaptide in reducing ischaemia-induced infarct size in canine and porcine models.4 5

Patients with clinical symptoms of STEMI undergoing primary PCI included in this study were grouped in low (n=184) and high (n=206) dose danegaptide (based on preclinical data) and placebo (n=195).4 Cardiac damage was assessed by cardiac magnetic resonance at days 2 and 90 and functional comparisons of ST-resolution following surgery, troponin T and creatine kinase-MB levels and all-cause mortality were made. Despite promising preclinical trials, Engstrom et al report that danegaptide did not improve outcomes in patients across multiple parameters including myocardial salvage index, total infarct size, ejection fraction or all-cause mortality.2 While there are no clear explanations as to why danegaptide effects did not translate from preclinical models, there are a number of suggestions proposed by the authors, including lack of efficient drug targeting, suboptimal dosing and minimal expected gains from pharmacological approaches.

Danegaptide is the result of 30+ years of development and testing of peptides which have been reported to reduce arrhythmia and infarct size. The pharmacological target for rotigaptide, and by extension danegaptide, is an as yet undetermined G-protein coupled receptor which initiates a selective opening of cardiac gap junction channels, especially those channels composed of the connexin 43 (Cx43) protein. Disruptions in cardiac conduction and subsequent arrhythmias are associated with reductions in Cx43 in the failing heart and in ischaemia. Rotigaptide has been shown to increase Cx43 protein synthesis and expression, stabilise channel localisation at the intercalated disc and improve conduction velocity in cardiac preparations.6 Thus, in their initial iterations as candidate antiarrhythmic peptides, the rational for their use was clear. It should be noted, however, that the antiarrhythmic effects of danegaptide were not replicated in recent porcine models or in the present clinical trial by Engstrom.4

There are a number of confounding factors between the modelling and treatment of ischaemia-reperfusion injury that may contribute to discrepancies between preclinical and clinical trial results. These include a lack of effective targeting of the drug to the affected area, potential suboptimal dosing and an inability to accurately model human disease. The ischaemic area lies below the vessel occlusion. Thus, bolus administration prior to reperfusion to increase circulating peptide levels, as performed in these studies, does not increase targeting to the affected region. As a result of this, the first contact of danegaptide on the affected myocardium occurs following restoration of flow, resulting in a relatively short exposure time in which to elicit a protective effect against reperfusion injury.

While much has been demonstrated in terms of Cx43 regulation by the peptides within cells, it is still not clear how they could limit ischaemic tissue damage. It has been suggested that danegaptide maintenance of gap junction channel signalling is protective. However, this seems counter-intuitive, as enhanced signalling could potentially allow for further transduction of damaging signals from the injured or dying cells. In addition, there are conflicting reports that pharmacologically inhibiting gap junction signalling is also protective. One further proposed mechanism is that danegaptide my act to stabilise mitochondrial Cx43, which is reported to limit generation of damaging reactive oxygen species. However, in recent studies, in murine cardiac cell preparations, danegaptide was found to exert its effects independent of mitochondrial Cx43.7 Thus, more insight is required into how the peptides may provide cardioprotection.

It is difficult to extrapolate the long-term effects of the peptides based on the preclinical studies used. In particular, preclinical models used left anterior descending-ligation surgeries of ischaemia followed by reperfusion and subsequently measured the effects of danegaptide after 4 hours.5 While the preclinical model identified benefits, no such gains were found in 2-day and 90-day measurements in patients in the phase 2 clinical trial by Engstrom et al. This could suggest that the long-term effects are not accurately captured in preclinical studies. Time to damage and the window for repair is also a critical consideration in therapeutically targeting ischaemia-reperfusion injuries. Most models of cardiac ischaemia suggest remodelling at the protein level; for example, Cx43 occurs within minutes of the onset of ischaemia, which can be inhibited by pretreatment with the peptides. However, in the best-case scenario, patients will not receive treatment until at least 1.5–2 hours post-ischaemia. Therefore, it is not clear if the window of opportunity for treatment is missed. This may be a confounding and unsurmountable variable in the treatment of patient with STEMI, regardless of the end target.

As with several other clinical trials targeting ischaemia-reperfusion injury, the key question is why this trial did not replicate the findings of several preclinical trials. One potential limitation lies in the preclinical models. Porcine models are currently the recommended route to trials in patients, although there are limitations on the types of analysis and conclusions that can be drawn from these. The porcine model simulates acute infarct in patients with non-coronary artery disease. In the present study by Engstrom et al, the median age of patients was 57–60 years, with history of cardiovascular disease. Therefore, the porcine model does not replicate years of reduced flow found in patients with coronary artery disease, prior to the ischaemic event. Reductions in flow in blocked arteries correspond with coronary collateral formation and is a hallmark of cardiac ischaemia. These divert blood flow to the ischaemic area and act to maintain the integrity of the myocardium during disease progression and during myocardial infarct. In porcine hearts, there are far fewer collaterals, providing an important anatomical difference between species. Without the presence of collaterals, it would not be possible to model effects of MVO of collateral arteries, which is a significant problem in PCI and occurs in around 50% of patients with STEMI.8 Despite this, in their study, Engstrom et al report only 5% of patients demonstrate extensive collateral formation (Rentrop Grade 2/3).

Overall, the investigators in this study should be congratulated for providing a well-balanced and controlled study. Unfortunately, the results indicate that this therapeutic in its current iteration and application does not lead to clinically significant improvements in patient prognosis. This work does add important data to the literature about focusing on gap junction channels in cardiac ischaemic events. However, these studies highlight the need for clarity on the utility of increasing signalling within ischaemic and necrotic tissues. Moving forward, there are key questions that still remain to be addressed including identification of a potential therapeutic window for the treatment of patients with STEMI—is 2 hours too late? In addition, the authors conclude there are only limited and incremental benefits to pharmacological approaches, given recent improvements reducing times to patient reperfusion and resulting reductions in infarct size. Despite this, and even in this well-controlled study, approximately, 2% of patients die within a 90-day period and up to 20% suffer serious adverse events, suggesting there are still areas for significant improvements that can be made in patient treatment.

References

Footnotes

  • Contributors All authors equally contributed to the writing of this manuscript.

  • Funding Funded in part by NIH P01 HL120840 (BEI).

  • Competing interests None declared.

  • Provenance and peer review Commissioned; internally peer reviewed.

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