Sublytic complement attack reduces infarct size in rabbit isolated hearts: evidence for C5a-mediated cardioprotection

Tanhehco, Elaine J.; Lee, Hee-Kyung; Lucchesi, Benedict R.

doi:10.1016/s0162-3109(00)00258-7

Cited by 11 publications

(8 citation statements)

References 42 publications

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“…Exposure of C5a at a sublytic dose prior to ischemia has also been shown to induce cardioprotection [40], possibly by triggering a preconditioning effect. The preclinical evidence by large, clearly supports a therapeutic possibility in inhibiting C5a related neutrophil activation, which is also in line with the findings in this study.…”

Section: Discussionmentioning

confidence: 99%

Treatment with the C5a receptor antagonist ADC-1004 reduces myocardial infarction in a porcine ischemia-reperfusion model

Pals

Koul

Andersson

et al. 2010

BMC Cardiovasc Disord

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BackgroundPolymorphonuclear neutrophils, stimulated by the activated complement factor C5a, have been implicated in cardiac ischemia/reperfusion injury. ADC-1004 is a competitive C5a receptor antagonist that has been shown to inhibit complement related neutrophil activation. ADC-1004 shields the neutrophils from C5a activation before they enter the reperfused area, which could be a mechanistic advantage compared to previous C5a directed reperfusion therapies. We investigated if treatment with ADC-1004, according to a clinically applicable protocol, would reduce infarct size and microvascular obstruction in a large animal myocardial infarct model.MethodsIn anesthetized pigs (42-53 kg), a percutaneous coronary intervention balloon was inflated in the left anterior descending artery for 40 minutes, followed by 4 hours of reperfusion. Twenty minutes after balloon inflation the pigs were randomized to an intravenous bolus administration of ADC-1004 (175 mg, n = 8) or saline (9 mg/ml, n = 8). Area at risk (AAR) was evaluated by ex vivo SPECT. Infarct size and microvascular obstruction were evaluated by ex vivo MRI. The observers were blinded to the treatment at randomization and analysis.ResultsADC-1004 treatment reduced infarct size by 21% (ADC-1004: 58.3 ± 3.4 vs control: 74.1 ± 2.9%AAR, p = 0.007). Microvascular obstruction was similar between the groups (ADC-1004: 2.2 ± 1.2 vs control: 5.3 ± 2.5%AAR, p = 0.23). The mean plasma concentration of ADC-1004 was 83 ± 8 nM at sacrifice. There were no significant differences between the groups with respect to heart rate, mean arterial pressure, cardiac output and blood-gas data.ConclusionsADC-1004 treatment reduces myocardial ischemia-reperfusion injury and represents a novel treatment strategy of myocardial infarct with potential clinical applicability.

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Section: Discussionmentioning

confidence: 99%

Treatment with the C5a receptor antagonist ADC-1004 reduces myocardial infarction in a porcine ischemia-reperfusion model

Pals

Koul

Andersson

et al. 2010

BMC Cardiovasc Disord

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“…Although the effects of C5a can be detrimental to the tissue, it has been shown to elicit neuroprotective and cardioprotective effects in vivo (24,35). In vitro pretreatment with sublytic concentrations of complement has been reported to prevent cellular damage from a subsequent exposure to a normally lytic concentration of complement (28,29).…”

Section: Discussionmentioning

confidence: 99%

Medroxyprogesterone acetate prevents the cardioprotective and anti-inflammatory effects of 17β-estradiol in an in vivo model of myocardial ischemia and reperfusion

Booth¹,

Lucchesi²

2007

American Journal of Physiology-Heart and Circulatory Physiology

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“…Infusion of 0·5 per cent normal human plasma, with presumably small amounts of activated complement, into rabbits subjected to myocardial ischaemia-reperfusion resulted in significantly smaller infarcts. On the other hand, heat inactivation of the plasma, or pretreatment with sCR1 or anti-C5a antibody, reversed the protective effect 51 . Rational drug design using small peptides has identified several candidates that can specifically compete with the binding of C5a and its receptor on neutrophils, leading to reduced chemotaxis 52 .…”

Section: Clinical Use Of Complement Inhibitors In Reperfusion Injurymentioning

confidence: 99%

Ischaemia–reperfusion is an event triggered by immune complexes and complement

Chan

Ibrahim

Verna

et al. 2003

British Journal of Surgery

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Evidence now points to complement and immune complexes as critical players in mediating reperfusion injury. Ischaemia is postulated to induce a phenotypical cellular change through the surface expression of a neoantigen. Preformed circulating natural IgM antibodies are then trapped and complement is activated. Final events leading to reperfusion injury include formation of the membrane attack complex and mast cell degranulation.

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Sublytic complement attack reduces infarct size in rabbit isolated hearts: evidence for C5a-mediated cardioprotection

Cited by 11 publications

References 42 publications

Treatment with the C5a receptor antagonist ADC-1004 reduces myocardial infarction in a porcine ischemia-reperfusion model

Treatment with the C5a receptor antagonist ADC-1004 reduces myocardial infarction in a porcine ischemia-reperfusion model

Medroxyprogesterone acetate prevents the cardioprotective and anti-inflammatory effects of 17β-estradiol in an in vivo model of myocardial ischemia and reperfusion

Ischaemia–reperfusion is an event triggered by immune complexes and complement

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