On the value of therapeutic interventions targeting the complement system in acute myocardial infarction

Emmens, Reindert W.; Wouters, Diana; Ham, S. Marieke van; Niessen, Hans W.M.; Krijnen, Paul A.J.

doi:10.1016/j.trsl.2016.10.005

Cited by 17 publications

(14 citation statements)

References 137 publications

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“…In the field of cardiovascular diseases, complement inhibition to reduce complications of acute myocardial infarction (AMI) has been explored in numerous animal and clinical studies (recently reviewed by Emmens et al, 2017), however, usually without a special focus on diabetes. One study in diabetic rats showed that treatment with FUT-175, a strong inhibitor of C1r and C1s that possibly also exhibited inhibitory effects on other complement and further serine proteases, significantly decreased infarct size, complement deposition and neutrophil accumulation in the diabetic heart when administered before reperfusion (La Bonte et al, 2008).…”

Section: Complement As a Therapeutic Target To Reduce Complications Imentioning

confidence: 99%

Role of complement in diabetes

Ajjan

Schroeder

2019

Molecular Immunology

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Accumulating evidence suggests a role for the complement system in the pathogenesis of diabetes and the vascular complications that characterise this condition. Complement proteins contribute to the development of type 1 diabetes (T1D) by enhancing the underlying organspecific autoimmune processes. Complement upregulation and activation is also an important feature of insulin resistance and the development of type 2 diabetes (T2D). Moreover, animal and human studies indicate that complement proteins are involved in the pathogenic mechanisms leading to diabetic microvascular and macrovascular complications. The adverse vascular effects of complement appear to be related to enhancement of the inflammatory process and the predisposition to a thrombotic environment, eventually leading to vascular occlusion. Complement proteins have been considered as therapeutic targets to prevent or treat vascular disease but studies have been mainly conducted in animal models, while human work has been both limited and inconclusive so far. Further studies are needed to understand the potential role of complement proteins as therapeutic targets for reversal of the pathological processes leading to T1D and T2D and for the prevention/treatment of diabetic vascular complications.

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Section: Complement As a Therapeutic Target To Reduce Complications Imentioning

confidence: 99%

Role of complement in diabetes

Ajjan

Schroeder

2019

Molecular Immunology

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“…Duration of treatment was relatively short with 4 h of reperfusion and conclusions about long-term myocardial complement activation, function and effect of coversin on LTB4 can therefore not be made. Thus, a pig closed-chest study with longer periods of treatment, reperfusion and observation should be performed prior to clinical trials investigating coversin in myocardial IRI [13, 40]. The trend to lower troponin-T and H-FABP levels during reperfusion in combination with reduced infarct size in coversin treated animals indicate that indeed myocardial IRI was reduced by coversin.…”

Section: Discussionmentioning

confidence: 99%

Complement factor 5 blockade reduces porcine myocardial infarction size and improves immediate cardiac function

et al. 2017

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Inhibition of complement factor 5 (C5) reduced myocardial infarction in animal studies, while no benefit was found in clinical studies. Due to lack of cross-reactivity of clinically used C5 antibodies, different inhibitors were used in animal and clinical studies. Coversin (Ornithodoros moubata complement inhibitor, OmCI) blocks C5 cleavage and binds leukotriene B4 in humans and pigs. We hypothesized that inhibition of C5 before reperfusion will decrease infarct size and improve ventricular function in a porcine model of myocardial infarction. In pigs (Sus scrofa), the left anterior descending coronary artery was occluded (40 min) and reperfused (240 min). Coversin or placebo was infused 20 min after occlusion and throughout reperfusion in 16 blindly randomized pigs. Coversin significantly reduced myocardial infarction in the area at risk by 39% (p = 0.03, triphenyl tetrazolium chloride staining) and by 19% (p = 0.02) using magnetic resonance imaging. The methods correlated significantly (R = 0.92, p < 0.01). Tissue Doppler echocardiography showed increased systolic displacement (31%, p < 0.01) and increased systolic velocity (29%, p = 0.01) in coversin treated pigs. Interleukin-1β in myocardial microdialysis fluid was significantly reduced (31%, p < 0.05) and tissue E-selectin expression was significantly reduced (p = 0.01) in the non-infarcted area at risk by coversin treatment. Coversin ablated plasma C5 activation throughout the reperfusion period and decreased myocardial C5b-9 deposition, while neither plasma nor myocardial LTB4 were significantly reduced. Coversin substantially reduced the size of infarction, improved ventricular function, and attenuated interleukin-1β and E-selectin in this porcine model by inhibiting C5. We conclude that inhibition of C5 in myocardial infarction should be reconsidered.Electronic supplementary materialThe online version of this article (doi:10.1007/s00395-017-0610-9) contains supplementary material, which is available to authorized users.

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“…The existing documents hold that inflammatory cells play an important role in infarcted myocardium infiltration, while increased inflammatory cells could continue to damage myocardial tissue as well ( 1 , 4 , 15 ). Therefore, the pathway and molecule that induce inflammation infiltration may be involved in the occurrence and development of acute myocardial infarction.…”

Section: Discussionmentioning

confidence: 99%

“…This could induce fatal complications such as rupture and cardiac tamponade. The typical clinical manifestation is sudden lancination of lower back, where the occurrence does not exceed 14 days ( 3 , 4 ). The main pathology manifests as retrogression of artery medial and infiltration of inflammatory cells ( 3 , 5 ).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of expression levels and mechanism of complement activation

Wang¹,

Liu

Jia³

et al. 2017

Experimental and Therapeutic Medicine

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The present study aimed to reveal the expression changes of complement system activation and complement activation product C3a receptor during acute myocardial infarction. Blood samples were collected from healthy individuals and from patients with coronary artery stenosis or acute myocardial infarction. The subjects received physical examination in hospital between January and July 2015 (n=5). Cytometric bead array was performed to measure the levels of complement system activation product anaphylatoxin C3a, C4a and C5a. Immunohistochemical investigations were performed in tissues of patients who underwent coronary artery bypass grafting between January and July 2015 to detect the expression of C3a receptor. The results of cytometric bead array showed that the content of complement activation products C3a, C4a and C5a in the plasma of patients with coronary artery stenosis and acute myocardial infarction were significantly higher than those of the control group (P<0.01). The results of immunoblotting suggested that the protein expression of C3a receptor in infarct tissues of patients with acute myocardial infarction was significantly higher than that of normal tissues adjacent to the infarcted area (P<0.05). There is complement system activation in patients with acute myocardial infarction. Additionally, the increase in the expression of complement C3a receptor in tissues of infarct area suggested that C3a-C3a receptor signaling pathway may be involved in the development of myocardial infarction.

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On the value of therapeutic interventions targeting the complement system in acute myocardial infarction

Cited by 17 publications

References 137 publications

Role of complement in diabetes

Role of complement in diabetes

Complement factor 5 blockade reduces porcine myocardial infarction size and improves immediate cardiac function

Evaluation of expression levels and mechanism of complement activation

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