Myocardial expression of the anaphylatoxin receptor C3aR is associated with cardiac inflammation and prognosis in patients with non‐ischaemic heart failure

Mueller, Karin; Patzelt, Johannes; Sauter, Manuela; Maier, Philipp; Gekeler, Sarah; Klingel, Karin; Kandolf, Reinhard; Seizer, Peter; Gawaz, Meinrad; Geisler, Tobias; Langer, Harald F.

doi:10.1002/ehf2.12298

Cited by 9 publications

(10 citation statements)

References 44 publications

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“…However, no quantitative changes were found in EMB NLPR3 pathway gene expression patterns. Although we cannot exclude that other, more HHV6-specific inflammatory pathways were involved at other time points of the disease course, our first preliminary data suggest that the NLRP3 pathway seems not to be regulated in the presence of low-level HHV6 DNA, at least in patients with mild inflammation [34,38,39].…”

Section: Discussionmentioning

confidence: 80%

The Spontaneous Course of Human Herpesvirus 6 DNA-Associated Myocarditis and the Effect of Immunosuppressive Intervention

Elsanhoury

Kühl

Stautner

et al. 2022

Viruses

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Introduction: This study investigated the spontaneous clinical course of patients with endomyocardial biopsy (EMB)-proven lymphocytic myocarditis and cardiac human herpesvirus 6 (HHV6) DNA presence, and the effectiveness of steroid-based intervention in HHV6-positive patients. Results: 756 heart failure (HF) patients underwent an EMB procedure to determine the underlying cause of unexplained HF. Low levels of HHV6 DNA, detectable by nested PCR only, were found in 10.4% of the cases (n = 79) of which 62% (n = 49) showed myocardial inflammation. The spontaneous course of patients with EMB-proven HHV6 DNA-associated lymphocytic myocarditis (n = 26) showed significant improvements in the left ventricular ejection fraction (LVEF) and clinical symptoms, respectively, in 15/26 (60%) patients, 3–12 months after disease onset. EMB mRNA expression of components of the NLRP3 inflammasome pathway and protein analysis of cardiac remodeling markers, analyzed by real-time PCR and MALDI mass spectrometry, respectively, did not differ between HHV6-positive and ‑negative patients. In another cohort of patients with ongoing symptoms related to lymphocytic myocarditis associated with cardiac levels of HHV6-DNA copy numbers <500 copies/µg cardiac DNA, quantified by real-time PCR, the efficacy and safety of steroid-based immunosuppression for six months was investigated. Steroid-based immunosuppression improved the LVEF (≥5%) in 8/10 patients and reduced cardiac inflammation in 7/10 patients, without an increase in cardiac HHV6 DNA levels in follow-up EMBs. Conclusion: Low HHV6 DNA levels are frequently detected in the myocardium, independent of inflammation. In patients with lymphocytic myocarditis with low levels of HHV6 DNA, the spontaneous clinical improvement is nearby 60%. In selected symptomatic patients with cardiac HHV6 DNA copy numbers less than 500 copies/µg cardiac DNA and without signs of an active systemic HHV6 infection, steroid-based therapy was found to be effective and safe. This finding needs to be further confirmed in large, randomized trials.

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Section: Discussionmentioning

confidence: 80%

The Spontaneous Course of Human Herpesvirus 6 DNA-Associated Myocarditis and the Effect of Immunosuppressive Intervention

Elsanhoury

Kühl

Stautner

et al. 2022

Viruses

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“…The C3aR expression was enhanced slightly but not significantly in the left ventricles of both polytrauma groups. In humans with non-ischemic heart failure, increased C3aR expression was associated with enhanced cardiac inflammation and progressive heart failure (48). Interestingly, the C3aR expression may correlate with the invasiveness of fracture treatment, indicating augmented inflammation and complement activation during femoral reaming (20).…”

Section: Discussionmentioning

confidence: 99%

Complement Activation and Organ Damage After Trauma—Differential Immune Response Based on Surgical Treatment Strategy

et al. 2020

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Background: The complement system is part of the innate immunity, is activated immediately after trauma and is associated with adult respiratory distress syndrome, acute lung injury, multiple organ failure, and with death of multiply injured patients. The aim of the study was to investigate the complement activation in multiply injured pigs as well as its effects on the heart in vivo and in vitro. Moreover, the impact of reamed vs. non-reamed intramedullary nailing was examined with regard to the complement activation after multiple trauma in pigs. Materials and Methods: Male pigs received multiple trauma, followed by femoral nailing with/without prior conventional reaming. Systemic complement hemolytic activity (CH-50 and AH-50) as well as the local cardiac expression of C3a receptor, C5a receptors1/2, and the deposition of the fragments C3b/iC3b/C3c was determined in vivo after trauma. Human cardiomyocytes were exposed to C3a or C5a and analyzed regarding calcium signaling and mitochondrial respiration. Results: Systemic complement activation increased within 6 h after trauma and was mediated via the classical and the alternative pathway. Furthermore, complement activation correlated with invasiveness of fracture treatment. The expression of receptors for complement activation were altered locally in vivo in left ventricles. C3a and C5a acted detrimentally on human cardiomyocytes by affecting their functionality and their mitochondrial respiration in vitro. Conclusion: After multiple trauma, an early activation of the complement system is triggered, affecting the heart in vivo as well as in vitro, leading to complement-induced Lackner et al. Complement Activation Induces Cardiac Dysfunction cardiac dysfunction. The intensity of complement activation after multiple trauma might correlate with the invasiveness of fracture treatment. Reaming of the femoral canal might contribute to an enhanced "second hit" response after trauma. Consequently, the choice of fracture treatment might imply the clinical outcome of the critically injured patients and might be therefore crucial for their survival.

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“…EPC transplantation attenuated astrocyte proliferation and reduced astrocyte-derived C3 expression at 3 and 14 days after cerebral ischemia. C3aR is one of the receptor of C3, and the interaction between C3 and C3aR has been widely recognized to mediate inflammatory response and exacerbate tissue injury during pathological conditions including major depressive disorder (MDD), 49 non-ischemic heart failure, 50 perioperative neurocognitive disorders (PND), 51 acute lung injury, 52 traumatic brain injury 34 and ischemic stroke. 16,53 In mice models of ischemic stroke, depletion of C3 or C3aR contributed to reduced granulocyte infiltration, inflammatory response and brain injury within three days after ischemia.…”

Section: Discussionmentioning

confidence: 99%

Endothelial progenitor cell transplantation alleviated ischemic brain injury via inhibiting C3/C3aR pathway in mice

Jiang

Wang

et al. 2019

J Cereb Blood Flow Metab

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Endothelial progenitor cell transplantation is a potential therapeutic approach in brain ischemia. However, whether the therapeutic effect of endothelial progenitor cells is via affecting complement activation is unknown. We established a mouse focal ischemia model ( n = 111) and transplanted endothelial progenitor cells into the peri-infarct region immediately after brain ischemia. Neurological outcomes and brain infarct/atrophy volume were examined after ischemia. Expression of C3, C3aR and pro-inflammatory factors were further examined to explore the role of endothelial progenitor cells in ischemic brain. We found that endothelial progenitor cells improved neurological outcomes and reduced brain infarct/atrophy volume after 1 to 14 days of ischemia compared to the control ( p < 0.05). C3 and C3aR expression in the brain was up-regulated at 1 day up to 14 days ( p < 0.05). Endothelial progenitor cells reduced astrocyte-derived C3 ( p < 0.05) and C3aR expression ( p < 0.05) after ischemia. Endothelial progenitor cells also reduced inflammatory response after ischemia ( p < 0.05). Endothelial progenitor cell transplantation reduced astrocyte-derived C3 expression in the brain after ischemic stroke, together with decreased C3aR and inflammatory response contributing to neurological function recovery. Our results indicate that modulating complement C3/C3aR pathway is a novel therapeutic target for the ischemic stroke.

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Myocardial expression of the anaphylatoxin receptor C3aR is associated with cardiac inflammation and prognosis in patients with non‐ischaemic heart failure

Cited by 9 publications

References 44 publications

The Spontaneous Course of Human Herpesvirus 6 DNA-Associated Myocarditis and the Effect of Immunosuppressive Intervention

The Spontaneous Course of Human Herpesvirus 6 DNA-Associated Myocarditis and the Effect of Immunosuppressive Intervention

Complement Activation and Organ Damage After Trauma—Differential Immune Response Based on Surgical Treatment Strategy

Endothelial progenitor cell transplantation alleviated ischemic brain injury via inhibiting C3/C3aR pathway in mice

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