The Quest for Antiinflammatory and Immunomodulatory Strategies in Heart Failure

Linthout, Sophie Van; Tschöpe, Carsten

doi:10.1002/cpt.1637

Cited by 18 publications

(15 citation statements)

References 98 publications

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“…Inflammation is an important driver of HF, by which its role in the pathogenesis of HFrEF and HFpEF differs (133,134). Although it plays a pathological role in the EAT of obese patients (46), pharmacological treatment with anti-inflammatory agents like steroids (135) cannot be recommended in HF patients with DM and/or metabolic syndrome (136).…”

Section: Anti-inflammatory Agentsmentioning

confidence: 99%

Epicardial Fat Expansion in Diabetic and Obese Patients With Heart Failure and Preserved Ejection Fraction—A Specific HFpEF Phenotype

Elsanhoury

Nelki

Kelle

et al. 2021

Front. Cardiovasc. Med.

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Graphical AbstractEpicardial adipose tissue (EAT)-related heart failure with preserved ejection fraction (HFpEF). Obesity and type 2 diabetes mellitus (T2DM) are common triggers of HFpEF, frequently associated with EAT expansion. EAT plays metabolic and mechanical roles in HFpEF development via para/vasocrine factors and pericardial restrain, respectively. Life-style modifications including healthy diet and regular exercise can quash the EAT expansion. Statins, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and fat-modulating antidiabetics including metformin, sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) agonists can target EAT. FFA, free fatty acids; AGEs, advanced glycation end-products; NO, nitric oxide; ROS, reactive oxygen species; Ang-II, angiotensin II; TGF-β, Transforming growth factor beta; MCP-1, monocyte chemoattractant protein 1; IL-6, interleukin 6; TNF-α, tumor necrosis factor alpha. Figure created via Servier Medical Art and BioRender tools.

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Section: Anti-inflammatory Agentsmentioning

confidence: 99%

Epicardial Fat Expansion in Diabetic and Obese Patients With Heart Failure and Preserved Ejection Fraction—A Specific HFpEF Phenotype

Elsanhoury

Nelki

Kelle

et al. 2021

Front. Cardiovasc. Med.

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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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“…via interferon-ß 29 ) or to balance key pathways of an uncontrolled inflammatory response without compromising viral control as shown for eplerenone 30 would be important for advanced therapy options in viral myocarditis. 31,32 As part of the inflammatory response in CVB3-induced myocarditis, a large number of immune cells including NK Figure 5 Colchicine decreases collagen deposition in Coxsackievirus B3-infected left ventricle-derived fibroblasts. To verify the impact of colchicine on the collagen protein level in CVB3-infected fibroblast (FB), a Sirius red (A) and crystal violet assay (B) were performed.…”

Section: Discussionmentioning

confidence: 99%

Colchicine prevents disease progression in viral myocarditis via modulating the NLRP3 inflammasome in the cardiosplenic axis

et al. 2022

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AimThe acute phase of a coxsackievirus 3 (CVB3)-induced myocarditis involves direct toxic cardiac effects and the systemic activation of the immune system, including the cardiosplenic axis. Consequently, the nucleotide-binding oligomerization domain-like receptor pyrin domain-containing-3 (NLRP3) inflammasome pathway is activated, which plays a role in disease pathogenesis and progression. The anti-inflammatory drug colchicine exerts its effects, in part, via reducing NLRP3 activity, and has been shown to improve several cardiac diseases, including acute coronary syndrome and pericarditis. The aim of the present study was to evaluate the potential of colchicine to improve experimental CVB3-induced myocarditis. Methods and results C57BL6/j mice were intraperitoneally injected with 1 × 10 5 plaque forming units of CVB3. After 24 h, mice were treated with colchicine (5 μmol/kg body weight) or phosphate-buffered saline (PBS) via oral gavage (p.o.). Seven days post infection, cardiac function was haemodynamically characterized via conductance catheter measurements. Blood, the left ventricle (LV) and spleen were harvested for subsequent analyses. In vitro experiments on LV-derived fibroblasts (FB) and HL-1 cells were performed to further evaluate the anti-(fibro)inflammatory and anti-apoptotic effects of colchicine via gene expression analysis, Sirius Red assay, and flow cytometry. CVB3 + colchicine mice displayed improved LV function compared with CVB3 + PBS mice, paralleled by a 4.7-fold (P < 0.01) and 1.7-fold (P < 0.001) reduction in LV CVB3 gene expression and cardiac troponin-I levels in the serum, respectively. Evaluation of components of the NLRP3 inflammasome revealed an increased percentage of apoptosis-associated speck-like protein containing a CARD domain (ASC)-expressing, caspase-1-expressing, and interleukin-1β-expressing cells in the myocardium and in the spleen of CVB3 + PBS vs. control mice, which was reduced in CVB3 + colchicine compared with CVB3 + PBS mice. This was accompanied by 1.4-fold (P < 0.0001), 1.7fold (P < 0.0001), and 1.7-fold (P < 0.0001) lower numbers of cardiac dendritic cells, natural killer cells, and macrophages, respectively, in CVB3 + colchicine compared with CVB3 + PBS mice. A 1.9-fold (P < 0.05) and 4.6-fold (P < 0.001) reduced cardiac gene expression of the fibrotic markers, Col1a1 and lysyl oxidase, respectively, was detected in CVB3 + colchicine mice compared with CVB3 + PBS animals, and reflected by a 2.2-fold (P < 0.05) decreased Collagen I/III protein ratio. Colchicine further reduced Col3a1 mRNA and collagen protein expression in CVB3-infected FB and lowered apoptosis and viral progeny release in CVB3-infected HL-1 cells. In both CVB3 FB and HL-1 cells, colchicine down-regulated the NLRP3 inflammasome-related components ASC, caspase-1, and IL-1β. Conclusions Colchicine improves LV function in CVB3-induced myocarditis, involving a decrease in cardiac and splenic NLRP3 inflammasome activity, without exacerbation of CVB3 load.

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The Quest for Antiinflammatory and Immunomodulatory Strategies in Heart Failure

Cited by 18 publications

References 98 publications

Epicardial Fat Expansion in Diabetic and Obese Patients With Heart Failure and Preserved Ejection Fraction—A Specific HFpEF Phenotype

Epicardial Fat Expansion in Diabetic and Obese Patients With Heart Failure and Preserved Ejection Fraction—A Specific HFpEF Phenotype

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

Colchicine prevents disease progression in viral myocarditis via modulating the NLRP3 inflammasome in the cardiosplenic axis

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