Management of Acute and Recurrent Pericarditis

Journal of the American College of Cardiology, Journal Year: 2020, Volume and Issue: 75(1), P. 76 - 92

Published: Jan. 1, 2020

Language: Английский

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NLRP3 inflammasome-mediated pyroptosis contributes to the pathogenesis of non-ischemic dilated cardiomyopathy

Redox Biology, Journal Year: 2020, Volume and Issue: 34, P. 101523 - 101523

Published: March 30, 2020

Dilated cardiomyopathy (DCM) is one of the most common causes heart failure, and underlying mechanism remains largely elusive. Here we investigated whether NLRP3 inflammasome-mediated pyroptosis contributes to non-ischemic DCM dissected mechanism. We found that hyper activated inflammasome with pyroptotic cell death cardiomyocytes were presented in myocardial tissues patients, which negatively correlated cardiac function. Doxorubicin (Dox)-induced characterization disclosed activation occurred Dox-treated tissues, but very marginal either NLRP3-/- or caspase-1-/- mice. Mechanistically, Dox enhanced expressions NOX1 NOX4 induced mitochondrial fission through dynamin-related protein 1 (Drp1) activation, leading via caspase-1-dependent manner. Conversely, both inhibitions Drp1 suppressed Dox-induced NLPR3 pyroptosis. The alterations expression, phosphorylation validated patients Importantly, Drp1-mediated consequent reversed by inhibition This study demonstrates for first time cardiomyocyte triggered caspase-1 causally dysfunction progression pathogenesis.

Language: Английский

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Inflammation and NLRP3 Inflammasome Activation Initiated in Response to Pressure Overload by Ca ²⁺ /Calmodulin-Dependent Protein Kinase II δ Signaling in Cardiomyocytes Are Essential for Adverse Cardiac Remodeling

Circulation, Journal Year: 2018, Volume and Issue: 138(22), P. 2530 - 2544

Published: Nov. 27, 2018

Inflammation is associated with cardiac remodeling and heart failure, but how it initiated in response to nonischemic interventions the absence of cell death not known. We tested hypothesis that activation Ca2+/calmodulin-dependent protein kinase II δ (CaMKIIδ) cardiomyocytes (CMs) pressure overload elicits inflammatory responses leading adverse remodeling.Mice which CaMKIIδ was selectively deleted from CMs (cardiac-specific knockout [CKO]) floxed control mice were subjected transverse aortic constriction (TAC). The effects CM-specific deletion on gene expression, inflammasome activation, macrophage accumulation, fibrosis assessed by quantitative polymerase chain reaction, histochemistry, ventricular echocardiography.TAC induced increases mRNA levels for proinflammatory chemokines cytokines ≤3 days, these significantly blunted when CM deleted. Apoptotic necrotic absent at this time. isolated TAC hearts mirrored robust markedly attenuated CKO. Priming NOD-like receptor pyrin domain-containing 3 inflammasome, measuring interleukin-1β levels, caspase-1 activity, interleukin-18 cleavage, increased day after hearts. These dependent Nuclear Factor-kappa B reactive oxygen species. Accumulation macrophages observed days 7 14 diminished CKO and, blocking Monocyte Chemotactic Protein-1 signaling, or inhibition activation. Fibrosis also heart. Ventricular dilation contractile dysfunction 42 Inhibition CaMKII, B, signaling first 1 2 weeks decreased remodeling, CaMKII did not.Activation triggers expression CMs. provide signals recruitment, fibrosis, myocardial Our work suggests importance targeting early prevent progression failure.

Language: Английский

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Interleukin‐1 Blockade Inhibits the Acute Inflammatory Response in Patients With ST‐Segment–Elevation Myocardial Infarction

Journal of the American Heart Association, Journal Year: 2020, Volume and Issue: 9(5)

Published: March 3, 2020

Background ST-segment-elevation myocardial infarction is associated with an intense acute inflammatory response and risk of heart failure. We tested whether interleukin-1 blockade anakinra significantly reduced the area under curve for hsCRP (high sensitivity C-reactive protein) levels during first 14 days in patients (VCUART3 [Virginia Commonwealth University Anakinra Remodeling Trial 3]). Methods Results conducted a randomized, placebo-controlled, double-blind, clinical trial 99 which were assigned to 2 weeks treatment once daily (N=33), twice (N=31), or placebo (N=35). was lower receiving versus (median, 67 [interquartile range, 39-120] 214 131-394] mg·day/L; P<0.001), without significant differences between arms. No found groups interval changes left ventricular end-systolic volume 1.4 -9.8 9.8] -3.9 -15.4 1.4] mL; P=0.21) ejection fraction 3.9% -1.6% 10.2%] 2.7% -1.8% 9.3%]; P=0.61) at 12 months. The incidence death new-onset failure hospitalization (9.4% 25.7% [P=0.046] 0% 11.4% [P=0.011], respectively), difference serious infection not different (14% 14%; P=0.98). Injection site reactions occurred more frequently (22%) (3%; P=0.016). Conclusions In presenting infarction, reduces systemic compared placebo. Clinical Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT01950299.

Language: Английский

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Focus on the Role of NLRP3 Inflammasome in Diseases

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(12), P. 4223 - 4223

Published: June 13, 2020

Inflammation is a protective reaction activated in response to detrimental stimuli, such as dead cells, irritants or pathogens, by the evolutionarily conserved immune system and regulated host. The inflammasomes are recognized innate sensors receptors that manage activation of caspase-1 stimulate inflammation response. They have been associated with several inflammatory disorders. NLRP3 inflammasome most well characterized. It so called because belongs family nucleotide-binding oligomerization domain-like (NLRs). Recent evidence has greatly improved our understanding mechanisms which activated. Additionally, increasing data animal models, supported human studies, strongly implicate involvement initiation progression disorders high impact on public health, metabolic pathologies (obesity, type 2 diabetes, atherosclerosis), cardiovascular diseases (ischemic non-ischemic heart disease), issues (liver diseases, bowel gut microbiome, rheumatoid arthritis) neurologic (Parkinson’s disease, Alzheimer’s multiple sclerosis, amyotrophic lateral sclerosis other neurological disorders), compared molecular platforms. This review will provide focus available knowledge about role these describe balance between harmful beneficial new therapies can be created for patients diseases.

Language: Английский

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Anticytokine Agents

Circulation Research, Journal Year: 2019, Volume and Issue: 124(3), P. 437 - 450

Published: Jan. 31, 2019

The recognition that atherosclerosis is a complex chronic inflammatory disorder mediated through both adaptive and innate immunity has led to the hypothesis anticytokine therapies targeting specific IL (interleukin) signaling pathways could serve as powerful adjuncts lipid lowering in prevention treatment of cardiovascular disease. Cytokines involved human can be broadly classified proinflammatory proatherogenic (such IL-1, IL-6, TNF [tumor necrosis factor]) or anti-inflammatory antiatherogenic IL-10 IL-1rA). recent CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study) shown IL-1β significantly reduce event rates without blood pressure lowering. In CANTOS, magnitude benefit this cytokine-targeted approach was associated reduction central cytokine IL-6 downstream clinical biomarker high-sensitivity CRP (C-reactive protein). By contrast, CIRT (Cardiovascular Inflammation Reduction Trial), low-dose methotrexate neither reduced IL-1β, nor lowered rates. Taken together, these 2 contemporary trials provide proof principle focused inhibition, not broad-spectrum therapy, likely crucial for atheroprotection. This review provides an overview cytokines atherosclerosis, potential benefits risks with targeted therapies, look future practices addressing residual risk.

Language: Английский

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Role of pyroptosis in cardiovascular diseases

International Immunopharmacology, Journal Year: 2018, Volume and Issue: 67, P. 311 - 318

Published: Dec. 17, 2018

Language: Английский

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Residual inflammatory risk associated with interleukin-18 and interleukin-6 after successful interleukin-1β inhibition with canakinumab: further rationale for the development of targeted anti-cytokine therapies for the treatment of atherothrombosis

European Heart Journal, Journal Year: 2019, Volume and Issue: 41(23), P. 2153 - 2163

Published: July 26, 2019

The Canakinumab Antiinflammatory Thrombosis Outcomes Study (CANTOS) established that targeting inflammation with interleukin-1β (IL-1β) inhibition can significantly reduce cardiovascular (CV) event rates in the absence of any beneficial effects on cholesterol. Yet, CANTOS participants treated both high-intensity statins and canakinumab remain at considerable risk for recurrent CV events. Both interleukin-18 (IL-18, which like IL-1β requires NLRP3 inflammasome activation) interleukin-6 (IL-6, a pro-inflammatory cytokine downstream IL-1) may contribute to events occur even therapy, thus represent novel targets treating atherothrombosis.Plasma samples from 4848 stable post-myocardial infarction patients who were assigned active or placebo within underwent measurement IL-18 IL-6 before after initiation using validated ELISA. All followed over median 3.7-year period (maximum 5 years) major adverse (MACE) all-cause mortality. Compared placebo, reduced levels dose-dependent manner yielding placebo-subtracted percent reductions 3 months 24.8%, 36.3%, 43.2% 50, 150, 300 mg doses, respectively (all P-values <0.001). By contrast, no dose altered measured <1%, all > 0.05). despite these differential plasma effects, either baseline on-treatment associated future For example, MACE, each tertile increase 15% [95% confidence interval (CI) 3-29%, P = 0.016], while 42% (95% CI 26-59%, < 0.0001). Similar observed MACE-plus, death, mortality, combination endpoint vascular inclusive revascularization procedures hospitalization congestive heart failure. In as well analyses, risks highest among those IL-6.There remains substantial residual inflammatory related These data support further pharmacologic development therapies atherothrombosis target signalling, simultaneously inhibit (such inhibitors).ClinicalTrials.gov NCT01327846.

Language: Английский

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Targeting the NLRP3 inflammasome in cardiovascular diseases

Pharmacology & Therapeutics, Journal Year: 2021, Volume and Issue: 236, P. 108053 - 108053

Published: Dec. 11, 2021

Language: Английский

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Guidelines for evaluating myocardial cell death

AJP Heart and Circulatory Physiology, Journal Year: 2019, Volume and Issue: 317(5), P. H891 - H922

Published: Aug. 16, 2019

Cell death is a fundamental process in cardiac pathologies. Recent studies have revealed multiple forms of cell death, and several them been demonstrated to underlie adverse remodeling heart failure. With the expansion area myocardial increasing concerns over rigor reproducibility, it important timely set guideline for best practices evaluating death. There are six major regulated observed pathologies, namely apoptosis, necroptosis, mitochondrial-mediated necrosis, pyroptosis, ferroptosis, autophagic In this article, we describe methods identify, measure, evaluate these modes addition, discuss limitations currently practiced mechanisms. Listen article's corresponding podcast at https://ajpheart.podbean.com/e/guidelines-for-evaluating-myocardial-cell-death/ .

Language: Английский

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