Effect of Interleukin-1 Blockade on Left Ventricular Systolic Performance and Work: A Post Hoc Pooled Analysis of 2 Clinical Trials

Buckley, Leo F.; Carbone, Salvatore; Trankle, Cory R.; Canada, Justin M.; Erdle, Claudia Oddi; Regan, Jessica A.; Viscusi, Michele Mattia; Kadariya, Dinesh; Billingsley, Hayley; Arena, Ross; Abbate, Antonio; Tassell, Benjamín W. Van

doi:10.1097/fjc.0000000000000591

Cited by 19 publications

(9 citation statements)

References 14 publications

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“…The control of paracrine IL-1/fibroblast signaling post-MI has been previously shown to regulate post-MI remodeling and improve cardiac function in animal models ( 36 , 37 ). Results from the CANTOS cardiovascular clinical trial indicates therapeutic blockade of IL-1 reduces cardiovascular events in patients with atherosclerotic vascular disease (reviewed in ( 38 , 39 )). Additional paracrine pathways identified indicate Spp1 and Serpine1 signaling pathways may be involved in the primary beneficial effect underlying the MCB-613 response in post-MI injured hearts.…”

Section: Discussionmentioning

confidence: 99%

A steroid receptor coactivator stimulator (MCB-613) attenuates adverse remodeling after myocardial infarction

Mullany

Rohira

Leach

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Progressive remodeling of the heart, resulting in cardiomyocyte (CM) loss and increased inflammation, fibrosis, and a progressive decrease in cardiac function, are hallmarks of myocardial infarction (MI)-induced heart failure. We show that MCB-613, a potent small molecule stimulator of steroid receptor coactivators (SRCs) attenuates pathological remodeling post-MI. MCB-613 decreases infarct size, apoptosis, hypertrophy, and fibrosis while maintaining significant cardiac function. MCB-613, when given within hours post MI, induces lasting protection from adverse remodeling concomitant with: 1) inhibition of macrophage inflammatory signaling and interleukin 1 (IL-1) signaling, which attenuates the acute inflammatory response, 2) attenuation of fibroblast differentiation, and 3) promotion of Tsc22d3-expressing macrophages—all of which may limit inflammatory damage. SRC stimulation with MCB-613 (and derivatives) is a potential therapeutic approach for inhibiting cardiac dysfunction after MI.

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Section: Discussionmentioning

confidence: 99%

A steroid receptor coactivator stimulator (MCB-613) attenuates adverse remodeling after myocardial infarction

Mullany

Rohira

Leach

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…It showed greater benefit in a dose and hsCRP-dependent fashion, a surrogate biomarker of IL-1 activity, confirming the concept of personalized treatment in HF (Ridker et al, 2018). Nevertheless, although the neutralization of IL-1β or the blockade of IL-1R1 were shown to be protective in human CHF and AHF (Van Tassell et al, 2012;Abbate et al, 2013;Van Tassell et al, 2014Cavalli et al, 2017;Buckley et al, 2018;Everett et al, 2019), circulating IL-1β values are frequently below detection limits, being very difficult to establish a correlation between IL-1β concentration and disease severity (Abbate et al, 2020).…”

Section: Anti-cytokine Therapiesmentioning

confidence: 92%

Inflammation in Human Heart Failure: Major Mediators and Therapeutic Targets

et al. 2021

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Inflammation has been recognized as a major pathophysiological contributor to the entire spectrum of human heart failure (HF), including HF with reduced ejection fraction, HF with preserved ejection fraction, acute HF and cardiogenic shock. Nevertheless, the results of several trials attempting anti-inflammatory strategies in HF patients have not been consistent or motivating and the clinical implementation of anti-inflammatory treatments for HF still requires larger and longer trials, as well as novel and/or more specific drugs. The present work reviews the different inflammatory mechanisms contributing to each type of HF, the major inflammatory mediators involved, namely tumor necrosis factor alpha, the interleukins 1, 6, 8, 10, 18, and 33, C-reactive protein and the enzymes myeloperoxidase and inducible nitric oxide synthase, and their effects on heart function. Furthermore, several trials targeting these mediators or involving other anti-inflammatory treatments in human HF are also described and analyzed. Future therapeutic advances will likely involve tailored anti-inflammatory treatments according to the patient’s inflammatory profile, as well as the development of resolution pharmacology aimed at stimulating resolution of inflammation pathways in HF.

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“…In addition, other smaller studies further support this concept. In two small clinical studies in HFrEF patients, anakinra treatment improved indicators of systolic function [80]. In a small group of patients with HFpEF and elevated hsCRP, treatment with anakinra reduced NT-proBNP, but failed to improve indicators of cardiorespiratory fitness [81].…”

Section: Targeting the Il-1 System In Human Heart Failure Patientsmentioning

confidence: 99%

Inflammatory Cytokines and Chemokines as Therapeutic Targets in Heart Failure

Hanna

Frangogiannis

2020

Cardiovasc Drugs Ther

230

170

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Heart failure exhibits remarkable pathophysiologic heterogeneity. A large body of evidence suggests that regardless of the underlying etiology, heart failure is associated with induction of cytokines and chemokines that may contribute to the pathogenesis of adverse remodeling, and systolic and diastolic dysfunction. The pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1, and IL-6 have been extensively implicated in the pathogenesis of heart failure. Inflammatory cytokines modulate phenotype and function of all myocardial cells, suppressing contractile function in cardiomyocytes, inducing inflammatory activation in macrophages, stimulating microvascular inflammation and dysfunction, and promoting a matrixdegrading phenotype in fibroblasts. Moreover, cytokine-induced growth factor synthesis may exert chronic fibrogenic actions contributing to the pathogenesis of heart failure with preserved ejection fraction (HFpEF). In addition to their role in adverse cardiac remodeling, some inflammatory cytokines may also exert protective actions on cardiomyocytes under conditions of stress. Chemokines, such as CCL2, are also upregulated in failing hearts and may stimulate recruitment of pro-inflammatory leukocytes, promoting myocardial injury, fibrotic remodeling, and dysfunction. Although experimental evidence suggests that cytokine and chemokine targeting may hold therapeutic promise in heart failure, clinical translation remains challenging. This review manuscript summarizes our knowledge on the role of TNF-α, IL-1, IL-6, and CCL2 in the pathogenesis of heart failure, and discusses the promises and challenges of targeted anti-cytokine therapy. Dissection of protective and maladaptive cellular actions of cytokines in the failing heart, and identification of patient subsets with overactive or dysregulated myocardial inflammatory responses are required for design of successful therapeutic approaches.

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Effect of Interleukin-1 Blockade on Left Ventricular Systolic Performance and Work: A Post Hoc Pooled Analysis of 2 Clinical Trials

Abstract: In this post hoc analysis, LVEes and LVEF increased significantly in patients treated with an IL-1 blocker but not in placebo-treated patients. An effect of IL-1 blockade on calculated PVA was not detected.

Cited by 19 publications

References 14 publications

A steroid receptor coactivator stimulator (MCB-613) attenuates adverse remodeling after myocardial infarction

A steroid receptor coactivator stimulator (MCB-613) attenuates adverse remodeling after myocardial infarction

Inflammation in Human Heart Failure: Major Mediators and Therapeutic Targets

Inflammatory Cytokines and Chemokines as Therapeutic Targets in Heart Failure

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