Inhibition of soluble TNFα prevents adverse atrial remodeling and atrial arrhythmia susceptibility induced in mice by endurance exercise

Lakin, Robert; Polidovitch, Nazari; Yang, Sibao; Guzmán, Camilo; Gao, Xiao‐Dong; Wauchop, Marianne; Burns, Judy; Izaddoustdar, Farzad; Backx, Peter H.

doi:10.1016/j.yjmcc.2019.01.012

Cited by 21 publications

(13 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This intriguing finding led us to several additional experiments in order to try to reveal possible source\s for this phenomenon. The results strongly argue against the involvement of systemic inflammation as an underlying mechanism based on direct serum measurements of inflammatory cytokines as well as the absence of atrial fibrosis which is expected to occur in the presence of systemic inflammation 31,32,46 . Post-operative AF due to the thoracotomy we performed in the implantation surgery is another option that should be considered.…”

Section: Scientific Reports |mentioning

confidence: 85%

An implantable system for long-term assessment of atrial fibrillation substrate in unanesthetized rats exposed to underlying pathological conditions

Klapper-Goldstein

Murninkas

Gillis

et al. 2020

Sci Rep

View full text Add to dashboard Cite

Atrial fibrillation (AF) is a progressive arrhythmia with underlying mechanisms that are not fully elucidated, partially due to lack of reliable and affordable animal models. Here, we introduce a system for long-term assessment of AF susceptibility (substrate) in ambulatory rats implanted with miniature electrodes on the atrium. Rats were subjected to excessive aldosterone (Aldo) or solvent only (Sham). An additional group was exposed to myocardial infarction (MI). AF substrate was tested two-and four-weeks post implantation and was also compared with implanted rats early post-implantation (Base). Aldo and MI increased the AF substrate and atrial fibrosis. In the MI group only, AF duration was correlated with the level of atrial fibrosis and was inversely correlated with systolic function. Unexpectedly, Shams also developed progressive AF substrate relative to Base individuals. Further studies indicated that serum inflammatory markers (IL-6, TNF-alpha) were not elevated in the shams. In addition, we excluded anxiety\depression due to social-isolation as an AF promoting factor. Finally, enhanced biocompatibility of the atrial electrode did not inhibit the gradual development of AF substrate over a testing period of up to 8 weeks. Overall, we successfully validated the first system for long-term AF substrate testing in ambulatory rats.Atrial fibrillation (AF) is a growing epidemic, entailing substantial economic costs, morbidity and mortality 1,2 . The pathophysiology of AF is multi-factorial in nature. It involves sources of sustained rapid electrical activity that can trigger arrhythmic episodes as well as pathological mechanisms which alter the electrical and structural substrate for AF in the atrial tissue 3-7 . A full understanding of the molecular mechanisms by which various underlying conditions and factors converge to progressively promote AF substrate is still lacking [8][9][10] . Drugs aimed to target the atrial remodeling (upstream therapies) are attractive new options to prevent AF perpetuation. However, early pre-clinical testing of such drugs is currently difficult due to the absence of reliable and affordable animal models.Traditionally, AF-related models have relied solely on large animals exposed to atrial tachypacing or heart failure 11 . However, over the last two decades, rodents have been increasingly used to study various mechanistic aspects in the pathophysiology of AF 12-18 , and the possibility of using rodents to test new therapies seems attractive. However, several technical limitations constrain the widespread utility of rodents in AF research. Particularly, the small and delicate rodent atria render the implantation of chronic pacing and recording

show abstract

Section: Scientific Reports |mentioning

confidence: 85%

An implantable system for long-term assessment of atrial fibrillation substrate in unanesthetized rats exposed to underlying pathological conditions

Klapper-Goldstein

Murninkas

Gillis

et al. 2020

Sci Rep

View full text Add to dashboard Cite

show abstract

“…The levels of TNF-α are also increased in patients with permanent AF, compared with patients with paroxysmal AF (23). Furthermore, soluble TNF-α predicts exercise-induced AF vulnerability (70). Finally, myeloperoxidase (MPO) produces hypohalous acid in response to infection.…”

Section: Inflammatory Biomarkers Are Correlated With Afmentioning

confidence: 99%

“…Other treatments suggesting a relationship between AF and inflammation include TNF-α gene ablation preventing structural remodeling of the atrium and decreased vulnerability of AF in response to exercise in exercised mice (70). Moreover, renal denervation can decrease inducibility of AF via reduction of sympathetic RAS activity and inhibition of inflammation and fibrosis in a model of renal impairment (106).…”

Section: Inflammation Suppression and Afmentioning

confidence: 99%

Evidence for Inflammation as a Driver of Atrial Fibrillation

Zhou

Dudley

2020

Front. Cardiovasc. Med.

View full text Add to dashboard Cite

Atrial fibrillation (AF) is one of the most common types of arrhythmias and increases cardiovascular morbidity and mortality. Current therapeutic approaches to AF that focus on rhythm control have high recurrence rates and no life prolongation value. While possible explanations include toxicity of current therapies, another likely explanation may be that current therapies do not address fundamental mechanisms of AF initiation and maintenance. Inflammation has been shown to affect signaling pathways that lead to the development of AF. This paper reviews the roles of inflammation in the occurrence, development, and mechanisms of AF and reviews the therapeutic implications of the correlation of inflammation and AF.

show abstract

“…For these studies, we used the 2 day mice and made the measurements 2 h following the final 90 min exercise bout, consistent with our RNA-seq measurements. Given that soluble TNF is required for exercise-induced atrial changes (Lakin et al, 2019), we first measured the activity of TNF-converting enzyme (TACE, or ADAM17), which is upregulated with mechanical stretch and releases active (soluble) TNF (Zhan et al, 2007). Indeed, TACE activity tended to be increased (P = 0.211) with swim (142 ± 4 pmol/min/µg, n = 5) compared to sedentary mice (129 ± 8 pmol/min/µg, n = 6), suggesting activation.…”

Section: Acute Effects Of Exercise On Atrial Pressures and Collagen Mmentioning

confidence: 99%

“…Moreover, rodent models have established that endurance exercise causes atrial fibrosis, inflammation, and hypertrophy (Guasch et al, 2013;Aschar-Sobbi et al, 2015), as seen in persistent AF patients (Oakes et al, 2009;Qu et al, 2009;Gramley et al, 2010). We previously demonstrated that the exercise-induced atrial changes were prevented by pharmacological and genetic blockade of tumor necrosis factor (TNF), a mechanosensitive and pro-inflammatory cytokine (Aschar-Sobbi et al, 2015;Lakin et al, 2019). However, when TNF blockade was introduced 3 weeks after the beginning of intense exercise, cardioprotection was lost, suggesting that pathways linked to exercise-induced adverse atrial remodeling occur early in the response to exercise.…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic Bioinformatic Analyses of Atria Uncover Involvement of Pathways Related to Strain and Post-translational Modification of Collagen in Increased Atrial Fibrillation Vulnerability in Intensely Exercised Mice

Yang

Liu

et al. 2020

Front. Physiol.

Self Cite

View full text Add to dashboard Cite

Atrial Fibrillation (AF) is the most common supraventricular tachyarrhythmia that is typically associated with cardiovascular disease (CVD) and poor cardiovascular health. Paradoxically, endurance athletes are also at risk for AF. While it is well-established that persistent AF is associated with atrial fibrosis, hypertrophy and inflammation, intensely exercised mice showed similar adverse atrial changes and increased AF vulnerability, which required tumor necrosis factor (TNF) signaling, even though ventricular structure and function improved. To identify some of the molecular factors underlying the chamber-specific and TNF-dependent atrial changes induced by exercise, we performed transcriptome analyses of hearts from wild-type and TNF-knockout mice following exercise for 2 days, 2 or 6 weeks of exercise. Consistent with the central role of atrial stretch arising from elevated venous pressure in AF promotion, all 3 time points were associated with differential regulation of genes in atria linked to mechanosensing (focal adhesion kinase, integrins and cell-cell communications), extracellular matrix (ECM) and TNF pathways, with TNF appearing to play a permissive, rather than causal, role in gene changes. Importantly, mechanosensing/ECM genes were only enriched, along with tubulin- and hypertrophy-related genes after 2 days of exercise while being downregulated at 2 and 6 weeks, suggesting that early reactive strain-dependent remodeling with exercise yields to compensatory adjustments. Moreover, at the later time points, there was also downregulation of both collagen genes and genes involved in collagen turnover, a pattern mirroring aging-related fibrosis. By comparison, twofold fewer genes were differentially regulated in ventricles vs. atria, independently of TNF. Our findings reveal that exercise promotes TNF-dependent atrial transcriptome remodeling of ECM/mechanosensing pathways, consistent with increased preload and atrial stretch seen with exercise. We propose that similar preload-dependent mechanisms are responsible for atrial changes and AF in both CVD patients and athletes.

show abstract

Inhibition of soluble TNFα prevents adverse atrial remodeling and atrial arrhythmia susceptibility induced in mice by endurance exercise

Cited by 21 publications

References 50 publications

An implantable system for long-term assessment of atrial fibrillation substrate in unanesthetized rats exposed to underlying pathological conditions

An implantable system for long-term assessment of atrial fibrillation substrate in unanesthetized rats exposed to underlying pathological conditions

Evidence for Inflammation as a Driver of Atrial Fibrillation

Transcriptomic Bioinformatic Analyses of Atria Uncover Involvement of Pathways Related to Strain and Post-translational Modification of Collagen in Increased Atrial Fibrillation Vulnerability in Intensely Exercised Mice

Contact Info

Product

Resources

About