scholarly journals JNK2, A Newly-Identified SERCA2 Enhancer, Augments an Arrhythmic [Ca 2+ ] SR Leak-Load Relationship

2020 ◽  
Author(s):  
JiaJie Yan ◽  
Dan J Bare ◽  
Jaime DeSantiago ◽  
Weiwei Zhao ◽  
Yiming Mei ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Heart Function ◽  
Ryanodine Receptors ◽  
Specific Inhibition ◽  
Increased Risk ◽  
Prevention And Treatment ◽  
Dual Action ◽  
Stress Kinase ◽  
Novel Therapeutic

Rationale: We recently discovered pivotal contributions of stress kinase JNK2 in increased risk of atrial fibrillation (AF) through enhanced diastolic sarcoplasmic reticulum (SR) Ca 2+ leak via ryanodine receptors (RyR2). However, the role of JNK2 in the function of the SR Ca 2+ -ATPase (SERCA2), essential in maintaining [Ca 2+ ] SR cycling during each heartbeat, is completely unknown. Objective: To test the hypothesis that JNK2 increases SERCA2 activity [Ca 2+ ] SR and exacerbates an arrhythmic [Ca 2+ ] SR leak-load relationship. Methods and Results: We used confocal Ca 2+ imaging in myocytes and HEK cells, biochemistry, dual Ca 2+ /voltage optical mapping in intact hearts from alcohol-exposed or aged mice (where JNK2 is activated). We found that JNK2, but not JNK1, increased SERCA2 uptake and consequently elevated [Ca 2+ ]SR load. JNK2 also associates with and phosphorylates SERCA2 proteins. JNK2 causally enhances SERCA2-ATPase activity via increased Vmax, without altering Ca 2+ affinity (Km). Unlike the CaMKII-dependent JNK2 action in SR Ca 2+ leak, JNK2-driven SERCA2 function was CaMKII-independent (not prevented by CaMKII inhibition). With CaMKII blocked, the JNK2-driven SR Ca 2+ loading alone did not significantly raise leak. However, with JNK2-CaMKII-driven SR Ca 2+ leak present, the JNK2-enhanced SR Ca 2+ uptake limited leak-induced reduction in SR Ca 2+ , normalizing Ca 2+ transient amplitude, but at a higher arrhythmogenic SR Ca 2+ leak. JNK2-specific inhibition completely normalized SR Ca 2+ handling, attenuated arrhythmic Ca 2+ activities, and alleviated AF susceptibility in aged and alcohol-exposed myocytes and intact hearts. Conclusions: We have identified a novel JNK2-induced activation of SERCA2. The dual-action of JNK2 in CaMKII-dependent arrhythmic SR Ca 2+ leak and a CaMKII-independent uptake exacerbates atrial arrhythmogenicity, while helping to maintain normal levels of Ca 2+ transients and heart function. JNK2 modulation may be a novel therapeutic target for AF prevention and treatment.

P2863Regional specific remodeling of cGMP pathway in human atrial fibrillation

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
N I Bork ◽  
N G Pavlidou ◽  
B Reiter ◽  
H Reichenspurner ◽  
T Christ ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Sinus Rhythm ◽  
Ryanodine Receptors ◽  
Membrane Receptors ◽  
Mrna Levels ◽  
Atrial Myocytes ◽  
Human Atrial Myocytes ◽  
Cgmp Pathway ◽  
The Right

Abstract Background Atrial fibrillation (AF) is accompanied by a profound remodeling of membrane receptors and alterations in cyclic nucleotides-dependent regulation of Ca2+-handling. Thus, while basal ryanodine receptors activity is upregulated, L-type calcium current (ICa,L) density is diminish in AF, due to local microdomain-specific cAMP dynamics. The same seems true for cGMP regulation in AF. In AF cGMP-mediated increase in ICa,L is blunted but NO-mediated attenuation of β-adrenoceptors stimulation-mediated increase is preserved. However, although the role of cGMP in controling atrial function and pathophysiology is controversial, no study has been ever performed in human myocytes to measure cGMP directly. Methods We isolated myocytes from the right and/or left atrium of 27 patients in sinus rhythm (SR), and with AF. Cells were then transfected with adenovirus to express the cytosolic FRET-based cGMP sensor red-cGES-DE5 and cultured for 48 hours. Förster resonance energy transfer (FRET) was used to measure cGMP in 61 living human atrial myocytes. We stimulated cells with the C-type natriuretic peptide CNP (100 nM and 1 μM), and the non-selective phosphodiesterases (PDEs) inhibitor IBMX (100 μM). Additionally, PDE specific inhibitors for PDE2 (Bay 60–7550, 100 nM) and PDE3 (Cilostamide, 10 μM) as well as inhibitor of the soluble guanylyl cyclase (ODQ, 50 μM) were used. We also measured PDE2 and PDE3 mRNA levels in atrial tissue samples from both groups of patients using RT-qPCR. Results We could show that stimulation with CNP increased cGMP levels in human atrial myocytes. However, in myocytes from patients with AF global cGMP responses to CNP and to IBMX was reduced compared to SR. Additionally, there was a difference in response to CNP and IBMX in patients with AF between the right and the left atria. Whereas in the right atria IBMX could further increase cGMP levels in the cell, in the left atria leaded to a reduction in cGMP levels. RT-qPCR showed a tendency of PDE3 to be reduced in AF. On the other hand, PDE2A gene expression was upregulated in the left atria. Conclusions We have shown that PDEs contributes cGMP signaling in the human atria and that they are involved in atrial pathophysiology. Now our data clearly show differences in cGMP regulation in cardiomyocytes isolated from left and right atrium from patients in atrial fibrillation and sinus rhythm. We observe a major role of PDEs, regulating cGMP pathway promoted by the reduced responses in AF, especially PDE2 in the left atria.

scholarly journals Diagnosis and Management of Left Atrium Appendage Thrombosis in Atrial Fibrillation Patients Undergoing Cardioversion

Medicina ◽  
2019 ◽  
Vol 55 (9) ◽  
pp. 511 ◽  
Author(s):  
Enrico Melillo ◽  
Giuseppe Palmiero ◽  
Adele Ferro ◽  
Paola Elvira Mocavero ◽  
Vittorio Monda ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Left Atrial ◽  
Left Atrial Appendage ◽  
Rhythm Control ◽  
Atrial Appendage ◽  
Thromboembolic Complications ◽  
Left Atrial Appendage Thrombus ◽  
Increased Risk ◽  
Pharmacological Cardioversion

Atrial fibrillation is the most common cardiac arrhythmia and is associated with an increased risk of stroke and thromboembolic complications. A rhythm control strategy with both electrical and pharmacological cardioversion is recommended for patients with symptomatic atrial fibrillation. Anticoagulant therapy for 3–4 weeks prior to cardioversion is recommended in order to avoid thromboembolic events deriving from restoring sinus rhythm. Transesophageal echocardiography has a pivotal role in this setting, excluding the presence of left atrial appendage thrombus before cardioversion. The aim of this review is to discuss the epidemiology and risk factors for left atrial appendage thrombosis, the role of echocardiography in the decision making before cardioversion, and the efficacy of different anticoagulant regimens on the detection and treatment of left atrial appendage thrombosis.

scholarly journals The counterintuitive role of exercise in the prevention and cause of atrial fibrillation

2020 ◽  
Vol 319 (5) ◽  
pp. H1051-H1058
Author(s):  
Benjamin J. R. Buckley ◽  
Gregory Y. H. Lip ◽  
Dick H. J. Thijssen
Keyword(s):  
Physical Activity ◽  
Risk Factors ◽  
Atrial Fibrillation ◽  
Cardiovascular Risk ◽  
Cardiovascular Risk Factors ◽  
Endurance Exercise ◽  
Premature Mortality ◽  
Beneficial Effects ◽  
Increased Risk

Atrial fibrillation (AF) is the most common cardiac arrhythmia, characterized by irregular atrial activity. AF is related to increased risk of thromboembolic events, heart failure, and premature mortality. Recent advances in our understanding of its pathophysiology include a potentially central role for inflammation and presence of cardiovascular risk factors. The role of physical activity and exercise in the development and progression of AF, however, are not yet fully understood. Physical activity is protective for modifiable cardiovascular risk factors, including those associated with AF. Indeed, emerging research has demonstrated beneficial effects of exercise on AF-specific outcomes, including AF recurrence postablation. Counterintuitively, the prevalence of AF in veteran endurance athletes seems higher compared with the general population. In this review, we discuss the novel evidence and underlying mechanisms underpinning the role of exercise as medicine in the development and management of AF but also the counterintuitive detrimental role of excessive endurance exercise. Finally, we advocate regular (but not long-term high-intensity endurance) exercise training as a safe and effective strategy to reduce the risk of incident AF and to minimize the associated risk of secondary cardiovascular events.

Effective treatments for suicidal youth

2021 ◽  
pp. 593-608
Author(s):  
David A. Brent
Keyword(s):  
Young Adults ◽  
Suicidal Ideation ◽  
Suicidal Behaviour ◽  
Best Practice ◽  
Suicidal Risk ◽  
Community Based ◽  
Treatment Of Depression ◽  
Increased Risk ◽  
Prevention And Treatment

This chapter reviews the efficacy of interventions designed to prevent the onset or recurrence of suicidal ideation or behaviour in adolescents and young adults. First, community-based universal interventions designed to decrease the incidence of suicidal ideation and behaviour in youth are reviewed. Second, interventions designed to reduce suicidal risk in those already identified as at increased risk for suicidal behaviour are discussed. Third, the role of the pharmacological treatment of psychiatric disorder, such as the treatment of depression, in the reduction of suicidal risk in adolescents is delineated. Finally, on the basis of this review, recommendations for best practice in the prevention and treatment of suicidal behaviour in youth are offered.

The risk of atrial fibrillation associated with hyperuricemia

2021 ◽  
Author(s):  
V. A. Chernyshov
Keyword(s):  
Oxidative Stress ◽  
Atrial Fibrillation ◽  
Elevated Serum ◽  
Renin Angiotensin System ◽  
Oxidase Inhibitor ◽  
Important Place ◽  
Xanthine Oxidase Inhibitor ◽  
Increased Risk ◽  
The Relationship

The article summarizes mechanisms, linking hyperuricemia, the elevated serum levels of uric acid (UA), and atrial fibrillation (AF), the most frequent cardiac arrhythmia. The actuality of the problem is explained by the fact that UA is considered as an independent risk marker of AF closely associated with the onset and subsequent persistence of AF as well as by the AF increased risk in males and females with hyperuricemia. It has been shown how hyperuricemia, combined with other AF risk factors, contributeы to the development of arrhythmia, as well as the role of hyperuricemia, oxidative stress and renin‑angiotensin system (RAS) activation in the AF pathogenesis. The consideration have been given to the hyperuricemia association with a prevalence of AF among the patients with carbohydrate exchange disorders such as metabolic syndrome and type 2 diabetes mellitus as well as to the relationship between hyperuricemia and endothelial vascular dysfunction, oxidative stress, high blood concentration of systemic inflammatory markers and insulin resistance (IR). Some mechanisms of hyperuricemia participation in cardiac remodeling as a risk factor of AF are adduced. In particular, the relationship between hyperuricemia and left atrial (LA) size that could be mediated through systemic inflammation and IR is discussed. A significance of a direct impaired action of UA on LA cardiomyocytes resulted in their structural and ionic remodeling is shown. The role of xanthinoxidase (XO) activation in initiation of oxidative stress and inflammation in cardiomyocytes and endothelial cells is discussed. All these mechanisms are emphasized to be able to shorten a potential of action of atrial cardiomyocytes as well as to reduce a threshold of re‑entry mechanism initiation and to promote an appearance of the first and the following AF episodes. An important place in the review is taken for an intracellular UA and its cellular transporters in the context of their participation in pathogenesis of AF. The possibilities of drug hyperuricemia correction have been described in regards the reduction of AF risk, in particular, the role of reducing of the oxidative stress intensity with the use of xanthine oxidase inhibitor allopurinol, the inhibitor of NADPH oxidase apocynin, the antioxidant N‑acetylcysteine in the reduction of the risk of onset and subsequent recurrences of AF episodes, and transition of arrhythmia in the persistent form. Some perspectives of probenecid (an inhibitor of UA intracellular transporter activity) usage in the reduction of AF risk due to such of its mechanisms as a reduction of intracellular UA accumulation and antiapoptotic action as well as an ability of this agent to inhibit a locally activated oxidative stress and locally activated tissue RAS are discussed. A significance of the further detailed study of pathophysiological mechanisms of AF in hyperuricemia is emphasized for elaboration of the most effective practical recommendations in prevention of this arrhythmia in persons with UA exchange disorders.

scholarly journals Newly Detected Atrial Fibrillation after Acute Stroke: A Narrative Review of Causes and Implications

Cardiology ◽  
2019 ◽  
Vol 144 (3-4) ◽  
pp. 112-121 ◽  
Author(s):  
Youcheng Wang ◽  
Yongsheng Qian ◽  
Daniel Smerin ◽  
Shujuan Zhang ◽  
Qingyan Zhao ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Ischemic Stroke ◽  
Acute Stroke ◽  
Adverse Outcomes ◽  
Stroke Recurrence ◽  
Stroke Patients ◽  
Increased Risk ◽  
Definition Of ◽  
Humoral Regulation

Cardiac arrhythmias occur frequently in patients with acute stroke, with atrial fibrillation (AF) being the most common. Newly detected AF may lead to increased risk of ischemic stroke, which in turn generates stroke recurrence and adverse outcomes. Currently, most studies are focusing on the role of AF in ischemic stroke and attributing cryptogenic ischemic stroke to previously undetected AF. However, in these studies, subjects used to have neither symptoms of palpitation nor evidence of AF. A better understanding of this association will contribute to the management and therapy for patients after clinical decisions regarding stroke patients. Currently, the definition of newly detected AF has not come to an agreement, and the pathophysiology remains incompletely understood, possibly involving complex alterations in both the autonomic network and humoral regulation. Therefore, this review aims to introduce the definition and epidemiology of newly detected AF after stroke with updated information and elucidate the potential pathophysi­ology, such as autonomic imbalance, catecholamine surge, poststroke systematic inflammation, and microvesicles and microRNAs.

Oral Anticoagulants in Patients With Atrial Fibrillation and End-Stage Renal Disease

2019 ◽  
Vol 24 (6) ◽  
pp. 499-508
Author(s):  
Junaid A. B. Zaman ◽  
Anil K. Bhandari
Keyword(s):  
Atrial Fibrillation ◽  
Renal Disease ◽  
End Stage Renal Disease ◽  
Oral Anticoagulants ◽  
Bleeding Risk ◽  
Additional Risk ◽  
Increased Risk ◽  
Stage Renal Disease ◽  
End Stage

The role of oral anticoagulants (OAC) in atrial fibrillation (AF) is well established. However, none of the randomized controlled trials included patients with end-stage renal disease (ESRD) leaving a lack of evidence in this large, challenging and unique patient group. Patients on hemodialysis (HD) with AF have additional risk factors for stroke due to vascular comorbidities, HD treatment, age, and diabetes. Conversely, they are also at increased risk of major bleeding due to uremic platelet impairment. Anticoagulants increase bleeding risk in patients with ESRD and HD up to 10-fold compared with non chronic kidney disease (CKD) patients on warfarin. There are conflicting data and recommendations regarding use of OACs in ESRD which will be reviewed in this article. We conclude by proposing a modified strategy for OAC use in ESRD based on the latest evidence.

scholarly journals The role of inflammatory markers in atrial fibrillation: a review

2012 ◽  
Vol 11 (5) ◽  
pp. 74-78
Author(s):  
S. V. Grigoryan ◽  
K. G. Adamyan ◽  
L. G. Azarapetyan
Keyword(s):  
Atrial Fibrillation ◽  
Inflammatory Markers ◽  
Pharmacological Therapy ◽  
Pleiotropic Effects ◽  
Prevention And Treatment

This review is focused on the role of latent inflammation in atrial fibrillation (AF) pathogenesis. The modern views and available evidence on the association between the levels of inflammatory markers and AF development and recurrence are presented. The justification for the use of pleiotropic effects of pharmacological therapy in AF prevention and treatment is discussed.

Abstract 16089: Clinical Outcomes Associated With Anti-coagulation versus No Anti-coagulation for Atrial Fibrillation Among Octogenarians and Nonagenarians; a Meta-analysis

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Kiro Barssoum ◽  
Ashish Kumar ◽  
Devesh Rai ◽  
Ahmed Elkaryoni ◽  
Samarthkumar J Thakkar ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Observational Studies ◽  
Meta Analysis ◽  
Outlier Analysis ◽  
Safety Outcome ◽  
Risk Of Bleeding ◽  
Cochrane Database ◽  
Efficacy Outcome ◽  
Increased Risk

Background: Octogenarians and nonagenarians are under-represented in major clinical trials studying the role of anticoagulation (AC) in atrial fibrillation (AF). These patients are at an increased risk of bleeding owing to their frailty, their propensity for falls, and frequently impaired kidney function. We performed a meta-analysis of studies that investigated the role of AC in these patients. Methods: We queried Medline, EmCare, CINHAL, Cochrane Database, and Google Scholar for studies investigating the role of AC for AF in octogenarians and nonagenarians. Our primary efficacy outcome was major thromboembolism (TE), and secondary safety outcome was major bleeding (MB). We used the PM method with HKSJ adjustment to estimate risk ratio (RR) with a 95% confidence interval (CI). Heterogeneity was assessed using Higgin’s I 2 . R version 3.6.2 was used for statistical analysis. Heterogeneity was addressed using outlier analysis. dmetar() package in R was used, and the pooled estimate was re-calculated, excluding the outliers. Results: Ten observational studies, including a total of 34,697 patients were included. There was no difference in the risk of TE [RR: 0.82, 95% CI: 0.49-1.38, I 2 =74%] or MB [RR: 1.00, 95% CI: 0.55-1.83, I 2 =88%] between the AC and Non-AC group. However, the pooled estimates were associated with considerable heterogeneity. Outlier analysis identified two studies "Perera et al., 2009" and "Yamashita et al., 2016" as an outlier for pooled estimation of TE, while [1] "Siu et al., 2014", "Bertozzo et al., 2016", "Ekerstad et al., 2018" and "Alnsasra et al., 2018" were outliers in the pooled estimate of MB. Following exclusion of outliers for each endpoint, the reanalyzed RR for TE and MB were [RR: 0.94, 95% CI: 0.82- 1.09, I 2 =0%] and [RR: 1.57, 95% CI: 1.41- 1.74, I 2 =0%]. Conclusion: There was no difference in the risk of TE, while the risk of MB increased with the use of AC for AF in octogenarians and nonagenarians.

Abstract 319: Role of Phosphodiesterases 4B and 4D in cAMP Signal Compartmentation Around Calcium Handling Proteins

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Axel E Kraft ◽  
Viacheslav O Nikolaev ◽  
Marco Conti
Keyword(s):  
Knockout Mice ◽  
Heart Function ◽  
Ryanodine Receptors ◽  
Critical Role ◽  
Specific Effect ◽  
Resonance Energy ◽  
Direct Analysis ◽  
Calcium Handling ◽  
Camp Signaling

Phosphodiesterase subfamilies 4B and 4D are critically involved in the regulation of cAMP signaling in mammalian cardiomyocytes. Alterations in activity of these enzymes in human hearts have been shown to result in arrhythmia and heart failure. The aim of this project was to systematically investigate specific roles of PDE4B and PDE4D in regulating cAMP dynamics in three distinct subcellular microdomains formed around Ca 2+ handling proteins, such as L-type calcium channels (LTCCs), sarco/endoplasmic reticulum Ca 2+ -ATPase (SERCA) and ryanodine receptors (RyRs), to understand their impact on heart function and disease. Transgenic mice expressing three different Förster resonance energy transfer (FRET) based cAMP biosensors targeted to caveolin rich plasma membrane, SERCA and RyR microdomains, were crossed with PDE4B and PDE4D knockout mice. Using FRET imaging in ventricular cardiomyocytes freshly isolated from wildtype and knockout mice, direct analysis of the specific effect of both PDE subfamilies in these microdomains could be performed by measuring the kinetics of local cAMP degradation. Our results indicate that the cAMP kinetics around the LTCC microdomain is critically regulated by PDE4B and PDE4D. So far was it has been known that the isoform that is associated with the RyR microdomain belongs to the PDE4D family, however we found PDE4B to be involved in regulating the cAMP signaling in this microdomain. PDE4D deletion also revealed the critical role of this subfamily for the control of cAMP dynamics in the SERCA microdomain of adult mouse cardiomyocytes. Basal levels of cAMP were elevated when PDE4B was absent from any of the PDE4B-regulated microdomain, whereas no such alterations were detected for PDE4D knockout cells. These data demonstrate that all three microdomains are differentially regulated by PDEs. Even within one organelle such as sarcoplasmic reticulum, we could show the existence of at least two distinct cAMP microdomains, i.e. around RyR and SERCA which are preferentially controlled by PDE4B and PDE4D, respectively. In the future, we aim to systematically analyze biochemical composition of the three microdomains, their distinct roles in cardiac function and disease as well as ways of their pharmacological modulation.

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