TUNDRA-AF: A mulTi-center, randomized, doUble-bliNded, placebo-controlled Dose-escalating study of the effects of K201 on the RestorAtion of sinus rhythm in subjects with symptomatic Atrial Fibrillation of recent onset - TUNDRA-AF

开始日期2011-02-11

申办/合作机构

Sequel Pharmaceuticals, Inc.

NCT01259622 / Terminated临床2期

A mulTi-center, Randomized, doUble-bliNded, Placebo-controlled Dose-escalating Study of the Effects of K201 on the RestorAtion of Sinus Rhythm in Subjects With Symptomatic Atrial Fibrillation of Recent Onset

The purpose of this study is to evaluate the effects of a single intravenous infusion of K201 compared to placebo in a dose escalating manner on conversion to sinus rhythm, reduction of subject's symptom score, and safety.

开始日期2011-02-01

申办/合作机构

Sequel Pharmaceuticals, Inc.

EUCTR2009-017838-44-DK / Not yet recruitingN/A

A Pilot Phase 2, Randomized, Double-Blind, Placebo-Controlled, Multi-Centered Safety, Tolerability and Preliminary Efficacy Study of K201 Oral for the Prevention of Atrial Fibrillation (AF) Recurrence in Subjects Post-Conversion from AF - ARCTIC-AF

开始日期2010-04-09

申办/合作机构

Sequel Pharmaceuticals, Inc.

100 项与 RYR2 x calcium channel x Sodium channels x Potassium channel 相关的临床结果

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100 项与 RYR2 x calcium channel x Sodium channels x Potassium channel 相关的转化医学

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0 项与 RYR2 x calcium channel x Sodium channels x Potassium channel 相关的专利（医药）

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项与 RYR2 x calcium channel x Sodium channels x Potassium channel 相关的文献（医药）

2024-08-01·Journal of Cellular Biochemistry

Divergent Biochemical Properties and Disparate Impact of Arrhythmogenic Calmodulin Mutations on Zebrafish Cardiac Function

Article

作者: Nounesis, George ; Kontogianni, Iris ; Nasrallah, Gheyath K ; Lai, F Anthony ; Nomikos, Michail ; Safieh-Garabedian, Bared ; Da'as, Sahar I ; Calver, Brian L ; Saleh, Alaaeldin ; Abdelrahman, Doua ; Thanassoulas, Angelos ; Hasan, Waseem

AbstractCalmodulin (CaM) is a ubiquitous, small cytosolic calcium (Ca2+)‐binding sensor that plays a vital role in many cellular processes by binding and regulating the activity of over 300 protein targets. In cardiac muscle, CaM modulates directly or indirectly the activity of several proteins that play a key role in excitation‐contraction coupling (ECC), such as ryanodine receptor type 2 (RyR2), l‐type Ca2+ (Cav1.2), sodium (NaV1.5) and potassium (KV7.1) channels. Many recent clinical and genetic studies have reported a series of CaM mutations in patients with life‐threatening arrhythmogenic syndromes, such as long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT). We recently showed that four arrhythmogenic CaM mutations (N98I, D132E, D134H, and Q136P) significantly reduce the binding of CaM to RyR2. Herein, we investigate in vivo functional effects of these CaM mutations on the normal zebrafish embryonic heart function by microinjecting complementary RNA corresponding to CaMN98I, CaMD132E, CaMD134H, and CaMQ136P mutants. Expression of CaMD132E and CaMD134H mutants results in significant reduction of the zebrafish heart rate, mimicking a severe form of human bradycardia, whereas expression of CaMQ136P results in an increased heart rate mimicking human ventricular tachycardia. Moreover, analysis of cardiac ventricular rhythm revealed that the CaMD132E and CaMN98I zebrafish groups display an irregular pattern of heart beating and increased amplitude in comparison to the control groups. Furthermore, circular dichroism spectroscopy experiments using recombinant CaM proteins reveals a decreased structural stability of the four mutants compared to the wild‐type CaM protein in the presence of Ca2+. Finally, Ca2+‐binding studies indicates that all CaM mutations display reduced CaM Ca2+‐binding affinities, with CaMD132E exhibiting the most prominent change. Our data suggest that CaM mutations can trigger different arrhythmogenic phenotypes through multiple and complex molecular mechanisms.

2024-06-01·Translational Research

Interleukin-33/ST2 axis involvement in atrial remodeling and arrhythmogenesis

Article

作者: Chen, Yi-Jen ; Cheng, Tzu-Yu ; Chen, Yao-Chang ; Lin, Fong-Jhih ; Lu, Yen-Yu ; Lee, Ting-I ; Li, Shao-Jung ; Kao, Yu-Hsun ; Higa, Satoshi ; Lee, Ting-Wei

Interleukin (IL)-33, a cytokine involved in immune responses, can activate its receptor, suppression of tumorigenicity 2 (ST2), is elevated during atrial fibrillation (AF). However, the role of IL-33/ST2 signaling in atrial arrhythmia is unclear. This study explored the pathological effects of the IL-33/ST2 axis on atrial remodeling and arrhythmogenesis. Patch clamping, confocal microscopy, and Western blotting were used to analyze the electrical characteristics of and protein activity in atrial myocytes (HL-1) treated with recombinant IL-33 protein and/or ST2-neutralizing antibodies for 48 hrs. Telemetric electrocardiographic recordings, Masson's trichrome staining, and immunohistochemistry staining of the atrium were performed in mice receiving tail vein injections with nonspecific immunoglobulin (control), IL-33, and IL-33 combined with anti-ST2 antibody for 2 weeks. IL-33-treated HL-1 cells had a reduced action potential duration, lower L-type Ca²⁺ current, greater sarcoplasmic reticulum (SR) Ca²⁺ content, increased Na⁺/Ca²⁺ exchanger (NCX) current, elevation of K⁺ currents, and increased intracellular calcium transient. IL-33-treated HL-1 myocytes had greater activation of the calcium-calmodulin-dependent protein kinase II (CaMKII)/ryanodine receptor 2 (RyR2) axis and nuclear factor kappa B (NF-κB) / NLR family pyrin domain containing 3 (NLRP3) signaling than did control cells. IL-33 treated cells also had greater expression of Nav1.5, Kv1.5, NCX, and NLRP3 than did control cells. Pretreatment with neutralizing anti-ST2 antibody attenuated IL-33-mediated activation of CaMKII/RyR2 and NF-κB/NLRP3 signaling. IL-33-injected mice had more atrial ectopic beats and increased AF episodes, greater atrial fibrosis, and elevation of NF-κB/NLRP3 signaling than did controls or mice treated with IL-33 combined with anti-ST2 antibody. Thus, IL-33 recombinant protein treatment promotes atrial remodeling through ST2 signaling. Blocking the IL-33/ST2 axis might be an innovative therapeutic approach for patients with atrial arrhythmia and elevated serum IL-33.

2024-04-01·Journal of Molecular and Cellular Cardiology

Adipocyte-mediated electrophysiological remodeling of human stem cell - derived cardiomyocytes

Article

作者: Tung, Leslie ; Morrissette-McAlmon, Justin ; Xu, William R ; Boheler, Kenneth R ; Teuben, Roald

Adipocytes normally accumulate in the epicardial and pericardial layers around the human heart, but their infiltration into the myocardium can be proarrhythmic. METHODS AND RESULTS: Human adipose derived stem/stromal cells and human induced pluripotent stem cells (hiPSC) were differentiated, respectively into predominantly white fat-like adipocytes (hAdip) and ventricular cardiomyocytes (CMs). Adipocytes cultured in CM maintenance medium (CM medium) maintained their morphology, continued to express adipogenic markers, and retained clusters of intracellular lipid droplets. In contrast, hiPSC-CMs cultivated in adipogenic growth medium displayed abnormal cell morphologies and more clustering across the monolayer. Pre-plated hiPSC-CMs co-cultured in direct contact with hAdips in CM medium displayed prolonged action potential durations, increased triangulation, slowed conduction velocity, increased conduction velocity heterogeneity, and prolonged calcium transients. When hAdip-conditioned medium was added to monolayer cultures of hiPSC-CMs, results similar to those recorded with direct co-cultures were observed. Both co-culture and conditioned medium experiments resulted in increases in transcript abundance of SCN10A, CACNA1C, SLC8A1, and RYR2, with a decrease in KCNJ2. Human adipokine immunoblots revealed the presence of cytokines that were elevated in adipocyte-conditioned medium, including MCP-1, IL-6, IL-8 and CFD that could induce electrophysiological changes in cultured hiPSC-CMs. CONCLUSIONS: Co-culture of hiPSC-CMs with hAdips reveals a potentially pathogenic role of infiltrating human adipocytes on myocardial tissue. In the absence of structural changes, hAdip paracrine release alone is sufficient to cause CM electrophysiological dysfunction mirroring the co-culture conditions. These effects, mediated largely by paracrine mechanisms, could promote arrhythmias in the heart.