Article
Cardiac & Cardiovascular Systems
Fariba Ahmadizar, Negin Soroush, M. Arfan Ikram, Jan A. Kors, Maryam Kavousi, Bruno H. Stricker
Summary: This study aimed to investigate the effects of hydroxychloroquine and chloroquine on electrocardiographic measures and sudden cardiac death. The results showed that current use of these drugs was associated with an increased QTc-interval duration and a higher risk of sudden cardiac death. Therefore, cardiotoxicity is a strong argument against using these drugs to treat COVID-19 infections, in addition to the controversial efficacy against the virus.
EUROPEAN JOURNAL OF PREVENTIVE CARDIOLOGY
(2022)
Article
Cardiac & Cardiovascular Systems
Jani T. Tikkanen, Tuomas Kentta, Kimmo Porthan, Olli Anttonen, Antti Eranti, Aapo L. Aro, Tuomas Kerola, Harri A. Rissanen, Paul Knekt, Markku Heliovaara, Arttu Holkeri, Anette Haukilahti, Teemu Niiranen, Jussi Hernesniemi, Antti Jula, Markku S. Nieminen, Robert J. Myerburg, Christine M. Albert, Veikko Salomaa, Heikki Huikuri, M. Juhani Junttila
Summary: This study found that prolonged QRS duration and QTc interval are associated with an increased risk of sudden cardiac death (SCD). However, when the QTc interval is deconstructed into QRS and JTc intervals, the repolarization component (JTc) appears to have no independent prognostic value.
Article
Multidisciplinary Sciences
Yoshiaki Kise, Go Kasuya, Hiroyuki H. Okamoto, Daichi Yamanouchi, Kan Kobayashi, Tsukasa Kusakizako, Tomohiro Nishizawa, Koichi Nakajo, Osamu Nureki
Summary: Mechanisms of modulation of Kv4 channel complexes by auxiliary subunits are central to the physiological function of channels in the brain and heart. The structures of Kv4.2-KChIP1 and Kv4.2-DPP6S complexes reveal that KChIP1 prevents N-type inactivation and stabilizes the S6 conformation, while DPP6S interacts with the S1 and S2 helices to accelerate voltage-dependent movement. KChIP1 and DPP6S do not directly interact with each other in the ternary complex, suggesting two distinct modes of modulation contribute to evoke A-type currents.
Article
Cardiac & Cardiovascular Systems
Victor Nauffal, Valerie N. Morrill, Sean J. Jurgens, Seung Hoan Choi, Amelia W. Hall, Lu-Chen Weng, Jennifer L. Halford, Christina Austin-Tse, Christopher M. Haggerty, Stephanie L. Harris, Eugene K. Wong, Alvaro Alonso, Dan E. Arking, Emelia J. Benjamin, Eric Boerwinkle, Yuan- Min, Adolfo Correa, Brandon K. Fornwalt, Susan R. Heckbert, Charles Kooperberg, Henry J. Lin, Ruth J.f. Loos, Kenneth M. Rice, Namrata Gupta, Thomas W. Blackwell, Braxton D. Mitchell, Alanna C. Morrison, Bruce M. Psaty, Wendy S. Post, Susan Redline, Heidi L. Rehm, Stephen S. Rich, Jerome I. Rotter, Elsayed Z. Soliman, Nona Sotoodehnia, Kathryn L. Lunetta, Patrick T. Ellinor, Steven A. Lubitz
Summary: Using data from large-scale biorepositories, this study found 54 independent loci associated with cardiac repolarization, including 21 novel loci. The findings suggest that both rare variants in genes underlying cardiac repolarization and polygenic risk play a role in determining the duration of QT interval in the population.
Article
Medicine, General & Internal
Ibrahim Akin, Michael Behnes, Julian Mueller, Jan Forner, Mohammad Abumayyaleh, Kambis Mashayekhi, Muharrem Akin, Thomas Bertsch, Kathrin Weidner, Jonas Rusnak, Dirk Grosse Meininghaus, Maximilian Kittel, Tobias Schupp
Summary: High levels of cTNI are associated with increased risk of all-cause mortality within 30 days in patients with ventricular tachyarrhythmias.
JOURNAL OF CLINICAL MEDICINE
(2022)
Article
Biochemistry & Molecular Biology
Wenlei Ye, Hongtu Zhao, Yaxin Dai, Yingdi Wang, Yu-hua Lo, Lily Yeh Jan, Chia-Hsueh Lee
Summary: This article reports the structures of the K(V)4 channel in inactivated, open, and closed states, elucidating the mechanisms of inactivation and voltage-dependent activation, particularly the mechanism of closed-state inactivation. The findings contribute to a better understanding of the functional regulation of ion channels.
Article
Cardiac & Cardiovascular Systems
Gherardo Finocchiaro, Davide Radaelli, Stefano D'Errico, Michael Papadakis, Elijah R. Behr, Sanjay Sharma, Joseph Westaby, Mary N. Sheppard
Summary: This study investigated the causes of sudden cardiac death (SCD) in adolescents and found that the most common autopsy finding was structurally normal heart, indicative of sudden arrhythmic death syndrome. Among young athletes, arrhythmogenic cardiomyopathy, coronary artery anomalies, and commotio cordis were more common causes of SCD.
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
(2023)
Article
Multidisciplinary Sciences
Junichi Sugita, Katsuhito Fujiu, Yukiteru Nakayama, Takumi Matsubara, Jun Matsuda, Tsukasa Oshima, Yuxiang Liu, Yujin Maru, Eriko Hasumi, Toshiya Kojima, Hiroshi Seno, Keisuke Asano, Ayumu Ishijima, Naoki Tomii, Masatoshi Yamazaki, Fujimi Kudo, Ichiro Sakuma, Ryozo Nagai, Ichiro Manabe, Issei Komuro
Summary: It has been demonstrated that cardiac resident macrophages are crucial regulators of cardiac impulse conduction through the production of Amphiregulin, contributing significantly to the prevention of sudden death.
NATURE COMMUNICATIONS
(2021)
Article
Medicine, General & Internal
Zhaohui Ni, Haijiao Jin, Renhua Lu, Li Zuo, Weimin Yu, Yuqing Ren, Qiongqiong Yang, Jie Xiao, Qinghong Zhang, Lihong Zhang, Xinzhou Zhang, Qinkai Chen, Chaosheng Chen, Guojian Shao, Qun Luo, Li Yao, Shuguang Qin, Hui Peng, Qing Zhao
Summary: The study aims to investigate the occurrence, recurrence, and treatment of hyperkalaemia in patients on haemodialysis in China. Approximately 600 patients will be enrolled and followed for 24 weeks. The findings will be disseminated through peer-reviewed publications and conference presentations.
Review
Genetics & Heredity
Li Fan, Ping Yin, Zuojun Xu
Summary: Sudden death in young adults can result from genetic and environmental factors, requiring an understanding of genetic etiology for prevention. The causes of sudden death are complex and varied, with genetic risk factors playing a significant role.
Article
Cardiac & Cardiovascular Systems
Hanna-Kaisa Nordenswan, Pauli Poyhonen, Jukka Lehtonen, Kaj Ekstrom, Valtteri Uusitalo, Meri Niemela, Tapani Vihinen, Kari Kaikkonen, Petri Haataja, Tuomas Kerola, Tuomas T. Rissanen, Aleksi Alatalo, Paivi Pietila-Effati, Markku Kupari
Summary: Current guidelines for ICD implantation in patients with clinically manifest CS do not effectively distinguish a truly low-risk group, as the 5-year risk of SCD approaches 5% even in the absence of ICD indications. Further research is needed to investigate prognostic factors, including the role of diagnostic histology. In the meantime, all patients with CS presenting with clinical cardiac manifestations should be considered for ICD implantation.
Article
Multidisciplinary Sciences
Andrew E. Radbill, Lucy Y. Lei, Sachin Y. Paranjape, Daniel J. Blackwell, Robert L. Abraham, Derek S. Chew, Satish R. Raj, Bjorn C. Knollmann
Summary: This study aimed to assess rate-dependence of clinical surrogates of contractility and repolarization in humans with hypertrophic cardiomyopathy. Findings show that rapid pacing trains triggered ventricular ectopy in hypertrophic cardiomyopathy patients, but not controls. However, there were no significant differences observed in surrogate measures for cardiac contractility, suggesting that altered length-dependent myofilament activation may not have significant clinical implications in these patients.
Article
Multidisciplinary Sciences
Karlien J. ter Meulen, Ben J. M. Hermans, Frank M. van der Sande, Bernard Canaud, Constantijn J. A. M. Konings, Jeroen P. Kooman, Tammo Delhaas
Summary: This study found that lower dialysate calcium concentration and citric-acid dialysate have a positive impact on calcification propensity in serum of haemodialysis patients, while possibly leading to a prolonged cardiac action potential. The use of citric-acid dialysate or lower dialysate calcium concentration significantly prolongs the QT interval corrected for heart rate, but the extent of prolongation is relatively limited.
SCIENTIFIC REPORTS
(2021)
Article
Medicine, General & Internal
Yusuke Miura, Satoshi Higuchi, Takashi Kohno, Yasuyuki Shiraishi, Mitsunobu Kitamura, Yuji Nagatomo, Makoto Takei, Shintaro Nakano, Ayumi Goda, Kyoko Soejima, Shun Kohsaka, Tsutomu Yoshikawa
Summary: Dyskalemia, especially hypokalemia, is associated with prognosis in heart failure patients, particularly in those with reduced ejection fraction. Hyperkalemia is not independently associated with prognosis.
JOURNAL OF CLINICAL MEDICINE
(2022)
Article
Neurosciences
Alexis Haddjeri-Hopkins, Monica Tapia, Jorge Ramirez-Franco, Fabien Tell, Beatrice Marqueze-Pouey, Marianne Amalric, Jean-Marc Goaillard
Summary: Dopaminergic neurons in the substantia nigra pars compacta display a unique electrical phenotype characterized by the role of the I-A current, previously thought to be exclusively carried by Kv4.3 potassium channels. The loss of Kv4.3 channel is associated with behavioral changes and a lack of compensatory changes in other ion currents. The biophysical property of I-A gating kinetics appears to play a key role in defining firing features.
Article
Clinical Neurology
Kyle E. Thomson, Cameron S. Metcalf, Thomas G. Newell, Jennifer Huff, Sharon F. Edwards, Peter J. West, Karen S. Wilcox
Article
Chemistry, Medicinal
Xiaoyang Li, Richard A. Himes, Lyndsey C. Prosser, Charleston F. Christie, Emma Watt, Sharon F. Edwards, Cameron S. Metcalf, Peter J. West, Karen S. Wilcox, Sherine S. L. Chan, C. James Chou
JOURNAL OF MEDICINAL CHEMISTRY
(2020)
Article
Clinical Neurology
Brett Goerl, Sarah Watkins, Cameron Metcalf, Misty Smith, Mark Beenhakker
Summary: The study found that CBDa-enriched hemp extracts demonstrated dose-dependent protection in rats, comparable but not more effective than CBD. Chylobinoid was more effective than Mg-CBDa despite lower CBDa content. Further comparisons of test compounds should be conducted through sub-chronic dosing in the MES test to assess safety and pharmacokinetic profiles, and CBDa should be evaluated in pharmacoresistant and chronic animal models of epilepsy.
Article
Clinical Neurology
Chelsea D. Pernici, Jeffrey A. Mensah, E. Jill Dahle, Kristina J. Johnson, Laura Handy, Lauren Buxton, Misty D. Smith, Peter J. West, Cameron S. Metcalf, Karen S. Wilcox
Summary: Dravet syndrome is a rare but catastrophic genetic epilepsy, with majority of patients carrying a mutation in the SCN1A gene and currently lacking effective antiseizure drugs. Patients with DS often first present with febrile seizures, followed by generalized tonic-clonic seizures that can continue throughout life. The DS mouse model evaluated in this study showed refractoriness to most antiseizure drugs, except for a few that elevated seizure thresholds.
Article
Clinical Neurology
Melissa Barker-Haliski, Kevin Knox, Dannielle Zierath, Zachery Koneval, Cameron Metcalf, Karen S. Wilcox, H. Steve White
Summary: The study focused on pharmacological characterization and methodological refinement of a moderate-throughput drug screening program using the post-KA-induced SE model to identify potential agents that may prevent or modify the burden of SRS. Although no adverse side effects were observed, neither phenobarbital nor everolimus significantly modified the disease or prevented the presentation of SRS.
Article
Clinical Neurology
Toshiya Nishi, Cameron S. Metcalf, Shinji Fujimoto, Shigeo Hasegawa, Maki Miyamoto, Eiji Sunahara, Sayuri Watanabe, Shinichi Kondo, H. Steve White
Summary: The study characterizes the anticonvulsive property of soticlestat in rodent models of epilepsy and suggests that it may be a novel class of antiseizure medications for the treatment of intractable epilepsy disorders.
Article
Neurosciences
Peter J. West, Kyle Thomson, Peggy Billingsley, Timothy Pruess, Carlos Rueda, Gerald W. Saunders, Misty D. Smith, Cameron S. Metcalf, Karen S. Wilcox
Summary: The study demonstrates that in this MTLE IAK model, pharmacoresistant seizures are resistant to two representative sodium channel-inhibiting ASDs (phenytoin and carbamazepine) and partially sensitive to GABA receptor modulating ASDs (diazepam and phenobarbital) or a mixed-mechanism ASD (valproate). This model is being incorporated into the NINDS-funded ETSP testing platform for treatment resistant epilepsy.
EXPERIMENTAL NEUROLOGY
(2022)
Review
Clinical Neurology
Juliet K. Knowles, Ingo Helbig, Cameron S. Metcalf, Laura S. Lubbers, Lori L. Isom, Scott Demarest, Ethan M. Goldberg, Alfred L. George, Holger Lerche, Sarah Weckhuysen, Vicky Whittemore, Samuel F. Berkovic, Daniel H. Lowenstein
Summary: The genetic basis of epilepsy is becoming better understood, opening up the possibility for precision treatments based on specific genetic causes. However, current medical therapy for epilepsy is still imprecise and mainly focused on reducing seizures empirically. Despite significant advancements in diagnosis and technology, there has been limited impact on clinical practice. Nevertheless, the epilepsy community is poised to make significant progress in precision therapy through continued innovations in gene discovery, diagnostics, and bioinformatics, increased accessibility to genetic testing, and a greater understanding of the natural course of the disease.
Article
Neurosciences
Ryley Collard, Miriam C. Aziz, Kevin Rapp, Connor Cutshall, Evalien Duyvesteyn, Cameron S. Metcalf
Summary: The pathophysiology of SUDEP is still not well understood, but recent studies suggest that diminished post-ictal respiratory control and depletion of neuropeptide galanin in the amygdala may contribute to the mortality. Enhancing galaninergic signaling shows potential in protecting against post-ictal respiratory collapse.
FRONTIERS IN NEURAL CIRCUITS
(2022)
Article
Multidisciplinary Sciences
Gaelle Batot, Cameron S. Metcalf, Laura A. Bell, Alberto Pauletti, Karen S. Wilcox, Sonja Broeer
Summary: This study explores the modeling of epilepsy caused by central nervous system (CNS) infection and its use as a platform for testing novel antiseizure compounds. The TMEV infection model in mice replicates the clinical symptoms of viral encephalitis and subsequent epilepsy in humans, and provides a means to investigate the mechanisms of epilepsy development and identify therapeutic targets for patients at risk.
JOVE-JOURNAL OF VISUALIZED EXPERIMENTS
(2022)
Article
Cell Biology
Marcin Jakubiec, Michal Abram, Miroslaw Zagaja, Marta Andres-Mach, Aleksandra Szewczyk, Gniewomir Latacz, Bartlomiej Szulczyk, Katarzyna Socala, Dorota Nieoczym, Piotr Wlaz, Cameron S. Metcalf, Karen Wilcox, Rafal M. Kaminski, Krzysztof Kaminski
Summary: In this study, a combinatorial chemistry approach was used to merge structural fragments of TRPV1 antagonists with a lead compound KA-104, resulting in the design and synthesis of a series of 22 original compounds. The obtained compounds displayed robust in vivo antiseizure activity and demonstrated a multimodal mechanism of action. Two of the most potent compounds, 53 and 60, showed promising pharmacological profiles and beneficial ADME-Tox properties, making them interesting candidates for future preclinical development in epilepsy and pain indications.
Article
Clinical Neurology
Jeffrey A. Mensah, Kristina Johnson, Christopher A. Reilly, Karen S. Wilcox, Joseph E. Rower, Cameron S. Metcalf
Summary: This study demonstrates the utility of PK analyses for understanding the seizure protection time course in mice and rats. The data indicate that distinct PK profiles of ASMs between mice and rats likely drive differences in drug efficacy between rodent models.
Article
Clinical Neurology
Cameron S. Metcalf, Saurabh Gagangras, Grzegorz Bulaj, H. Steve White
Summary: This study evaluated the combination of 810-2 with commonly used antiseizure medications and found that the combination of 810-2 with levetiracetam (LEV) showed a synergistic interaction, suggesting its potential as an add-on therapy for patients with epilepsy.
Article
Clinical Neurology
Lisa Coles, Patrick A. Forcelli, Karine Leclercq, Anna-Maria Katsarou, Brian D. Klein, Heidrun Potschka, Rudiger Koehling, Lauren Harte-Hargrove, Aristea S. Galanopoulou, Cameron S. Metcalf
Summary: In order to address concerns over rigor and reproducibility in preclinical studies, the ILAE/AES Task Force has developed common data elements and case report forms for epilepsy research. These forms have been adapted and refined to cover various aspects of preclinical drug screening. They provide a standardized approach to collect data on general pharmacology, pharmacokinetics, pharmacodynamics, tolerability, and elements of rigor and reproducibility. The case report forms can be used widely in the epilepsy research community.
Article
Clinical Neurology
Cameron S. Metcalf, Fabiola Vanegas, Tristan Underwood, Kristina Johnson, Peter J. West, Misty D. Smith, Karen S. Wilcox
Summary: The study evaluated the efficacy of antiseizure medications and anti-inflammatory compounds in reducing seizure burden in C57Bl/6J mice infected with Theiler's murine encephalomyelitis virus (TMEV). Several prototype ASMs and anti-inflammatory drugs showed promising results in reducing seizures, with some exhibiting mechanisms of action beyond traditional ASMs. This highlights the importance of evaluating compounds from different mechanistic classes in the TMEV model for potential treatment of infection-induced seizures.
