Featured
-
-
Article
| Open AccessPractical intelligent diagnostic algorithm for wearable 12-lead ECG via self-supervised learning on large-scale dataset
Intelligent diagnostic algorithms for ECG are becoming increasingly important to reduce the workload of cardiologists, enable telemedicine and real-time monitoring. Here, the authors show a model based on self-supervised learning that can classify 60 diagnostic terms for ECG.
- Jiewei Lai
- , Huixin Tan
- & Wei Yang
-
Article
| Open AccessE-cigarettes and their lone constituents induce cardiac arrhythmia and conduction defects in mice
The use of E-cigarettes has increased despite the unknown long-term effects. Here the authors show that e-cigarette aerosols alter cardiac conduction, repolarization, and autonomic regulation in mice, contingent on the chemical composition of e-liquids and partly through parasympathetic modulation.
- Alex P. Carll
- , Claudia Arab
- & Daniel J. Conklin
-
Article
| Open AccessTmem65 is critical for the structure and function of the intercalated discs in mouse hearts
The intercalated disc (ICD) is a membrane structure of the cardiac muscle involved in normal heart function. Here the authors report that knockdown of the ICD-bound transmembrane protein 65 results in impaired ICD structure, abnormal cardiac electrophysiology and cardiomyopathy in mice.
- Allen C. T. Teng
- , Liyang Gu
- & Anthony O. Gramolini
-
Article
| Open AccessSelective optogenetic control of Gq signaling using human Neuropsin
Gq proteins are one of four major classes of G proteins; optogenetic receptors for selective and repetitive activation of Gq proteins with fast kinetics are lacking. Here the authors report UV light-dependent Gq signalling using human Neuropsin (hOPN5) and demonstrate its potential as an optogenetic tool.
- Ahmed Wagdi
- , Daniela Malan
- & Tobias Bruegmann
-
Article
| Open AccessHeterogeneous repolarization creates ventricular tachycardia circuits in healed myocardial infarction scar
Ventricular arrhythmias after heart attack are a leading cause of death. Here the authors show, in a porcine model, that KCNE3 and KCNE4 upregulation and a unique pattern of repolarization heterogeneity in the scar facilitate reentrant ventricular tachycardia.
- Kamilla Kelemen
- , Ian D. Greener
- & J. Kevin Donahue
-
Article
| Open AccessMicroRNA-365 regulates human cardiac action potential duration
An abnormal cardiac action potential underlies different types of cardiac arrhythmias. Here the authors show that microRNA-365 regulates the cardiac action potential by modulating key cardiac repolarizing channels.
- Dena Esfandyari
- , Bio Maria Ghéo Idrissou
- & Stefan Engelhardt
-
Article
| Open AccessSynthetic recovery of impulse propagation in myocardial infarction via silicon carbide semiconductive nanowires
Silicon-based materials have the ability to support bioelectrical activity. Here the authors show how injectable silicon carbide nanowires reduce arrhythmias and rapidly restore conduction in a myocardial infarction model.
- Paola Lagonegro
- , Stefano Rossi
- & Michele Miragoli
-
Article
| Open AccessCardiac radiotherapy induces electrical conduction reprogramming in the absence of transmural fibrosis
Noninvasive cardiac radiotherapy may effectively manage ventricular tachycardia in refractory patients, but its radiobiologic mechanisms of action are unclear. Here, the authors show that photon radiation durably and favourably reprograms cardiac conduction in the absence of transmural fibrosis suggesting this could be the mechanism through which cardiac radiotherapy to modulates arrhythmia susceptibility.
- David M. Zhang
- , Rachita Navara
- & Stacey L. Rentschler
-
Article
| Open AccessDistinct circadian mechanisms govern cardiac rhythms and susceptibility to arrhythmia
Cardiac function fluctuates greatly across the day and night, but this is not simply a consequence of our changing behaviour. The authors highlight the role of the body’s circadian clock in regulating the heart electrical activity, including a time-of-day dependent susceptibility to cardiac arrhythmias.
- Edward A. Hayter
- , Sophie M. T. Wehrens
- & David A. Bechtold
-
Article
| Open AccessCardiac macrophages prevent sudden death during heart stress
Cardiac immune cells play various roles in the maintenance of homeostasis and diseases in the heart. Here the authors show that cardiac resident macrophages are a critical regulator of cardiac impulse conduction through amphiregulin production, contributing to the prevention of sudden death.
- Junichi Sugita
- , Katsuhito Fujiu
- & Issei Komuro
-
Article
| Open AccessPathological conformations of disease mutant Ryanodine Receptors revealed by cryo-EM
Ryanodine Receptors (RyRs) release Ca2+ from the endoplasmic and sarcoplasmic reticulum. Mutations in RyR are linked to malignant hyperthermia (MH), myopathies, and arrhythmias. Here, a collection of cryoEM structures provides insights into the molecular consequences of MHrelated RyR mutation R615C, and how apoCaM opens RyR1.
- Kellie A. Woll
- , Omid Haji-Ghassemi
- & Filip Van Petegem
-
Article
| Open AccesscAMP-dependent regulation of HCN4 controls the tonic entrainment process in sinoatrial node pacemaker cells
The involvement of cAMP-dependent regulation of HCN4 in the chronotropic heart rate response is a matter of debate. Here the authors use a knockin mouse model expressing cAMP-insensitive HCN4 channels to discover an inhibitory nonfiring cell pool in the sinoatrial node and a tonic and mutual interaction between firing and nonfiring pacemaker cells that is controlled by cAMP-dependent regulation of HCN4, with implications in chronotropic heart rate responses.
- Stefanie Fenske
- , Konstantin Hennis
- & Christian Wahl-Schott
-
Article
| Open AccessImpaired neuronal sodium channels cause intranodal conduction failure and reentrant arrhythmias in human sinoatrial node
The role of of voltage-gated sodium channels (Nav) in pacemaking and conduction of the human sinoatrial node is unclear. Here, the authors investigate existence and function of neuronal and cardiac Nav in human sinoatrial nodes, and demonstrate their alterations in explanted human diseased hearts.
- Ning Li
- , Anuradha Kalyanasundaram
- & Vadim V. Fedorov
-
Article
| Open AccessAugmentation of myocardial If dysregulates calcium homeostasis and causes adverse cardiac remodeling
The depolarizing funny current contributing to cardiac pacemaking is upregulated in the myocardium of failing and infarcted hearts, but whether the current is implied in disease mechanisms is unclear. Here the authors generate HCN4 transgenic mice and show that upregulation of funny current to the levels observed in human heart failure alters calcium homeostasis leading to cardiac remodelling and arrhythmia.
- Pessah Yampolsky
- , Michael Koenen
- & Patrick A. Schweizer
-
Article
| Open AccessDNA damage-induced PARP1 activation confers cardiomyocyte dysfunction through NAD+ depletion in experimental atrial fibrillation
Atrial fibrillation (AF) is accompanied by a detrimental loss of functional cardiomyocytes. Here, Zhang et al. show that AF-induced cardiomyocyte dysfunction is a consequence of DNA damage-mediated PARP1 activation, which leads to depletion of NAD+ and further oxidative stress and DNA damage, and identify PARP1 inhibition as a potential therapeutic strategy in the treatment of AF.
- Deli Zhang
- , Xu Hu
- & Bianca J. J. M. Brundel
-
Article
| Open AccessRare truncating variants in the sarcomeric protein titin associate with familial and early-onset atrial fibrillation
Common genetic variants in structural proteins contribute to risk of atrial fibrillation (AF). Here, using whole-exome sequencing, the authors identify rare truncating variants in TTN that associate with familial and early-onset AF and show defects in cardiac sarcomere assembly in ttn.2-mutant zebrafish.
- Gustav Ahlberg
- , Lena Refsgaard
- & Morten S. Olesen
-
Article
| Open AccessLong non-coding RNA CCRR controls cardiac conduction via regulating intercellular coupling
Long noncoding RNAs have been shown to play a role in cardiovascular disease. Here, the authors identify a lncRNA named CCRR, whose downregulation in failing hearts causes cardiac conduction disturbances by altering the endocytic trafficking of Cx43.
- Yong Zhang
- , Lihua Sun
- & Baofeng Yang
-
Article
| Open AccessIdentification of small-molecule ion channel modulators in C. elegans channelopathy models
Mutations in the voltage-gated K+ channel human ether-a-go-go-related gene (hERG) lead to Long-QT syndrome, causing life-threatening cardiac arrhythmia. Here the authors use C. elegans as a platform to run a channelopathy drug screen, identifying drugs to target hERG mutants.
- Qiang Jiang
- , Kai Li
- & Shi-Qing Cai
-
Article
| Open AccessPR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity
Abnormal PR interval duration is associated with risk for atrial fibrillation and heart block. Here, van Setten et al. identify 44 PR interval loci in a genome-wide association study of over 92,000 individuals and find genetic overlap with QRS duration, heart rate and atrial fibrillation.
- Jessica van Setten
- , Jennifer A. Brody
- & Nona Sotoodehnia
-
Article
| Open AccessInactivation of KCNQ1 potassium channels reveals dynamic coupling between voltage sensing and pore opening
KCNQ1 is a voltage-gated potassium channel that is important in cardiac and epithelial function. Here the authors present a mechanism for KCNQ1 activation and inactivation in which voltage sensor activation promotes pore opening more effectively in the intermediate open state than the fully open state, generating inactivation.
- Panpan Hou
- , Jodene Eldstrom
- & Jianmin Cui
-
Article
| Open AccessLoss-of-activity-mutation in the cardiac chloride-bicarbonate exchanger AE3 causes short QT syndrome
Mutations in potassium and calcium channel genes have been associated with cardiac arrhythmias. Here, Jensen et al. show that an anion transporter chloride-bicarbonate exchanger AE3 is also responsible for the genetically-induced mechanism of cardiac arrhythmia, suggesting new therapeutic targets for this disease
- Kasper Thorsen
- , Vibeke S. Dam
- & Henrik K. Jensen
-
Article
| Open AccessRegion and cell-type resolved quantitative proteomic map of the human heart
The human heart is composed of distinct regions and cell types, but relatively little is known about their specific protein composition. Here, the authors present a region- and cell type-specific proteomic map of the healthy human heart, revealing functional differences and potential cell type markers.
- Sophia Doll
- , Martina Dreßen
- & Matthias Mann
-
Article
| Open AccessPlakophilin-2 is required for transcription of genes that control calcium cycling and cardiac rhythm
It is believed that mutations in desmosomal adhesion complex protein plakophilin 2 (PKP2) cause arrhythmia due to loss of cell-cell communication. Here the authors show that PKP2 controls the expression of proteins involved in calcium cycling in adult mouse hearts, and that lack of PKP2 can cause arrhythmia in a structurally normal heart.
- Marina Cerrone
- , Jerome Montnach
- & Mario Delmar
-
Article
| Open AccessDisruption of cardiac cholinergic neurons enhances susceptibility to ventricular arrhythmias
Catheter ablation is a common therapy for atrial fibrillation but disrupts cardiac cholinergic neurons. Here the authors report that cholinergic neurons innervate heart ventricles and show that their ablation leads to increased susceptibility to ventricular arrhythmias in mouse models and in patients.
- Christiane Jungen
- , Katharina Scherschel
- & Christian Meyer
-
Article
| Open AccessMacrophage-dependent IL-1β production induces cardiac arrhythmias in diabetic mice
Ventricular arrhythmia is a leading cause of death in patients with diabetes. Here the authors show that inflammasome activation and ILK-1β production in cardiac macrophages cause arrhythmia in diabetic mice, which can be successfully treated using agonists to IL-1β receptor or NLRP3 inhibitors.
- Gustavo Monnerat
- , Micaela L. Alarcón
- & Emiliano Medei
-
Article
| Open AccessFhf2 gene deletion causes temperature-sensitive cardiac conduction failure
Fever is a defence mechanism against infection, but it may also cause abnormal heart rhythm viaunknown mechanism. Here the authors identify FHF2 protein as a key regulator of myocardial excitability that protects the heart against conduction failure in response to an increase in body temperature.
- David S. Park
- , Akshay Shekhar
- & Glenn I. Fishman
-
Article
| Open AccessCardiac sodium channel palmitoylation regulates channel availability and myocyte excitability with implications for arrhythmia generation
Cardiac voltage-gated sodium channels (Nav1.5) are crucial regulators of heart electric activity. Here the authors show that palmitoylation, a process of lipid modification of cysteine residues, modulates Nav1.5 function and affects cardiomyocyte excitability, representing a potential target in treating cardiac diseases.
- Zifan Pei
- , Yucheng Xiao
- & Theodore R. Cummins
-
Article
| Open AccessArrhythmia risk stratification of patients after myocardial infarction using personalized heart models
Sudden arrhythmic death is a leading cause of mortality, however approaches to identify at-risk patients are of low sensitivity and specificity. Here, the authors develop a personalized approach to assess arrhythmia risk in post-infarction patients based on cardiac imaging and computational modelling that significantly outperforms existing clinical metrics.
- Hermenegild J. Arevalo
- , Fijoy Vadakkumpadan
- & Natalia A. Trayanova
-
Article
| Open AccessA mutation in the atrial-specific myosin light chain gene (MYL4) causes familial atrial fibrillation
Here, Michael Gollob and colleagues perform a whole exome sequencing study to identify a mutation in the atrial-specific myosin light chain gene MYL4 in a small family with autosomal dominant familial atrial fibrillation. They also test the functionality of this MYL4mutation in zebrafish cardiac function and recapitulate disease-related phenotypes.
- Nathan Orr
- , Rima Arnaout
- & Michael H. Gollob
-
Article
| Open AccessGenome-wide screening identifies a KCNIP1 copy number variant as a genetic predictor for atrial fibrillation
Tsai et al. here utilize a multi-stage genome-wide association study in Taiwanese population to show a copy number variation in the intron of potassium interacting channel 1 gene (KCNIP1) to be strongly associated with atrial fibrillation. The study also examines the functionality of KCNIP1 in heart electrophysiological function using cultured myocytes and zebrafish.
- Chia-Ti Tsai
- , Chia-Shan Hsieh
- & Jiunn-Lee Lin
-
Article
| Open AccessArrhythmogenesis in Timothy Syndrome is associated with defects in Ca2+-dependent inactivation
Timothy Syndrome (TS) is a multisystem disorder caused by two mutations leading to dysfunction of the CaV1.2 channel. Here, Dick et al. uncover a major and mechanistically divergent effect of both mutations on Ca2+/calmodulin-dependent inactivation of CaV1.2 channels, suggesting genetic variant-tailored therapy for TS treatment.
- Ivy E. Dick
- , Rosy Joshi-Mukherjee
- & David T. Yue
-
Article |
Evolutionarily conserved intercalated disc protein Tmem65 regulates cardiac conduction and connexin 43 function
Mechanical and electrical activity in the heart is propagated through unique cardiomyocyte membrane structures, the intercalated discs (ID). Sharma et al.identify a novel ID protein, Tmem65, that controls Ca2+ signalling and electrical coupling by interacting with and functionally regulating the gap junction protein Cx43.
- Parveen Sharma
- , Cynthia Abbasi
- & Anthony O. Gramolini
-
Article
| Open AccessTargeting protein tyrosine phosphatase σ after myocardial infarction restores cardiac sympathetic innervation and prevents arrhythmias
Chondroitin sulfate proteoglycans (CSP) in the myocardial scar inhibit the tissue’s reinnervation, rendering it prone to arrhythmia. Here the authors show that blocking the activity of the CSP receptor, protein tyrosine phosphatase receptor σ, promotes scar reinnervation and prevents arrhythmia in mice.
- R. T. Gardner
- , L. Wang
- & B. A. Habecker
-
Article |
Increased atrial arrhythmia susceptibility induced by intense endurance exercise in mice requires TNFα
Endurance exercise is associated with an increased risk of atrial fibrillation. Here, the authors show the adipokine TNFα is a crucial mediator of exercise-induced atrial fibrillation and irreversible atrial remodelling characterized by fibrosis and inflammation.
- Roozbeh Aschar-Sobbi
- , Farzad Izaddoustdar
- & Peter H. Backx
-
Article |
The small-molecule BGP-15 protects against heart failure and atrial fibrillation in mice
Atrial fibrillation and heart failure often coexist but are difficult to treat. Here the authors report a therapeutic strategy for atrial fibrillation and heart failure in mice, based on the activating effect of a small molecule, BGP-15, on IGF1 receptor signalling.
- Geeta Sapra
- , Yow Keat Tham
- & Julie R. McMullen
-
Article |
Large-scale mutational analysis of Kv11.1 reveals molecular insights into type 2 long QT syndrome
Type 2 Long QT syndrome is a cardiac disease associated with hundreds of individual mutations within the Kv11.1 potassium channel. Here, the authors systematically investigate the trafficking defects associated with different types of Kv11.1 mutations and to what extent they can be corrected pharmacologically.
- Corey L. Anderson
- , Catherine E. Kuzmicki
- & Craig T. January
-
Article |
Multiscale cardiac modelling reveals the origins of notched T waves in long QT syndrome type 2
Patients with the Long QT Syndrome type 2 have abnormal cardiac electrical activity, which is diagnosed by an electrocardiogram (ECG) that shows a prolonged QT interval and a notched T wave. Here the authors uncover the origins of this signature ECG phenotype by using a multi-scale cardiac modelling.
- Arash Sadrieh
- , Luke Domanski
- & Adam P Hill
-
Article |
Cardiac arrhythmia induced by genetic silencing of ‘funny’ (f) channels is rescued by GIRK4 inactivation
The ‘funny’ current (If) is important for the generation and regulation of the heart’s automaticity. Here the authors show that If silencing through genetic modification of the f-channel component HCN4 causes heart arrhythmia by altering Ca2+handling in pacemaker myocytes.
- Pietro Mesirca
- , Jacqueline Alig
- & Matteo E. Mangoni
-
Article |
Carbon monoxide inhibits inward rectifier potassium channels in cardiomyocytes
Following myocardial infarction, patients are at risk for reperfusion-induced ventricular fibrillation, a life-threatening condition. Here, Liang et al. show that the known ventricular fibrillation preventive effects of carbon monoxide are mediated through the inhibition of a subset of inward-rectifying potassium channels.
- Shenghui Liang
- , Quanyi Wang
- & Yuchun Gu
-
Article
| Open AccessExercise training reduces resting heart rate via downregulation of the funny channel HCN4
Endurance athletes are known to have a low resting heart rate. Here, D'Souza et al.propose that training-induced bradycardia is the result of electrophysiological changes in the sinus node, challenging the classical view that training-induced bradycardia is caused by increased activity of the autonomic nervous system.
- Alicia D’Souza
- , Annalisa Bucchi
- & Mark R. Boyett
-
Article |
Perturbation of sodium channel structure by an inherited Long QT Syndrome mutation
Perturbation of the cardiac voltage-gated sodium channel, NaV1.5, by drugs or inherited mutation can underlie and trigger cardiac arrhythmias. Here, the role of the NaV1.5 carboxy terminus in channel inactivation is investigated, and structural details of an arrhythmia associated H6 mutant are reported.
- Ian W. Glaaser
- , Jeremiah D. Osteen
- & Robert S. Kass