Medicine › Cardiology and Cardiovascular Medicine

Cardiac electrophysiology and arrhythmias

Works Count: 130166

Wikipedia

Description

This cluster of papers focuses on the molecular mechanisms, genetic testing, and clinical aspects of cardiac arrhythmias, including Long-QT Syndrome, Brugada Syndrome, and Sudden Cardiac Death. It explores the role of ion channels, calcium signaling, and arrhythmogenic ion-channel remodeling in the heart.

Keywords

Arrhythmias; Long-QT Syndrome; Sudden Cardiac Death; Ion Channels; Cardiac Electrophysiology; Genetic Testing; Calcium Signaling; Ryanodine Receptor; Brugada Syndrome; Cardiac Channelopathies

Opioid Complications and Side Effects

2008-03-14

Ramsin Benyamin

Medications which bind to opioid receptors are increasingly being prescribed for the treatment of multiple and diverse chronic painful conditions. Their use for acute pain or terminal pain is well … Medications which bind to opioid receptors are increasingly being prescribed for the treatment of multiple and diverse chronic painful conditions. Their use for acute pain or terminal pain is well accepted. Their role in the long-term treatment of chronic noncancer pain is, however, controversial for many reasons. One of the primary reasons is the well-known phenomenon of psychological addiction that can occur with the use of these medications. Abuse and diversion of these medications is a growing problem as the availability of these medications increases and this public health issue confounds their clinical utility. Also, the extent of their efficacy in the treatment of pain when utilized on a chronic basis has not been definitively proven. Lastly, the role of opioids in the treatment of chronic pain is also influenced by the fact that these potent analgesics are associated with a significant number of side effects and complications. It is these phenomena that are the focus of this review. Common side effects of opioid administration include sedation, dizziness, nausea, vomiting, constipation, physical dependence, tolerance, and respiratory depression. Physical dependence and addiction are clinical concerns that may prevent proper prescribing and in turn inadequate pain management. Less common side effects may include delayed gastric emptying, hyperalgesia, immunologic and hormonal dysfunction, muscle rigidity, and myoclonus. The most common side effects of opioid usage are constipation (which has a very high incidence) and nausea. These 2 side effects can be difficult to manage and frequently tolerance to them does not develop; this is especially true for constipation. They may be severe enough to require opioid discontinuation, and contribute to under-dosing and inadequate analgesia. Several clinical trials are underway to identify adjunct therapies that may mitigate these side effects. Switching opioids and/or routes of administration may also provide benefits for patients. Proper patient screening, education, and preemptive treatment of potential side effects may aid in maximizing effectiveness while reducing the severity of side effects and adverse events. Opioids can be considered broad spectrum analgesic agents, affecting a wide number of organ systems and influencing a large number of body functions.

Genetic basis and molecular mechanism for idiopathic ventricular fibrillation

1998-03-01

Qiuyun Chen , Glenn E. Kirsch , Danmei Zhang +7 more

Cardiac Electrophysiology: From Cell to Bedside

1991-06-15

Douglas P. Zipes , José Jalife

Cardiac Electrophysiology: From Cell to Bedside defines the entire state of current scientific and clinical knowledge in this subspecialty. In response to the many major recent developments in the field, … Cardiac Electrophysiology: From Cell to Bedside defines the entire state of current scientific and clinical knowledge in this subspecialty. In response to the many major recent developments in the field, Drs. Zipes and Jalife have completely updated this modern classic, making the 5th Edition the most significant revision yet. From our latest understanding of ion channels, molecular genetics, and cardiac electrical activity through newly recognized syndromes, unique needs of special patient populations, and new diagnostic and therapeutic options, you'll find all the state-of-the-art guidance you need to make informed, effective clinical decisions. What's more, a significantly restructured organization, a new full-color layout, and full-text online access make reference easier than ever.

A mechanistic link between an inherited and an acquird cardiac arrthytmia: HERG encodes the IKr potassium channel

1995-04-01

Michael C. Sanguinetti , Changan Jiang , Mark Curran +1 more

Two components of cardiac delayed rectifier K+ current. Differential sensitivity to block by class III antiarrhythmic agents.

1990-07-01

Michael C. Sanguinetti , Nancy K. Jurkiewicz

An envelope of tails test was used to show that the delayed rectifier K+ current (IK) of guinea pig ventricular myocytes results from the activation of two outward K+ currents. … An envelope of tails test was used to show that the delayed rectifier K+ current (IK) of guinea pig ventricular myocytes results from the activation of two outward K+ currents. One current was specifically blocked by the benzenesulfonamide antiarrhythmic agent, E-4031 (IC50 = 397 nM). The drug-sensitive current, "IKr" exhibits prominent rectification and activates very rapidly relative to the slowly activating drug-insensitive current, "IKs." IKs was characterized by a delayed onset of activation that occurs over a voltage range typical of the classically described cardiac IK. Fully activated IKs, measured as tail current after 7.5-s test pulses, was 11.4 times larger than the fully activated IKr. IKr was also blocked by d-sotalol (100 microM), a less potent benzenesulfonamide Class III antiarrhythmic agent. The activation curve of IKr had a steep slope (+7.5 mV) and a negative half-point (-21.5 mV) relative to the activation curve of IKs (slope = +12.7 mV, half-point = +15.7 mV). The reversal potential (Erev) of IKr (-93 mV) was similar to EK (-94 mV for [K+]o = 4 mM), whereas Erev of IKs was -77 mV. The time constants for activation and deactivation of IKr made up a bell-shaped function of membrane potential, peaking between -30 and -40 mV (170 ms). The slope conductance of the linear portion of the fully activated IKr-V relation was 22.5 S/F. Inward rectification of this relation occurred at potentials greater than -50 mV, resulting in a voltage-dependent decrease in peak IKr at test potentials greater than 0 mV. Peak IKr at 0 mV averaged 0.8 pA/pF (n = 21). Although the magnitude of IKr was small relative to fully activated IKs, the two currents were of similar magnitude when measured during a relatively short pulse protocol (225 ms) at membrane potentials (-20 to +20 mV) typical of the plateau phase of cardiac action potentials.

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KvLQT1 and IsK (minK) proteins associate to form the IKS cardiac potassium current

1996-11-01

Jacques Barhanin , Florian Lesage , Eric Guillemare +3 more

Reconstruction of the action potential of ventricular myocardial fibres

1977-06-01

George W. Beeler , H. Réuter

1. A mathematical model of membrane action potentials of mammalian ventricular myocardial fibres is described. The reconstruction model is based as closely as possible on ionic currents which have been … 1. A mathematical model of membrane action potentials of mammalian ventricular myocardial fibres is described. The reconstruction model is based as closely as possible on ionic currents which have been measured by the voltage‐clamp method. 2. Four individual components of ionic current were formulated mathematically in terms of Hodgkin—Huxley type equations. The model incorporates two voltage‐ and time‐dependent inward currents, the excitatory inward sodium current, i Na , and a secondary or slow inward current, i s , primarily carried by calcium ions. A time‐independent outward potassium current, i K 1 , exhibiting inward‐going rectification, and a voltage‐ and time‐dependent outward current, i x 1 , primarily carried by potassium ions, are further elements of the model. 3. The i Na is primarily responsible for the rapid upstroke of the action potential, while the other current components determine the configuration of the plateau of the action potential and the re‐polarization phase. The relative importance of inactivation of i s and of activation of i x 1 for termination of the plateau is evaluated by the model. 4. Experimental phenomena like slow recovery of the sodium system from inactivation, frequency dependence of the action potential duration, all‐or‐nothing re‐polarization, membrane oscillations are adequately described by the model. 5. Possible inadequacies and shortcomings of the model are discussed.

Sudden Death Due to Cardiac Arrhythmias

2001-11-15

Heikki V. Huikuri , A Castellanos , Robert J. Myerburg

This review article summarizes important changes in our approach to the serious public health problem of sudden death from ventricular arrhythmias. This review article summarizes important changes in our approach to the serious public health problem of sudden death from ventricular arrhythmias.

Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias

1996-01-01

Q. Wang , Mark Curran , Igor Splawski +7 more

HRS/EHRA Expert Consensus Statement on the State of Genetic Testing for the Channelopathies and Cardiomyopathies

2011-07-26

Michael J. Ackerman , Silvia G. Priori , Stephan Willems +7 more

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HL-1 cells: A cardiac muscle cell line that contracts and retains phenotypic characteristics of the adult cardiomyocyte

1998-03-17

William C. Claycomb , Nicholas A. Lanson , Beverly S. Stallworth +4 more

We have derived a cardiac muscle cell line, designated HL-1, from the AT-1 mouse atrial cardiomyocyte tumor lineage. HL-1 cells can be serially passaged, yet they maintain the ability to … We have derived a cardiac muscle cell line, designated HL-1, from the AT-1 mouse atrial cardiomyocyte tumor lineage. HL-1 cells can be serially passaged, yet they maintain the ability to contract and retain differentiated cardiac morphological, biochemical, and electrophysiological properties. Ultrastructural characteristics typical of embryonic atrial cardiac muscle cells were found consistently in the cultured HL-1 cells. Reverse transcriptase–PCR-based analyses confirmed a pattern of gene expression similar to that of adult atrial myocytes, including expression of α-cardiac myosin heavy chain, α-cardiac actin, and connexin43. They also express the gene for atrial natriuretic factor. Immunohistochemical staining of the HL-1 cells indicated that the distribution of the cardiac-specific markers desmin, sarcomeric myosin, and atrial natriuretic factor was similar to that of cultured atrial cardiomyocytes. A delayed rectifier potassium current ( I Kr ) was the most prominent outward current in HL-1 cells. The activating currents displayed inward rectification and deactivating current tails were voltage-dependent, saturated at ≫+20 mV, and were highly sensitive to dofetilide (IC 50 of 46.9 nM). Specific binding of [ 3 H]dofetilide was saturable and fit a one-site binding isotherm with a K d of 140 +/− 60 nM and a B max of 118 fmol per 10 5 cells. HL-1 cells represent a cardiac myocyte cell line that can be repeatedly passaged and yet maintain a cardiac-specific phenotype.

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Total Excitation of the Isolated Human Heart

1970-06-01

D Durrer , R. Th. van Dam , G. E. FREUD +3 more

To obtain information concerning the time course and instantaneous distribution of the excitatory process of the normal human heart, studies were made on isolated human hearts from seven individuals who … To obtain information concerning the time course and instantaneous distribution of the excitatory process of the normal human heart, studies were made on isolated human hearts from seven individuals who died from various cerebral conditions, but who had no history of cardiac disease. Measurements were made from as many as 870 intramural terminals. In the isolated human hearts three endocardial areas were synchronously excited 0 to 5 msec after the start of the left ventricular activity potential. These areas increased rapidly in size during the next 5 to 10 msec and became confluent in 15 to 20 msec. The left ventricular areas first excited were (1) high on the anterior paraseptal wall just below the attachment of the mitral valve; (2) central on the left surface of the interventricular septum and (3) posterior paraseptal about one third of the distance from apex to base. The last part of the left ventricle to be activated usually was the posterobasal area. Endocardial activation of the right ventricle was found to start near the insertion of the anterior papillary muscle 5 to 10 msec after onset of the left ventricular cavity potential. Septal activation started in the middle third of the left side of the interventricular septum, somewhat anteriorly, and at the lower third at the junction of the septum and posterior wall. The epicardial excitation pattern reflected the movements of the intramural excitation wave. Conduction velocity was determined in one heart by an appropriate stimulation technic. Atrial excitation, explored in two hearts, spread more or less according to concentric isochronic lines. Control studies, carried out on five canine hearts, disclosed that the pattern of ventricular excitation did not change after isolation and perfusion. However, total excitation was completed earlier in the isolated heart, and conduction velocity increased. Careful mapping illustrations are presented.

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Risk Stratification in the Long-QT Syndrome

2003-05-07

Silvia G. Priori , Peter J. Schwartz , Carlo Napolitano +7 more

Mutations in potassium-channel genes KCNQ1 (LQT1 locus) and KCNH2 (LQT2 locus) and the sodium-channel gene SCN5A (LQT3 locus) are the most common causes of the long-QT syndrome. We stratified risk … Mutations in potassium-channel genes KCNQ1 (LQT1 locus) and KCNH2 (LQT2 locus) and the sodium-channel gene SCN5A (LQT3 locus) are the most common causes of the long-QT syndrome. We stratified risk according to the genotype, in conjunction with other clinical variables such as sex and the length of the QT interval.We evaluated 647 patients (386 with a mutation at the LQT1 locus, 206 with a mutation at the LQT2 locus, and 55 with a mutation at the LQT3 locus) from 193 consecutively genotyped families with the long-QT syndrome. The cumulative probability of a first cardiac event, defined as the occurrence of syncope, cardiac arrest, or sudden death before the age of 40 years and before the initiation of therapy, was determined according to genotype, sex, and the QT interval corrected for heart rate (QTc). Within each genotype we also assessed risk in the four categories derived from the combination of sex and QTc (<500 msec or > or =500 msec).The incidence of a first cardiac event before the age of 40 years and before the initiation of therapy was lower among patients with a mutation at the LQT1 locus (30 percent) than among those with a mutation at the LQT2 locus (46 percent) or those with a mutation at the LQT3 locus (42 percent) (P<0.001 by Fisher's exact test). Multivariate analysis showed that the genetic locus and the QTc, but not sex, were independent predictors of risk. The QTc was an independent predictor of risk among patients with a mutation at the LQT1 locus and those with a mutation at the LQT2 locus but not among those with a mutation at the LQT3 locus, whereas sex was an independent predictor of events only among those with a mutation at the LQT3 locus.The locus of the causative mutation affects the clinical course of the long-QT syndrome and modulates the effects of the QTc and sex on clinical manifestations. We propose an approach to risk stratification based on these variables.

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Mortality and Morbidity in Patients Receiving Encainide, Flecainide, or Placebo

1991-03-21

Debra S. Echt , Philip R. Liebson , L. Brent Mitchell +7 more

In the Cardiac Arrhythmia Suppression Trial, designed to test the hypothesis that suppression of ventricular ectopy after a myocardial infarction reduces the incidence of sudden death, patients in whom ventricular … In the Cardiac Arrhythmia Suppression Trial, designed to test the hypothesis that suppression of ventricular ectopy after a myocardial infarction reduces the incidence of sudden death, patients in whom ventricular ectopy could be suppressed with encainide, flecainide, or moricizine were randomly assigned to receive either active drug or placebo. The use of encainide and flecainide was discontinued because of excess mortality. We examined the mortality and morbidity after randomization to encainide or flecainide or their respective placebo.

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Coassembly of KVLQT1 and minK (IsK) proteins to form cardiac IKS potassium channel

1996-11-01

Michael C. Sanguinetti , Mark Curran , Anruo Zou +4 more

Atrial Fibrillation Begets Atrial Fibrillation

1995-10-01

M. C. E. F. Wijffels , C Kirchhof , Rick Dorland +1 more

Background In this study we tested the hypothesis that atrial fibrillation (AF) causes electrophysiological changes of the atrial myocardium which might explain the progressive nature of the arrhythmia. Methods and … Background In this study we tested the hypothesis that atrial fibrillation (AF) causes electrophysiological changes of the atrial myocardium which might explain the progressive nature of the arrhythmia. Methods and Results Twelve goats were chronically instrumented with multiple electrodes sutured to the epicardium of both atria. Two to 3 Weeks after implantation, the animals were connected to a fibrillation pacemaker which artificially maintained AF. Whereas during control episodes of AF were short lasting (6±3 seconds), artificial maintenance of AF resulted in a progressive increase in the duration of AF to become sustained (>24 hours) after 7.1±4.8 days (10 of 11 goats). During the first 24 hours of AF the median fibrillation interval shortened from 145±18 to 108±8 ms and the inducibility of AF by a single premature stimulus increased from 24% to 76%. The atrial effective refractory period (AERP) shortened from 146±19 to 95±20 ms (−35%) (S 1 S 1 , 400 ms). At high pacing rates the shortening was less (−12%), pointing to a reversion of the normal adaptation of the AERP to heart rate. In 5 goats, after 2 to 4 weeks of AF, sinus rhythm was restored and all electrophysiological changes were found to be reversible within 1 week. Conclusions Artificial maintenance of AF leads to a marked shortening of AERP, a reversion of its physiological rate adaptation, and an increase in rate, inducibility and stability of AF. All these changes were completely reversible within 1 week of sinus rhythm.

MiRP1 Forms IKr Potassium Channels with HERG and Is Associated with Cardiac Arrhythmia

1999-04-01

Geoffrey W. Abbott , Federico Sesti , Igor Splawski +5 more

A novel potassium channel gene has been cloned, characterized, and associated with cardiac arrhythmia. The gene encodes MinK-related peptide 1 (MiRP1), a small integral membrane subunit that assembles with HERG, … A novel potassium channel gene has been cloned, characterized, and associated with cardiac arrhythmia. The gene encodes MinK-related peptide 1 (MiRP1), a small integral membrane subunit that assembles with HERG, a pore-forming protein, to alter its function. Unlike channels formed only with HERG, mixed complexes resemble native cardiac IKr channels in their gating, unitary conductance, regulation by potassium, and distinctive biphasic inhibition by the class III antiarrhythmic E-4031. Three missense mutations associated with long QT syndrome and ventricular fibrillation are identified in the gene for MiRP1. Mutants form channels that open slowly and close rapidly, thereby diminishing potassium currents. One variant, associated with clarithromycin-induced arrhythmia, increases channel blockade by the antibiotic. A mechanism for acquired arrhythmia is revealed: genetically based reduction in potassium currents that remains clinically silent until combined with additional stressors.

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A model of the ventricular cardiac action potential. Depolarization, repolarization, and their interaction.

1991-06-01

C H Luo , Yoram Rudy

A mathematical model of the membrane action potential of the mammalian ventricular cell is introduced. The model is based, whenever possible, on recent single-cell and single-channel data and incorporates the … A mathematical model of the membrane action potential of the mammalian ventricular cell is introduced. The model is based, whenever possible, on recent single-cell and single-channel data and incorporates the possibility of changing extracellular potassium concentration [K]o. The fast sodium current, INa, is characterized by fast upstroke velocity (Vmax = 400 V/sec) and slow recovery from inactivation. The time-independent potassium current, IK1, includes a negative-slope phase and displays significant crossover phenomenon as [K]o is varied. The time-dependent potassium current, IK, shows only a minimal degree of crossover. A novel potassium current that activates at plateau potentials is included in the model. The simulated action potential duplicates the experimentally observed effects of changes in [K]o on action potential duration and rest potential. Physiological simulations focus on the interaction between depolarization and repolarization (i.e., premature stimulation). Results demonstrate the importance of the slow recovery of INa in determining the response of the cell. Simulated responses to periodic stimulation include monotonic Wenckebach patterns and alternans at normal [K]o, whereas at low [K]o nonmonotonic Wenckebach periodicities, aperiodic patterns, and enhanced supernormal excitability that results in unstable responses ("chaotic activity") are observed. The results are consistent with recent experimental observations, and the model simulations relate these phenomena to the underlying ionic channel kinetics.

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hERG potassium channels and cardiac arrhythmia

2006-03-01

Michael C. Sanguinetti , Martin Tristani‐Firouzi

The wavefront phenomenon of ischemic cell death. 1. Myocardial infarct size vs duration of coronary occlusion in dogs.

1977-11-01

K A Reimer , J. E. Lowe , Margaret M. Rasmussen +1 more

Irreversible ischemic myocardial cell injury developes in an increasing number of cells as the duration of coronary occlusion is prolonged. The present study quantitates myocardial necrosis produced by 40 minutes, … Irreversible ischemic myocardial cell injury developes in an increasing number of cells as the duration of coronary occlusion is prolonged. The present study quantitates myocardial necrosis produced by 40 minutes, 3 hours, or 6 hours of temporary circumflex coronary occlusion (CO) followed by 2 to 4 days of reperfusion, or by 24 or 96 hours of permanent circumflex ligation in pentobarbital anesthetized open chest dogs. After 40 minutes of ischemia, myocyte necrosis was subendocardial but with increasing duration of coronary occlusion, irreversible injury progressed as a wavefront toward the subepicardium. Transmural necrosis was 38 +/- 4% after 40 min, 57 +/- 7% after 3 hours, 71 +/- 7% after 6 hours and 85 +/- 2% after 24 hours of ischemic injury. These results document the presence of a subepicardial zone of ischemic but viable myocardium which is available for pharmacologic or surgical salvage for at least three and perhaps six hours following circumflex occlusion in the dog.

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HRS/EHRA/APHRS Expert Consensus Statement on the Diagnosis and Management of Patients with Inherited Primary Arrhythmia Syndromes

2013-08-30

Silvia G. Priori , Arthur A.M. Wilde , Minoru Horie +7 more

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Cardiac excitation–contraction coupling

2002-01-01

Donald M. Bers

New ideas about atrial fibrillation 50 years on

2002-01-01

Stanley Nattel

Sudden Cardiac Death in the United States, 1989 to 1998

2001-10-30

Zhi‐Jie Zheng , Janet B. Croft , Wayne H. Giles +1 more

Background Sudden cardiac death (SCD) is a major clinical and public health problem. Methods and Results United States (US) vital statistics mortality data from 1989 to 1998 were analyzed. SCD … Background Sudden cardiac death (SCD) is a major clinical and public health problem. Methods and Results United States (US) vital statistics mortality data from 1989 to 1998 were analyzed. SCD is defined as deaths occurring out of the hospital or in the emergency room or as “dead on arrival” with an underlying cause of death reported as a cardiac disease (ICD-9 code 390 to 398, 402, or 404 to 429). Death rates were calculated for residents of the US aged ≥35 years and standardized to the 2000 US population. Of 719 456 cardiac deaths among adults aged ≥35 years in 1998, 456 076 (63%) were defined as SCD. Among decedents aged 35 to 44 years, 74% of cardiac deaths were SCD. Of all SCDs in 1998, coronary heart disease (ICD-9 codes 410 to 414) was the underlying cause on 62% of death certificates. Death rates for SCD increased with age and were higher in men than women, although there was no difference at age ≥85 years. The black population had higher death rates for SCD than white, American Indian/Alaska Native, or Asian/Pacific Islander populations. The Hispanic population had lower death rates for SCD than the non-Hispanic population. From 1989 to 1998, SCD, as the proportion of all cardiac deaths, increased 12.4% (56.3% to 63.9%), and age-adjusted SCD rates declined 11.7% in men and 5.8% in women. During the same time, age-specific death rates for SCD increased 21% among women aged 35 to 44 years. Conclusions SCD remains an important public health problem in the US. The increase in death rates for SCD among younger women warrants additional investigation.

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A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome

1995-03-01

Mark Curran , Igor Splawski , Katherine W. Timothy +3 more

Mutations in the Cardiac Ryanodine Receptor Gene ( hRyR2 ) Underlie Catecholaminergic Polymorphic Ventricular Tachycardia

2001-01-16

Silvia G. Priori , Carlo Napolitano , Natascia Tiso +5 more

Background —Catecholaminergic polymorphic ventricular tachycardia is a genetic arrhythmogenic disorder characterized by stress-induced, bidirectional ventricular tachycardia that may degenerate into cardiac arrest and cause sudden death. The electrocardiographic pattern of … Background —Catecholaminergic polymorphic ventricular tachycardia is a genetic arrhythmogenic disorder characterized by stress-induced, bidirectional ventricular tachycardia that may degenerate into cardiac arrest and cause sudden death. The electrocardiographic pattern of this ventricular tachycardia closely resembles the arrhythmias associated with calcium overload and the delayed afterdepolarizations observed during digitalis toxicity. We speculated that a genetically determined abnormality of intracellular calcium handling might be the substrate of the disease; therefore, we considered the human cardiac ryanodine receptor gene ( hRyR2 ) a likely candidate for this genetically transmitted arrhythmic disorder. Methods and Results —Twelve patients presenting with typical catecholaminergic polymorphic ventricular tachycardia in the absence of structural heart abnormalities were identified. DNA was extracted from peripheral blood lymphocytes, and single-strand conformation polymorphism analysis was performed on polymerase chain reaction–amplified exons of the hRyR2 gene. Four single nucleotide substitutions leading to missense mutations were identified in 4 probands affected by the disease. Genetic analysis of the asymptomatic parents revealed that 3 probands carried de novo mutations. In 1 case, the identical twin of the proband died suddenly after having suffered syncopal episodes. The fourth mutation was identified in the proband, in 4 clinically affected family members, and in none of 3 nonaffected family members in a kindred with 2 sudden deaths that occurred at 16 and 14 years, respectively, in the sisters of the proband. Conclusions —We demonstrated that, in agreement with our hypothesis, hRyR2 is a gene responsible for catecholaminergic polymorphic ventricular tachycardia.

SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome

1995-03-01

Qing Wang , Jiaxiang Shen , Igor Splawski +6 more

Genotype-Phenotype Correlation in the Long-QT Syndrome

2001-01-02

Peter J. Schwartz , Silvia G. Priori , Carla Spazzolini +7 more

Background —The congenital long-QT syndrome (LQTS) is caused by mutations on several genes, all of which encode cardiac ion channels. The progressive understanding of the electrophysiological consequences of these mutations … Background —The congenital long-QT syndrome (LQTS) is caused by mutations on several genes, all of which encode cardiac ion channels. The progressive understanding of the electrophysiological consequences of these mutations opens unforeseen possibilities for genotype-phenotype correlation studies. Preliminary observations suggested that the conditions (“triggers”) associated with cardiac events may in large part be gene specific. Methods and Results —We identified 670 LQTS patients of known genotype (LQT1, n=371; LQT2, n=234; LQT3, n=65) who had symptoms (syncope, cardiac arrest, sudden death) and examined whether 3 specific triggers (exercise, emotion, and sleep/rest without arousal) differed according to genotype. LQT1 patients experienced the majority of their events (62%) during exercise, and only 3% occurred during rest/sleep. These percentages were almost reversed among LQT2 and LQT3 patients, who were less likely to have events during exercise (13%) and more likely to have events during rest/sleep (29% and 39%). Lethal and nonlethal events followed the same pattern. Corrected QT interval did not differ among LQT1, LQT2, and LQT3 patients (498, 497, and 506 ms, respectively). The percent of patients who were free of recurrence with β-blocker therapy was higher and the death rate was lower among LQT1 patients (81% and 4%, respectively) than among LQT2 (59% and 4%, respectively) and LQT3 (50% and 17%, respectively) patients. Conclusions —Life-threatening arrhythmias in LQTS patients tend to occur under specific circumstances in a gene-specific manner. These data allow new insights into the mechanisms that relate the electrophysiological consequences of mutations on specific genes to clinical manifestations and offer the possibility of complementing traditional therapy with gene-specific approaches.

Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development

2003-04-01

W REDFERN , Leif Carlsson , Alice Davis +7 more

To attempt to determine the relative value of preclinical cardiac electrophysiology data (in vitro and in vivo) for predicting risk of torsade de pointes (TdP) in clinical use.Published data on … To attempt to determine the relative value of preclinical cardiac electrophysiology data (in vitro and in vivo) for predicting risk of torsade de pointes (TdP) in clinical use.Published data on hERG (or I(Kr)) activity, cardiac action potential duration (at 90% repolarisation; APD(90)), and QT prolongation in dogs were compared against QT effects and reports of TdP in humans for 100 drugs. These data were set against the free plasma concentrations attained during clinical use (effective therapeutic plasma concentrations; ETPC(unbound)). The drugs were divided into five categories: (1) Class Ia and III antiarrhythmics; (2) Withdrawn from market due to TdP; (3) Measurable incidence/numerous reports of TdP in humans; (4) Isolated reports of TdP in humans; (5) No reports of TdP in humans.Data from hERG (or I(Kr)) assays in addition to ETPC(unbound) data were available for 52 drugs. For Category 1 drugs, data for hERG/I(Kr) IC(50), APD(90), QTc in animals and QTc in humans were generally close to or superimposed on the ETPC(unbound) values. This relationship was uncoupled in the other categories, with more complex relationships between the data. In Category 1 (except amiodarone), the ratios between hERG/I(Kr) IC(50) and ETPC(unbound) (max) ranged from 0.1- to 31-fold. Similar ranges were obtained for drugs in Category 2 (0.31- to 13-fold) and Category 3 (0.03- to 35-fold). A large spread was found for Category 4 drugs (0.13- to 35700-fold); this category embraced an assortment of mechanisms ranging from drugs which may well be affecting I(Kr) currents in clinical use (e.g. sparfloxacin) to others such as nifedipine (35700-fold) where channel block is not involved. Finally, for the majority of Category 5 drugs there was a >30-fold separation between hERG/I(Kr) activity and ETPC(unbound) values, with the notable exception of verapamil (1.7-fold), which is free from QT prolongation in man; this is probably explained by its multiple interactions with cardiac ion channels.The dataset confirms the widely-held belief that most drugs associated with TdP in humans are also associated with hERG K(+) channel block at concentrations close to or superimposed upon the free plasma concentrations found in clinical use. A 30-fold margin between C(max) and hERG IC(50) may suffice for drugs currently undergoing clinical evaluation, but for future drug discovery programmes, pharmaceutical companies should consider increasing this margin, particularly for drugs aimed at non-debilitating diseases. However, interactions with multiple cardiac ion channels can either mitigate or exacerbate the prolongation of APD and QT that would ensue from block of I(Kr) currents alone, and delay of repolarisation per se is not necessarily torsadogenic. Clearly, an integrated assessment of in vitro and in vivo data is required in order to predict the torsadogenic risk of a new candidate drug in humans.

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The ventricular complex in left ventricular hypertrophy as obtained by unipolar precordial and limb leads

1949-02-01

Maurice Sokolow , Thomas P. Lyon

ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death

2006-08-31

Douglas P. Zipes , A. John Camm , Martin Borggrefe +7 more

New type of cardiomyopathy associated with diabetic glomerulosclerosis

1972-11-01

Shirley Rubler , Joel Dlugash , Yusuf Ziya Yuceoglu +3 more

A model for human ventricular tissue

2004-03-12

Kirsten ten Tusscher , Denis Noble , Penelope J. Noble +1 more

The experimental and clinical possibilities for studying cardiac arrhythmias in human ventricular myocardium are very limited. Therefore, the use of alternative methods such as computer simulations is of great importance. … The experimental and clinical possibilities for studying cardiac arrhythmias in human ventricular myocardium are very limited. Therefore, the use of alternative methods such as computer simulations is of great importance. In this article we introduce a mathematical model of the action potential of human ventricular cells that, while including a high level of electrophysiological detail, is computationally cost-effective enough to be applied in large-scale spatial simulations for the study of reentrant arrhythmias. The model is based on recent experimental data on most of the major ionic currents: the fast sodium, L-type calcium, transient outward, rapid and slow delayed rectifier, and inward rectifier currents. The model includes a basic calcium dynamics, allowing for the realistic modeling of calcium transients, calcium current inactivation, and the contraction staircase. We are able to reproduce human epicardial, endocardial, and M cell action potentials and show that differences can be explained by differences in the transient outward and slow delayed rectifier currents. Our model reproduces the experimentally observed data on action potential duration restitution, which is an important characteristic for reentrant arrhythmias. The conduction velocity restitution of our model is broader than in other models and agrees better with available data. Finally, we model the dynamics of spiral wave rotation in a two-dimensional sheet of human ventricular tissue and show that the spiral wave follows a complex meandering pattern and has a period of 265 ms. We conclude that the proposed model reproduces a variety of electrophysiological behaviors and provides a basis for studies of reentrant arrhythmias in human ventricular tissue.

Drug-Induced Prolongation of the QT Interval

2004-03-03

Dan M. Roden

The single most common cause of the withdrawal or restriction of the use of marketed drugs has been QT-interval prolongation associated with polymorphic ventricular tachycardia, or torsade de pointes, a … The single most common cause of the withdrawal or restriction of the use of marketed drugs has been QT-interval prolongation associated with polymorphic ventricular tachycardia, or torsade de pointes, a condition that can be fatal. This review summarizes the current knowledge about molecular and clinical predictors of drug-induced QT-interval prolongation and torsade de pointes and discusses how new molecular predictors of drug action might be incorporated into drug-development programs and clinical practice. A general approach to drugs suspected of causing this problem is presented.

A dynamic model of the cardiac ventricular action potential. I. Simulations of ionic currents and concentration changes.

1994-06-01

C H Luo , Yoram Rudy

A mathematical model of the cardiac ventricular action potential is presented. In our previous work, the membrane Na+ current and K+ currents were formulated. The present article focuses on processes … A mathematical model of the cardiac ventricular action potential is presented. In our previous work, the membrane Na+ current and K+ currents were formulated. The present article focuses on processes that regulate intracellular Ca2+ and depend on its concentration. The model presented here for the mammalian ventricular action potential is based mostly on the guinea pig ventricular cell. However, it provides the framework for modeling other types of ventricular cells with appropriate modifications made to account for species differences. The following processes are formulated: Ca2+ current through the L-type channel (ICa), the Na(+)-Ca2+ exchanger, Ca2+ release and uptake by the sarcoplasmic reticulum (SR), buffering of Ca2+ in the SR and in the myoplasm, a Ca2+ pump in the sarcolemma, the Na(+)-K+ pump, and a nonspecific Ca(2+)-activated membrane current. Activation of ICa is an order of magnitude faster than in previous models. Inactivation of ICa depends on both the membrane voltage and [Ca2+]i. SR is divided into two subcompartments, a network SR (NSR) and a junctional SR (JSR). Functionally, Ca2+ enters the NSR and translocates to the JSR following a monoexponential function. Release of Ca2+ occurs at JSR and can be triggered by two different mechanisms, Ca(2+)-induced Ca2+ release and spontaneous release. The model provides the basis for the study of arrhythmogenic activity of the single myocyte including afterdepolarizations and triggered activity. It can simulate cellular responses under different degrees of Ca2+ overload. Such simulations are presented in our accompanying article in this issue of Circulation Research.

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Sudden Cardiac Death

1998-11-24

Douglas P. Zipes , Hein J.J. Wellens

AHA/ACCF/HRS Recommendations for the Standardization and Interpretation of the Electrocardiogram

2009-03-01

Borys Surawicz , Rory Childers , Barbara J. Deal +1 more

Sudden Cardiac Arrest Associated with Early Repolarization

2008-05-07

Michel Haı̈ssaguerre , Nicolas Derval , Frédéric Sacher +7 more

Early repolarization is a common electrocardiographic finding that is generally considered to be benign. Its potential to cause cardiac arrhythmias has been hypothesized from experimental studies, but it is not … Early repolarization is a common electrocardiographic finding that is generally considered to be benign. Its potential to cause cardiac arrhythmias has been hypothesized from experimental studies, but it is not known whether there is a clinical association with sudden cardiac arrest.We reviewed data from 206 case subjects at 22 centers who were resuscitated after cardiac arrest due to idiopathic ventricular fibrillation and assessed the prevalence of electrocardiographic early repolarization. The latter was defined as an elevation of the QRS-ST junction of at least 0.1 mV from baseline in the inferior or lateral lead, manifested as QRS slurring or notching. The control group comprised 412 subjects without heart disease who were matched for age, sex, race, and level of physical activity. Follow-up data that included the results of monitoring with an implantable defibrillator were obtained for all case subjects.Early repolarization was more frequent in case subjects with idiopathic ventricular fibrillation than in control subjects (31% vs. 5%, P<0.001). Among case subjects, those with early repolarization were more likely to be male and to have a history of syncope or sudden cardiac arrest during sleep than those without early repolarization. In eight subjects, the origin of ectopy that initiated ventricular arrhythmias was mapped to sites concordant with the localization of repolarization abnormalities. During a mean (+/-SD) follow-up of 61+/-50 months, defibrillator monitoring showed a higher incidence of recurrent ventricular fibrillation in case subjects with a repolarization abnormality than in those without such an abnormality (hazard ratio, 2.1; 95% confidence interval, 1.2 to 3.5; P=0.008).Among patients with a history of idiopathic ventricular fibrillation, there is an increased prevalence of early repolarization.

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Electrical, contractile and structural remodeling during atrial fibrillation

2002-05-01

Maurits A. Allessie

The natural history of atrial fibrillation (AF) is characterized by a gradual worsening with time. The recent finding that AF itself produces changes in atrial function and structure has provided … The natural history of atrial fibrillation (AF) is characterized by a gradual worsening with time. The recent finding that AF itself produces changes in atrial function and structure has provided a possible explanation for the progressive nature of this arrhythmia. Electrical remodeling (shortening of atrial refractoriness) develops within the first days of AF and contributes to an increase in stability of AF. However, 'domestication of AF' must also depend on a 'second factor' since the persistence of AF continues to increase after electrical remodeling has been completed. Atrial contractile remodeling (loss of contractility) leads to a reduced atrial transport function after cardioversion of AF. An important clinical consequence is that during several days after restoration of sinus rhythm, the risk of atrial thrombus formation is still high. In addition, the reduction of atrial contractility during AF may enhance atrial dilatation which may add to the persistence of AF. Tachycardia-induced structural remodeling takes place in a different time domain (weeks to months). Myolysis probably contributes to the loss of atrial contractile force. Although it might explain the loss of efficacy of pharmacological cardioversion and the development of permanent AF, the role of structural remodeling in the progression of AF is still unclear. Atrial structural remodeling also occurs as a result of heart failure and other underlying cardiovascular diseases. The associated atrial fibrosis might explain intra-atrial conduction disturbances and the susceptibility for AF. Thus, both AF itself and the underlying heart disease are responsible for the development of the arrhythmogenic substrate. New strategies for prevention and termination of AF should be build on our knowledge of the mechanisms and time course of AF-induced atrial remodeling.

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Specific Pharmacology of Calcium in Myocardium, Cardiac Pacemakers, and Vascular Smooth Muscle

1977-04-01

A. Fleckenstein

Due to the massive data sets available for drug candidates, modern drug discovery has advanced to the big data era. Central to this shift is the development of artificial intelligence … Due to the massive data sets available for drug candidates, modern drug discovery has advanced to the big data era. Central to this shift is the development of artificial intelligence approaches to implementing innovative modeling based on the dynamic, ...Read More

Right bundle branch block, persistent ST segment elevation and sudden cardiac death: A distinct clinical and electrocardiographic syndrome

1992-11-01

Pedro Brugada , Josép Brugada

A Comparison of Antiarrhythmic-Drug Therapy with Implantable Defibrillators in Patients Resuscitated from Near-Fatal Ventricular Arrhythmias

1997-11-27

The Antiarrhythmics versus Implantable Defibrillators Investigators

Patients who survive life-threatening ventricular arrhythmias are at risk for recurrent arrhythmias. They can be treated with either an implantable cardioverter–defibrillator or antiarrhythmic drugs, but the relative efficacy of these … Patients who survive life-threatening ventricular arrhythmias are at risk for recurrent arrhythmias. They can be treated with either an implantable cardioverter–defibrillator or antiarrhythmic drugs, but the relative efficacy of these two treatment strategies is unknown.

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A Randomized Study of the Prevention of Sudden Death in Patients with Coronary Artery Disease

1999-12-16

Alfred E. Buxton , Kerry L. Lee , John D. Fisher +3 more

Empirical antiarrhythmic therapy has not reduced mortality among patients with coronary artery disease and asymptomatic ventricular arrhythmias. Previous studies have suggested that antiarrhythmic therapy guided by electrophysiologic testing might reduce … Empirical antiarrhythmic therapy has not reduced mortality among patients with coronary artery disease and asymptomatic ventricular arrhythmias. Previous studies have suggested that antiarrhythmic therapy guided by electrophysiologic testing might reduce the risk of sudden death.

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Preliminary Report: Effect of Encainide and Flecainide on Mortality in a Randomized Trial of Arrhythmia Suppression after Myocardial Infarction

1989-08-10

The occurrence of ventricular premature depolarizations in survivors of myocardial infarction is a risk factor for subsequent sudden death, but whether antiarrhythmic therapy reduces the risk is not known. The … The occurrence of ventricular premature depolarizations in survivors of myocardial infarction is a risk factor for subsequent sudden death, but whether antiarrhythmic therapy reduces the risk is not known. The Cardiac Arrhythmia Suppression Trial (CAST) is evaluating the effect of antiarrhythmic therapy (encainide, flecainide, or moricizine) in patients with asymptomatic or mildly symptomatic ventricular arrhythmia (six or more ventricular premature beats per hour) after myocardial infarction. As of March 30, 1989, 2309 patients had been recruited for the initial drug-titration phase of the study: 1727 (75 percent) had initial suppression of their arrhythmia (as assessed by Holter recording) through the use of one of the three study drugs and had been randomly assigned to receive active drug or placebo. During an average of 10 months of follow-up, the patients treated with active drug had a higher rate of death from arrhythmia than the patients assigned to placebo. Encainide and flecainide accounted for the excess of deaths from arrhythmia and nonfatal cardiac arrests (33 of 730 patients taking encainide or flecainide [4.5 percent]; 9 of 725 taking placebo [1.2 percent]; relative risk, 3.6; 95 percent confidence interval, 1.7 to 8.5). They also accounted for the higher total mortality (56 of 730 [7.7 percent] and 22 of 725 [3.0 percent], respectively; relative risk, 2.5; 95 percent confidence interval, 1.6 to 4.5). Because of these results, the part of the trial involving encainide and flecainide has been discontinued. We conclude that neither encainide nor flecainide should be used in the treatment of patients with asymptomatic or minimally symptomatic ventricular arrhythmia after myocardial infarction, even though these drugs may be effective initially in suppressing ventricular arrhythmia. Whether these results apply to other patients who might be candidates for antiarrhythmic therapy is unknown.

Brugada Syndrome: Report of the Second Consensus Conference

2005-01-18

Charles Antzelevitch , Pedro Brugada , Martin Borggrefe +7 more

Since its introduction as a clinical entity in 1992, the Brugada syndrome has progressed from being a rare disease to one that is second only to automobile accidents as a … Since its introduction as a clinical entity in 1992, the Brugada syndrome has progressed from being a rare disease to one that is second only to automobile accidents as a cause of death among young adults in some countries. Electrocardiographically characterized by a distinct ST-segment elevation in the right precordial leads, the syndrome is associated with a high risk for sudden cardiac death in young and otherwise healthy adults, and less frequently in infants and children. Patients with a spontaneously appearing Brugada ECG have a high risk for sudden arrhythmic death secondary to ventricular tachycardia/fibrillation. The ECG manifestations of Brugada syndrome are often dynamic or concealed and may be unmasked or modulated by sodium channel blockers, a febrile state, vagotonic agents, α-adrenergic agonists, β-adrenergic blockers, tricyclic or tetracyclic antidepressants, a combination of glucose and insulin, hypo- and hyperkalemia, hypercalcemia, and alcohol and cocaine toxicity. In recent years, an exponential rise in the number of reported cases and a striking proliferation of articles defining the clinical, genetic, cellular, ionic, and molecular aspects of the disease have occurred. The report of the first consensus conference, published in 2002, focused on diagnostic criteria. The present report, which emanated from the second consensus conference held in September 2003, elaborates further on the diagnostic criteria and examines risk stratification schemes and device and pharmacological approaches to therapy on the basis of the available clinical and basic science data.

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2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death

2018-08-16

Sana M. Al‐Khatib , William G. Stevenson , Michael J. Ackerman +7 more

Risk Stratification and Survival after Myocardial Infarction

1983-08-11

We assessed the role of physiologic measurements of heart function in predicting mortality after myocardial infarction. Most of the 866 patients enrolled in our multicenter study underwent 24-hour Holter monitoring … We assessed the role of physiologic measurements of heart function in predicting mortality after myocardial infarction. Most of the 866 patients enrolled in our multicenter study underwent 24-hour Holter monitoring and determination of the resting radionuclide ventricular ejection fraction before discharge. Univariate analyses showed a progressive increase in cardiac mortality during one year as the ejection fraction fell below 0.40 and as the number of ventricular ectopic depolarizations exceeded one per hour. Only four risk factors among eight prespecified variables were independent predictors of mortality: an ejection fraction below 0.40, ventricular ectopy of 10 or more depolarizations per hour, advanced New York Heart Association functional class before infarction, and rales heard in the upper two thirds of the lung fields while the patient was in the coronary-care unit. Various combinations of these four factors identified five risk subgroups with two-year mortality rates ranging from 3 per cent (no factors) to 60 per cent (all four factors).

Excitation-Contraction Coupling and Cardiac Contractile Force

2010-01-01

Donald M. Bers , Yujie Zhu

1. Major cellular structures involved in E-C coupling. 2. Myofilaments: The end effector of E-C Coupling. 3. Sources and sinks of activator calcium. 4. Cardiac action potentials and ion channels. … 1. Major cellular structures involved in E-C coupling. 2. Myofilaments: The end effector of E-C Coupling. 3. Sources and sinks of activator calcium. 4. Cardiac action potentials and ion channels. 5. Ca influx via sarcolemmal Ca channels. 6. Na/Ca exchange and the sarcolemmal Ca-pump. 7. Sarcoplasmic reticulum Ca uptake, content and release. 8. Excitation-contraction coupling. 9. Control of cardiac contraction by SR and sarcolemmal Ca fluxes. 10. Cardiac inotropy and Ca mismanagement. References. Index.

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Timolol-Induced Reduction in Mortality and Reinfarction in Patients Surviving Acute Myocardial Infarction

1981-04-02

A multicenter double-blind randomized study was carried out to compare the effect of timolol (10 mg twice daily) with that of placebo in patients surviving acute myocardial infarction. Treatment was … A multicenter double-blind randomized study was carried out to compare the effect of timolol (10 mg twice daily) with that of placebo in patients surviving acute myocardial infarction. Treatment was started seven to 28 days after infarction in 1884 patients (945 taking timolol, and 939 placebo), who represented 52 per cent of those evaluated for entry; the patients were followed for 12 to 33 months (mean, 17). There were 152 deaths in the placebo group and 98 in the timolol group. When deaths that occurred during treatment or within 28 days of withdrawal were considered, the cumulated sudden-death rate over 33 months was 13.9 per cent in the placebo group and 7.7 per cent in the timolol group--a reduction of 44.6 per cent (P = 0.0001). The cumulated reinfarction rate was 20.1 per cent in the placebo group and 14.4 per cent in the timolol group (P = 0.0006). We conclude that long-term treatment with timolol in patients surviving acute myocardial infarction reduces mortality and the rate of reinfarction.

2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death

2022-08-26

Katja Zeppenfeld , Jacob Tfelt‐Hansen , Marta Riva +7 more

Vedran Velagic (Croatia), Sami Viskin (Israel) Vedran Velagic (Croatia), Sami Viskin (Israel)

Effect of Acetazolamide in a Child with CACNA1A Channelopathy, Refractory Seizures, and ADHD

2025-06-25

T. Santhosh , Prakriti Ramamurthy , Divya Nagabushana | Annals of Child Neurology

In Response

2025-06-25

Shiyun Jin , Shufang He , Ye Zhang | Anesthesia & Analgesia

An integrated platform for 2‐D and 3‐D optical and electrical mapping of arrhythmias in Langendorff‐perfused rabbit hearts

2025-06-25

Jimena G. Siles-Paredes , Vinícius Silva , Tainan Cerqueira Neves +6 more | The Journal of Physiology

Abstract Electrophysiological mapping is essential for understanding these mechanisms and guiding therapeutic treatments. However, approaches such as invasive electrical mapping, body surface mapping and electrocardiographic imaging face challenges, including low … Abstract Electrophysiological mapping is essential for understanding these mechanisms and guiding therapeutic treatments. However, approaches such as invasive electrical mapping, body surface mapping and electrocardiographic imaging face challenges, including low spatial resolution, far‐field interference and signal processing limitations. By contrast, panoramic optical mapping, using fluorescent dyes, offers high spatial resolution and allows direct measurement of cellular action potential ex situ . Can the integration of panoramic optical mapping with electrical mapping overcome the limitations of the above‐cited techniques and provide deeper insights into arrhythmic mechanisms? To investigate this, we developed an experimental setup that combines 3‐D panoramic optical mapping with multi‐electrode epicardial electrical mapping and non‐invasive electrical mapping (torso‐tank setup) for electrocardiographic imaging in Langendorff‐perfused rabbit hearts. Our results confirm the feasibility of using simultaneous optical and electrical mapping under sinus rhythm, as well as in atrial and ventricular arrhythmias, using time, frequency and phase analyses. During sinus rhythm and ventricular tachycardia, wavefront propagation showed concordance between modalities, where diverges are observed for atrial arrhythmias. Dominant frequency analysis could recover the frequency of activation better than the inverse of cycle length, and outcomes from all mapping modalities agreed. Reconstructed electrograms presented a good similarity compared to electrograms. By correlating optical and electrical mapping, clinically relevant arrhythmia markers and targets for ablation, from invasive and non‐invasive mapping can be better understood and localised. This platform could also serve as a test bed for studying drug effects, connecting changes from cellular action potential levels to whole‐heart electrophysiology. image Key points Cardiac arrhythmias are still a significant challenge in electrophysiology, with advancements in experimental and clinical research improving our understanding of mechanisms and target for ablation. Current electrical mapping technology, both invasive and non‐invasive, is used in science and by commercial systems to identify arrhythmic episodes and mechanisms, but has several limitations mimicking the true electrophysiology behaviour. Optical mapping uses fluorescent dyes to measure transmembrane action potentials with high spatial resolution. When combined with electrical mapping, it can enhance cardiac arrhythmia studies and mapping technologies. A novel 3‐D platform that integrates panoramic and electrical mapping techniques (epicardium, non‐invasive torso‐tank and electrocardiographic imaging) is presented and validated in isolated rabbit hearts, highlighting that the mapping strategies do not always agree, helping to further improve commercial systems.

FDA's insights: implementing new strategies for evaluating drug-induced QTc prolongation

2025-06-25

Yanyan Claire Ji , Lars Johannesen , Christine Garnett | Journal of Pharmacokinetics and Pharmacodynamics

Abstract The questions and answers (Q&A) document for ICH E14/S7B provides the following advancements for QTc assessment: concentration-QTc modeling (C-QTc) as the primary analysis, accepting alternative approaches (Q&A 5.1 and … Abstract The questions and answers (Q&A) document for ICH E14/S7B provides the following advancements for QTc assessment: concentration-QTc modeling (C-QTc) as the primary analysis, accepting alternative approaches (Q&A 5.1 and 6.1) to thorough QT (TQT) studies, and incorporating an integrated nonclinical risk assessment as supporting evidence. Based on QT study reports reviewed by the FDA between 2016 and 2024, changes to the E14 guideline have resulted in a 34% decrease in the proportion of TQT studies, while the use of C-QTc analysis as the primary analysis has significantly increased. Studies using C-QTc instead of by-time analysis as the primary analysis reduced median sample sizes by 67%, 42%, and 35% for parallel, nested crossover, and crossover studies, respectively. The white paper C-QTc model was used for 60% of drugs that prolonged the QTc interval. From 2020 to 2024, reviews incorporating an integrated nonclinical risk assessment have also increased. The advancements in QTc assessments have streamlined QTc assessment and made clinical trials less resource-intensive. As the advancements continue to evolve the drug safety evaluation is likely to become even more adaptive and enable more precise and targeted QTc assessment.

Maturation of human cardiac organoids enables complex disease modeling and drug discovery

2025-06-25

Mark Pocock , Janice D. Reid , Harley Robinson +7 more | Nature Cardiovascular Research

Hybrid electrotherapy approach with successful combination of leadless atrial pacemaker and subcutaneous cardioverter-defibrillator for secondary prevention of sudden cardiac death in patient with long QT syndrome

2025-06-24

Krzysztof Boczar , Anna Rydlewska , Mateusz Ulman +2 more | Kardiologia Polska

Arrhythmia Inducibility in the CAVB Dog Model, A Critical Analysis on Underlying Factors

2025-06-24

Joanne J.A. van Bavel , Henriëtte D.M. Beekman , Marien J. C. Houtman +2 more | Cardiovascular Toxicology

A Scary Tale of a Twisted Storm: A Case Report of Torsades De Pointes in Acquired Long QT Syndrome

2025-06-23

Andrew Sefenu Dzebu , Edem Draffor , Orlando Henriquez Italin | Cureus

Network Pharmacology Approaches to Myocardial Infarction Reperfusion Injury: Exploring Mechanisms, Pathophysiology, and Novel Therapies

2025-06-23

Joy Das , Ashok Kumar Sah , Ranjay Kumar Choudhary +7 more | Biomedicines

Myocardial infarction (MI) remains a leading cause of morbidity and mortality worldwide. While timely reperfusion therapies such as percutaneous coronary intervention (PCI) and thrombolysis are essential for salvaging ischemic myocardium, … Myocardial infarction (MI) remains a leading cause of morbidity and mortality worldwide. While timely reperfusion therapies such as percutaneous coronary intervention (PCI) and thrombolysis are essential for salvaging ischemic myocardium, they can paradoxically exacerbate tissue injury through a process known as myocardial infarction reperfusion injury (MIRI). MIRI can contribute to up to 50% of the final infarct size, significantly diminishing the benefits of revascularization and leading to worsened cardiac outcomes. The pathophysiology of MIRI involves complex, interrelated mechanisms including oxidative stress, calcium overload, mitochondrial dysfunction, inflammatory responses, apoptosis, and dysregulated autophagy. Post-reperfusion recovery is further complicated by structural and functional abnormalities such as microvascular obstruction, endothelial dysfunction, and myocardial stunning. Clinically, distinguishing reperfusion injury from ischemic damage is challenging and often requires the use of sensitive biomarkers, such as cardiac troponins, alongside advanced imaging modalities. Although a range of pharmacological (e.g., antioxidants, calcium channel blockers, mitochondrial stabilizers, anti-inflammatory agents) and non-pharmacological (e.g., hypothermia, gene therapy, stem cell-based therapies) interventions have shown promise in preclinical studies, their clinical translation remains limited. This is largely due to the multifactorial and dynamic nature of MIRI. In this context, network pharmacology offers a systems-level approach to understanding the complex biological interactions involved in MIRI, facilitating the identification of multi-target therapeutic strategies. Integrating network pharmacology with omics technologies and precision medicine holds potential for advancing cardioprotective therapies. This review provides a comprehensive analysis of the molecular mechanisms underlying MIRI, examines the current clinical challenges, and explores emerging therapeutic strategies. Emphasis is placed on bridging the translational gap through validated, multi-target approaches and large-scale, multicenter clinical trials. Ultimately, this work aims to support the development of innovative and effective interventions for improving outcomes in patients with myocardial infarction.

Caveolin 3 Variant T78M in a Large Family With Brugada Syndrome: Clinical Features and Coexistence of ADRB1 and GRK5 Gene Mutation

2025-06-23

Francesco Santoro , Maria D’Apolito , Ilaria Ragnatela +7 more | Journal of Cardiovascular Electrophysiology

Genetic mutations involving sodium channel Nav 1.5 have been linked with Brugada Syndrome (BrS). Caveolin-3(CAV-3) is a protein that could modulate Nav1.5 function. Aim of the study is to characterize … Genetic mutations involving sodium channel Nav 1.5 have been linked with Brugada Syndrome (BrS). Caveolin-3(CAV-3) is a protein that could modulate Nav1.5 function. Aim of the study is to characterize a multi-generational family with BrS and CAV-3 gene mutation. Clinical and genetic investigations were performed. Genetic testing was performed with whole-exome sequencing (WES). Variants found by WES were evaluated in all family members by bidirectional capillary Sanger resequencing. The effect of the mutation was investigated by using in silico prediction of pathogenicity. Index case was a 58-year-old man with BrS, that needed an implantable cardioverter defibrillator (ICD) due to resuscitated cardiac arrest. WES of the index case identified a missense mutation p.(Thr78Met) of the CAV3 gene and two additionally variants: ADRB1 p.(Leu353Met) and GRK5 p.(Thr129Met). Six out of 11 family members had BrS ECG and were all CAV-3 mutation carriers. Three family members had CAV-3 mutation and ADRB1 and GRK5 variants. ICD implant was needed in four family members. All patients with CAV-3, ADRB1 and GRK5 gene mutations underwent ICD implant due to cardiac arrest or arrhythmic syncope. Another patient with CAV-3 mutation only, had and ICD implant due to spontaneous BrS type 1 ECG and positive electrophysiological study. Caveolin 3 p.(Thr78Met) gene mutation could be associated with BrS. This mutation if combined with other susceptible BrS gene variations as ADRB1 p.(Leu353Met) and GRK5 p.(Thr129Met), could have an increased arrhythmic risk.

Human Cardiomyocytes Obtained by Directed Differentiation of Human Induced Pluripotent Stem Cells as Isoprenaline-Based Model to Evaluate Arrhythmogenicity

2025-06-22

Kovalenko Sandaara , Sheida Frolova , S.A. Romanova +3 more | Genes and Cells

Effects of Sugammadex and Rocuronium on the Electro-mechanical Activity of Cardiac Myocytes

2025-06-20

Oğuzhan Arun , Nihal Öztürk , Orhan Erkan +4 more | Korean journal of anesthesiology

Sugammadex reverses the effects of steroidal neuromuscular-blocking agents, such as rocuronium, by encapsulating these agents. Its cardiovascular adverse effects include QTc prolongation, hypotension, bradycardia, atrioventricular block, atrial fibrillation, and asystole. … Sugammadex reverses the effects of steroidal neuromuscular-blocking agents, such as rocuronium, by encapsulating these agents. Its cardiovascular adverse effects include QTc prolongation, hypotension, bradycardia, atrioventricular block, atrial fibrillation, and asystole. Additionally, rocuronium has cardiac side effects, such as bradycardia, hypotension, cardiac arrest, circulatory collapse, and ventricular fibrillation. Herein, we investigated the effects of sugammadex, rocuronium, and combined rocuronium + sugammadex on cardiac electrophysiological parameters. In vitro experiments were performed using ventricular myocytes obtained from male Wistar rats. Myocyte contraction and relaxation responses were recorded along with action potential (AP), and L-type calcium (ICaL) and potassium channel currents (Ito, Iss, and IK1). Sugammadex caused dose-dependent decreases in myocyte contraction and relaxation responses. Rocuronium had no effect in this respect, whereas its co-administration with sugammadex led to decreased contraction responses. Sugammadex prolonged the AP repolarization phase, whereas rocuronium prolonged all AP phases. Co-administration of sugammadex and rocuronium did not significantly affect AP parameters. Sugammadex suppressed the peak ICaL value, while rocuronium caused an even greater decrease. Co-administration of these drugs further decreased the current-voltage characteristics of the ICaL. However, no significant effects were observed on the potassium currents. Separate or combined administration of sugammadex and rocuronium had various effects on myocyte contractility, AP, and ICaL, which could cause significant changes leading to adverse cardiac events. Further experimental and clinical studies are required to understand the clinical consequences of the modulatory effects of these drugs on cardiac electrophysiological parameters.

Challenges in the treatment of patients with Brugada syndrome: The current role of ablation

2025-06-20

William J. Young , Pier D. Lambiase | Kardiologia Polska

Brugada syndrome is an inherited ion channelopathy associated with an increased risk for ventricular arrhythmia and sudden death. Current management strategies to reduce arrhythmic risk are limited, with few pharmacological … Brugada syndrome is an inherited ion channelopathy associated with an increased risk for ventricular arrhythmia and sudden death. Current management strategies to reduce arrhythmic risk are limited, with few pharmacological options that may be ineffective or cause side-effects leading to suboptimal dosing or cessation of treatment. There is substantial interest therefore in determining the long-term efficacy and safety profile of catheter ablation, to targeting triggers and electrophysiological substrates for ventricular arrhythmia. With the recent publication of small, randomized trials including the BRAVE study, the level of evidence is improving. However, the balance of risk verses benefit across the arrhythmic risk spectrum remains unclear and procedural technical challenges remain, particularly given most patients will require an epicardial approach for catheter ablation. This review outlines the current evidence in the published literature and highlights gaps in knowledge that should be prioritised in future studies.

Chemical Stability Testing of Solutions for Intraventricular Irrigations via IRRA flow Ventricular Drain System

2025-06-20

Jeffrey Garavaglia , Anthony DeBastiani , Jessica Peaslee +1 more | Hospital Pharmacy

Purpose: Advances have been made with delivery of medications via continuous intrathecal irrigating ventricular drains such as IRRAflow (IRRAS). Medications including vancomycin, tobramycin, daptomycin and nicardipine are currently being used … Purpose: Advances have been made with delivery of medications via continuous intrathecal irrigating ventricular drains such as IRRAflow (IRRAS). Medications including vancomycin, tobramycin, daptomycin and nicardipine are currently being used as ventricular irrigations via the IRRAflow device. The purpose of this study was to evaluate the chemical stability of minute concentrations of daptomycin, nicardipine, tobramycin, and vancomycin for administration via IRRAflow intrathecal catheters. Methods: Commercially available formulations of daptomycin, nicardipine, tobramycin, and vancomycin were each diluted in separate normal saline (NS) 1000 mL bags to final concentrations of daptomycin 2 mg/1000 mL NS, nicardipine 2.5 mg/1000 mL NS, tobramycin 4 mg/1000 mL NS, and vancomycin 4 mg/1000 mL NS. Samples from each compound were transferred into 2.5 mL glass vials and evaluated in triplicate fashion using ultra-performance liquid chromatography and tandem mass spectrometry (LC-MS/MS). Each injection was analyzed in comparison to its respective calibration curve and a mean result for each time point was determined. The concentration of the samples was tested at 0, 6 and 12-hours for vancomycin, daptomycin, and tobramycin and 0, 4 and 8-hours for nicardipine. All irrigations were kept at room temperature and were not protected from light. Results: All samples tested were found to be chemically stable at various testing time points. Daptomycin retained a mean of 94.3% of initial concentration at 12 hours while tobramycin retained 93.1% of its initial concentration at 12 hours. Vancomycin samples were found to be 92.9% of initial concentration at 12 hours and nicardipine maintained a mean of 90.6% of initial concentration at 8 hours. Future studies could assess these conditions to potentially further stability data. Conclusion: With use of LC-MS, we demonstrated that dilute concentrations of vancomycin, daptomycin, and tobramycin maintain at least 90% of initial concentration for 12 hours at room temperature, whereas nicardipine remained chemically stable for 8 hours at room temperature.

Catecholaminergic Polymorphic Ventricular Tachycardia in a Pregnant Woman

2025-06-20

Kuky Cahya Hamurajib , Giovanna Renee Tan , Priyo Eko Hedi Herlambang +1 more | Maternal-Fetal Medicine

A Rare Case of Atypical Electrocardiogram Changes in Subtotal Occlusion of the Left Main Coronary Artery

2025-06-19

Honglin Ni , Zhicheng Gao , Jun Yao | Annals of Noninvasive Electrocardiology

ABSTRACT Acute occlusion of the left main coronary artery (LMCA) is one of the most severe forms of acute coronary syndrome. Besides the typical electrocardiogram changes, it is important to … ABSTRACT Acute occlusion of the left main coronary artery (LMCA) is one of the most severe forms of acute coronary syndrome. Besides the typical electrocardiogram changes, it is important to promptly recognize atypical changes and hasten revascularization therapy without delays. By analyzing specific cases, this work revealed that ST‐segment elevation in aVR and aVL leads, accompanied by newly developed bifascicular block that cannot be ruled out as pathological, but without ST‐segment deviation in the chest leads, highly indicates a rare electrocardiographic manifestation of complete occlusion of the LMCA. On the other hand, subtotal occlusion represents an even rarer scenario.

Demographics, Clinical features and Genetics of Common Inherited Arrhythmias in Oman

2025-06-19

Kadhiya Al Azri , Ismail Al Abri , Maryam Al Shehhi +4 more | Journal of the Saudi Heart Association

Inherited arrhythmia syndromes (IAS) are a group of rare disorders that result from genetic mutations in several genes including congenital long QT syndrome, Brugada syndrome (BrS), short QT syndrome, and … Inherited arrhythmia syndromes (IAS) are a group of rare disorders that result from genetic mutations in several genes including congenital long QT syndrome, Brugada syndrome (BrS), short QT syndrome, and Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). Affected individuals may have various symptoms including sudden cardiac death (SCD). Few reports have highlighted long QT syndrome from the Arbian Gulf region. The current study aims to describe demographics of children and adults with inherited arrhythmia syndromes; report the presenting clinical features, genetic mutations and management strategies. This is a descriptive retrospective study that included Omani children and adults with inherited arrhythmia syndromes who were diagnosed and treated at the National Heart Centre (NHC) of the Royal Hospital, between 2006 and 2022. Data collected include patient demographics, geographical distribution, clinical features, genetic reports and management strategies. A total of one hundred and six Omani patients were included. Sixty-six (62.3 %) were males, and 71 (67 %) were adults at diagnosis and 35 (33 %) were children. Three inherited arrhythmia syndromes were found including Long QT, Brugada and catecholaminergic polymorphic ventricular tachycardia (CPVT) and these accounted for 58 (54.7 %), 39 (36.8 %) and 9 (8.5 %), respectively. Seventy-six (71.7 %) of the patients were from consanguineous families. The clinical features varied based on the type of arrhythmia. The treatment modalities constituted of beta blockers and antiarrhythmics, implantable cardioverter defibrillators (ICDs), pacemakers, and left sympathetic ganglionectomy (LSGs). Seventy-one individuals (66.9 %) underwent genetic testing. It is important to highlight that 36 (50.7 %) individuals were with pathogenic or likely pathogenic variants and 13 (18.3 %) individuals were with variants of uncertain significance (VUS) in different IAS related genes. The current study is the first comprehensive study on the inherited arrhythmia syndromes in Oman and the Arabian Gulf countries. It provides insight about the demographic, clinical and genetic profile of the most common IAS in the region, hence helping in early detection of different types of IAS types and prevention of sudden cardiac death in patients and their relatives. Continuous research efforts in the genetic and cellular mechanisms underlying these disorders will help to identify potential targets for improved disease-specific treatments.

Broad Electrocardiogram Syndromes Spectrum: From Common Emergencies to Particular Electrical Heart Disorders—Part II

2025-06-19

Alexandr Ceasovschih , Anastasia Balta , Victorița Șorodoc +7 more | Diagnostics

The electrocardiogram (ECG) remains a cornerstone of modern cardiology, providing rapid, non-invasive, and widely accessible diagnostic insights. While ECG interpretation is an essential skill for clinicians, certain patterns can be … The electrocardiogram (ECG) remains a cornerstone of modern cardiology, providing rapid, non-invasive, and widely accessible diagnostic insights. While ECG interpretation is an essential skill for clinicians, certain patterns can be subtle or atypical, posing diagnostic challenges. In our previous review (doi.org/10.3390/jpm12111754), we explored several uncommon ECG syndromes with significant clinical implications. However, the spectrum of electrocardiographic abnormalities extends far beyond those initially discussed. In this second installment, we expand our discussion of rare and underrecognized ECG syndromes, including Long QT, Jervell and Lange-Nielsen, Romano-Ward, Andersen-Tawil, Timothy, Short QT, and Twiddler's syndromes, as well as Noonan, Barlow's, Bundgaard, BRASH, Carvajal, Naxos, and Danon disease. We highlight their clinical context, characteristic findings, and implications for diagnosis and management. These conditions range from acute, life-threatening emergencies requiring immediate intervention to chronic electrical disorders necessitating long-term monitoring and risk stratification. By broadening our focus, we aim to enhance awareness and recognition of these entities, ultimately improving patient outcomes through timely and accurate diagnosis.

Cinobufagin induced myocardial cell toxicity in H9c2 cells via inhibiting histone methyltransferase SMYD1 expression

2025-06-19

Huimin Wu , Chen Wang , Hong Zhang +7 more | Toxicology Mechanisms and Methods

Cardiotoxicity of traditional Chinese medicines (TCM) is an important factor in pharmacogenetic cardiovascular diseases, which directly affects the clinical use of TCM. Recently, cinobufagin (CBG), the active substance of Toad … Cardiotoxicity of traditional Chinese medicines (TCM) is an important factor in pharmacogenetic cardiovascular diseases, which directly affects the clinical use of TCM. Recently, cinobufagin (CBG), the active substance of Toad venom, has shown as a potential anti-tumor natural product. However, its cardiotoxicity limits the clinical application and the intrinsic mechanism is unclear. Here, we found that CBG induced oxidative stress and cell apoptosis in rat cardiomyocytes (H9c2), which caused cardiomyocyte injury. SET and MYND domain containing 1 (SMYD1) is a histone methyltransferase containing a SET-MYND domain, which is specifically expressed only in cardiomyocytes and skeletal muscle cells. RNA-Seq analysis revealed that the expression of SMYD1 was significantly decreased in the CBG treated H9c2 cells. Overexpression of SMYD1 alleviated CBG-induced myocardial injury, while knockdown of SMYD1 did the opposite. To summary, our study indicated that CBG induced cell apoptosis and oxidative stress via suppressing the expression of SMYD1 and ultimately leaded to myocardial toxicity. This research revealed the side-effects of CBG in myocardial toxicity and provided mechanism basis in specific disease conditions for CBG therapy.

Arrhythmic Complications in Acute Coronary Syndrome: Mechanisms, Manifestations, and Management

2025-06-18

Karnika Senthilkumar , Umashankar Lakshmanadoss , Paul Chacko | IntechOpen eBooks

Acute Coronary Syndrome (ACS) is frequently complicated by cardiac arrhythmias, which significantly contribute to morbidity and mortality. The pathophysiological basis of these arrhythmias includes ischemia-induced electrophysiological disturbances, electrolyte imbalances, autonomic … Acute Coronary Syndrome (ACS) is frequently complicated by cardiac arrhythmias, which significantly contribute to morbidity and mortality. The pathophysiological basis of these arrhythmias includes ischemia-induced electrophysiological disturbances, electrolyte imbalances, autonomic dysfunction, and reperfusion injury. This review examines the spectrum of arrhythmias in ACS, including ventricular tachyarrhythmias (ventricular tachycardia and ventricular fibrillation), bradyarrhythmias (sinus bradycardia, atrioventricular blocks), and atrial arrhythmias (atrial fibrillation). We discuss risk stratification, mechanisms, ECG characteristics, and evidence-based management strategies. Early recognition and treatment of arrhythmias in ACS are crucial to prevent sudden cardiac death and improve patient outcomes.

Novel causative RYR2 indel variant with exon and intron involvement inducing exon 13 skipping in a family exhibiting catecholaminergic polymorphic ventricular tachycardia

2025-06-18

Ju Hyeon Shin , Taek Kyu Park , Sung‐A Chang +7 more | Frontiers in Genetics

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic disorder marked by exercise or stress-induced arrhythmias that lead to syncope or sudden cardiac death. Mutations of the RYR2 gene can cause … Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic disorder marked by exercise or stress-induced arrhythmias that lead to syncope or sudden cardiac death. Mutations of the RYR2 gene can cause either CPVT or calcium release deficiency syndrome, with varying impacts on calcium release in cardiomyocytes. These mutations are predominantly missense variants associated with a gain-of-function mechanism. In this report, we present a novel pathogenic RYR2 indel variant in a family afflicted with CPVT based on comprehensive molecular investigations. The proband was a 15-year-old girl who suffered a cardiac arrest during exercise and exhibited frequent premature ventricular beats on a treadmill test, which was consistent with CPVT. Using next-generation sequencing and Sanger sequencing, a novel RYR2 indel variant, NM_001035.3:c.1006-44_1007delinsATTTTG, was identified. Sanger sequencing confirmed the presence of this variant in her mother, who also showed frequent premature ventricular beats on a treadmill test. Further RNA analysis revealed that this variant caused aberrant splicing, resulting in the skipping of exon 13 (r.1006_1170del), which would disrupt the intramolecular domain interactions. This discovery led to the classification of the variant as a likely pathogenic variant. We identified a novel RYR2 indel variant responsible for CPVT and expanded the mutational spectrum of RYR2 -related CPVT, emphasizing the importance of comprehensive genetic approaches for variant classification.

Incremental Prognostic Value of Hippocampal Metabolic Activity for Sudden Cardiac Death in Patients With Heart Failure With Reduced Ejection Fraction

2025-06-18

Zhongyue Shi , Mingkai Yun , Binbin Nie +7 more | Journal of the American Heart Association

Background Hippocampal injury is linked to cognitive impairment and cardiac events in patients with heart failure with reduced ejection fraction. However, the predictive value of hippocampal metabolic activity (HMA) for … Background Hippocampal injury is linked to cognitive impairment and cardiac events in patients with heart failure with reduced ejection fraction. However, the predictive value of hippocampal metabolic activity (HMA) for sudden cardiac death (SCD) and the underlying mechanisms remain unclear. This study aimed to evaluate the independent and incremental predictive value of HMA over myocardial scar for SCD‐related events in patients with heart failure with reduced ejection fraction and to explore the potential mechanism. Methods This prospective study included 270 patients with heart failure with reduced ejection fraction undergoing gated single‐photon emission computed tomography and brain/cardiac 18 F‐fluorodeoxyglucose positron emission tomography. HMA and myocardial scarring were evaluated. The independent and incremental predictive values of HMA for SCD‐related events were explored via the log‐rank test, Cox model, C statistic, global χ 2 test, and net reclassification improvement. Mediation analysis was used to examine the direct and indirect effects of HMA on SCD‐related events by setting left ventricular electrical instability as a mediator. Results Overall, 34 (12.6%; median follow‐up, 4.3 years) patients experienced SCD‐related events. Functional myocardial scarring and HMA were strongly associated with SCD‐related events (all P <0.01). HMA resulted in significant incremental improvements in prognostic value (χ 2 increased by 6.598), discrimination (C statistics of 0.760 versus 0.715), and reclassification (net reclassification improvement, 25.6%) for SCD‐related events. HMA was associated with SCD‐related events via corrected QT interval. Conclusions Functional myocardial scarring and HMA had strong independent prognostic value in the risk stratification of SCD‐related events in patients with heart failure with reduced ejection fraction. Additionally, HMA had incremental prognostic value based on myocardial scarring. HMA impairment may induce SCD‐related events, partly mediated by corrected QT interval.

Role of Dynamical Instability in QT Interval Variability and Early Afterdepolarization Propensity

2025-06-17

Daisuke Sato , Bence Hegyi , Crystal M. Ripplinger +1 more | bioRxiv (Cold Spring Harbor Laboratory)

Abstract Beat-to-beat variability of the QT interval (QTV) is a well-established marker of cardiac health, with increased QTV (> 5 ms) often associated with a higher risk of arrhythmias. However, … Abstract Beat-to-beat variability of the QT interval (QTV) is a well-established marker of cardiac health, with increased QTV (> 5 ms) often associated with a higher risk of arrhythmias. However, the underlying mechanisms contributing to this phenomenon remain poorly understood. Recently, we showed that cardiac instability is a major cause of QTV. Early afterdepolarizations (EADs) are abnormal electrical oscillations that occur during the plateau phase of the cardiac action potential (AP), often arising when the membrane potential becomes unstable. In this study, we use a physiologically detailed computational model of rabbit ventricular myocytes with stochastic ion channel gating to investigate the relationship between QTV and EAD propensity. We found that increased AP duration (APD) variability, which serves as a surrogate for QTV on the ECG at the single-cell level, can arise even in the absence of apparent EADs, driven by intrinsic dynamical instability. As the cellular state approaches the threshold for EAD generation, small perturbations in membrane voltage are amplified, leading to increased APD variability. The phase-plane analysis in the voltage-calcium channel inactivation space demonstrates that proximity to the EAD-generating basin of attraction strongly influences repolarization variability, establishing a mechanistic link between QTV and EAD propensity. Furthermore, we observed that QTV increases at longer pacing cycle lengths (PCLs), distinguishing it from alternans-associated APD variability, which increases at shorter PCLs. These findings suggest that increased QTV may serve as an early indicator of arrhythmic risk before the manifestation of EADs, potentially offering a critical window for preventive intervention. Our results provide novel insights into the fundamental mechanisms underlying QTV and its potential role in arrhythmia prediction. Significance statement This study investigates the relationship between beat-to-beat variability of the QT interval (QTV) and the propensity for early afterdepolarizations (EADs), abnormal electrical oscillations linked to life-threatening arrhythmias. Using a computational model, we show that increased QTV can precede apparent EADs, driven by inherent dynamical instability of cardiac cells. As cells approach an arrhythmia-prone state, small membrane voltage fluctuations are amplified, increasing repolarization variability and thus QTV. Furthermore, QTV increases with slower heart rates, distinguishing it from alternans, another type of instability arising at faster rates. Thus, increased QTV may serve as an early warning signal for arrhythmia risk, potentially enabling preventative interventions. Our results provide novel insights into the fundamental mechanisms underlying QTV and its potential role in arrhythmia prediction.

ASSOCIATION OF CORRECTED QT INTERVAL WITH MICROVASCULAR COMPLICATIONS OF TYPE 2 DIABETES MELLITUS

2025-06-17

Tejashree Pasumarthy , Fareeha Afreen , Pooja Naik +1 more | Journal of Population Therapeutics and Clinical Pharmacology

Interatrial Block and Supraventricular Arrhythmias. Clinical Implications of Bayés’ Syndrome

2025-06-17

Ricardo J. Esper | Revista Argentina de Cardiología

The role of A-kinase anchoring proteins in cardiovascular diseases and recent advances

2025-06-17

Xu Zhang , Feng Zhu , Zufei Xiao +1 more | Frontiers in Cell and Developmental Biology

Cardiovascular diseases are a major global health concern, leading to high morbidity, mortality, and disability rates. Scaffold proteins, particularly A-kinase anchoring proteins (AKAPs), play a crucial role in signal transduction … Cardiovascular diseases are a major global health concern, leading to high morbidity, mortality, and disability rates. Scaffold proteins, particularly A-kinase anchoring proteins (AKAPs), play a crucial role in signal transduction within the cardiovascular system. This review provides a comprehensive analysis of AKAPs’ involvement in the pathogenesis of cardiovascular diseases, emphasizing their key function in coordinating diverse signaling molecules, directing them to specific cellular microdomains, and minimizing signal interference. Disruptions in these interactions are linked to several cardiovascular disorders, such as cardiac hypertrophy, myocardial apoptosis, heart failure, arrhythmias, dysfunction in myocardial contraction and relaxation, and hypertension. Our goal was to explore the therapeutic potential of targeting the AKAP signaling pathway and offer new perspectives for the development and application of cardiovascular drugs that modulate AKAP signaling complexes.

Arrhythmogenic mechanisms in pregnancy and principles of treat-ment of arrhythmias in pregnant women

2025-06-17

Natal'ya Kirkina , K. Son'kina | Clinical Medicine and Pharmacology

According to the latest data for June 2024, the frequency of arrhythmias in pregnant women was 68%. Most often, these are arrhythmias on the background of concomitant pathology, although the … According to the latest data for June 2024, the frequency of arrhythmias in pregnant women was 68%. Most often, these are arrhythmias on the background of concomitant pathology, although the possibility of "benign arrhythmias" that occur as a result of normal physiological processes during pregnancy cannot be excluded. Sinus tachycardia, ventricular and atrial extrasystole are more common in pregnant women. The higher the gestation period, the higher the risk of arrhyth-mias: 1st trimester - 23.4%, 2nd trimester - 46.3%, 3rd trimester - 61.7%. In this article, we will analyze some of the mechanisms of arrhythmias without previous pathology against the back-ground of a normal pregnancy, as well as find out the principles of treatment of arrhythmias, groups of drugs that can be used in this group of patients.

Case Report of Long <scp>QT</scp> Syndrome in a Patient With Syncope

2025-06-17

C. Chen , Ruojun Wang , Ken‐Pen Weng +1 more | The Kaohsiung Journal of Medical Sciences

Evaluation of CACNA1C-Positive Patients Evaluated in a Tertiary Genetic Heart Rhythm Clinic

2025-06-17

Liwei Yu , Raquel Neves , Martijn Bos +4 more | Journal of Cardiovascular Translational Research

Macrolide Antibiotic Mediated Cardiac Arrhythmias: Emerging Concepts and Clinical Implications

2025-06-16

Fatima Iqbal , Alyssa Derouen , Rui Ren +4 more | Biomedicines

The macrolide class of antibiotics are widely utilized in clinical settings for a broad range of bacterial infections and have additional roles as immunomodulatory agents. Although efficacious with a good … The macrolide class of antibiotics are widely utilized in clinical settings for a broad range of bacterial infections and have additional roles as immunomodulatory agents. Although efficacious with a good safety profile overall, they have been associated with prolongation of the QT interval and development of the polymorphic ventricular tachycardia, Torsades de pointes (TdP). In a 2020 scientific statement, the American Heart Association (AHA) classified azithromycin, clarithromycin and erythromycin as QT-prolonging drugs known to cause TdP and the online database, CredibleMeds, that maintains a list of drugs known to cause QT prolongation classifies these drugs as having an increased risk of QT prolongation. The mechanism of this risk has been delineated to involve macrolide binding to and a blockade of delayed rectifier potassium channels that conduct rapid potassium current, Ikr, during repolarization, leading to prolonged repolarization and subsequent QT prolongation. Studies investigating this association have revealed variable results, with several suggesting that the risk of QT prolongation and TdP with macrolide use may be highly dependent on underlying patient risk factors and comorbidities. In the present investigation, we summarize current evidence on association of macrolide antibiotics, azithromycin, clarithromycin and erythromycin, with the development of QT prolongation and TdP, pathophysiology of and risk factors predisposing to development of these events, the role of implementation of strategies to reduce this risk and highlight emerging research.

Electrocardiogram abnormalities in left bundle branch block and out-of-hospital cardiac arrest

2025-06-15

Niels Hald , Ann-Maria Jensen , Signe Riddersholm +7 more | Journal of Electrocardiology

Left bundle branch block (LBBB) can be a marker of cardiovascular risk. This study investigates how electrocardiogram (ECG) measurements can be utilized in risk stratification of LBBB patients. Using registry … Left bundle branch block (LBBB) can be a marker of cardiovascular risk. This study investigates how electrocardiogram (ECG) measurements can be utilized in risk stratification of LBBB patients. Using registry data from the Copenhagen General Practitioners Laboratory, first-time LBBB ECGs were identified from 2001 to 2015. Different ECG parameters were extracted including P-wave duration, PR interval, QRS duration, QRS area, QTc, JTc intervals and heart rate. Data were stratified according to the median values of these parameters (below vs above). The outcome was out-of-hospital cardiac arrest (OHCA), and the crude 5-year risk of OHCA was calculated for each subgroup. Multivariable Cox proportional hazards regression was employed to assess associations of ECG parameters with OHCA. We identified 4644 patients with incident LBBB contributing to a combined 35,113 person-years follow-up (median age 75 [25th - 75th percentiles 66-83] years; male sex, 62 %). Over the study period, all-cause mortality was 50 % and 4 % reached the primary outcome. The crude 5-year risk of OHCA revealed significant associations for QRS duration >150 ms (p = 0.01) and JTc duration >317 ms (p = 0.03). Multivariable analysis showed a higher hazard ratio (HR) for OHCA associated with QRS duration >150 ms (HR 1.41 [95 % CI 1.06-1.88]), QTc duration >464 ms (HR 1.43 [95 % CI 1.08-1.90]), JTc duration >317 ms (HR 1.50 [95 % CI 1.13-2.00]) and heart rate > 72/min (HR 1.48 [95 % CI 1.12-1.97]). This study provides insights into associations between specific ECG parameters and the risk of OHCA in patients with LBBB. This holds the potential for risk stratification and targeted intervention in this population, and individuals with LBBB and these specific ECG abnormalities might benefit from earlier referral to investigation by specialists.

Molecular Mechanisms of L-Type Calcium Channel Dysregulation in Heart Failure

2025-06-15

A. Khalid , Abdel-Aziz A Ahmed , Randeep Gill +3 more | International Journal of Molecular Sciences

The L-type calcium channels (LTCCs) function as the main entry points that convert myocyte membrane depolarization into calcium transients, which drive every heartbeat. There is increasing evidence to show that … The L-type calcium channels (LTCCs) function as the main entry points that convert myocyte membrane depolarization into calcium transients, which drive every heartbeat. There is increasing evidence to show that maladaptive remodeling of these channels is the cause of heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). Recent experimental, translational, and clinical studies have improved our understanding of the roles LTCC expression, micro-domain trafficking, and post-translational control have in disrupting excitation-contraction coupling, provoking arrhythmias, and shaping phenotype specific hemodynamic compromise. We performed a systematic search of the PubMed and Google Scholar databases (2015-2025, English) and critically evaluated 17 eligible publications in an effort to organize the expanding body of work. This review combines existing data about LTCC density and T-tubule architecture with β-adrenergic and Ca2⁺/calmodulin-dependent protein kinase II (CaMKII) signaling and downstream sarcoplasmic reticulum crosstalk to explain how HFrEF presents with contractile insufficiency and how HFpEF shows diastolic calcium overload and stiffening. Additionally, we highlight the emerging therapeutic strategies aimed at restoring calcium homeostasis such as CaMKII inhibitors, ryanodine receptor type 2 (RyR2) stabilizers, and selective LTCC modulators without compromising systolic reserve. The review establishes LTCC dysregulation as a single mechanism that causes myocardial dysfunction while remaining specific to each phenotype, thus offering clinicians and researchers a complete reference for current concepts and future precision therapy approaches in heart failure.

Spatial Approach to Cardiac Electrical Dynamics: Evaluation of Surrogate Biomarkers of Differences in Drug-Induced Multichannel Block

2025-06-15

Pablo Daniel Cruces , Pedro David Arini | Archives of Medical Research

Feasibility of Machine Learned Intracardiac Electrograms to Predict Postinfarction Ventricular Scar Topography

2025-06-13

Kasun De Silva , Timothy Campbell , Richard G. Bennett +7 more | Circulation Arrhythmia and Electrophysiology

BACKGROUND: Accurate delineation of scar patterns is valuable for guiding catheter ablation of ventricular tachycardia. We hypothesized that scar and its pattern of distribution can be determined from intracardiac electrograms … BACKGROUND: Accurate delineation of scar patterns is valuable for guiding catheter ablation of ventricular tachycardia. We hypothesized that scar and its pattern of distribution can be determined from intracardiac electrograms using computational signal processing and that further improvements in classification can be achieved with a convolutional neural network. METHODS: A total of 5 sheep underwent anteroseptal infarction (plus 1 healthy control) with electroanatomic mapping (129±12 days post-infarct). A whole-heart histological model of the postinfarction scar was created and coregistered to ventricular electrograms. Electrograms were matched to scar pattern categories; no scar, at least endocardial scar: at least intramural scar (intramural scar sparing the endocardium), or epicardial-only scar (epicardial scar sparing the endocardium/intramural space). A suite of signal-processing features was extracted from bipolar electrograms. Furthermore, bipolar and unipolar electrograms were used to train a time series convolutional neural network (InceptionTime). RESULTS: A total of 11 551 electrograms were matched to 451 biopsies. Bipolar and unipolar voltage alone were poor classifiers of scar patterns. For each of the scar labels, 20 bipolar electrogram features (predominantly within the frequency domain) yielded an area under the curve of 0.815, 0.810, 0.704, and 0.681 to predict no scar, at least endocardial scar, at least intramural scar, and epicardial-only scar, respectively. Substantial improvement was achieved with a convolutional neural network trained on unipolar electrograms: areas under the curve and accuracy (averaged across wavefronts) were 0.977 and 0.929 for no scar, 0.970 and 0.919 for at least endocardial scar, 0.909 and 0.959 for at least intramural scar and 0.926 and 0.958 for epicardial-only scar. CONCLUSIONS: Convolutional neural network-derived analysis of unipolar electrogram data has excellent predictive value for determination of scar patterns. Computational analyses of electrogram data beyond voltage and other time-domain features are necessary to improve the identification of arrhythmogenic sites in the ventricle.

QT Prolongation and Torsades De Pointes Due to Undiagnosed Sheehan Syndrome: A Rare Cause of Lethal Arrhythmia

2025-06-13

Yuto Oshizaka , Reina Suzuki , Shunsuke Funasaki +2 more | Cureus

Tilt-induced changes in f-wave characteristics during atrial fibrillation: an experimental and computational investigation

2025-06-13

Mostafa Abdollahpur , Chiara Celotto , Carlos Sánchez +6 more | Frontiers in Physiology

Introduction This study explores transient and stationary effects of sympathetic and parasympathetic stimulation on f-wave characteristics in atrial fibrillation (AF) patients undergoing a tilt test. Transient phase is defined as … Introduction This study explores transient and stationary effects of sympathetic and parasympathetic stimulation on f-wave characteristics in atrial fibrillation (AF) patients undergoing a tilt test. Transient phase is defined as the initial 2-minute interval following each postural change, reflecting immediate autonomic adaptation, whereas steady phase refers to the subsequent interval (from 3 minutes post-change until phase end) representing a stable autonomic state. Methods Our primary aim is to investigate how the two branches of the autonomic nervous system (ANS) influence the f-wave frequency time series ( <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="m1"><mml:mrow><mml:mi>f</mml:mi><mml:mrow><mml:mo stretchy="false">(</mml:mo><mml:mrow><mml:mi>m</mml:mi></mml:mrow><mml:mo stretchy="false">)</mml:mo></mml:mrow></mml:mrow></mml:math> ). An analysis of <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="m2"><mml:mrow><mml:mi>f</mml:mi><mml:mrow><mml:mo stretchy="false">(</mml:mo><mml:mrow><mml:mi>m</mml:mi></mml:mrow><mml:mo stretchy="false">)</mml:mo></mml:mrow></mml:mrow></mml:math> in terms of the mean over time ( <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="m3"><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant="script">F</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant="normal">f</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:math> ) and the magnitude of respiration-modulated <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="m4"><mml:mrow><mml:mi>f</mml:mi><mml:mrow><mml:mo stretchy="false">(</mml:mo><mml:mrow><mml:mi>m</mml:mi></mml:mrow><mml:mo stretchy="false">)</mml:mo></mml:mrow></mml:mrow></mml:math> variations ( <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="m5"><mml:mrow><mml:mi mathvariant="normal">Δ</mml:mi><mml:msub><mml:mrow><mml:mi mathvariant="script">F</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant="normal">f</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:math> ) is conducted during baseline supine rest (B), head-down tilt (HDT) and head-up tilt (HUT). We analyzed data from a previous study in which 24 patients with persistent AF underwent a tilt test protocol, during which electrocardiograms (ECGs) were recorded. A model-based method was used to extract <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="m6"><mml:mrow><mml:mi>f</mml:mi><mml:mrow><mml:mo stretchy="false">(</mml:mo><mml:mrow><mml:mi>m</mml:mi></mml:mrow><mml:mo stretchy="false">)</mml:mo></mml:mrow></mml:mrow></mml:math> series from the ECG. Subsequently, an orthogonal subspace projection method was employed to quantify <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="m7"><mml:mrow><mml:mi mathvariant="normal">Δ</mml:mi><mml:msub><mml:mrow><mml:mi mathvariant="script">F</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant="normal">f</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:math> , considering an ECG-derived respiratory signal. Electrophysiological computational simulations were conducted on 2D and 3D human atrial persistent AF models to aid the interpretation of clinical findings. Various levels of cholinergic stimulation by acetylcholine and <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="m8"><mml:mrow><mml:mi>β</mml:mi></mml:mrow></mml:math> -adrenergic stimulation by isoproterenol were tested in the models. The temporal modulation of acetylcholine, representing changes associated with respiration, was cyclically modeled using sinusoidal waveforms. Results Analysis of the clinical data showed a decrease in <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="m9"><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant="script">F</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant="normal">f</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:math> from B to HDT and an increase from HDT to HUT. During HDT, <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="m10"><mml:mrow><mml:mi mathvariant="normal">Δ</mml:mi><mml:msub><mml:mrow><mml:mi mathvariant="script">F</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant="normal">f</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:math> initially increased in the transient phase before decreasing in the steady phase, then rose again during HUT. Analysis of the simulated data showed that increasing the concentration of Isoproterenol and/or acetylcholine resulted in a rise in <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="m11"><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant="script">F</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant="normal">f</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:math> . Additionally, the magnitude of <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="m12"><mml:mrow><mml:mi mathvariant="normal">Δ</mml:mi><mml:msub><mml:mrow><mml:mi mathvariant="script">F</mml:mi></mml:mrow><mml:mrow><mml:mi>f</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:math> was shown to be associated with the extent of acetylcholine fluctuation. Discussion These results suggest that changes in f-wave frequency characteristics during HUT and HDT could be linked to changes in sympathetic activity, with parasympathetic activity possibly modulating the effects of sympathetic activity rather than being an independent driver of fibrillatory rate changes.

1872-LB: Impaired Coronary BK Channel Function and Sorbs2 Downregulation in Human Diabetes

2025-06-13

XIAOWEI XIONG , XIAOJING SUN , Brent L. Quam +7 more | Diabetes

Introduction and Objective: The large-conductance Ca2+-activated K+ (BK) channel is critical in regulation coronary circulation, with its expression tightly regulated by Sorbin and SH3 domain-containing protein 2 (Sorbs2). Sorbs2 expression … Introduction and Objective: The large-conductance Ca2+-activated K+ (BK) channel is critical in regulation coronary circulation, with its expression tightly regulated by Sorbin and SH3 domain-containing protein 2 (Sorbs2). Sorbs2 expression is downregulated in coronary arteries, contributing to BK channelopathy and vasculopathy in diabetic animals. However, the role of Sorbs2 in BK channel function in human vessels remains unclear. Methods: Using patch-clamp, video microscopy, and immunoblotting approaches, we examined Sorbs2 expression and BK channel function in coronary arteries from atrial appendages of patients undergoing CABG surgery. Results: Coronary microvessels were dissected from 9 type 1 diabetic (T1D) patients (6 males and 3 females, 62.8±3.3 years), 20 type 2 diabetic (T2D) patients (11 males and 9 females, 66.6±1.8 years), and 27 non-diabetic controls (18 males and 9 females, 68.8±2.0 years). Cardiac systolic function was similar across the groups (LVEF: 54.0±5.6% for T1D, 50.5±3.0% for T2D, and 56.8±1.9% for controls). However, BK channel-mediated maximal coronary vasodilation was reduced in T1D (27.3±3.4%)* and T2D (54.3±5.0%)* compared to controls (74.0±4.9%). BK channel activation to Ca2+ was also impaired, with EC50 values of 2.26±0.18 μM*# (T1D), 0.89±0.07 μM* (T2D), and 0.41±0.04 μM (controls). The expression of the BK channel α-subunit, but not the β1-subunit, was downregulated by 49.8%* in T1D and 42.6%* in T2D, accompanied by a decrease in Sorbs2 expression of 87.2%*# (T1D) and 37.5%* (T2D), respectively. *: p&lt;0.05 vs. controls. #: p&lt;0.05 vs. T2D. Conclusion: Diminished coronary BK channel function in human diabetes is associated with down-expression of Sorbs2, with a more pronounced decline in T1D. Disclosure X. Xiong: None. X. Sun: None. B. Quam: None. B. Stanga: None. J. Stulak: None. R. Daly: Other Relationship; Neochord, Inc. Consultant; UNOS. K. Greason: None. P. Tang: None. P. Spencer: None. Q. Chai: None. Y. Cha: None. H. Lee: None. T. Lu: None. Funding NHLBI, HL161821

Brugada Syndrome: Channelopathy and/or Cardiomyopathy

2025-06-13

Michele Ciabatti , Pasquale Notarstefano , Chiara Zocchi +4 more | Cardiogenetics

Brugada syndrome (BrS) has been traditionally considered a pure electrical disorder without an underlying structural substrate. However, early ECG studies showed the presence of depolarization abnormalities in this condition, while … Brugada syndrome (BrS) has been traditionally considered a pure electrical disorder without an underlying structural substrate. However, early ECG studies showed the presence of depolarization abnormalities in this condition, while many studies based on advanced imaging have suggested the presence of subtle structural alterations. On the other hand, electrophysiological study (EPS) and electroanatomic mapping (EAM) techniques have provided important data regarding right ventricular functional and structural arrhythmic substrate. More recently, histology and immunology shed light on the possible role of fibrotic and inflammatory substrates in BrS. Notably, a significant overlap between electro anatomical and structural features in BrS and arrhythmogenic cardiomyopathy has been proposed. In this review, we summarized the physio pathological pathways and substrate underlying BrS. A deeper knowledge of the structural abnormalities involved in the pathogenesis of this disease could improve our diagnostic and prognostic approach, while novel findings regarding the role of inflammation and immune activation could potentially lead to new therapeutic strategies for BrS.

Possibilities and difficulties of diagnostics of hereditary arrhythmic syndromes in real clinical practice

2025-06-13

Iskenderov Bg , Т. В. Лохина , Л. Ф. Бурмистрова | Journal of Arrhythmology

The review article discusses current aspects of diagnostics of hereditary arrhythmic syndromes, according to clinical guidelines, and difficulties that have arisen in real clinical practice, as well as possible ways … The review article discusses current aspects of diagnostics of hereditary arrhythmic syndromes, according to clinical guidelines, and difficulties that have arisen in real clinical practice, as well as possible ways to solve them. A systemic and multidisciplinary approach to solving these problems will contribute to increasing the effectiveness of clinical genetic studies and thereby improving the prevention of malignant arrhythmias and sudden cardiac death.

Safety of out-of-hospital initiation of flecainide in patients with atrial and ventricular arrhythmias and structurally normal heart

2025-06-13

Ahmed El‐Damaty , Eman Noaman Ismail , Ahmed Shabban Khalil +1 more | Journal of Arrhythmology

Aim . This study aimed at investigating the safety of out-of-hospital initiation of flecainide in patients presenting with atrial or ventricular arrhythmias and structurally normal heart. Methods . Patients were … Aim . This study aimed at investigating the safety of out-of-hospital initiation of flecainide in patients presenting with atrial or ventricular arrhythmias and structurally normal heart. Methods . Patients were followed 1 week, 1 month and 2 months after drug initiation either in person or through phone interviews and were asked to report symptoms suggestive of sustained arrhythmia, syncope, aborted sudden death and/or emergency room (ER) visits. QRS duration and QTc intervals were measured in a 12-lead ECG at each follow up. Patients were asked to fill out a treatment satisfaction questionnaire for medication (TSQM), four weeks after drug initiation. Results . The mean patient age was 48.5 ± 15.7 years, 36 patients (52%) were females. The most frequent presenting arrhythmia was premature ventricular contractions in 34 (45.3%) patients followed by paroxysmal atrial fibrillation in 22 (29.3%) patients. There was a significant increase in the mean QRS duration (89.9 ± 6.8 msec vs 91.1±7 msec, P <0.001) and the mean QTc interval (417.4 ±10.6 msec vs 418 ± 10.4 msec, P = 0.025) at 1 week compared to baseline. Only one patient (1.3%) had a clinically significant (more than 25%) increase in the QRS duration requiring drug discontinuation. There was no reported life-threatening ventricular arrhythmia, syncope, ER visits or aborted sudden cardiac death. There was 6.7% incidence of cardiac adverse events including conduction system abnormalities and atrial flutter, 4% of patients experienced non-resolving extracardiac manifestations. The overall drug discontinuation rate was 10.7%. The mean TSQM score for effectiveness domain was 70.4 ± 23.8 while the mean of the side effects domain was 94.3 ± 14.6, that of convenience domain was 65.2 ± 10.5 and that of global satisfaction was 72.8 ± 21.8. Conclusion . Out-of-hospital initiation of flecainide is safe and thus feasible, there was no reported documented or suspected life-threatening ventricular arrhythmias. Cardiac and extracardiac adverse events requiring drug discontinuation was effectively detected through clinical and ECG outpatient follow up.

Dual pathology of lower urinary tract obstruction and Brugada syndrome: A rare cause of non-immune hydrops fetalis

2025-06-13

Vaishnavi Verma , Sidra Anjum , Monica Singh +3 more | European Journal of Obstetrics & Gynecology and Reproductive Biology

Early-Stage Morphogenesis of T-Tubules in Rat Cardiomyocytes: The Role of pBIN1

2025-06-13

Qianjin Guo , J. Liang , Hongtao Li +7 more | Circulation Research

BACKGROUND: Transverse tubules (TTs) are tubular invaginations of myocyte membrane forming junctions with sarcoplasmic reticulum and are essential for excitation-contraction coupling. Although it is known that TTs begin to develop … BACKGROUND: Transverse tubules (TTs) are tubular invaginations of myocyte membrane forming junctions with sarcoplasmic reticulum and are essential for excitation-contraction coupling. Although it is known that TTs begin to develop 2 weeks after birth in rodent cardiomyocytes, the spatial profile and molecular mechanisms of TT morphogenesis are not clear. Understanding the molecular mechanism of TT morphogenesis may provide potential solutions for TT loss in pathogenic conditions such as hypertrophy and heart failure. METHODS: To understand early stage morphogenesis of cardiac TTs, we utilized a scanning electron microscope equipped with a focused ion beam to reconstruct a 3-dimensional spatial profile of developing TT network in cardiomyocytes from 2-week-old rats. We created tamoxifen-inducible cardiac-specific knockout rats to explore the role of exons 11 and 13 of the BIN1 (bridging integrator 1) gene. RESULTS: We found that TTs began to develop as intracellular membrane hubs around Z-discs, from which pseudopod-like tubules budded in a relatively random way toward different directions without necessarily connecting to the cell surface. A tubule network forms when membrane branches from adjacent hubs are interconnected. Cardiac-specific knockout of BIN1 exon 13 suppressed TT microfolds. In contrast, cardiac-specific knockout of BIN1 exon 11, which encodes the PIBM (phosphoinositide-binding motif), suppressed the formation of budding tubules, resulting in a sparse tubule network with swollen membrane hubs. Due to the underdeveloped TT network, TT-sarcoplasmic reticulum couplon density/size and excitation-contraction coupling gain in 11KO cardiomyocytes were decreased, similar to those occurring in failing heart cells. CONCLUSIONS: TTs start to develop as budding tubules branching from membrane hubs around Z-discs. This process depends at least partially on the tubulation function of pBIN1 (BIN1 isoforms with PIBM [Bin1+11 and Bin1+11+17]), which is constitutively expressed in rat and human cardiomyocytes. Defective TT morphogenesis due to altered BIN1 splicing in cardiomyocytes may have potential implications in heart diseases.

Electrodiffusion dynamics in the cardiomyocyte dyad at nano-scale resolution using the Poisson-Nernst-Planck (PNP) equations

2025-06-12

Karoline Horgmo Jæger , Aslak Tveito | PLoS Computational Biology

During each heartbeat, a voltage wave propagates through the cardiac muscle, triggering action potentials in approximately two billion cardiomyocytes. This electrical activity ensures the coordinated contraction of the heart, which … During each heartbeat, a voltage wave propagates through the cardiac muscle, triggering action potentials in approximately two billion cardiomyocytes. This electrical activity ensures the coordinated contraction of the heart, which is essential for its pumping function. A key event in this process is the opening of voltage-gated calcium channels in the cell membrane, allowing calcium ions to enter the cardiac dyad and triggering a large-scale release of calcium ions from the sarcoplasmic reticulum through ryanodine receptors. This process is fundamental to cardiac function because calcium subsequently binds to troponin, initiating the conformational changes necessary for myofilament contraction. The cardiac dyad is characterized by a very small volume with steep ionic concentration gradients, which is challenging for detailed mathematical modeling. Traditionally, the dyadic calcium concentration has been approximated using spatially averaged values or modeled with reaction-diffusion equations. However, at the nanometer (nm) and nanosecond (ns) scales, such approximations may be insufficient. At this resolution, the Poisson-Nernst-Planck (PNP) system provides a detailed continuous representation of the underlying electrodiffusion dynamics. Here, we present a nano-scale computational model, representing dyad dynamics using the PNP system. Potassium, sodium, and calcium channels are incorporated in the cell membrane, along with the sodium-calcium exchanger. We demonstrate the formation of the Debye layer in the resting state and highlight how both diffusive and electrical effects are required to maintain this equilibrium. Additionally, we show that cross-species ion interactions in the dyad are electrical, and that diffusion models fail to capture this effect. Finally, we illustrate how the dyad width and diffusion coefficient influence local ionic concentrations and the timing of calcium arrival at the ryanodine receptors. These results provide new insights into the electrodiffusive properties of the dyad and clarify when solving the full PNP system is necessary for accurate modeling.