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Background: Myotonic dystrophy type 1 (DM1) is a multiorgan disorder with significant cardiac involvement. ECG abnormalities, including arrhythmias, occur in 80 % of DM1 patients and are the second-most common cause of death after respiratory complications; however, the mechanisms underlying the arrhythmogenesis remain unclear. The objective of this study was to investigate the basis of the electrophysiological abnormalities in DM1 using the DMSXL mouse model., Methods: ECG parameters were evaluated at baseline and post flecainide challenge. Calcium transient and action potential parameters were evaluated in Langendorff-perfused hearts using fluorescence optical mapping. Calcium transient/sparks were evaluated in ventricular myocytes via confocal microscopy. Protein and mRNA levels for calcium handling proteins were evaluated using western blot and RT-qPCR, respectively., Results: DMSXL mice showed arrhythmic events on ECG including premature ventricular contractions and sinus block. DMSXL mice showed increased calcium transient time to peak without any change to voltage parameters. Calcium alternans and both sustained and non-sustained ventricular tachyarrhythmias were readily inducible in DMSXL mice. The confocal experiments also showed calcium transient alternans and increased frequency of calcium sparks in DMSXL cardiomyocytes. These calcium abnormalities were correlated with increased RyR2 phosphorylation without changes to the other calcium handling proteins., Conclusions: The DMSXL mouse model of DM1 exhibited enhanced arrhythmogenicity associated with abnormal intracellular calcium handling due to hyperphosphorylation of RyR2, pointing to RyR2 as a potential new therapeutic target in DM1 treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Cardiac K + channelopathies account for a significant proportion of arrhythmias and sudden cardiac death (SCD) in subjects without structural heart disease. It is well recognized that genetic defects are key factors in many cases, and in practice, the term cardiac channelopathies currently coincides with inherited cardiac channelopathies. However, mounting evidence demonstrate that not only genetic alterations but also autoimmune and inflammatory factors can cause cardiac K + -channel dysfunction and arrhythmias in the setting of a structurally normal heart. In particular, it has been demonstrated that specific autoantibodies as well as inflammatory cytokines can modulate expression and/or function of different K + channels in the heart, resulting in a disruption of the cardiac action potential and arrhythmias/sudden cardiac death. Awareness about the existence of these newly recognized forms is essential to identify and adequately manage affected patients. In the present review, we focus on autoimmune and inflammatory K + channelopathies as a novel mechanism for cardiac arrhythmias and analyze the recent advancements in this topic, providing complementary basic, clinical, and population health perspectives., (Copyright © 2019 Heart Rhythm Society. All rights reserved.)

Increased proinflammatory interleukin-6 (IL-6) levels are associated with acquired long QT-syndrome (LQTS) in patients with systemic inflammation, leading to higher risks for life-threatening polymorphic ventricular tachycardia such as Torsades de Pointes. However, the functional and molecular mechanisms of this association are not known. In most cases of acquired LQTS, the target ion channel is the human ether-á-go-go-related gene (hERG) encoding the rapid component of the delayed rectifier K current, IKr, which plays a critical role in cardiac repolarization. Here, we tested the hypothesis that IL-6 may cause QT prolongation by suppressing IKr. Electrophysiological and biochemical assays were used to assess the impact of IL-6 on the functional expression of IKr in HEK293 cells and adult guinea-pig ventricular myocytes (AGPVM). In HEK293 cells, IL-6 alone or in combination with the soluble IL-6 receptor (IL-6R), produced a significant depression of IKr peak and tail current densities. Block of IL-6R or Janus kinase (JAK) reversed the inhibitory effects of IL-6 on IKr. In AGPVM, IL-6 prolonged action potential duration (APD) which was further prolonged in the presence of IL-6R. Similar to heterologous cells, IL-6 reduced endogenous guinea pig ERG channel mRNA and protein expression. The data are first to demonstrate that IL-6 inhibition of IKr and the resulting prolongation of APD is mediated via IL-6R and JAK pathway activation and forms the basis for the observed clinical QT interval prolongation. These novel findings may guide the development of targeted anti-arrhythmic therapeutic interventions in patients with LQTS and inflammatory disorders., Competing Interests: The authors have declared that no competing interests exist.

Ambulatory ECG (AECG) is very commonly employed in a variety of clinical contexts to detect cardiac arrhythmias and/or arrhythmia patterns which are not readily obtained from the standard ECG. Accurate and timely characterization of arrhythmias is crucial to direct therapies that can have an important impact on diagnosis, prognosis or patient symptom status. The rhythm information derived from the large variety of AECG recording systems can often lead to appropriate and patient-specific medical and interventional management. The details in this document provide background and framework from which to apply AECG techniques in clinical practice, as well as clinical research., (© 2017 International Society for Holter and Noninvasive Electrocardiology, Heart Rhythm Society, and Wiley Periodicals, Inc.)

In the last decade, there have been considerable advances in the understanding of the pathophysiology of malignant ventricular tachyarrhythmias (VT) and sudden cardiac death (SCD). Over 80% of SCD occurs in patients with organic heart disease. However, approximately 10%-15% of SCD occurs in the presence of structurally normal heart, and the majority of these patients are young. In this group of patients, changes in genes encoding cardiac ion channels produce modifications of the function of the channel resulting in an electrophysiological substrate of VT and SCD. Collectively, these disorders are referred to as cardiac ion channelopathies. The four major syndromes in this group are: the long QT syndrome (LQTS), the Brugada syndrome (BrS), the short QT syndrome (SQTS), and the catecholaminergic polymorphic ventricular tachycardia (CPVT). Each of these syndromes includes multiple subtypes with different and sometimes complex cardiac ion channel genetic abnormalities. Many are associated with other somatic and neurological abnormalities besides the risk of VT and SCD. The current management of cardiac ion channelopathies can be summarized as follows: (1) in symptomatic patients, the implantable cardioverter defibrillator (ICD) is the only viable option; (2) in asymptomatic patients, risk stratification is necessary, followed by either the ICD, pharmacotherapy, or a combination of both. A genotype-specific approach to pharmacotherapy requires a thorough understanding of the molecular-cellular basis of arrhythmogenesis in cardiac ion channelopathies as well as the specific drug profile., (Copyright © 2015. Published by Elsevier Inc.)

Left ventricular hypertrophy (LVH) poses an independent risk of increased morbidity and mortality, including atrial arrhythmias, ventricular arrhythmias, and sudden cardiac death. The most common causes of LVH are hypertension and valvular heart disease. Electrocardiography and echocardiography are the first steps in the diagnosis and evaluation of therapy in patients with LVH. Cardiac MRI is the gold standard in diagnosis and assessment of response to therapy. Management of LVH should be based on etiology, evidence, and guideline adherence. Timely and optimal management of the underlying cause of LVH results in improvement (regression) of LVH and its related complications., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: The aim of the study is to contrast the role of conventional ambulatory electrocardiographic monitoring (AEM) artifacts with a less emphasized problem with potentially more serious implications, that is, the failure to recognize, and therefore misinterpret, a genuine arrhythmia episode in the AEM recording., Methods: The study material included 500 Holter recordings and 500 recordings from the cardiac telemetry unit., Results: Electrocardiographic (ECG) artifacts were more common in telemetry recordings (5.6%) compared to Holter recordings (4%) for a total of 4.8%. There were 35 examples of misinterpretation of AEM recordings (3.5%). These were significantly more common in telemetry recordings (2.6%) compared to Holter recordings (0.9%). The most common ECG artifacts were examples of pseudo ventricular tachyarrhythmia (VT). The majority of misinterpretation (26 of 35 examples) were fast supraventricular tachyarrhythmias with aberrant QRS (including six examples of atrial flutter with periods of 1:1 atrioventricular conduction) that were misdiagnosed as ventricular VT. Other examples were misinterpretation of arrhythmic episodes consistent with sick sinus syndrome, pacemaker malfunction, and long QT syndrome. Only 5 of 48 examples of AEM artifacts resulted in management errors of commission or errors of omission compared to all 35 examples of misinterpretation., Conclusions: Compared to conventional artifacts in AEM, misinterpretation of nonartifactual arrhythmic episodes consistently resulted in management errors. Misinterpretation was significantly more common with telemetry recordings compared to Holter ECG. This highlights the need for more appropriate training of the entire clinical team in charge of the management of the cardiac telemetry unit., (© 2014 Wiley Periodicals, Inc.)

In recent years, cultured cardiac cell monolayers have become a contemporary experimental preparation for the study of fundamental mechanisms that underlie normal and pathologic electrophysiology at the tissue level. Ion channels and gap junctions in the cardiomyocyte monolayer may be modulated using drugs that suppress or enhance certain channels/junctions, or by genetic silencing or overexpression. The cardiomyocyte monolayer is particularly well suited for studies of functional electrophysiologic properties of mixtures of cardiac and noncardiac cells (eg, myofibroblasts), which otherwise would be difficult to investigate. Optical mapping of monolayers has provided insight into mechanisms that can set the stage for arrhythmias, such as unidirectional conduction block, gap junction uncoupling, ischemia, alternans, and anisotropy, and continues to enhance our understanding of basic electrophysiologic mechanisms., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Unlabelled: Pervious biochemical and hemodynamic studies have highlighted the important role of εPKC in cardioprotection during ischemic preconditioning. However, little is known about the electrophysiological consequences of εPKC modulation in ischemic hearts. Membrane permeable peptide εPKC selective activator and inhibitor were used to investigate the role of εPKC modulation in reperfusion arrhythmias., Methods: Protein transduction domain from HIV-TAT was used as a carrier for peptide delivery into intact Langendorff perfused guinea pig hearts. Action potentials were imaged and mapped (124 sites) using optical techniques and surface ECG was continuously recorded. Hearts were exposed to 30 min stabilization period, 15 min of no-flow ischemia, followed by 20 min reperfusion. Peptides (0.5 μM) were infused as follows: (a) control (vehicle-TAT peptide; TAT-scrambled ψεRACK peptide); (b) εPKC agonist (TAT-ψεRACK); (c) εPKC antagonist (TAT-εV1)., Results: Hearts treated with εPKC agonist ψεRACK had reduced incidence of ventricular tachycardia (VT, 64%) and fibrillation (VF, 50%) compared to control (VT, 80%, P<0.05) and (VF, 70%, P < 0.05). However, the highest incidence of VT (100%, P < 0.05) and VF (80%) occurred in hearts treated with εPKC antagonist peptide εV1 compared to control and to εPKC agonist ψεRACK. Interestingly, at 20 min reperfusion, 100% of hearts treated with εPKC agonist ψεRACK exhibited complete recovery of action potentials compared to 40% (P < 0.05) of hearts treated with εPKC antagonist peptide, εV1 and 65% (P < 0.5) of hearts in control. At 20 min reperfusion, maps of action potential duration from εPKC agonist ψεRACK showed minimal dispersion (48.2 ± 9 ms) compared to exacerbated dispersion (115.4 ± 42 ms, P < 0.05) in εPKC antagonist and control (67 ± 20 ms, P<0.05). VT/VF and dispersion from hearts treated with scrambled agonist or antagonist peptides were similar to control., Conclusion: The results demonstrate that εPKC activation by ψεRACK peptide protects intact hearts from reperfusion arrhythmias and affords better recovery. On the other hand, inhibition of εPKC increased the incidence of arrhythmias and worsened recovery compared to controls. The results carry significant therapeutic implications for the treatment of acute ischemic heart disease by preconditioning-mimicking agents., (Published by Elsevier Inc.)

This consensus guideline was prepared on behalf of the International Society for Holter and Noninvasive Electrocardiology and is cosponsored by the Japanese Circulation Society, the Computers in Cardiology Working Group on e-Cardiology of the European Society of Cardiology, and the European Cardiac Arrhythmia Society. It discusses the electrocardiographic phenomenon of T-wave alternans (TWA) (i.e., a beat-to-beat alternation in the morphology and amplitude of the ST-segment or T-wave). This statement focuses on its physiological basis and measurement technologies and its clinical utility in stratifying risk for life-threatening ventricular arrhythmias. Signal processing techniques including the frequency-domain Spectral Method and the time-domain Modified Moving Average method have demonstrated the utility of TWA in arrhythmia risk stratification in prospective studies in >12,000 patients. The majority of exercise-based studies using both methods have reported high relative risks for cardiovascular mortality and for sudden cardiac death in patients with preserved as well as depressed left ventricular ejection fraction. Studies with ambulatory electrocardiogram-based TWA analysis with Modified Moving Average method have yielded significant predictive capacity. However, negative studies with the Spectral Method have also appeared, including 2 interventional studies in patients with implantable defibrillators. Meta-analyses have been performed to gain insights into this issue. Frontiers of TWA research include use in arrhythmia risk stratification of individuals with preserved ejection fraction, improvements in predictivity with quantitative analysis, and utility in guiding medical as well as device-based therapy. Overall, although TWA appears to be a useful marker of risk for arrhythmic and cardiovascular death, there is as yet no definitive evidence that it can guide therapy., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Electrolyte disorders can alter cardiac ionic currents kinetics and depending on the changes can promote proarrhythmic or antiarrhythmic effects. The present report reviews the mechanisms, electrophysiolgical (EP), electrocardiographic (ECG), and clinical consequences of electrolyte disorders. Potassium (K⁺) is the most abundent intracellular cation and hypokalemia is the most commont electrolyte abnormality encountered in clinical practice. The most significant ECG manifestation of hypokalemia is a prominent U wave. Several cardiac and non cardiac drugs are known to suppress the HERG K⁺ channel and hence the I(K), and especially in the presence of hypokalemia, can result in prolonged action potential duration and QT interval, QTU alternans, early afterdepolarizations, and torsade de pointes ventricular tachyarrythmia (TdP VT). Hyperkalemia affects up to 8% of hospitalized patients mainly in the setting of compromised renal function. The ECG manifestation of hyperkalemia depends on serum K⁺ level. At 5.5-7.0 mmol/L K⁺, tall peaked, narrow-based T waves are seen. At > 10.0 mmol/L K⁺, sinus arrest, marked intraventricular conduction delay, ventricular techycardia, and ventricular fibrillation can develop. Isolated abnormalities of extracellular calcium (Ca⁺⁺) produce clinically significant EP effects only when they are extreme in either direction. Hypocalcemia, frequently seen in the setting of chronic renal insufficiency, results in prolonged ST segment and QT interval while hypercalcemia, usually seen with hyperparathyroidism, results in shortening of both intervals. Although magnesium is the second most abudent intracellular cation, the significance of magnesium disorders are controversial partly because of the frequent association of other electrolyte abnormalities. However, IV magnesium by blocking the L-type Ca(⁺⁺) current can successfully terminate TdP VT without affecting the prolonged QT interval. Finally, despite the frequency of sodium abnormalities, particularly hyponatremia, its EP effects are rarely clinically significant.

In the last decade there have been considerable advances in the understanding of the pathophysiology of malignant ventricular tachyarrhythmias (VA) and Sudden Cardiac Death (SCD). Over 80% of SCD occurs in patients with organic heart disease. However, approximately 10-15% of SCD occurs in the presence of structurally normal heart and the majority of those patients are young. In this group of patients, changes in genes encoding cardiac ion channels produce modification of the function of the channel resulting in an electrophysiological substrate of VA and SCD. Collectively these disorders are referred to as Cardiac Ion Channelopathies. The 4 major syndromes in this group are: The Long QT Syndrome (LQTS), the Brugada Syndrome (BrS), the Short QT Syndrome (SQTS), and the Catecholaminergic Polymorphic VT (CPVT). Each of these syndromes includes multiple subtypes with different and sometimes complex genetic abnormalities of cardiac ion channels. Many are associated with other somatic and neurological abnormalities besides the risk of VA and SCD. The current management of cardiac ion channelopathy could be summarized as follows: 1) in symptomatic patients, the implantable cardioverter defibrillator (ICD) is the only viable option; 2) in asymptomatic patients, risk stratification is necessary followed by the ICD, pharmacotherapy, or a combination of both. A genotype-specific approach to pharmacotherapy requires a thorough understanding of the molecular-cellular basis of arrhythmogenesis in cardiac ion channelopathies as well as the specific drug profile.

Background: The coexistence of cardiac hypertrophy (H) and ischemia (I) can create a particularly arrhythmogenic substrate. Most studies investigate the effects of global I on H. However, global I is not a good surrogate model of the clinical situation., Objective: The purpose of this study was to investigate the electrophysiological effects of regional I superimposed on H using optical mapping of membrane voltage., Methods: We investigated the guinea pig model of left ventricular H (LVH) induced by suprarenal banding of abdominal aorta. Twelve hearts with or without LVH were mounted in a Langendorff preparation, and regional I was induced by 20 minutes of ligation of the left anterior descending artery., Results: Left ventricle epicardial action potential duration (APD) was significantly prolonged in the LVH group compared with controls. I significantly shortened APD in the I risk zone in both groups, but the percentages of APD shortening (28% vs. 40%) and the magnitudes of shortening (57 +/- 18 vs. 105 +/- 32 ms) were greater in the LVH group. The greater dispersion of repolarization (DR) across the border of the I zone resulted in arcs of functional conduction block and circulating wave fronts. Tachycardia-dependent APD alternans developed more often in the LVH group, and the area of alternans versus the area of the I zone was significantly larger. Ventricular tachyarrhythmias (VTs) developed in all 12 hearts with LVH including six non-self-terminating VTs, compared with four control hearts with self-terminating VT., Conclusion: Regional I superimposed on LVH resulted in greater DR at the border between the I and non-I zones as well as in a greater tendency to develop APD alternans. Both arrhythmogenic mechanisms correlated with an increased incidence of VT.

Background: The correlation between spontaneous calcium oscillations (S-CaOs) and arrhythmogenesis has been investigated in a number of theoretical and experimental in vitro models. There is an obvious lack of studies that directly investigate how the kinetics of S-CaOs correlates with a specific arrhythmia in the in vivo heart., Objectives: The purpose of the study is to investigate the correlation between the kinetics of S-CaOs and arrhythmogenesis in the intact heart using an experimental model of ischemia/reperfusion (I/R)., Methods: Perfused Langendorff guinea pig (GP) hearts were subjected to global I/R (10-15 minutes/10-15 minutes). The heart was stained with a voltage-sensitive dye (RH237) and loaded with a Ca2+ indicator (Rhod-2 AM). Membrane voltage (Vm) and intracellular calcium transient (Ca(i)T) were simultaneously recorded with an optical mapping system of two 16 x 16 photodiode arrays. S-CaOs were considered to arise from a localized focal site within the mapped surface when these preceded the associated membrane depolarizations by 2-15 ms., Results: In 135 episodes of ventricular arrhythmias from 28 different GP experiments, 23 were linked to S-CaOs that were considered to arise from or close to the mapped epicardial window. Self-limited or sustained S-CaOs had a cycle length of 130-430 ms and could trigger propagated ventricular depolarizations. Self-limited S-CaOs that followed the basic beat action potential (AP)/Ca(i)T closely resembled phase 3 early afterdepolarizations. Fast S-CaOs could remain confined to a localized site (concealed) or exhibit varying conduction patterns. This could manifest as (1) an isolated premature beat (PB), bigeminal, or trigeminal rhythm; (2) ventricular tachycardia (VT) when a regular 2:1 conduction from the focal site develops; or (3) ventricular fibrillation (VF) when a complex conduction pattern results in wave break and reentrant excitation., Conclusions: The study examined, for the first time in the intact heart, the correlation between the kinetics of focal S-CaOs during I/R and arrhythmogenesis. S-CaOs may remain concealed or manifest as PBs, VT, or VF. A "benign looking" PB during I/R may represent "the tip of the iceberg" of an underlying potentially serious arrhythmic mechanism.

The cardiovascular drug carvedilol is characterized by multiple pharmacological actions, which translate into a wide-spectrum therapeutic potential. Its major molecular targets are membrane adrenoceptors, ion channels, and reactive oxygen species. Carvedilol's favorable hemodynamic effects are due to the fact that the drug competitively blocks beta(1)-, beta(2)-, and alpha(1)- adrenoceptors. Several additional properties have been documented and may be clinically important, including antioxidant, antiproliferative/antiatherogenic, anti-ischemic, and antihypertrophic effects. The antiarrhythmic action of carvedilol may be related to a combination of its beta-blocking effects with its modulating effects on a variety of ion channels and currents. Several studies suggest that the drug may be useful in reducing cardiac death in high-risk patients with prior myocardial infarction and/or heart failure, as well as for primary and secondary prevention of atrial fibrillation. This article will review experimental data available on the electrophysiologic properties of carvedilol, with a focus on their clinical relevance.