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Cardiac electrical alternans (CEA), manifested as T-wave alternans in ECG, is a clinical biomarker for predicting cardiac arrhythmias and sudden death. However, the mechanism underlying the spontaneous transition from CEA to arrhythmias remains incompletely elucidated. In this study, multiscale rabbit ventricular models were used to study the transition and a potential role of INa in perpetuating such a transition. It was shown CEA evolved into either concordant or discordant action potential (AP) conduction alternans in a homogeneous one-dimensional tissue model, depending on tissue AP duration and conduction velocity (CV) restitution properties. Discordant alternans was able to cause conduction failure in the model, which was promoted by impaired sodium channel with either a reduced or increased channel current. In a two-dimensional homogeneous tissue model, a combined effect of rate- and curvature-dependent CV broke-up alternating wavefronts at localised points, facilitating a spontaneous transition from CEA to re-entry. Tissue inhomogeneity or anisotropy further promoted break-up of re-entry, leading to multiple wavelets. Similar observations have also been seen in human atrial cellular and tissue models. In conclusion, our results identify a mechanism by which CEA spontaneously evolves into re-entry without a requirement for premature ventricular complexes or pre-existing tissue heterogeneities, and demonstrated the important pro-arrhythmic role of impaired sodium channel activity. These findings are model-independent and have potential human relevance.

Abstract: Atrial fibrillation (AF) has been linked to increased inward rectifier potassium current, I K1, either due to AF-induced electrical remodelling, or from functional changes due to the Kir2.1 V93I mutation. The aim of this simulation study was to identify at cell and tissue levels'' mechanisms by which increased I K1 facilitates and perpetuates AF. The Courtemanche et al. human atrial cell action potential (AP) model was modified to incorporate reported changes in I K1 induced by the Kir2.1 V93I mutation in both heterozygous (Het) and homozygous (Hom) mutant forms. The modified models for wild type (WT), Het and Hom conditions were incorporated into homogeneous 1D, 2D and 3D tissue models. Restitution curves of AP duration (APD), effective refractory period (ERP) and conduction velocity (CV) were computed and both the temporal and the spatial vulnerability of atrial tissue to re-entry were measured. The lifespan and tip meandering pattern of re-entry were also characterised. For comparison, parallel simulations were performed by incorporating into the Courtmanche et al. model a linear increase in maximal I K1 conductance. It was found that the gain-in-function of V93I ‘mutant’I K1 led to abbreviated atrial APs and flattened APD, ERP and CV restitution curves. It also hyperpolarised atrial resting membrane potential and slowed down intra-atrial conduction. V93I ‘mutant’I K1 reduced the tissue''s temporal vulnerability but increased spatial vulnerability to initiate and sustain re-entry, resulting in an increased overall susceptibility of atrial tissue to arrhythmogenesis. In the 2D model, spiral waves self-terminated for WT (lifespan < 3.3 s) tissue, but persisted in Het and Hom tissues for the whole simulation period (lifespan > 10 s). The tip of the spiral wave meandered more in WT tissue than in Het and Hom tissues. Increased I K1 due to augmented maximal conductance produced similar results to those of Het and Hom Kir2.1 V93I mutant conditions. In the 3D model the dynamic behaviour of scroll waves was stabilized by increased I K1. In conclusion, increased I K1 current, either by the Kir2.1 V93I mutation or by augmented maximal conductance, increases atrial susceptibility to arrhythmia by increasing the lifespan of re-entrant spiral waves and the stability of scroll waves in 3D tissue, thereby facilitating initiation and maintenance of re-entrant circuits. [Copyright &y& Elsevier]

Abstract: Objectives: Although previous studies in dogs have indicated a minimal role for changes in I K1 in the shortening of action potential duration (APD) associated with atrial fibrillation (AF), in humans, there is evidence for significant AF-induced up-regulation of this current. In this computer model study, we investigated the relative contributions of the remodeling of I K1, L-type calcium current, and other remodeled ionic channel currents to AF-induced APD reduction in human atrium. Methods: Two computer models of electrical activity of human atrial cell were modified by incorporating experimental data of AF-induced changes in human atrial ionic channel conductance and kinetics reported by Bosch et al. (I CaL, I to, I K1, and I Na) (AF-1) and Workman et al. (I CaL, I to, and I K1) (AF-2). The roles and relative importance of individually remodeled ion channels in the APD reduction in human atrium were evaluated by the removal and exclusive methods, in which remodeling of specific currents was omitted, or considered in isolation, in the two models. Results: When tested together, previously reported AF-induced changes in sarcolemmal ion currents result in marked shortening of atrial APD90. With the AF-1 remodeled parameters, there is a 62% reduction in APD90 for the Nygren et al. model, and a 68% reduction for the Courtemanche et al. model, which are comparable to experimental results of 60% reduction seen in humans. When tested individually, AF-1-induced changes in I CaL, I K1, or I to alone result in APD90 reduction of 20%, 64%, and −10%, respectively, for the Nygren et al. model, and 27%, 40%, and 11.6%, respectively, for the Courtemanche et al. model. With the AF-2 remodeled parameters, there is a 47% reduction in APD90 for the Nygren et al. model and a 49% reduction for the Courtemanche et al. model, which are also comparable to experimental results of 45% reduction. When tested individually, AF-2-induced changes in I CaL or I K1 alone result in APD90 reduction of 20% and 40%, respectively, for the Nygren et al. model, and 14% and 21%, respectively, for the Courtemanche et al. model. Conclusion: Previously reported changes in L-type Ca2+ current are insufficient to account for the observed reduction in atrial APD associated with persistent AF. Up-regulation of I K1 has a greater influence on atrial APD in the human model. [Copyright &y& Elsevier]

Presents a correspondence on several medical issues in Great Britain. Update on shortages in nursing manpower in several districts; Approaches to improve the funding of National Health Service; Efforts for immunization due to increase incidence on Hepatitis B.

Introduction: The inferior nodal extension (INE), compact node (CN) and penetrating/His bundle (PB/HB) form the atrioventricular (AV) conduction axis and are responsible for conduction and delay of the action potential from the atria to the ventricles. With ageing, dysfunction of the AV conduction axis results in prolongation of the PR interval and AV block.Methods: We have compared the INE, CN and PB/HB from male rats 3 months old (n 9) and 2 years old (n 8). From survival curves, 3 month old rat correspond to 20 yearr old human, whereas 2 year old rat correspond to 70 year old human. Morphological characteristics of these tissues were studied using Masson's trichrome (MT) and picrosirius red (PR) on serial histological sections. Protein expression was studied using immunofluorescence and confocal microscopy. Qualitative signal intensity of proteins investigated was measured using Volocity software.Results: MT staining showed that the cells of INE, CN and PB were more loosely packed and irregularly arranged thus showing myocardial disarray in old rats. PR staining showed that total collagen content was greater in CN and PB with ageing. There was an age dependent cellular hypertrophy in all regions of the AV conduction axis. Immunohistochemistry revealed that Cx43 (the major gap junction in the heart) down regulates in PB (P<0.05), but Cx40 (important gap junction in the atria and AV conduction axis) up regulates in INE and CN (P<0.05) in old rats. With ageing, there was a down regulation of Nav1.5 (major cardiac Na+channel) in CN and PB (P<0.05), up regulation of Cav1.3 (L-type Ca2+ channel) in PB (P<0.05) and in terms of Ca2+ handling proteins, downregulation of RyR2 in CN, PB (P<0.05) and up regulation of SERCA2a in PB (P<0.05). There was also trend to downregulation of HCN4 in PB/HB bundle (P=0.051)Conclusion: Ageing is associated with structural changes to the tissues in the AV conduction axis, which include myocardial disarray, fibrosis and hypertrophy. Ageing is also associated with changes in the expression of ion channels, gap junction proteins and Ca2+ handling proteins. These changes may explain the age dependent dysfunction of AV conduction axis. [ABSTRACT FROM PUBLISHER]

Hypertrophic cardiomyopathy (HCM) is a heterogeneous condition with potentially serious manifestations. Management has traditionally comprised therapies to palliate symptoms and implantable cardioverter-defibrillators to prevent sudden cardiac death. The need for disease-modifying therapies has been recognized for decades. More recently, an increasing number of novel and repurposed therapies hypothesized to target HCM disease pathways have been evaluated, culminating in the recent regulatory approval of mavacamten, a novel oral myosin inhibitor. HCM poses several unique challenges for clinical trials, which are important to recognize when designing trials and interpreting findings. This manuscript discusses the key considerations in the context of recent and ongoing randomized trials, including the roles of genotype, phenotype and symptom status in patient selection, the evidence base for clinical and mechanistic outcome measurements, trial duration and sample size., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disorder which usually presents in the first or second decade of life with syncope, which is typically induced by emotional stress or exercise. We describe a large family with a history of three sudden unexpected deaths. Investigations in the sibling of a deceased individual affected by emotion-induced syncope revealed ventricular bigeminy. Molecular genetic testing was performed on one symptomatic individual and a missense mutation in RYR2 was identified consistent with a diagnosis of CPVT. Subsequent cascade testing of family members excluded 37 of 43 individuals from risk and facilitated preventative intervention. This case highlights the value of genotyping in sudden cardiac death by defining the precise diagnosis and through the identification and exclusion of at-risk individuals. < Learning objective: The diagnosis of CPVT should be considered in families with a history of sudden death in a previously asymptomatic young person. Cascade molecular genetic testing should be undertaken as, if a pathogenic mutation is found, this can distinguish it from other arrhythmogenic disorders and can identify at-risk individuals allowing treatment to be targeted at those in need, thus helping to reduce the mortality associated with the condition.>.

Hypertrophic cardiomyopathy (HCM) is the most common genetic cause of cardiomyopathy worldwide. Significant advances and widespread availability of genetic testing have improved detection of the sarcomeric mutations that cause HCM, but have also highlighted the significance of inborn errors of metabolism (IEM) or metabolic storage disorders that can mimic HCM ('HCM phenocopies'). These conditions cannot always be reliably differentiated on the basis of imaging alone. Whilst HCM phenocopies are relatively rare, it is crucial to distinguish these conditions at an early stage as their natural history, management and prognosis vary significantly from that of HCM with sarcomeric mutations. This review illustrates the salient features of HCM phenocopies and stresses the need for a high level of suspicion for these conditions in the assessment of cardiac hypertrophy.

Objectives: Although previous studies in dogs have indicated a minimal role for changes in I(K1) in the shortening of action potential duration (APD) associated with atrial fibrillation (AF), in humans, there is evidence for significant AF-induced up-regulation of this current. In this computer model study, we investigated the relative contributions of the remodeling of I(K1), L-type calcium current, and other remodeled ionic channel currents to AF-induced APD reduction in human atrium., Methods: Two computer models of electrical activity of human atrial cell were modified by incorporating experimental data of AF-induced changes in human atrial ionic channel conductance and kinetics reported by Bosch et al. (I(CaL), I(to), I(K1), and I(Na)) (AF-1) and Workman et al. (I(CaL), I(to), and I(K1)) (AF-2). The roles and relative importance of individually remodeled ion channels in the APD reduction in human atrium were evaluated by the removal and exclusive methods, in which remodeling of specific currents was omitted, or considered in isolation, in the two models., Results: When tested together, previously reported AF-induced changes in sarcolemmal ion currents result in marked shortening of atrial APD(90). With the AF-1 remodeled parameters, there is a 62% reduction in APD(90) for the Nygren et al. model, and a 68% reduction for the Courtemanche et al. model, which are comparable to experimental results of 60% reduction seen in humans. When tested individually, AF-1-induced changes in I(CaL), I(K1), or I(to) alone result in APD(90) reduction of 20%, 64%, and -10%, respectively, for the Nygren et al. model, and 27%, 40%, and 11.6%, respectively, for the Courtemanche et al. model. With the AF-2 remodeled parameters, there is a 47% reduction in APD(90) for the Nygren et al. model and a 49% reduction for the Courtemanche et al. model, which are also comparable to experimental results of 45% reduction. When tested individually, AF-2-induced changes in I(CaL) or I(K1) alone result in APD(90) reduction of 20% and 40%, respectively, for the Nygren et al. model, and 14% and 21%, respectively, for the Courtemanche et al. model., Conclusion: Previously reported changes in L-type Ca(2+) current are insufficient to account for the observed reduction in atrial APD associated with persistent AF. Up-regulation of I(K1) has a greater influence on atrial APD in the human model.

Background: Episodes of atrial fibrillation (AF) are known to cause both a rapid reduction in atrial refractoriness (atrial electrical remodeling) and a more delayed increase in AF stability thought to be due to a so-called "second factor." The aim of this study was to quantify the effects and time course of such a factor on AF stability in the chronic goat model., Methods and Results: AF was maintained in 6 goats by burst atrial pacing for 3 consecutive 4-week periods separated a mean of 6+/-2.1 days of sinus rhythm. Six days of sinus rhythm was just sufficient for refractoriness changes to reverse fully in all goats. Atrial effective refractory period, AF inducibility, and duration of individual episodes of AF were assessed at regular intervals. There was a progressive reduction from month 1 to 2 to 3 in the mean duration of burst pacing required to induce individual episodes of AF of 60 seconds (178+/-251, 110+/-102, and 21+/-30 hours), 1 hour (229+/-224, 136+/-104, and 68+/-51 hours), and 24 hours (277+/-218, 192+/-190, and 102+/-75 hours; P<0.03). The frequency with which AF was induced during extrastimulus pacing increased progressively from 16.7% in month 1 to 31.7% in month 2 and 46.9% in month 3 (P<0.001)., Conclusions: Sequential 4-week periods of atrial fibrillation result in a progressive increase in AF stability independent of baseline atrial refractory period. This finding suggests the presence of a second factor in the self-perpetuation of AF with a time course comparable to that of AF-induced ultrastructural changes in the atria.