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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.

A study published in the journal Diabetes, Obesity & Metabolism examined the impact of hybrid closed-loop (HCL) insulin delivery on cardiac rhythm in older adults with type 1 diabetes (T1D). The study found that HCL devices improved glucose control and reduced the risk of low blood sugar, but did not have a significant impact on cardiac rhythm. The study suggests that HCL systems can be beneficial for managing T1D in older adults without negatively affecting cardiac rhythm. However, more research is needed to understand the relationship between glucose control and cardiac rhythm in individuals with T1D. [Extracted from the article]

Tachycardia is excessively fast beating of the heart. A variety of different physiological dysfunctions may lead to tachycardia, and proper diagnosis of the underlying cause is critical to selecting the proper treatment. When the source of the tachycardia is not within the thick muscular ventricles of the heart, the condition is called supraventricular tachycardia. Quite often, the abnormality lies in the electrically excitable tissues that regulate the beating of the heart, the sino-atrial node and the atrioventricular node. The drug verapamil is frequently used to terminate paroxysmal supraventricular tachycardia. Curiously, however, a drug recently approved to treat this condition is actually one of the oldest. Less than two years ago, adenosine was approved for the treatment of supraventricular tachycardia. This naturally occurring substance plays an important role in many of a cell's regulatory processes; it is also converted into one of the nucleotides that make up DNA. Adenosine was first used in the treatment of supraventricular tachycardia in 1933, but only recently has the attention of researchers again focussed on this potentially useful substance. The authors provide a detailed review of the current state of knowledge about adenosine and its use in the treatment of tachycardias. While adenosine may be directly useful in the treatment of some forms of tachycardia, its effectiveness may prove to be useful for diagnostic purposes as well. For example, when ventricular tachycardia is erroneously diagnosed as supraventricular tachycardia, treatment with verapamil may actually worsen the condition. However, the failure of the condition to respond immediately to adenosine may demonstrate that the diagnosis was incorrect and lead to proper treatment for the patient. This review describes how the combination of electrocardiography and adenosine administration can be used in the management of tachycardias. (Consumer Summary produced by Reliance Medical Information, Inc.)

Background: The sinoatrial/sinus node (SAN) is the primary pacemaker of the heart. In humans, SAN is surrounded by the paranodal area (PNA). Although the PNA function remains debated, it is thought to act as a subsidiary atrial pacemaker (SAP) tissue and become the dominant pacemaker in the setting of sinus node disease (SND). Large animal models of SND allow characterization of SAP, which might be a target for novel treatment strategies for SAN diseases. Methods: A goat model of SND was developed (n = 10) by epicardially ablating the SAN and validated by mapping of emergent SAP locations through an ablation catheter and surface electrocardiogram (ECG). Structural characterization of the goat SAN and SAP was assessed by histology and immunofluorescence techniques. Results: When the SAN was ablated, SAPs featured a shortened atrioventricular conduction, consistent with the location in proximity of atrioventricular junction. SAP recovery time showed significant prolongation compared to the SAN recovery time, followed by a decrease over a follow-up of 4 weeks. Like the SAN tissue, the SAP expressed the main isoform of pacemaker hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) and Na+/Ca2+ exchanger 1 (NCX1) and no high conductance connexin 43 (Cx43). Structural characterization of the right atrium (RA) revealed that the SAN was located at the earliest activation [i.e., at the junction of the superior vena cava (SVC) with the RA] and was surrounded by the paranodal-like tissue, extending down to the inferior vena cava (IVC). Emerged SAPs were localized close to the IVC and within the thick band of the atrial muscle known as the crista terminalis (CT). Conclusions: SAN ablation resulted in the generation of chronic SAP activity in 60% of treated animals. SAP displayed development over time and was located within the previously discovered PNA in humans, suggesting its role as dominant pacemaker in SND. Therefore, SAP in goat constitutes a promising stable target for electrophysiological modification to construct a fully functioning pacemaker. [ABSTRACT FROM AUTHOR]

Background: Aging is associated with an increased incidence of atrioventricular nodal (AVN) dysfunction.Objective: The aim of this study was to investigate the structural and functional remodeling in the atrioventricular junction (AVJ) with aging.Methods: Electrophysiology, histology, and immunohistochemistry experiments on male Wistar Hannover rats aged 3 months (n = 24) and 2 years (n = 15) were performed. Atrio-His (AH) interval, Wenkebach cycle length (WBCL), and AVN effective refractory period (AVNERP) were measured. Cesium (2 mM) was used to block hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, while ryanodine (2 μM) was used to block ryanodine 2 (RyR2) channels. Protein expression from different regions of the AVJ was studied using immunofluorescence. The expression of connexins (connexin 43 and connexin 40), ion channels (Hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4), voltage sensitive sodium channel (Nav1.5), and L-Type calcium channel (Cav1.3)), and calcium handling proteins (RyR2 and sarco/endoplasmic reticulum calcium ATPaset type 2a (SERCA2a)) were measured. Morphological characteristics were studied with histology.Results: Without drugs to block HCN and RyR2 channels, there was prolongation of the AH interval, WBCL, and AVNERP (P < .05) with aging. In young rats only, cesium prolonged the AH interval, WBCL, and AVNERP (P < .01). Ryanodine prolonged the AH interval and WBCL (P < .01) in both young and old rats. Immunofluorescence revealed that with aging, connexin 43, HCN4, Nav1.5, and RyR2 downregulate in the regions of the AVJ and connexin 40, SERCA2a, and Cav1.3 upregulate (P < .05). Aging results in cellular hypertrophy, loosely packed cells, a decrease in the number of nuclei, and an increase in collagen content.Conclusion: Heterogeneous ion channel expression changes were observed in the AVJ with aging. For the first time, we have shown that HCN and RyR2 play an important role in AVN dysfunction with aging. [ABSTRACT FROM AUTHOR]

Aims: Atrial stunning, a loss of atrial mechanical contraction, can occur following a successful cardioversion. It is hypothesized that persistent atrial fibrillation-induced electrical remodeling (AFER) on atrial electrophysiology may be responsible for such impaired atrial mechanics. This simulation study aimed to investigate the effects of AFER on atrial electro-mechanics. Methods and Results: A 3D electromechanical model of the human atria was developed to investigate the effects of AFER on atrial electro-mechanics. Simulations were carried out in 3 conditions for 4 states: (i) the control condition, representing the normal tissue (state 1) and the tissue 2–3 months after cardioversion (state 2) when the atrial tissue recovers its electrophysiological properties after completion of reverse electrophysiological remodelling; (ii) AFER-SR condition for AF-remodeled tissue with normal sinus rhythm (SR) (state 3); and (iii) AFER-AF condition for AF-remodeled tissue with re-entrant excitation waves (state 4). Our results indicate that at the cellular level, AFER (states 3 & 4) abbreviated action potentials and reduced the Ca2+ content in the sarcoplasmic reticulum, resulting in a reduced amplitude of the intracellular Ca2+ transient leading to decreased cell active force and cell shortening as compared to the control condition (states 1 & 2). Consequently at the whole organ level, atrial contraction in AFER-SR condition (state 3) was dramatically reduced. In the AFER-AF condition (state 4) atrial contraction was almost abolished. Conclusions: This study provides novel insights into understanding atrial electro-mechanics illustrating that AFER impairs atrial contraction due to reduced intracellular Ca2+ transients. [ABSTRACT FROM AUTHOR]

Background Electrogram fractionation and atrial fibrosis are both thought to be pathophysiological hallmarks of evolving persistence of atrial fibrillation (AF), but recent studies in humans have shown that they do not colocalize. The interrelationship and relative roles of fractionation and fibrotic change in AF persistence therefore remain unclear. Objective The aim of the study was to examine the hypothesis that electrogram fractionation with increasing persistence of AF results from localized conduction slowing or block due to changes in atrial connexin distribution in the absence of fibrotic change. Methods Of 12 goats, atrial burst pacemakers maintained AF in 9 goats for up to 3 consecutive 4-week periods. After each 4-week period, 3 goats underwent epicardial mapping studies of the right atrium and examination of the atrial myocardium for immunodetection of connexins 43 and 40 (Cx43 and Cx40) and quantification of connective tissue. Results Despite refractoriness returning to normal in between each 4-week period of AF, there was a cumulative increase in the prevalence of fractionated atrial electrograms during both atrial pacing (control and 1, 2, and 3 months period of AF 0.3%, 1.3% ± 1.5%, 10.6% ± 2%, and 17% ± 5%, respectively; analysis of variance, P < .05) and AF (0.3% ± 0.1%, 2.3% ± 1.2%, 14% ± 2%, and 23% ± 3%; P < .05) caused by colocalized areas of conduction block during both pacing (local conduction velocity <10 cm/s: 0.1% ± 0.1%, 0.3% ± 0.6%, 6.5% ± 3%, and 6.9% ± 4%; P < .05) and AF (1.5% ± 0.5%, 2.7% ± 1.1%, 10.1% ± 1.2%, and 13.6% ± 0.4%; P < .05), associated with an increase in the heterogeneity of Cx40 and lateralization of Cx43 (lateralization scores: 1.75 ± 0.89, 1.44 ± 0.31, 2.85 ± 0.96, and 2.94 ± 0.31; P < .02), but not associated with change in connective tissue content or net conduction velocity. Conclusion Electrogram fractionation with increasing persistence of AF results from slow localized conduction or block associated with changes in atrial connexin distribution in the absence of fibrotic change. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) is self-perpetuating, via mechanisms of acute electrical remodelling and 'second factors' acting over a longer time course. Renin-angiotensin system (RAS) blockade may inhibit AF self-perpetuation. We evaluated the effects of RAS blockade with candesartan in a burst-paced goat model of lone AF in which both mechanisms are known to operate. Bioactivity of oral candesartan was demonstrated in 10 goats by inhibition of the pressor effect of angiotensin II. The effects of candesartan on electrical remodelling were assessed in 12 placebo and 12 candesartan-treated goats in a 28-day burst pacing protocol. To assess the effects of candesartan on second factors (structural remodelling), 16 goats underwent further 28-day periods of burst pacing (two periods in 16 goats, three periods in eight goats) each separated by periods of sinus rhythm sufficient for electrical remodelling to reverse. There was a progressive rise in angiotensin levels in both groups. Candesartan (0.5 mg/kg/day) achieved a 76% blunting of the pressor effect of angiotensin II and had no effect on electrical remodelling; the half time for fall of atrial effective refractory period (AERP) was 22.3 ± 4.9 h (placebo) and 22.0 ± 3.2 h (candesartan) (p = ns). Candesartan had no effect on AF stability, which progressively increased over successive 28-day periods (ANOVA p < 0.05). Candesartan had no effect on atrial electrical remodelling or the operation of 'second factors' in a goat model of lone AF. These findings suggest that any benefits of RAS blockade in patients with AF are unlikely to be due to direct effects on atrial remodelling. [ABSTRACT FROM AUTHOR]

Abstract: Background: Heart failure (HF) and atrial fibrillation (AF) are common disorders that frequently occur together and are associated with an increased risk of thromboembolism. This thromboembolic risk may be reduced by anticoagulation with warfarin but not without introducing new hemorrhagic risks. Methods and Results: Current guidelines recommend the use of anticoagulation in patients with HF and chronic AF and paroxysmal AF (PAF) that is symptomatic or frequent and prolonged enough to be detected by electrocardiogram. However, the evidence supporting these recommendations is weak and does not take account of research indicating that the prothrombotic risk is higher in more severe HF. Conclusions: An area not addressed by current guidelines is anticoagulation in patients with HF and short, asymptomatic episodes of AF. These issues need to be resolved with further studies using implanted devices to detect such asymptomatic PAF. [Copyright &y& Elsevier]

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]

The article discusses the upstream management of atrial fibrillation (AF) which involves treating the abnormalities that are thought to predispose certain patient groups to this arrhythmia. It examines the predisposing clinical factors for AF. It also explains the underlying electrophysiological mechanisms of AF, AF development in animal models, and effects of therapies in animal models of AF in the setting of structural heart disease or inflammation.

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]

FITCHET, A., et al. : Holter Monitoring vs Tilt Testing in the Investigation of Suspected Vasovagal Syncope. --> The aim of this study was to compare the diagnostic yield of 48‐hour Holter monitoring with head‐up tilt (HUT) test in patients presenting with blackouts suggestive of vasovagal syncope. One hundred and eighteen consecutive patients, 68 women, aged (mean [SD])50 ± 20  years(range 16–88 years), underwent 48‐hour Holter monitoring and 60° HUT test within 3 months. Endpoints were symptom‐ECG correlation during Holter monitoring and positive HUT test. Syncope occurred in 3 (3%) patients during Holter monitoring, the rhythm being sinus tachycardia in all. Presyncope was reported in 22 (19%), the rhythm being sinus tachycardia in 6, persistent atrial fibrillation in 2, and normal sinus rhythm in the remainder. Asymptomatic arrhythmias were recorded in 103 (87%) patients. Positive HUT tests occurred in 39 (33%), the pattern being mixed (VASIS type 1) in 14 (36%), cardioinhibitory (VASIS type 2) in 3 (8%), and vasodepressor (VASIS type 3) in 22 (56%). Change in patient management occurred in 3 (3%) patients following Holter monitoring and 39 (33%) patients following HUT test. Holter monitoring produces a low yield of clinically useful information in the investigation of suspected vasovagal syncope. An HUT test should be considered the primary investigation of choice in such patients. (PACE 2003; 26[Pt. I]:1523–1527) [ABSTRACT FROM AUTHOR]

Amiodarone and AF. Introduction: Amiodarone is effective in preventing the recurrence of atrial fibrillation (AF) after cardioversion (CV). Dispersion of atrial refractoriness may be relevant to the generation of AF. We designed a study to determine the electrophysiologic effects of amiodarone in patients with previous early recurrence of AF after CV. Methods and Results: Fifteen patients with previous AF recurrence (without antiarrhythmic drugs) after CV (CV1) were selected for amiodarone therapy and repeat CV (CV[sub amio]). Prior to CV1, mean AF cycle length (AFCL) had been recorded at four atrial sites (right atrial appendage [RAA], distal coronary sinus [DCS], right atrial lateral wall [LAT], and interatrial septum [IAS]) and dispersion of AFCL had been calculated. These patients were treated with amiodarone and, prior to CV[sub amio], AFCL was recorded at the four atrial sites as for CV1. Between CV1 and CV[sub amio], AFCL increased at all atrial sites: 153 ± 13 msec to 179 ± 14 msec at RAA, 144 ± 12 msec to 174 ± 18 msec at DCS, 158 ± 13 msec to 182 ± 16 msec at LAT, and 161 ± 18 msec to 181 ± 17 msec at IAS. Dispersion of AFCL decreased from 24 ± 10 msec at CV1 to 15 ± 11 msec at CV[sub amio] (P = 0.01) . The median time in sinus rhythm increased from 3.12 hours post CV1 to 28 days post CV[sub amio] (P < 0.02) . Conclusion: Amiodarone causes a reduction in the dispersion of AFCL. This action may be relevant to the beneficial effects of amiodarone in patients with AF.(J Cardiovasc Electrophysiol, Vol. 14, pp. 485-491, May 2003). [ABSTRACT FROM AUTHOR]