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Publicado também em: https://repositorio.unifesp.br/handle/11600/56388 e https://repositorio.unifesp.br/handle/11600/56970 NCATS NIH HHS Univ Hosp Magdeburg, Dept Cardiol & Intens Care Med, St Vincenz Hosp Paderborn, Working Grp Mol Electrophysiol, Magdeburg, Germany Univ Melbourne, Royal Melbourne Hosp, Melbourne, Vic 3050, Australia Ctr Privado Cardiol, San Miguel De Tucuman, Argentina Yale Univ, New Haven, CT USA European Univ Quiron Madrid, Madrid, Spain Vet Gen Hosp, Taipei, Taiwan Cedars Sinai Med Ctr, Inst Heart, Los Angeles, CA 90048 USA Univ Parma, Parma, Italy Mt Sinai Sch Med, New York, NY USA Univ Duisburg Essen, Inst Pharmacol, West German Heart & Vasc Ctr, Essen, Germany Univ Fed Sao Paulo, Sao Paulo, Brazil Penn State Univ, Penn State Heart & Vasc Inst, Hershey, PA USA Sorbonne Univ, Pitie Salpetriere Hosp, AP HP, Dept Cardiol,INSERM,UMR S1166,ICAN, Paris, France Boston Univ, Sch Med, Boston Med Ctr, Boston, MA 02118 USA Univ Leipzig, Heart Ctr, Leipzig, Germany Royal Brompton Hosp, London, England Imperial Coll London, London, England UH Case Med Ctr, Cleveland, OH USA Univ Michigan, Ann Arbor, MI 48109 USA Korea Univ, Med Ctr, Seoul, South Korea Univ Birmingham, Birmingham, W Midlands, England Anzhen Hosp, Beijing, Peoples R China Univ Calif San Francisco, San Francisco, CA 94143 USA Vanderbilt Univ, 221 Kirkland Hall, Nashville, TN 37235 USA Univ Tsukuba, Ibaraki, Japan Univ Adelaide, South Australian Hlth & Med Res Inst, Ctr Heart Rhythm Disorders, Adelaide, SA, Australia Royal Adelaide Hosp, Adelaide, SA, Australia UPB, Univ CES, Ctr Especializados San Vicente Fdn & Clin CES, Electrophysiol Deparment, Medellin, Colombia Cleveland Clin, Dept Mol Cardiol, Cleveland, OH 44106 USA Univ Montreal, Montreal Heart Inst, Res Ctr, 5000 Belanger St E, Montreal, PQ H1T 1C8, Canada McGill Univ, Montreal, PQ, Canada Univ Duisburg Essen, Fac Med, Inst Pharmacol, West German Heart & Vasc Ctr, Essen, Germany Univ Fed Sao Paulo, Sao Paulo, Brazil NCATS NIH HHS: UL1 TR001863 Web of Science

In a recent issue of HeartRhythm, Maron and Sharma shared their opinions regarding a mandatory, national cardiovascular screening program for athletes in the United States. The point/counterpoint centered on the inclusion (or not) of a resting 12-lead electrocardiogram (ECG) in addition to a history and physical examination during preparticipation screening of athletes. In response to these articles, we were invited to write a position paper on cardiovascular screening in athletes and to “agree with one position or the other, or with neither, or conclude that more information is needed before an opinion can be offered.” Rather than restate the arguments for and against ECG screening and the many points on which these experts disagree, we hope to reframe this debate in an attempt to help the medical community refocus on ways to improve cardiovascular screening in young athletes. Over the past decade, the debate on ECG screening has become highly polarized. While there is much known about sudden cardiac death (SCD) in athletes and screening intended to prevent such tragedies, there is just as much unknown. Continuing efforts are seriously needed to fill these knowledge gaps. This article outlines areas in which physicians on either side of the debate will likely agree; presents current acceptable screening practices and their requirements and limitations; and puts forth research directions that may help answer some of the remaining questions.

Background Permanent atrial pacing usually involves lead placement in the right atrial appendage (RAA). Anatomical studies addressing features predisposing to complications are scanty. Objective To assess the morphology of RAA in the perspective of pacing, including the morphology of tenia sagittalis (TS) and the spatial relationship with the aorta. Methods The gross anatomy of the RAA has been analyzed in a consecutive series of 100 hearts following a case of iatrogenic perforation of the aorta by active fixation lead located in the RAA. Transmural RAA sections were taken from 40 hearts to assess the wall thickness at the level of pectinate muscles (PMs) and of inter-PMs spaces and the distance between adjacent PMs. Results The TS was present in 90% of cases (single trunk, 76%; double trunk, 13%; and triple trunk, 1%), demarcating the proximal antral RAA region (facing the adjacent aorta) from the distal saccular RAA region (facing the pulmonary infundibulum). The RAA free wall in the inter-PMs spaces is usually paper-thin and translucent. Histomorphometric analysis reveals that the RAA wall mean thickness was 1.38 ± 0.05 mm (range 0.64–4.25 mm) at the level of PMs and 0.39 ± 0.23 mm (range 0.09–1.05 mm) at the level of inter-PMs spaces. The mean distance between adjacent PMs was 0.88 ± 0.99 mm (range 0.04–4.12 mm). Conclusion In 90% of hearts, a well-defined TS separates the distal saccular from the proximal antral RAA, the latter being closely adjacent to the ascending aorta. The paper-thin wall between PMs is potentially at risk of perforation, and aortic injury could occur when active fixation leads are anchored in the antral RAA, as demonstrated in an iatrogenic fatal case.

Remote monitoring (RM) of Cardiac Implantable Electronic devices (CIEDs) has become routine practice owing to the advances in biomedical engineering, the advent of interconnectivity between the devices through the internet, and the demonstrated improvement in patient outcomes, survival, and hospitalizations. However, this increased dependency on the Internet of Things (IoT) comes with its risks in the form of cybersecurity lapses and possible attacks. While there has not been a cyberattack leading to patient harm reported in literature to date, the threat is real and has been demonstrated in research laboratory scenarios and echoed in patient concerns. The CIED universe comprises a complex interplay of devices, connectivity protocols, and sensitive information flow between the devices and the central cloud server. Various manufacturers use proprietary software and black-boxed connectivity protocols which are susceptible to hacking. In this paper, we discuss the fundamentals of the CIED ecosystem, the potential security vulnerabilities, a historical overview of such vulnerabilities reported in literature, and recommendations regarding improving the security of the CIED ecosystem and patient safety.

Heart Rhythm has recently published a series of articles reflecting a lively and healthy debate about the functional importance of midmyocardial (M) cells.1–4 One group of scientists has challenged the now classic notions about the role of M cells in cardiac electrophysiology,1,4 while another group has defended the evidence.2,3 The three coauthors of the present paper have been invited to resolve the debate and to “agree with one position or the other, or with neither, or conclude that more information is needed before an opinion can be offered.” Rather than comment on the veracity of the observations described in the position papers by these two esteemed groups1,2 or the reservations expressed in their rebuttals,3,4 we chose to briefly summarize the main points of contention, to review the significance of the issue, and to describe additional work that could provide new insights into the pertinence of the M-cell concept to in vivo physiology.

“The general aim of this series of papers is to determine the laws which govern movements of ions during electrical activity.” So states the first of five papers (78 figures in total) in which Hodgkin, Huxley, and Katz laid the foundation of modern electrophysiology in 1952. 1 Their work predicted (by sheer deductive power) the existence of transmembrane proteins that form ion-selective and voltage- and timedependent hydrophilic pores. The identity of those proteins was discovered decades later, through a fascinating piece of science history in which physiology guided molecular discovery. The rapid expansion of molecular and biochemical techniques brought about the conclusion that poreforming proteins do not work autonomously, but instead they are one piece in a complex molecular puzzle. As such, through more than 60 years of research, our view of the ionic currents has evolved. First described as electrical events of unknown molecular origin, they are now seen as the output of multiple pieces that work together with outstanding spatiotemporal precision to ensure the safe movement of electrical charge into the cell. The identity of each molecular piece of the puzzle and their exact position in the cellular machinery are fundamental questions that occupy a number of laboratories today.

t f It seems so simple: a cardiac pacemaker, an agglomeration of cells operating communally to generate a signal, cycling and recycling with admirable precision over the lifetime of an individual. Logic might dictate that either a set of self-reinforcing and continually interactive processes initiates the signal and the various permutations on its behavior or a single master process is at the core of pacemaker activity. Absolutists might argue that both cannot exist because a single master process suggests a core of function in full control over downstream events, whereas the alternative processes are not only plausible but also contradict the single master’s existence. Of course, for those who are not absolutists, integration of these 2 antithetical universes is easily conceivable. The X-factor here is Mother Nature’s intent: She appears to have Her own designs that we puny mortals try to understand. This sets the stage for the 2 papers under review. Their titles, “The funny current has a major pacemaking role in the sinus node” and “The funny current in the context of the coupled clock pacemaker system,” do not posit antithetical functions within the same universe. Rather they bespeak variations on a theme within that universe, creating disarray in the point– counterpoint balance of the proposed argument. Were the authors engaging in philosophical debate we might expect: thesis: If—not the Ca clock—drives the cardiac pacemaker; antithesis: the Ca clock—not If—drives the cardiac pacemaker. Synthesis would be achieved via negation of one or the other process or by understanding them as belonging to a community of interactive events. Interestingly, both parties to this discussion really do accept the 2 processes as part of a community: it is in the weight they assign to the processes that their opinions differ. We will provide 2 levels of comment: one relates to the information presented in each paper supporting the authors’ story while marginalizing that of their opponents. The other steps back to ask what we as scientists are doing by engag

Catheter ablation of ventricular tachycardia (VT) has evolved in recent years, especially in patients with ischemic heart disease. Data from prospective studies show that VT catheter ablation reduces the risk of recurrent VT; however, there is paucity of data on the effect of VT catheter ablation on mortality and patient centered outcomes such as quality of life. Performing randomized clinical trials of VT catheter ablation can be fraught with challenges, and as a result, several prior trials of VT catheter ablation had to be stopped prematurely. The main challenges are inability to blind the patient to therapy to obtain a traditional control group, high cross-over rates between the two arms of the study, patient refusal to participate in trials in which they have an equal chance of receiving a “pill” versus an invasive procedure, heterogeneity of mapping and ablation techniques as well as catheters and equipment, rapid evolution of technology that may make findings of any long trial less relevant to clinical practice, lack of consensus on what constitutes acute procedural and long-term success, and presentation of patients to electrophysiologists late in the course of their disease. In this paper, a panel of experts on VT catheter ablation and/or clinical trials of VT catheter ablation review challenges faced in conducting prior trials of VT catheter ablation and offer potential solutions for those challenges. It is hoped that the proposed solutions will enhance the feasibility of randomized clinical trials of VT catheter ablation.

Objective To review the literature systematically to determine whether noninvasive or invasive risk stratification, such as with an electrophysiological study of patients with asymptomatic pre-excitation, reduces the risk of arrhythmic events and improves patient outcomes. Methods PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials (all January 1, 1970, through August 31, 2014) were searched for randomized controlled trials and cohort studies examining noninvasive or invasive risk stratification in patients with asymptomatic pre-excitation. Studies were rejected for low-quality design or the lack of an outcome, population, intervention, or comparator of interest or if they were written in a language other than English. Results Of 778 citations found, 9 studies met all the eligibility criteria and were included in this paper. Of the 9 studies, 1 had a dual design–a randomized controlled trial of ablation versus no ablation in 76 patients and an uncontrolled prospective cohort of 148 additional patients–and 8 were uncontrolled prospective cohort studies (n=1,594). In studies reporting a mean age, the range was 32 to 50 years, and in studies reporting a median age, the range was 19 to 36 years. The majority of patients were male (range, 50% to 74%), and 250 ms) developed in 0% to 16%, malignant atrial fibrillation (shortest RR interval ≤250 ms) in 0% to 9%, and ventricular fibrillation in 0% to 2%, most of whom were children in the last case. Conclusions The existing evidence suggests risk stratification with an electrophysiological study of patients with asymptomatic pre-excitation may be beneficial, along with consideration of accessory-pathway ablation in those deemed to be at high risk of future arrhythmias. Given the limitations of the existing data, well-designed and well-conducted studies are needed.

Ventricular arrhythmias remain a leading cause of sudden cardiac death (SCD) in the United States. Triggered activity (TA) is one of the major mechanisms causing tachyarrhythmias, the other two common causes being automaticity and reentry.1 TA occurs when one or multiple spontaneously generated heart beats originate from an action potential that produces an afterdepolarization large enough to reach threshold membrane potential.2 Historically, afterdepolarizations have been characterized as early (EAD) or delayed (DAD) depending on whether they originate before or after completion of repolarization, respectively.3 The cellular origin of DADs has long been attributed to abnormal Ca2+ release from the sarcoplasmic reticulum (SR), leading to activation of inward Na+/Ca2+-exchanger current (INCX). Several recent studies also have implicated abnormal SR Ca2+ release as a mechanisms underlying EADs, in addition to the ‘traditional’ mechanism involving reactivation of the L-type Ca2+ current by changes in membrane potential.4, 5 The principal Ca2+ release channel on the SR is the type 2 ryanodine receptors (RyR2), which is activated by the relatively small amount of Ca2+ that enters the cytosol via voltage-dependent L-type Ca2+ channels during phase 2 of the action potential. This process of Ca2+-induced Ca2+ release (CICR) then results in a quantitatively much greater release of Ca2+ from the SR, which triggers myocyte contraction.6 Relaxation occurs during diastole when cytosolic Ca2+ is returned into the SR by the Ca2+-ATPase (SERCA2a) or extruded from the cell by NCX. An alternative theory for activation of RyR2 has been proposed by Jiang et al.7, who suggested that RyR2 can open independent of Ca2+ influx as a result of ‘store overload-induced Ca2+ release’ (SOICR). At this time, there is little or no solid experimental evidence for this SOICR phenomenon and its relevance for cardiac arrhythmias.8 However, it is clear that the level of SR Ca2+ loading sensitizes RyR2 channels to release, although the molecular mechanisms responsible for this feature remain unclear. In patients with ‘catecholaminergic polymorphic ventricular tachycardia’ (CPVT), inherited mutations in RyR2 cause TA and lethal tachyarrhythmias.9, 10 Single channel recordings have revealed that these pathogenic RyR2 mutations increase the probabilistic opening of RyR2.10 Abnormal mutant RyR2 openings have also been shown to initiate spontaneous SR Ca2+ sparks and arrhythmogenic SR Ca2+ waves in ventricular myocytes from mice with RyR2 mutations.5, 11 Importantly, these abnormal SR Ca2+ release events occur in the absence of elevated SR Ca2+ contents.5, 12 It is believed that local elevations of [Ca2+] at one Ca2+ release unit can trigger Ca2+ release of neighboring RyR2 clusters, resulting in subcellular propagation and the formation of Ca2+ waves. Thus, abnormal Ca2+ waves underlying afterdepolarizations can occur as a result of ‘leaky’ RyR2 even in the absence of Ca2+ store overload. Under certain conditions such as elevated adrenergic tone, these Ca2+ waves occur in a sufficient number of myocytes leading to TA at the tissue level, which can lead to arrhythmia induction.11, 13 In view of the important role of ‘leaky’ RyR2 in the development of afterdepolarizations and TA, a new class of antiarrhythmic drugs was developed that normalizes RyR2 channel functions without completely blocking the channel during CICR.6 The first example of a compound in this class is the benzothiazepine derivative JTV519 (also known as K201), which was shown to reduce RyR2 open probability and prevent ventricular tachycardia in a mouse model of FKBP12.6 deficiency.14 Lehnart et al.15 also demonstrated that JTV519 normalizes channel dysfunction caused by CPVT-linked missense mutations in RyR2. Subsequently, several JTV519 derivatives (referred to as ‘Rycals’) have been developed with improved RyR2-specificity, reduce off-target effects, and enhance oral availability.16 Compound S107 was shown to suppress premature ventricular contractions (PVCs) and spontaneous sustained VT in mdx mice, a mouse model of Duchenne’s muscular dystrophy.17 The class 1c antiarrhythmic drug flecainide was also shown to reduce the open probability of RyR2 in a calsquestrin-deficient (Casq2−/−) mouse model of CPVT and to reduce the occurrence of ventricular arrhythmias in CPVT patients.18 Hillard et al.19 subsequently demonstrated that flecainide reduces salutatory Ca2+ wave propagation between adjacent Ca2+ release units by inhibition of open state RyR2, without affecting SR Ca2+ content. Moreover, flecainide was shown to suppress spontaneous Ca2+ release events in RyR2 mutant mice heterozygous for CPVT-linked mutation R4496C (R4496/+).20 Most recently, Dr. Chen’s group reported that the nonselective beta-blocker carvedilol and three related analogues (VK-II-86, CS-I-34 and CS-I-59) suppressed ventricular tachyarrhythmias in the R4496/+ mouse model of CPVT by reducing RyR2 open probability.21 Unlike other beta blockers, carvedilol suppressed the occurrence of spontaneous Ca2+ waves in ventricular myocytes isolated from R4496/+ mice. However, the mechanisms by which carvedilol analogous suppressed SR Ca2+ release and afterdepolarizations remained unclear. In this issue of HeartRhythm, Maruyama et al.22 tested the hypothesis that a new carvedilol analogue VK-II-36 prevents TA through the suppression of EADs. Optical mapping studies of [Ca2+] and voltage in the epicardial surface of ventricles of R4496/+ mice revealed EADs and DADs coinciding with SCaEs at artificially slowed heart rates. Interestingly, the carvedilol analogue VK-II-36 prevented both types of afterdepolarizations, indicating that ‘leaky’ RyR2 were responsible for both EADs and DADs in this model. The findings are consistent with an important role for SR Ca2+ ‘leak’ in the pathogenesis of EADs, and they confirm that reactivation of L-type Ca2+ channels is not necessarily required for EAD genesis. The paper also represents the first demonstration of antiarrhythmic effects of the carvedilol analogue VK-II-36 in a large animal model. In a rabbit model of acquired long QT syndrome induced by IKr blocker R-4031, VK-II-36 reduced action potential duration (APD) and dispersion. Those effects appeared to be caused by inhibition of abnormal SR Ca2+ release events, since the effects of VK-II-36 were primarily on the regions with long APDs. On the other hand, it remains to be established whether VK-II-36 has ‘off target’ effects on ion channels other than RyR2, which could modulate APD independent of VK-II-36’s effect on SR Ca2+ release. In addition, it would be interesting to determine in future studies how VK-II-86 compares to other carvedilol analogues in terms of its dose response, RyR2 selectivity, and oral availability.21 The findings of the paper by Maruyama et al.22 also are significant because they suggest that RyR2-modulating antiarrhythmic drugs could prevent triggered activity associated with EADs, not just DADs. It remains to be established whether this is true for carvedilol derivatives only, or for the entire class of RyR2 modulators that also includes JTV519, S107, and flecainide. The clinical indications for carvedilol derivatives and RyR2 modulators in general go beyond the rare inherited arrhythmia syndrome, as RyR2 gain-of-function activity has been causally linked to atrial fibrillation and lethal ventricular arrhythmias in failing hearts in various animal models. The lack of beta-blocking effects of the carvedilol analogue represents a favorable feature and suggests that these drugs could prevent arrhythmias without negative inotropic or chronotropic effects. Thus, inhibition of abnormal SR Ca2+ release via RyR2 represents a promising target for antiarrhythmic drug development.

Congenital long QT syndrome (LQTS) is an inherited syndrome characterized by prolongation of the QT interval on the electrocardiogram and an increased susceptibility to life-threatening ventricular arrhythmias. Mutations in the SCN5A gene, which encodes the α-subunit of the cardiac Na+ channel, represent the third most common cause of LQTS, behind mutations in potassium channel genes KCNQ1 and KCNH2. Moreover, mutations in SCN5A have been linked to other types of inherited channelopathies, including the Brugada syndrome (BRS1), progressive familial heart block type 1 (PFHBI), sick sinus syndrome type 1 (SSS1), idiopathic ventricular fibrillation (IVF), familiar atrial standstill, dilated cardiomyopathy type 1E (CMD1E), and sudden infant death syndrome (SIDS)1. In total, more than 400 unique DNA variants have been reported in SCN5A, of which at least more than 80 mutations were linked to LQTS alone (see inherited arrhythmia data base: http://www.fsm.it/cardmoc/). Mutations in the SCN5A gene associated with LQTS typically cause a gain-of-function phenotype resulting in enhanced Na+ entry into the cardiomyocyte during the repolarization period 2. Each Na+ channel α-subunit (Nav1.5) consists of four structurally homologous domains (DI-DIV), each comprising six transmembrane segments (S1-S6). Most mutations in Nav1.5 disrupt fast inactivation and thereby cause a persistent (or sustained) Na+ current. However, some Na+ channel mutations rather enhance window currents when inactivation occurs at more depolarized potentials, resulting in delayed repolarization in the absence of persistent Na+ current 3. Other biophysical mechanisms of Nav1.5 dysfunction causally linked to LQTS include faster recovery from inactivation, slower inactivation, and a larger peak Na+ current (INa) density 1. Regardless of the underlying mechanism, gain-of-function defects in Nav1.5 disrupt the delicate balance between depolarization and repolarization during the action potential plateau phase, thus delaying repolarization and increasing the risk of lethal ventricular arrhythmias. Postmortem studies have revealed that SCN5A mutations may be the most prevalent genetic cause of sudden infant death syndrome (SIDS), which is the unexpected, sudden death of a child under age 1 in which autopsy does not reveal an explainable cause of death 4. Most SCN5A mutations found in SIDS victims cause biophysical phenotypes similar to those associated with mutations found in older children or adults with LQTS. However, a few SIDS-linked mutations in SCN5A exhibit sustained INa only under acidic conditions, suggesting that environmental factors such as hypoxia or acidosis might contribute to the lethal arrhythmias in susceptible infants 5. In addition, several papers have reported even earlier, prenatal diagnosis of LQTS linked to SCN5A mutations. Such variants were identified in several parts of the channel (e.g., R43Q, L619F, F627L, A1186T, P1332L, F1473C, F1486del, R1623Q, V1763M, N1774D) 6–9. The most common prenatal manifestations of LQTS include sinus bradycardia and atrioventricular block, presumably due to excessive refractory periods related to delayed repolarization. In addition, irregular heart rates due to ventricular ectopy and ventricular tachycardia are commonly observed. In more than half of all published cases, in utero demise occurred during the third trimester 6–9. Previous biophysical analysis of the abovementioned SCN5A variants did not reveal biophysical defects distinct from those described for SCN5A mutations found in individuals with a postnatal diagnosis of LQTS. Therefore, it has remained unclear why fetuses with SCN5A mutations exhibit more severe repolarization defects and higher mortality rates compared to older mutation carriers. In the current issue of HeartRhythm, Murphy et al. 10 described an interesting case report of a fetus carried by a 29-year-old primiparous, otherwise healthy woman, who was diagnosed at 20 weeks of gestation with frequent premature ventricular contractions, which represents the earliest described case of fetal LQTS. The fetus developed episodes of ventricular ectopy, which soon thereafter progressed into polymorphic ventricular tachycardia, extreme QTc interval prolongation, and hydrops fetalis. Because of the extent of the clinical deterioration, pregnancy was terminated at the request of the family. Genetic analysis revealed a novel, de novo, heterozygous missense mutation (L409P) in SCN5A, as well as homozygosity for the common nonsynonymous variant R558 11. The biophysical features of the mutant Na+ channels were studied using whole cell patch clamp of tsA201 cells expressing recombinant Nav1.5 channels with mutation L409P and polymorphism R558. These Nav1.5-L409P/R558 mutant channels exhibited reduced peak current density, depolarized shifts in voltage-dependence of activation and inactivation, and faster recovery from inactivation. In addition, a much larger persistent Na+ current was measured, which is a common feature among most LQTS-linked Na+ channel mutants 1. Next, the authors explored the interesting hypothesis that the severe clinical manifestations of LQTS in the affected fetus were due to alternative splicing of a SCN5A transcript expressed during the fetal period. In human fetal hearts, alternative exon 6A is more abundant than in infant or adult heart. Compared to the adult isoform, fetal Nav1.5-L409P/R558 channels exhibited a more pronounced shift in fast inactivation and an even larger persistent Na+ current. Moreover, the fetal isoform exhibited a slower activation rise time and slower inactivation kinetics, similar to previous reports 12. These exacerbated changes in Na+ channel gating may explain the severity of the clinical phenotype in the fetus with the L409P mutation and R588 polymorphism. The replacement of exon 6 by exon 6a as a result of alternative splicing results in the substitution of 7 amino acids in the fetal Nav1.5 channel. Onkal et al. 12 demonstrated that replacement of a single negatively charged aspartate at position 211 in the adult isoform with a positively charged lysine residue in the fetal isoform introduces a positive charge in the S3 domain adjacent to the S4 voltage sensor of domain I. This particular amino acid substitution was shown to be primarily responsible for the functional effects of exon 6 splicing on Nav1.5 channel parameters. The present study by Murphy et al. 10 revealed that the electrophysiological effects of the R558 polymorphism were similar in the adult and fetal Nav1.5 isoforms. However, when the L409P mutation was added to the R558 polymorphism, more pronounced Na+ channel dysfunction was observed in case of the fetal splice variant. This suggests that alternative splicing of the fetal isoform might be the primary reason for the severe fetal manifestation of arrhythmias in carriers of SCN5A mutations. Since most genes causally linked to LQTS are also subject to alternative splicing, it would be interesting to determine whether the effects of mutations in other cardiac ion channels are also more potent in the fetal splice variants. Finally, it was shown that the R558 polymorphism independently contributed to enhancement of Nav1.5 channel dysfunction caused by the L409P mutation. This observation highlights the importance of SCN5A polymorphisms in terms of Na+ channel electrophysiology. For example, polymorphism S1103Y, which is commonly found in African Americans, has been linked to SIDS 13. Another variant, R1193Q, commonly found in Asians 14 may also increase the risk of SIDS and prenatal death 15. Moreover, polymorphism V1951L found in Latinos 16 also modulates the biophysical effects of SCN5A mutations 17, and has been identified in a victim of SIDS 5. In conclusion, the paper by Murphy et al. 10 suggests that the unusual severity and early onset of ventricular arrhythmias in a fetus with an SCN5A mutation could be attributed to synergistic effects of a disease-causing mutation, a polymorphism, and an alternative splice variant. It would be important to consider the contributions of each of these three factors in future studies of SCN5A variants associated with fetal or perinatal arrhythmias and sudden cardiac death.

Our poor understanding of the mechanisms of atrial fibrillation (AF) is humbling. Although valuable insights have been gained after decades of active research, the simple question of whether it is caused by reentry or focal activity remains unanswered, even if we tried to do so just in relative terms. More than a century ago, Winterberg suggested that AF was the consequence of multiple ectopic foci.1 Decades later, the idea that a single rapid-firing site could lead to AF was proven by Scherf2 and Prinzmetal,3 who showed that focal injection of aconitine (a sodium channel opener) produced rapid regular focal activations at the injection site, but global atrial fibrillatory activation patterns. However, when Moe and Abildskov4, 5 proposed the multiple wavelet hypothesis, it became accepted that AF was caused by self-perpetuating activation wavelets that propagated on heterogeneous atrial tissue. Indeed, mapping studies were able to demonstrate such multiple wavelets,6 and it became accepted that a minimum of 4–6 wavelets were required to sustain AF.7 However, Allessie et al had also previously demonstrated functional reentry in the atrium in the absence of an anatomical substrate,8 which supported the idea that reentry –by definition a self-sustainable process- could underlie the mechanisms of perpetuation of AF. How could a periodic phenomenon such as reentry underlie a chaotic and aperiodic one such as AF? Rapidly activating rotors may lead to global fibrillatory activation patterns if drifting,9 or if activations stemming from the rotor fail to conduct 1:1 to neighboring tissues. This so-called fibrillatory conduction has been shown to be caused by wavebreak in anatomically-determined locations, such as pectinate muscles.10 Support for relatively stable rotors as the engine of AF came from a series of works from Jalife’s laboratory, showing fast, local periodicity11 and reentry in the left atrium12 that led to stable left-to-right frequency gradients13 during sustained AF. A predilection for left atrial reentry to occur in the neighborhood of the pulmonary veins was also evident: Arora et al14 showed detailed optical mapping of such local reentry, and Chen’s group emphasized the complex underlying histological patterns in this region (including the ligament of Marshall), that could lead to reentry,15 a concept that had been predicted by Spach decades earlier16 and that seems to be relevant in ventricular fibrillation as well.17 In the clinical realm, the concept of focal discharges as a cause of AF got enormous support with Haissaguerre et al’s seminal finding that ectopic beats from the pulmonary veins initiated AF.18 Mechanistically, focal beats triggering AF were shown to arise from electrogenic sodium/calcium exchange in situations of calcium overload.19, 20 During ongoing AF, however, focal activations have been harder to prove. Indeed, Atienza et al21 postulated that frequency acceleration by adenosine administration during AF supported reentry as the primary mechanism of AF maintenance. In this issue of Heart Rhythm, Yamazaki and colleagues22 report on the effects of several pharmacological interventions in the activation patterns of AF induced by mechanical stretch (stretch–related AF, SRAF). This is a well-established model, previously described by the authors, that leads to sustained AF for hours. The central purpose in this work is to assess the relative relevance of focal activations vs. reentry in the maintenance of AF. Using this model of sustained AF, the authors then attempted to suppress intracellular calcium-derived afterdepolarizations with caffeine or ryanodine and showed that either of these two drugs succeeded at terminating AF (10/13 cases). When on top of the physiological alterations created by stretch, the authors added the combined administration of acetylcholine and isoproterenol, then caffeine or ryanodine failed to terminate AF (1/11 cases). The authors correlate these differential effects with the specific activation patterns of AF, suggesting that without acetylcholine/isoproterenol, AF is maintained by focal activations (which would be suppressed by caffeine or ryanodine), whereas with acetylcholine/isoproterenol, reentry plays an increasingly predominant role, which becomes seemingly exclusive when caffeine or ryanodine are added and focal activations are suppressed. Although the overall interpretation seems rather simple and it is not without important caveats, this is a commendable, rigorous effort to attempt to correlate mapped activation patterns with the underlying physiological conditions leading to AF. Furthermore, the authors complement their results with computer simulations to show how focal discharges interact with rotor core meandering dynamics. While answering some important questions, the paper raises more additional questions that remain unanswered. Important caveats relate to the methods of suppression of intracellular calcium-derived afterdepolarizations. The authors chose ryanodine or caffeine. A better drug regime would have included thapsigargin along with ryanodine to completely disable the calcium cycling, which has been shown to suppress focal discharges in AF models.23 The calcium chelator BAPTA would have also been an uncontroversial eliminator of calcium-induced arrhythmogenesis.24 Additionally, it is unclear whether conclusions drawn from a very specific form of AF (stretch-related) apply to others. The overall picture remains complex. One conclusion that can be safely drawn from this paper is that AF is an ever-changing phenomenon whose mechanisms vary depending on the underlying physiological conditions. Thus, rotors and focal activations do not seem to have a fixed hierarchy. AF may be sustained by a rotor from which daughter wavelets emanate but propagate in an irregular pattern due to fibrillatory conduction. However, the rotor’s stability is subject to continuous threats by focal activitations that may arise at any given time by a triggered activity mechanism.19, 20 Arguably, the irregularity of fibrillatory conduction would enhance the generation of triggered activity by promoting relative pauses, and focal activations would still owe their existence to their triggering beats and indirectly to the mother rotor. Thus, the mother rotor seems to be a promiscuous source of offspring wavelets, both by direct emanation and by indirect triggering. What this paper illustrates is that AF seems to be a continuous struggle between two related phenomena: 1) the tendency of wavelets to self-organize as rotors, 2) the triggered beats that can invade the rotor and extinguish it, or form a new rotor. Each can lead to one another, and either can predominate depending on the underlying conditions. Additional questions remain regarding the mechanistic, clinical, prognostic and therapeutic relevance of focal- vs. rotor-driven AF: Are activation patterns merely a reflection of the underlying atrial physiology -as in this paper- applicable to clinical scenarios where AF develops, for example hypertensive AF vs lone AF? Clinically, do the activation patterns impact the long-term stability of AF? Do they impact the clinical course of AF (paroxysmal or persistent)? Or its thrombogenic potential? Or the susceptibility to different therapies, ablative, antiarrhythmic or substrate-based (i.e. ACE inhibitors)? All electrophysiologists ablating AF have experienced the enormous variability of activation patterns in different patients, as reflected by intracardiac recordings. The current paper illustrates mechanistic variations of AF caused by different underlying physiological conditions, and perhaps suggests that our focus should be not so much on AF itself, but the conditions that generate it.

[EN] BACKGROUND Dominant frequency (DF) and rotor mapping have been proposed as noninvasive techniques to guide localization of drivers maintaining atrial fibrillation (AF). OBJECTIVE The purpose of this study was to evaluate the robustness of both techniques in identifying atrial drivers noninvasively under the effect of electrical noise or model uncertainties. METHODS Inverse-computed DFs and phase maps were obtained from 30 different mathematical AF simulations. Epicardial highest dominant frequency (HDF) regions and rotor location were compared with the same inverse-computed measurements after addition of noise to the ECG, size variations of the atria, and linear or angular deviations in the atrial location inside the thorax. RESULTS Inverse-computed electrograms (EGMs) individually correlated poorly with the original EGMs in the absence of induced uncertainties (0.45 +/- 0.12) and were worse with 10-dB noise (0.22 +/- 0.11), 3-cm displacement (0.01 +/- 0.02), or 36 degrees rotation (0.02 +/- 0.03). However, inverse-computed HDF regions showed robustness against induced uncertainties: from 82% +/- 18% match for the best conditions, down to 73% +/- 23% for 10-dB noise, 77% +/- 21% for 5-cm displacement, and 60% +/- 22% for 36 degrees rotation. The distance from the inverse-computed rotor to the original rotor was also affected by uncertainties: 0.8 +/- 1.61 cm for the best conditions, 2.4 +/- 3.6 cm for 10-dB noise, 4.3 +/- 3.2 cm for 4-cm displacement, and 4.0 +/- 2.1 cm for 36 degrees rotation. Restriction of rotor detections to the HDF area increased rotor detection accuracy from 4.5 +/- 4.5 cm to 3.2 +/- 3.1 cm (P < .05) with 0-dB noise. CONCLUSION The combination of frequency and phase-derived measurements increases the accuracy of noninvasive localization of atrial rotors driving AF in the presence of noise and uncertainties in atrial location or size., This work was supported in part by grants from Generalitat Valenciana (ACIF/2013/021); Instituto de Salud Carlos III-FEDER (Fondo Europeo de Desarrollo Regional) and Ministerio de Ciencia e Innovacion (PI13-01882, PI13-00903, PI14/00857, PI16/01123, IJCI-2014-22178, DTS16/00160 and Red RIC RD12.0042.0001); Spanish Society of Cardiology (Clinical Research Grant 2015); and the National Heart, Lung, and Blood Institute (P01-HL039707, P01-HL087226, and Q1 R01-HL118304). Dr. Atienza served on the advisory board of Medtronic and Sorin. Dr. Berenfeld received research support from Medtronic and St. Jude Medical; and is a cofounder and Scientific Officer of Rhythm Solutions, Inc., Research and Development Director for S.A.S. Volta Medical, and consultant to Acutus Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

M A c a i a p H t s e R q e v p f s 6 p a p a n o ntroduction trial fibrillation (AF) may cause embolic stroke and conestive heart failure (CHF) and increases mortality in paients with CHF. AF causes symptoms in some patients but ay be asymptomatic in others. One of the principal causes f symptoms and ventricular dysfunction is the rapid venricular response (RVR) often associated with AF. In some atients, a high vagal tone, or atrioventricular (AV) nodal isease, limits the ventricular response to AF to nearly ormal heart rates at rest and during exercise. These patients re often asymptomatic and do not develop tachycardiaediated ventricular dysfunction. In other patients, howver, AV nodal conduction is rapid, resulting in excessively igh ventricular rates at rest and during exercise. These atients are often highly symptomatic and may have tachyardia-mediated ventricular dysfunction, requiring AV odal blocking drugs such as beta receptor blockers, calium channel blockers, and digitalis, alone or in combinaion, to control ventricular rate. However, pharmacological rate control is often difficult, nd AV node–blocking drugs may cause side effects, inluding hypotension, CHF, and marked bradycardia or auses. Consequently, the nonpharmacological approaches f AV node modification or AV node ablation and paceaker implantation were developed and widely impleented in patients with AF and pharmacologically refracory RVR. This paper will review the role of AV node odification and AV node ablation with pacemaker implanation as methods for ventricular rate control in patients ith AF.

This paper, presented on the occasion of the 1st Annual Douglas Zipes Lecture at the 2005 Scientific Sessions of the Heart Rhythm Society, briefly reviews current knowledge on the role of gap junctions in normal cardiac electrophysiology and the contributions of gap junction remodeling in the pathogenesis of malignant ventricular arrhythmias and sudden cardiac death. It highlights recent advances and new research directions in gap junction biology.

The multifunctional Ca2+ and calmodulin-dependent protein kinase II (CaMKII) has emerged as an interesting proarrhythmic and procardiomyopathic signaling molecule with therapeutic potential. The importance of this growing body of evidence showing that CaMKII plays a central role in myocardial disease is evidenced, in part, by this thematic series dedicated to CaMKII. The first reports that CaMKII could participate in ion channel biology in heart were in 1994 when separate papers from the Anderson, Bers and Lakatta groups identified CaMKII as a signal that was important for L-type Ca2+ current (ICa) facilitation. CaMKII induces L-type Ca2+ channels to enter a highly active gating mode, characterized by long and frequent openings,1 which can underlie arrhythmia-inducing afterdepolarizations (the topic of xyz Pitt). I became interested in the potential for CaMKII to act as a proarrhythmic, feed-forward, signal to L-type Ca2+ channels when I was a trainee in cardiovascular medicine and electrophysiology at Stanford. I was fortunate to develop a collaboration with Howard Schulman, who discovered CaMKII when he was a post-doctoral fellow in the laboratory of Paul Greengard in 1978.2 Initial investigations of CaMKII were focused on its role in non-cardiac tissue, particularly by neuroscientists but, in my opinion, the current best understood role of CaMKII as a disease signal is in the cardiovascular system. Our group was the first to identify CaMKII as a proarrhythmic signaling molecule.3 But since the time of these early reports, work from many laboratories represented in this series, and from others, has shown that CaMKII promotes pathological membrane excitability, hypertrophic transcription, activates cell death machinery and disturbs intracellular Ca2+ homeostasis. The diversity of these processes sparked the realization that CaMKII acts as a master regulator of cellular processes that are intimately involved in heart failure and arrhythmias. It may be that the apparent vulnerability in the design of the CaMKII pathway is a natural consequence of the multiple downstream CaMKII targets and the core physiological roles of CaMKII in myocardium. For example, by targeting sarcolemmal ion channels and intracellular Ca2+ homeostatic proteins, CaMKII is positioned to serve as a physiological interface between membrane excitability and sarcoplasmic reticulum Ca2+ release, two processes that are essential for excitation-contraction coupling.4 However, this interface is also a hotspot for linking pathological membrane excitability (i.e. arrhythmias) and contractile dysfunction (i.e. heart failure).

Cardiac arrhythmias in general, and atrial fibrillation (AF), in particular, are important global health problems. Despite extensive studies, arrhythmia mechanisms remain unclear. The problem is complicated because heart function is affected by a complex integration of numerous biochemical and biophysical processes within and among cardiac cells. Interactions within SA node, the primary hearts' pacemaker that initiates and regulates the cardiac rhythm, results in one such critical unsolved complexity. Joung et al. 1 have recently applied a method of simultaneous recording of intracellular Ca2+ and membrane potential to approach the riddle of complex/intimate interactions between electrophysiology and intracellular Ca2+ signaling within cells comprising SA node. In this issue of HeartRhythm, Joung et al. 2 combined their method with measurements of expression of Ca2+ cycling proteins to explore the mechanisms of SA node dysfunction in AF. Voltage-gated sarcolemmal ion currents are the proximal cause of an action potential (AP) as originally described by Hodgkin and Huxley based on voltage clamp data. In silico, the ensemble, or system, of the sarcolemmal electrogenic molecules (ion channels and transporters) of cardiac pacemaker cell can generate rhythmic APs, e.g. in 12 SA node cell (SANC) numerical models 3). Therefore, this system of ion currents can be envisioned as a membrane voltage oscillator or “membrane clock” (M clock). The classical perspective on cardiac pacemaker cell function is that the M clock is the ultimate cardiac pacemaker clock, i.e. its function is not only necessary, but also sufficient to drive normal automaticity. However, in addition to an M clock, cardiac pacemaker cells have another intrinsic oscillatory subsystem that resides within the cell: the sarcoplasmic reticulum (SR) pumps and periodically releases Ca2+ 4. While a potential role of the Ca cycling in normal function of cardiac pacemaker cells had been envisioned 5,6 and experimentally demonstrated r-10 long ago, recent extensive studies (during last decade) have discovered the spatiotemporal characteristics of the SR Ca2+ cycling and its interactions with the M clock (review 11). Confocal measurements in isolated pacemaker cells detect Localized submembrane Ca2+ Releases (LCR's) generated by the SR via ryanodine receptors (RyRs) during the late diastolic depolarization (DD) 12,13. The integrated Ca2+ signal of these multiple LCRs during DD represents diastolic Ca2+ release (Fig.3 in 14) that was observed by Joung et al. 1 as Late Diastolic Ca2+ elevation (LDCAE) in the primary region (i.e. impulse initiating part) of the isolated intact dog SA node. The spontaneous Ca2+ releases are referred to as an intracellular “Ca2+ clock” because their occurrence is periodic during voltage clamp 15, in detergent-permeabilized SANC 16, and in silico (when membrane currents set to zero) 17. In nature, i.e., in spontaneously firing SANC, in contrast to in silico or skinned or voltage-clamped cells, Ca2+ and M clocks do not exist in isolation of each other: Numerous and complex interactions via membrane voltage, submembrane Ca2+, and protein phosphorylation occur between the two subsystem clocks (M clock and Ca2+ clock), and the subsystems become mutually entrained forming the full pacemaker cell SYSTEM or the master pacemaker clock (reviews 11,18). The two interacting clock subsystems do not just simply coexist within the pacemaker system but their interaction confers robustness and flexibility to the cardiac pacemaker function as discussed in a recent review 11 and demonstrated in a numerical study that predicts LDCAE 17. Specifically, the presence of Ca2+ clock extends the fail-safe variations of membrane clock parameters, such as L-type Ca2+ current (ICaL) conductance and, vice versa, the presence of some membrane components, such as funny current (If), increases the fail-safe variations of Ca2+ clock parameters, such as Ca2+ pumping rate11. In the context of the concept of a coupled clock system, the finding of Joung et al study 2 that RyR2 are down regulated, and LDCAE are absent in their experimental AF model, can be interpreted to indicate that the Ca2+ clock subsystem is impaired in AF, resulting probably in decreased robustness and flexibility of the pacemaker system. In other words, the impairment of diastolic Ca2+ releases shifts the operation of SANC likely towards less safe (i.e. susceptible to arrhythmia) operation. But what about SANC M clock changes in AF? A recent study by Yeh et al. 19 has identified that major electrophysiological changes of SANC in experimentally induced AF in dogs include a 50% reduction in If conductance and a 33% reduction in slow delayed rectifier K+ current (IKs). Their numerical simulations showed that IKs change had almost no effect on SANC rhythm (less than 1% cycle length change) and the If change resulted in a cycle length increase of ∼9%. But a change of this magnitude seems to be a relatively moderate effect, i.e. far from trouble. However, taking into account that the robustness of coupled clock system had been compromised by Ca2+ clock impairment identified by Joung et al 2 and discussed above, is it possible that this If change could be critical for SANC function? We believe that the answer to this question is not trivial, and presently can be approached only by numerical integration of changes of both Ca2+ and M clocks. Accordingly, we used our recently developed prototype model of interacting Ca2+ clock and M clock in rabbit SANC 17 and performed numerical simulations to illustrate that it is indeed possible, at least at the level of a single pacemaker cell (Fig.1). The 50% reduction in If conductance produced a moderate rate reduction of the simulated AP firing rate (i.e. similar to numerical modeling by Yeh et al. 19). The absence of Ca2+ release, with If remaining intact, however, substantially slowed the rate by ∼40%, but AP firing still remained rhythmic (Fig.1C). However when the “impaired” Ca2+ release was combined with the “impaired” If function, the spontaneous beating became irregular. Figure 1 The combined impairment of M clock and Ca2+ clock in AF can result in generation of irregular action potentials by SA node cells. Simulations by a recent numerical model of rabbit SANC 17 illustrate spontaneous action potentials (top traces), funny current ... These simple “first order” estimates illustrate that: interactions of subsystem clocks are crucial to the generation of spontaneous APs of a normal rate and rhythm, and when both M clock and Ca clock are impaired in AF (or in any other experimental or pathological conditions), uncoupling of M clock and Ca clock can push the master pacemaker clock towards its limits of fail safe operation. Specific, detailed mechanisms of the system changes in AF and their numerical integration, specifically in canine SANC and SA node (and, ultimately, in human SA node), however, merit further studies. These additional mechanisms include characterization and integration of components of PKA and CaMKII-dependent phosphorylation (e.g. phosphorylation of phospholamban, SERCA, RyR, L-type Ca2+ channels), sarcolemmal ion exchangers (e.g. Na+/Ca2+ exchanger and Na+/K+ pump), ion channel kinetics, intracellular contacts (e.g. via connexins), and mechanical factor, i.e. strain. An additional important requirement is a further improvement of both selectivity and spatiotemporal resolution of LDCAE recording within SA node. Such improvements will permit a determination of whether LDCAE exists during basal beating in large animals like canines as the case for rabbit and mouse, as well as whether LDCAE can propagate within the SA node. An intriguing question is also how expression of sarcolemmal electrogenic molecules (ion channels and transporters) and Ca2+ cycling proteins (especially RyR as found by Joung et al. 2) is regulated, the nature and kinetics of the molecular dysregulation in AF, and whether, in particular, changes in RyRs and AF are concomitantly reversed by cessation of chronic pacing. In summary, the study by Joung et al. 2 in this issue of Heart Rhythm suggests that rhythm disturbances in canine experimental AF are caused, at least in part, by a failure of Ca2+ clock function, specifically its release from SR via RyR2. However, the extent to which this mechanism contributes to AF requires further studies aimed to integration of changes in Ca2+ cycling proteins, their phosphorylation status, and changes in sarcolemmal electrogenic molecules. We believe that an important lesson from the recent papers by Joung et al. 1,2 and Yeh et al. 19 and our simple simulations (Fig.1) is that to be informative, future studies of cardiac pacemaker function, either normal or abnormal, must include integration of the two mutually entrained subsystems, Ca2+ clock and membrane clock, the Yin and Yang of the cardiac pacemaker cell function.

Differences in the time course of repolarization of the three predominant myocardial cell types have been shown to contribute to the inscription of the T wave of the electrocardiogram (ECG). Voltage gradients developing as a result of the different time course of repolarization of phases 2 and 3 in the three cell types give rise to opposing voltage gradients on either side of the M region, which are in part responsible for the inscription of the T wave.1 In the case of an upright T wave, the epicardial response is the earliest to repolarize and the M cell action potential is the latest. In the coronary-perfused wedge preparation, repolarization of the epicardial action potential coincides with the peak of the T wave and repolarization of the M cells is coincident with the end of the T wave, so that the interval from the peak to the end of the T wave provides a measure of transmural dispersion of repolarization (TDR). Based on these early studies, the Tpeak-Tend interval in precordial ECG leads was suggested to provide an index of transmural dispersion of repolarization.2 More recent studies have also provided guidelines for the estimation of transmural dispersion of repolarization in the case of more complex T waves, including negative, biphasic and triphasic T waves.3 In such cases, the interval from the nadir of the first component of the T wave to the end of the T wave was shown to provide an electrocardiographic approximation of TDR. While these relationships are relatively straight forward in the coronary-perfused wedge preparation, extrapolation to the surface ECG recorded in vivo must be approached with great caution and will require careful validation. The Tpeak-Tend interval is unlikely to provide an absolute measure of transmural dispersion in vivo, as elegantly demonstrated by Xia and coworkers4. However, changes in this parameter are thought to be capable of reflecting changes in spatial dispersion of repolarization, particularly TDR, and thus may be prognostic of arrhythmic risk under a variety of conditions.5-10 Takenaka et al. recently demonstrated exercise-induced accentuation of the Tpeak-Tend interval in LQT1 patients, but not LQT2.9 These observations coupled with those of Schwartz et al.11, demonstrating an association between exercise and risk for TdP in LQT1, but not LQT2, patients, point to the potential value of Tpeak-Tend in forecasting risk for the development of Torsade de Pointes (TdP). Direct evidence in support of Tpeak-Tend as an index to predict TdP in patients with long QT syndrome (LQTS) was provided by Yamaguchi and co-workers.12 These authors concluded that Tpeak-Tend is more valuable than QTc and QT dispersion as a predictor of TdP in patients with acquired LQTS. Shimizu et al. demonstrated that Tpeak-Tend, but not QTc, predicted sudden cardiac death in patients with hypertrophic cardiomyopathy.8 In a case-controlled study comparing 30 cases of acquired bradyarrhythmias complicated by TdP and 113 cases with uncomplicated bradyarrhythmias, Topilski et al found that QT, QTc and Tpeak-Tend intervals were strong predictors of TdP, with the best single discriminator being a prolonged Tpeak-Tend. 13 Watanabe et al. demonstrated that prolonged Tpeak-Tend is associated with inducibility as well as spontaneous development of ventricular tachycardia (VT) in high risk patients with organic heart disease.10 These interesting studies demonstrating an association between an increase in Tpeak-Tend and arrhythmic risk notwithstanding, direct validation of Tpeak-Tend measured at the body surface as an index of TDR is still lacking. Guidelines for such validation have been suggested repeatedly.1, 3, 14 Because the precordial leads view the electrical field across the ventricular wall, Tpeak-Tend would be expected to be most representative of TDR in these leads. The precordial leads are unipolar leads placed on the chest that are referenced to Wilson central terminal. The direction of these leads is radially outward from the “center” of the heart, the center of the Einthoven triangle. Unlike the precordial leads, the bipolar limb leads, including leads I, II, and III, do not look across the ventricular wall. While Tpeak-Tend intervals measured in these limb leads may provide an index of TDR, they are more likely to reflect global dispersion, including apico-basal and interventricular dispersion of repoalrization.4, 15 A large increase in TDR is likely to be arrhythmogenic because the dispersion of repolarization and refractoriness occurs over a very short distance (the width of the ventricular wall), creating a steep repolarization gradient.16, 17 It is the steepness of the repolarization gradient rather than the total magnitude of dispersion that determines its arrhythmogenic potential. Apico-basal or interventricular dispersion of repolarization is less informative because it may or may not be associated with a steep repolarization gradient and thus may or may not be associated with arrhythmic risk. The other critical point to consider is that TDR can be highly variable in different regions of the ventricular myocardium, particularly under pathophysiologic conditions. Consequently, it is important to measure Tpeak-Tend independently in each of the precordial leads and it is inadvisable to average Tpeak-Tend among several leads.4 Because LQTS is principally a left ventricular disorder, TDR is likely to be greatest in the left ventricular wall or septum and thus to be best reflected in left precordial leads or V3, respectively. Yamaguchi et al. in their study of acquired LQTS targeted lead V5.12 In contrast, because Brugada syndrome is a right ventricular disorder, TDR is greatest in the right ventricular free wall and thus is best reflected in the right precordial leads. For this reason, Castro et al. targeted lead V2 in their study.18 The criteria for validation of Tpeak-Tend as an index of TDR are therefore fairly simple, requiring 1) that individual precordial leads, and not bipolar limb leads, be evaluated and 2) that TDR be present at baseline and significantly augmented as a result of an intervention. In a recent paper published in Heart Rhythm, Opthof and co-workers15 set out to test the hypothesis Tpeak-Tend interval reflects transmural dispersion. Plunge electrodes were used to quantitate transmural and global dispersion of repolarization and Tpeak-Tend (Tp-e) was measured only in a single limb lead, lead II, under conditions in which TDR was essentially non-existent: 2.7-14.5 ms. The use of two anesthetics, propofol and isoflurane, known to suppress sodium channel currents in a variety of cells including M cells, together with the use of a pacing rate of 130 bpm, resulted in essentially no TDR. The recording of precordial ECGs was not possible in this open chest dog model. Thus the two fundamental criteria for validation were not met and the study as designed, for reasons discussed above, could come to no other conclusion than that reached, which is that “Tp-e does not correlate with transmural dispersion of repolarization, but is an index of total dispersion of repolarization”. Thus, the quest for direct validation or invalidation of Tpeak-Tend measured at the body surface as an index of TDR remains unfulfilled. Although most studies to date concur that Tpeak-Tend provides a measure of spatial dispersion of repolarization, the extent to which an augmented Tpeak-Tend interval is prognostic of arrhythmic risk depends on the proximity of the regions displaying disparate repolarization times (i.e., repolarization gradient). Consequently, it would be helpful to know to what extent Tpeak-Tend provides an index of TDR, in which case the differences in refractoriness are ensured to be within close proximity. To this end, it is noteworthy that an ideal model in which to test the hypothesis is in the chronic atrioventricular (AV) block dog treated with IKr blockers, since changes in Tpeak-Tend could be accurately correlated with TDR in a model that displays prominent TDR, and additionally correlated with the risk for development of TdP.

t l t m It is hard to believe today that the concept of reentrant xcitation as an important cause of cardiac arrhythmias as questioned in my professional lifetime. However, nce the occurrence of reentry was proven, first in animal odels of arrhythmias and later in patients, it led to the evelopment of interventional electrophysiology with a oal of being able to destroy (ablate) a crucial part of the eentrant circuit, thereby preventing the reentrant arhythmia. This idea stemmed from what Waldo (Personal ommunication) called the “Mines’ test” in our discusions about reentry. In his classic paper on circus moveent in the early 20th century, Gregory Mines showed hat cutting through the loop that formed the reentrant athway in a simple in vitro model stopped reentry. The ines’ test was first used successfully to prevent arrhythias associated with bypass tracts, which seemed like an mazing accomplishment at the time. Since then, the rocedure of ablation has proved very effective for some upraventricular arrhythmias, such as AV nodal reentrant achycardia and some types of atrial flutter. The success f ablation in these circumstances is due to the predictble location of the reentrant circuits that are targeted for estruction. Unfortunately, ablation of ventricular tachyardia (VT) associated with healed myocardial infarction as been less successful because locating the reentrant ircuit is problematic and procedures for doing so are xtremely time consuming. Current approaches include nduction of the tachycardia with programmed stimulaion, mapping activation with multiple roving catheters, nd entrainment from multiple sites. Because tachycarias must be sustained and hemodynamically tolerated in rder for these techniques to be applied, only some tachyardias are amenable to this approach. To add to the omplexity, patients can have tachycardias with multiple orphologies, suggesting the possibility that different achycardias arise from different reentrant circuits and

In this issue of HeartRhythm, Reddy et al1 report the 12-month clinical results of the TOuCh+ for CATheter Ablation (TOCCATA) study, in which pulmonary vein isolation (PVI) was performed in 32 patients with paroxysmal atrial fibrillation (AF) using a novel open-irrigated radiofrequency (RF) ablation catheter (TactiCath, Endosense SA, Geneva, Switzerland) with a contact force (CF) sensor at the distal tip. The main conclusion of the study was that average CF during ablation was an important determinant of clinical outcome. In the study, a mean CF >20 g predicted the best outcomes (80% freedom from AF recurrence over 12 months), whereas all 5 patients with mean CF 100 g of CF during the procedure. The one perforation event in the study was preceded by an elevated CF of 137 g during catheter manipulation, highlighting the fact that perforation does not have to occur during ablation but rather can occur with just catheter manipulation. Reddy at al1 present clinical follow-up data for 32 of these 34 AF patients, with 1 patient excluded for persistent AF and withdrawal of the other patient prior to 3 months of follow-up. The outcome of interest in these 32 patients was the absence of sustained AF, atrial flutter, or atrial tachycardia for over 30 seconds during 12 months of follow-up or confirmed isolation of all 4 pulmonary veins during a repeat procedure. Recurrent arrhythmia was assessed both clinically and with 7-day Holter monitoring performed 3 months, 6 months, and 12 months after ablation. Based on these criteria, only 15 patients remained without any recurrences during the 12 months after ablation, but a total of 17 patients were classified as having successful outcomes because 2 additional patients with recurrences had confirmed PVI at the time of the second procedure. Of note, a successful outcome did not require patients to be off antiarrhythmic drugs, and no blanking periods were applied. The reader should note the differences between this definition of 1-year success and the definition provided in the most recent HRS/ EHRA/ECAS Expert Consensus Statement on Atrial Fibrillation Ablation, in which 1-year success is defined as freedom from AF/atrial flutter/atrial tachycardia off antiarrhythmic drug therapy as assessed from the end of a 3-month blanking period to 12 months following the ablation procedure.7 The reader should also note that the statistically significant comparisons reported in the paper were only between the extremes of CF because the small sample size limited the statistical power of the study. For example, although the success rate for the 10 patients with >20 g of mean CF appears to be qualitatively higher than that for the 17 patients with 10 to 20 g of mean CF, the difference in success rates between the 17 patients with >20 g of mean CF and the 5 patients with 1000 gs and the 8 patients with FTI

The current generation of implantable cardioverter-defibrillators (ICDs) possesses diagnostic features that provide a unique opportunity to study the events preceding—and perhaps precipitating—cardiac arrest. Recordings of ventricular fibrillation in outpatient setting were exceedingly rare in the pre-ICD era. Today, intracardiac electrograms preceding potentially lethal ventricular arrhythmias are available in unlimited quantity. Systematic analysis of the pre-arrhythmic data has yielded insights into the pathogenesis of spontaneous arrhythmias that would be difficult to obtain in any other manner. For example, it appears that an increase in repolarization lability—in the form of T-wave alternans and T-interval variability—precedes or predicts the onset of entricular arrhythmias. This supports the role of repolarzation variability and T-wave alternans in human arrhythogenesis. More prosaically, electrogram analysis indicates proarrhythmic role of ventricular pacing in some recipints of ICD. Other reports describe the frequent occurence of short–long–short RR intervals and fairly stable atterns of heart rate sequences before the onset of arrhythia in individual patients, suggesting a theoretical posibility of individualized pacing algorithms for ventricular rrhythmia suppression. In general, the information stored n the device memory can be used to address a wide variety f questions. The paper by Sullivan et al in this issue of HeartRhythm analyzed stored intracardiac electrograms to assess the effectiveness of antitachycardia pacing (ATP) in patients enrolled in the Inhibition of Unnecessary RV Pacing With AVSH in ICDs (INTRINSIC RV) study. This was a large randomized trial comparing 2 bradycardia pacing modes in recipients of dual-chamber ICDs regarding their effect on mortality and heart failure hospitalization. The results of the trial were published elsewhere. In the present report, Sullivan et al retrospectively evaluated the efficacy of ATP therapy in those patients in whom it was programmed. Ironically, ATP programming was not specified in INTRINSIC RV; it was in fact discouraged, since the default tachycardia programming option consisted of a single ventricular fibrillation zone over 185 beats/min to be treated with shocks only.

m o e s t Five years ago, a viewpoint paper in this journal discussed the potential relevance of myocyte–nonmyocyte interaction for heart rhythm. At the time, the expression cardiac nonmyocyte” was largely seen to be equivalent to broblast, and heart-rhythm relevant interaction was conidered mainly in terms of electrotonic coupling between eterotypic cells, which—if present in vivo—was thought to orm 3 principal configurations worthy of consideration

Figure 2 The twisted stylet is bent flush to the lead body, and the free lengths of the stylet are wrapped around the lead. The stylet arms are then twisted again perpendicular to the lead with a needle driver. A crucial factor in the success of a lead extraction is maintaining control of the lead body. Control of the lead can be obtained by using multiple tools. A lead locking stylet is usually placed down the pace-sense conductor of the lead to be extracted and secured. Spectranetics (Colorado Springs, CO) offers a line of lead locking devices, and Cook Medical (Bloomington, IN) offers the Liberator Beacon Tip Locking Stylet. When the lead locking device or stylet is retracted more forcibly relative to the outer components of the lead, there is an increased chance that the inner components will unravel and control of the lead may be lost. To keep the lead as one piece, the outer components of the lead need to be compressed onto the inner stylet. The outer body of the lead is usually secured with a long silk tie and half hitches may be tied to distribute the tension about the proximal portion of the lead. Cook Medical has developed the One-Tie lead compression coil that is akin to a paper clip that is wound around the lead locking stylet and half around the outer lead body. The purpose of this device is to compress the lead in a

The incidence of persistent and permanent AF will likely continue to increase as the population ages and as patients with structural heart disease live longer. Many catheter-based ablation techniques have been developed to treat AF. This paper will review which of these approaches have been demonstrated to be effective for ablation of persistent and permanent AF. Because current approaches are associated with an unacceptable rate of ablation failure and proarrhythmia, further efforts are needed to develop better techniques and tools to safely, effectively, and permanently isolate the PV antra, to identify which sites are critical to the maintence of AF, and to create durable transmural linear lesions to interrupt intraatrial reentry.

t a a c o ntroduction rugada syndrome is an increasingly recognized cause of udden cardiac arrest, defined by characteristic electrocariogram (ECG) findings and features suggesting a direct or amily history of ventricular tachyarrhythmias. However, he mechanisms for arrhythmogenesis remain controversial. nimal studies suggest that the ECG “Brugada sign” reects loss of action potential dome in the epicardium but not n the endocardium, enabling extra beats (from phase 2 eentry) to interact with transmural repolarization dispersion o initiate reentry. However, elegant mapping of an exlanted heart from a patient with Brugada syndrome howed only broad restitution of propagation (slow conducion at rapid rates) from occult scar. Steep rate-response restitution) of action potential duration (APD) and transural APD dispersion, which may theoretically facilitate eentry, were not seen. In this paper, we describe steep PD restitution as well as broadened restitution of propaation in vivo in the right ventricular (RV) endocardium of patient with Brugada syndrome, near syncope, and easily nduced ventricular fibrillation (VF).

I am deeply grateful and honored to receive the 2006 Distinguished Scientist Award from the Heart Rhythm Society. Many outstanding individuals have received this award since it was established in 1982, and it is humbling to realize that my small feet are walking in the footsteps of these giants. I would be remiss if I did not thank the numerous colleagues, fellows, and students who performed most of the work leading to the papers of which I am a coauthor.

In the current issue of HeartRhythm, Chinitz et al present a novel scoring system (atrial fibrillation ablation [AFA] score) for evaluating the quality and success of catheter ablation for the treatment of paroxysmal atrial fibrillation (AF). We have paraphrased the words attributed to Sir Winston Churchill to give context to the transience of the wins and losses perceived in the greater battle against the formidable opponent of AF. We did this in order to shed light, and to pause and think of the direction AF ablation— the most prolific business in interventional electrophysiology —is taking. In their article, Chinitz et al underline the fact that a scoring system that incorporates quality and success has not been available for AF ablation and that the current use of AF recurrence as an outcome measure has limitations. The AFA score takes into account disparate factors such as lesion delivery, complications, and outcomes in order to evaluate the results and quality of AF ablation and allows for comparison of different techniques. This is achieved by incorporating 6 procedural features, half of which estimate efficacy and the other three reflect the relative acute safety of the procedure. A very strong emphasis is made on the total number of procedures performed, as seen in the relatively high score achieved by radiofrequency ablation in their article compared with emerging balloon techniques (cryo and laser), even though both redo and reconduction rates are quite similar among all methods, as seen in their Table 1. Although one would consider the novelty of this score may lie (if validated against meaningful outcomes) in its value in showing differences among manufacturers, operators, techniques, and institutions, the devil is always in the details. Like all creative concepts, this concept paper raises more questions than provides solutions to the problem at hand. What would this difference in score mean to the patient we hope to care for? The user of this score will not take into account the very premise for performing the procedure, that is, symptom relief. The score will only allow for comparison of nonpharmacologic treatment strategies that strictly target the pulmonary veins and does not permit comparison of AF

Objectives/background The aim of this article is to critically review the data accumulated to date on the application of cardiac resynchronization therapy (CRT) via biventricular pacing techniques to manage patients with advanced heart failure. The data from studies evaluating the effects of long-term right ventricular (RV) pacing are also briefly reviewed. Methods MEDLINE and selective journal searches of English-language reports and a search of references of relevant papers were conducted. Results Cardiac dyssynchrony as reflected by a prolonged QRS complex, often in the form of left bundle branch block, is encountered in about 30% of patients with moderate-to-advanced heart failure. Among these patients, 10% to 15% are candidates for CRT via biventricular pacing. Accumulated evidence from randomized controlled studies over the last few years has indicated a significant hemodynamic and clinical improvement conferred by CRT to class III or IV heart failure patients with idiopathic or ischemic dilated cardiomyopathy having a low left ventricular ejection fraction (≤35%) and a wide QRS complex (≥120–150 ms). Newer data suggest a significant reduction in overall mortality and heart failure hospitalization, particularly when CRT is combined with automatic defibrillator backup. Technical advances with percutaneous methods accessing the tributaries of the cardiac veins have raised the success rate of implantation of left ventricular leads to >90%. Further confirmation from ongoing trials is awaited, and more data from cost-effectiveness studies are needed before CRT is considered for prime time therapy in the heart failure population. If the data confirm a survival benefit from CRT, use of this electrical therapy at earlier stages of heart failure might be contemplated. New evidence from recent studies suggests a deleterious effect of the long-standing practice of producing an iatrogenic left bundle branch block by conventional RV apical pacing in patients receiving permanent pacemakers. Thus, having already become poignantly aware of the harmful effects of spontaneous left bundle branch block, this emerging new evidence about RV apical pacing would dictate a change of attitude and direct our attention to alternate sites of pacing, such as the left ventricle and/or the RV outflow tract, if not for all patients then at least for those with left ventricular dysfunction. Conclusions CRT offers hemodynamic and clinical improvement to patients with moderate-to-advanced heart failure, and it might significantly prolong survival in selected patients, particularly if devices with defibrillation backup are used. Further confirmatory data from randomized mortality trials are needed, and issues of cost efficacy must be resolved before this vital therapeutic alternative is ready for prime time therapy of heart failure patients.

a It is expected that an electrophysiologist’s attention is singularly focused on the heart. There exists, however, an interplay between the heart and other organ systems that greatly affects not only the pathophysiology of cardiac arrhythmias but also the ability to effectively manage them. Perhaps nowhere is this relationship more profound than in patients with chronic kidney disease (CKD), in whom the elevated risk of sudden cardiac death (SCD) is increasingly apparent yet the approach to prevention muddled in uncertainty. CKD is growing in incidence and prevalence, and this fact alone will touch every aspect of medicine including electrophysiology. Current estimates suggest that mild to moderate kidney dysfunction is present in one-third of all US adults, a 3-fold increase over the last decade fueled by the aging of the population and the epidemics of obesity, diabetes, and hypertension. Similarly, the number of patients with end-stage renal disease is expected to more than triple by the year 2030. Cardiovascular mortality due to SCD is inversely and exponentially proportional to renal function and is a major cause of death among all patients with renal disease. In the Heart and Estrogen Replacement Study, an estimated glomerular filtration rate (eGFR) of 40 cm/min was strongly associated with SCD even after adjustment for incident congestive heart failure and myocardial infarction. Similarly, a study of 19,440 patients undergoing cardiac catheterization showed that the risk of SCD increased by 1.1 for every 10 cm/min decline in eGFR. In patients with end-stage renal disease, results rom retrospective database analyses and prospective trials re remarkably consistent in demonstrating that SCD is esponsible for approximately 25% of all-cause mortality. It is in this context that the accompanying paper by Dalal et al provides mechanistic insights into the link between CKD and SCD. By using patients enrolled in the Arrhythmia Genetics in the Netherlands Study, the authors compared the risk of developing ventricular fibrillation (VF) at the time of the first acute ST-segment elevation myocardial

s r a p t Antiarrhythmia devices—pacemakers and implantable cardioverter-defibrillators (ICDs)—are expensive scarce world resources that are available to the majority of the population in the economic “haves” countries but rarely to those without means in the economic “have-nots” countries. Impoverished or developing nations implant what devices they can primarily for life-threatening atrioventricular block, often only in younger patients. ICDs, for any indications, are beyond their scope of practice for all but the richest minority. Generators, leads, and the technical knowledge to implant devices are often obtained through humanitarian assistance, for example, the Pacemaker Banks established under the direction of the philanthropic organization Heartbeat International. Physicians trained and working in rst-world countries with ties to the developing nations ssist in pacemaker implantation and follow-up. Generators are often donated by manufacturers to the humanitarian organizations, typically outright or at a markedly reduced cost. New devices approaching end of shelf life are commonly used. Despite these programs, available data show that pacemaker implant rates in developing countries are a fraction of that in first-world countries. Although difficult to quantify, there is certainly significant morbidity and mortality associated with limited access to pacemakers. One clear bottleneck is the limited supply of new pacemaker generators. In the current issue of HeartRhythm, Baman et al provide one solution to the scarcity of pacemaker generators— that being the reuse of appropriate devices from deceased patients. The group from the University of Michigan has published extensively on this topic in the last 2 years, including a case report, a case series, 2 position/review papers, a meta-analysis, and an original manuscript evaluating societal views—perhaps another example of “reuse.” In the current work, the authors evaluate the effect of a mailed informational flyer and a Web site (My HeartYour Heart) targeted at funeral directors on the collection of explanted devices. The program led to the donation of over 3000 explanted devices primarily from Florida and Michigan. In 550 (21%) of the collected devices there was

The congenital long QT syndromes (LQTS) are a group of rare genetic disorders caused by mutations in genes that encode for cardiac ion channels; causing prolongation of ventricular action potential (APD), delayed repolarization and carry a high risk for the life-threatening polymorphic ventricular tachycardia, Torsades de Pointes (TdP).1 Congenital LQTS may result from mutations that disrupt any number of ion currents, including IKs, IKr, and INa. In contrast, the mechanism by which drugs cause acquired LQTS is almost always block of the rapid component of the delayed rectifier potassium current, IKr. This KCNH2 channel is blocked by drugs with diverse structures encompassing many different drug classes, including antiarrhythmics, antipsychotics, antibiotics and antihistamines and can exhibit a phenotype similar to carriers of mutations in KCNH2 (LQTS2).2,3 The Food and Drug Administration (FDA) in the “critical path initiative” report and later in “thorough QT/QTc studies (TQT)”, laid emphasis on the need to develop new methods of assessing QT-prolonging effect of new drugs.4 In recent years more than 50 prescriptions drugs have been identified that prolong QT interval and of these, more than 30 have been associated with TdP.5 As the QT interval is a surrogate marker of IKr-block, and the development of TdP is inevitably accompanied by QT interval prolongation, great attention has been focused on this marker. However, the QT interval characterizes only the total duration of repolarization, ignores any abnormalities of repolarization sequence and requires normalization for the patient’s heart rate due to inherent confounding phenomenon such as QT lag and hysteresis.6,7 In recent years due to the availability of digital electrocardiograms (ECGs), T-wave morphology has gained importance both as a surrogate and as a predictor of adverse cardiac events in patients with congenital and acquired LQTS.8 Individuals with heterozygous mutations in the KCNQ1 gene (LQTS1) exhibit a normal to generous amplitude of the T wave and a broad-based T wave pattern without a distinct T wave onset,9 whereas individuals with mutations in KCNH2 (LQTS2) exhibit low amplitude T waves with a notched, double-hump and a distinct second protuberance above the apex of the T wave.10 Further, T wave heterogeneity is seen in individuals with LQTS3 (SCN5A mutations) and LQT7 (KCNJ2 mutations).11 With the advent of the so-called principal component analysis (PCA) based on algebraic decomposition of multilead ECG signals, vectorcardiographic T-wave loop has been shown to be an important predictor of adverse cardiac events in patients with LQTS,12 acute myocardial infarction,13 and in the general population.14 In this issue of Heart Rhythm, Couderc et al.16 asked the important question whether certain cardiac ventricular repolarization parameters, as quantified by ECG and used to generate eigenleads by applying PCA, could predict the acquired and congenital forms of LQTS and if these abnormalities are association with adverse cardiac events in patients with KCNH2 mutations. These parameters were first developed in a learning cohort and then validated in separate validation cohort. The study population composed of 411 healthy individuals exposed to moxifloxacin (IKr-blocker) in a cross-over design from seven TQT studies with a set of 4,784 digital ECGs available for analyses. A second set of ECG data composed of 1,674 paper ECGs from 622 subjects with genetically tested KCNH2 mutations (321 non-carriers and 301 carriers). After digitization and quality control, 150 digital ECGs from non-carrier and 143 digital ECGs from LQTS2 mutation carriers were included in the final analysis. Quantification of cardiac ventricular repolarization included: QT apex (QTa), Tpeak to Tend (TpTe), the amplitude of the T wave (Tamp), and the left and right slopes of the T wave (αL, αR). PCA was used to generate early and late repolarization durations (ERD30%, ERD50%, LRD30% and LRD50%) by eigenleads (ev1 and ev2) to analyze the T loop by quantifying T roundness. In LQTS2 carriers, cardiac events were categorized as cardiac arrest, syncope, and sudden cardiac death. QTc prolongation was seen in the healthy subset of patients after moxifloxacin administration as compared to placebo and in LQTS2 carriers compared to non-carrier family members. All scalar parameters, determined by lead II and vectorial parameters (lead ev1), were significantly different between LQTS2 mutation carriers and non-carriers. In a multivariate moxifloxacin prediction model, none of the scalar parameters contributed significantly and only ERD30% from the vectorial parameters contributed a 12% increased probability of being on moxifloxacin. In the LQTS2 prediction model, the left tangent of the T wave (αL) corresponded to ~ 60% increased probability of carrying a KCNH2 mutation for each 1.5 μV/ms decrease in slope measured by either scalar or vectorial method. This model held true even when QTc was dichotomized to

Anatomical and functional data collected over the past two decades have led our group and others to propose the presence of a complex neuronal hierarchy that controls regional cardiac function 1. The maintenance of adequate cardiac function during basal conditions, as well as in the presence of stressors, ultimately depends upon the transduction characteristics of cardiac afferent neurons located in various levels of the cardiac neuronal hierarchy. It is the interdependent reflex processing of that sensory information at the peripheral and central aspects of the hierarchy for cardiac control that ultimately determines the efferent neuronal outflows that modulate regional cardiac function 1. With regards to neural control of cardiac electrical stability, numerous lines of investigation have indicated that heterogeneous activation of select neuronal populations within the cardiac nervous system predisposes the heart to arrhythmias 2-5. Furthermore, other studies have shown there are inherent differences between animals with respect to reflexes evoked in response to acute cardiac stress such that i) reflex-induced changes in efferent neuronal output (sympathetic and parasympathetic) that remain coordinated, especially within and between intrathoracic processing networks, represent “electrically” stable states vs ii) those in which such reflex processing is heterogeneous - thereby leading to disruption of normal efferent neuronal outputs to the heart to induce cardiac electrical instability 1, 4. With the onset and progression of chronic cardiac disease, interactions between cardiac efferent nerves and cardiomyocytes remodel and the characteristics of these adjustments are fundamental to the etiology of disease progression. More importantly, recent studies have indicated that targeted modification of select elements within the cardiac nervous system provides novel opportunities for effective management of arrhythmias. The paper by Shen et.al. 6 “Patterns of baseline autonomic nerve activity and the development of pacing-induced sustained atrial fibrillation” evaluates the potential differential contribution of the cardiac nervous system to induction of atrial arrhythmias using a rapid-pacing induced animal model of atrial fibrillation. Extracellular neural activity was continuously and simultaneously recorded from the left stellate ganglia, left vagus nerve, and from the left superior intrinsic cardiac ganglionated plexus. The characteristics of that neural activity were related to the spontaneous generation of paradoxical atrial tachycardia (PAT) and the time to onset of sustained atrial fibrillation (AF). The primary conclusions for the study were: 1) that ambulatory dogs with higher levels of sympthovagal correlation and higher vagal tone exhibited faster induction of sustained AF by rapid pacing; and 2) the majority (75%) of animals, which did not demonstrate these activity patterns, exhibited increased vagal activity in the week preceding the pacing-induced induction of sustained AF in association with a progressive reduction in indices of sympathetic activity. The coordination of cardiac efferent neuronal activities in the regulation of regional cardiac indices is critically dependent upon the stochastic nature of cardiovascular sensory information processed by peripheral (intrinsic cardiac ganglia, intrathoracic extracardiac ganglia) as well as central (spinal cord and brainstem) components of the cardiac neuronal hierarchy 1. While the interactions within this system usually act to compensate for normal cardiovascular perturbations, this neuroaxis can be catastrophically disrupted by stresses that induce highly localized and excessive input signals to specific nexus points within the hierarchy 2, 4, 7. Recording of extracellular activity from specific nexus points in the cardiac nervous system has provided important insights into the neurocardiological interactions sub-serving cardiac control. First and foremost, has been the characterization of the complex functional and neurochemical diversity evident within these peripheral ganglia, including multiple cell types (afferent, efferent and local circuit neurons) which utilize a variety of putative neurotransmitters to affect cardiac control 1, 8. Rather than being obligatory relays for descending projections, the majority of intrinsic cardiac neurons recorded using such recording techniques are likely to be local circuit ones that are involved in the coordination of intra- and interganglionic neuronal reflex activities with resultant modulation of regional cardiac function 9, 10. Moreover, in conjunction with end-organ effects, interactions between sympathetic and parasympathetic efferents can occur within intrinsic cardiac ganglia, with major effects on the control of cardiac electrical function 11. Stellate/middle cervical ganglia neuroanatomy exhibits a similar network complexity, including the capacity for interganglionic interactions with the intrinsic cardiac nervous system independent of higher center influences 10 and with only a subset of these neurons projecting directly to the heart 12. Vagal fiber recordings likewise represent a heterogeneous population of efferent and afferent projections to cardiac and non-cardiac structures. These factors should be considered and controlled for when possible when interrupting neural activity from various levels of the cardiac nervous system. That being said, the current study from Shen et. al. 6 does provide important new information with respect to the potential contributions of different patterns of autonomic activities as related to cardiac electrical stability. In animals with strong left-sided sympathovagal coordination, there is an increased incidence of sympathovagal co-activations with increased incidence of PAT, yet the incidence of PAT is 20% of co-activation episodes. Future studies should consider if there are unique characteristics of unit and\or population discharge that predispose to arrhythmia formation. When considering nerve-end effector interactions, the direct relationship between stellate ganglion neuronal activity and heart rate is expected, yet a similar direct relationship between recorded vagal activity and heart rate is reported. While indeed this may reflect a potential for co-activation as the authors propose, it is counter to classical concepts of reciprocal innervation 13 with parasympathetic predominance. Indeed, this study supports the emerging concept of differential control of regional cardiac function as manifest by interdependent and nested feedback networks that comprise the cardiac nervous system. This study further substantiates the neural remodeling that accompanies end-effector remodeling associated with the cardiac stress of rapid-pace. Future studies should expand on this concept, especially as related to the cardiac stress-induced changes in functional and neurochemical/neurohumoral alterations in the cardiac nervous system and the cardiac tissues they innervate. Recent studies have indicated that targeting the cardiac nervous system provides new and novel opportunities for effective management of cardiac arrhythmias. Methodologies employed include pharmacological 14, physical 15, 16 and/or electrical 17, 18 means to target specific nexus points within its associated neural networks. While ablation therapy has demonstrated efficacy in AF management 16, 19, 20, such procedures destroy critical elements of the cardiac nervous system that are essential for coordinating regional cardiac function. Recent studies have indicated that local circuit neurons in the cardiac nervous system may be regarded as a potential therapeutic target in arrhythmia suppression. Stabilization of such neurons, either pharmacologically 2, 14 or with electrical neuromodulation 17, has the potential to stabilize the multiple components within the intrinsic cardiac nervous system, reduce the arrhythmogenic potential to nerve imbalances, while at the same time preserving regulatory networks.

It is estimated that more that 2 million Americans are afflicted with atrial fibrillation (AF) and that this number is growing rapidly,1 making it the number one cardiovascular disease in this country. Risk factors for AF include other cardiovascular illness such as myocardial infarction or heart failure along with aging, inflammatory response to disease or injury, genetic abnormalities, obesity or no known obvious cause1. Risk of death increases two-fold in patients with AF2 and quality of life for patients with symptomatic AF has been reported to be lower than patients without AF2. The most devastating potential consequence of AF is stroke which has been reported to increase by over 5 fold3. Additionally, AF is associated with increased ventricular tachycardiac and arrhythmic heart failure2. Recently an association of atrial fibrillation with the development of Alzheimer’s disease also has been suggested4. These negative clinical outcomes make it critical to identify therapeutic treatments. While some risk factors are not possible to affect, such as genetic load and aging, others are more easily addressed. For example, addressing obesity in the patient populations may be helpful in decreasing the AF burden. Another easily addressed issue could be inflammation. A new article by Kume et al5 in this issue of Heart Rhythm focuses on inflammation and lends support to the idea that decreasing the inflammatory response that occurs in cardiovascular disease may decrease the risk for development of atrial fibrillation in this at-risk population5. One of the more interesting molecular biology findings in terms of inflammation is the role of one of the Peroxisome Proliferation-Activated Receptors (PPARs) family members, PPARγ. PPARs were originally described as ligand-dependent transcription factors important in cellular metabolism lipid transport6. Further studies identified the role of this key activator of gene expression in the regulation of brown fat differentiation7 but its role in cardiac tissue is less clear. PPAR-γ activation has been shown to limit the inflammatory response,6 thus is an interesting potential target for altering inflammation in the atria. The first studies to examine this possibility showed that indeed, activation of PPAR-γ by the drug pioglitazone is associated with attenuation of atrial fibrosis and subsequent fibrillation8 in a tachypacing model of induced heart failure and atrial fibrillation. These authors determined that pioglitazone treatment inhibited the formation of heart failure-induced atrial fibrillation by activation of the ERK/MAPK pathways primarily affecting the cardiomyocytes. This new study by Kume et al5 suggests that pressure overload induced fibrosis, as would be found in hypertensive patients, may also be attenuated by activation of PPAR-γ in part by affecting the formation of myofibroblasts. Many cardiovascular diseases such as heart failure and myocardial infarction are associated with an ongoing inflammatory response which includes infiltration of immune cells such as monocytes and macrophages into the atrial tissue where they produce and secrete inflammatory cytokines which then act upon the resident cells of the atria including both myocytes and fibroblasts. In biopsies from AF patients, inflammatory infiltrates such as monocytes and macrophages are commonly seen9. They appear to migrate from the endocardial surface into the subendocardial region with fewer immune cells found in the midmyocardium9. These cells then produce and secrete a number of cytokines that alter the delicate balance of Matrix Metalloproteinases (MMPs) and their endogenous inhibitors, the Tissue Inhibitors of MMPs (TIMPs)10. This imbalance leads to expansion of the extracellular matrix. Additionally, many of these cytokines help to initiate and support the transformation of resident fibroblasts into reactive myofibroblasts11, an event which then augments the systemic inflammatory response. Myocytes respond to cytokines by activating the hypertrophic signaling cascades12 and initiating inside out signaling via the integrins12 which stimulates collagen production and deposition. Activation of TNF-α, IL-1β, IL-6 and TGF-β receptors all lead to activation of gene programs that upregulate the formation and deposition of collagen via the myofibroblasts. Thus inflammation in the atria leads to increased fibrosis via the increased deposition of collagen and cellular hypertrophy both of which correlate with formation of the arrhythmogenic substrate. In some ways, fibrosis can be beneficial by filling in areas where the myocytes may have died out and helping scaffold the remaining cells. This event is far outweighed by the negative effects of fibrosis which include widening of the extracellular space that leads to decreased connectivity between the myocytes which helps maintain the fibrillatory events in the atria13. Pioglitazone belongs to a family of drugs first described as insulin-enhancers, the Thiazolidinediones14. They were found to increase the reactivity to insulin in cases of insulin-resistance by activating PPAR-γ. This novel mechanism for increasing insulin sensitivity revolutionized the treatment of Type II Diabetes although cautionary notes were very quickly added to the literature due to the potential for increased liver disease15. Other studies found no hepatotoxicity with pioglitazone specifically16 suggesting that this family member may be the safest option in treatment. The first inklings that these drugs could have beneficial off target effects was suggested by Ricote et al.17 in a paper that showed that activation of PPAR-γ inhibited the production of inflammatory cytokines by monocytes. From there, studies began to crop up showing that pioglitazone decreased atherosclerosis18, attenuated Parkinson’s Disease19 and a number of other inflammatory based diseases (for review see reference 20). Thus it appears that the general effect of pioglitazone, outside of its role in increasing insulin sensitivity, causes an overall immune suppression. Due to the fact that the myocardial tissue has somewhat limited regeneration capabilities, the response to injury is critical to minimizing damage. This includes a tightly orchestrated inflammatory response. The body’s primary response to injury, including cardiac injury, is activation of the inflammatory response. The associated release of cytokines and chemokines mediates increases in blood flow, capillary permeability and aids in the increase of inflammatory cells to perform “clean up” duties in the injured heart21. These processes, when well controlled, help heal the heart and if they are completely eliminated may increase overall injury. On the other hand, this response cannot be too long or scar formation and fibrosis dominate the tissue. Thus, while the studies of Kume et al, described here are suggestive of a positive effect of immune suppression in pressure overload heart failure,5 this should be tempered with a modicum of caution. Before we dive headlong into pioglitazone treatment for heart disease, it might be important to understand more about the positive roles of the inflammatory response so that we do not accidentally throw out the baby (healing) with the bathwater (fibrosis).

The congenital long QT syndromes (LQTS) are a group of genetic disorders that affect cardiac ion channels, are characterized by prolongation of the QT interval, and carry a risk for the life-threatening ventricular tachycardia, Torsades de Pointes. Shortly after the autosomal recessive syndrome of congenital deafness, prolongation of the QT interval, and sudden cardiac death was described by Jervell and Lange-Nielsen in 1957,1 Romano and Ward each independently described an “autosomal dominant” form without congenital deafness.2, 3 In the late 1990’s, the first 5 LQTS genes were identified, all of which encode ion channel subunits that underlie the cardiac action potential.4–7 The most commonly affected genes, KCNQ1 and KCNH2 (underlying LQT1 and LQT2 respectively), encode proteins that form the α-subunits of 2 major repolarizing potassium currents, IKs and IKr. Two other LQTS genes encode for the corresponding β-subunits (KCNE1 and KCNE2 underlying LQT5 and LQT6, respectively). The other major LQTS gene, SCN5A (underlying LQT3) encodes the α-subunit of the cardiac sodium channel. Additional ion channel mutations have been associated with rare arrhythmia syndromes (Andersen-Tawil syndrome, KCNJ2 and Timothy syndrome, CACNA1C) that may include QT prolongation, as well as significant extracardiac phenotypes.8 Andersen-Tawil syndrome (ATS) patients do not uniformly display prolonged QT intervals, and due to clinical features that differ from LQTS, is better termed ATS1 rather than LQT7.9 The previously-termed LQT4 has been linked to mutations in ANK2, encoding the structural protein ankyrin-B, which when mutated, results in altered localization and expression of ion channels.10 Patients with ANK2 mutations do not uniformly have prolonged QT intervals, and it has been suggested that LQT4 be renamed ‘sick sinus syndrome associated with bradycardia’ or ‘ankyrin-B syndrome’.11 The incidence of congenital LQTS has been estimated at 1 in 5000, and the incidence of Jervell-Lange-Nielsen (JLN) syndrome estimated as 1 in 500 congenitally deaf individuals. Without treatment, 13% of LQTS patients will suffer cardiac arrest or sudden death prior to 40 years of age; when syncopal events are included, 36% will have symptoms by age 40.12 The JLN syndrome is more severe, with 90% experiencing syncope, cardiac arrest, or sudden death by age 18, and mortality exceeding 25% even with therapy.13 Important clinical differences among affected patients depending on the underlying affected gene have been observed – so called genotype-phenotype correlation. As the majority (>90%) of genotyped LQTS patients have LQT1, LQT2, or LQT3 most of the differences are observed among these genotypes, and include different ECG T-wave patterns,14 clinical course,15 triggers of cardiac events,16 response to sympathetic stimulation,17, 18 and effectiveness and limitations of β-blocker therapy.19 Over the past decade, genetic testing for LQTS, particularly the three most common genotypes of LQT1 to LQT3, was performed in a few research laboratories worldwide with very high diagnostic yield. However, since 2004, clinical LQTS genetic testing has become available through a commercially available diagnostic test (FAMILION), which provides mutational analysis of the 3 major LQTS-susceptibility genes along with the 2 minor genes (KCNE1 [LQT5] and KCNE2 [LQT6]). Clinically, genetic testing has been used to not only risk-stratify patients, but also guide treatment decisions, and precisely elucidate the carrier status of potential at-risk relatives. To date, hundreds of non-synonymous mutations and splice-site altering mutations have been identified in the 12 LQTS- or LQTS overlap-susceptibility genes. In this issue of Heart Rhythm, Kapplinger et al20 describe the spectrum and prevalence of mutations in the first 2500 cases scanned for mutations in 5 of the LQTS-susceptibility genes at FAMILION. The major results are: 1) 36% of all patients tested hosted a possible LQTS-causing mutation; 2) 91% of the mutation-positive cases had single genotypes while the remaining 9% had >1 mutation and 3) 60% of the mutations were novel to this cohort. All prior publications on the yield of genetic testing in consecutive patients originated in a few research laboratories. In general, those laboratories will only perform genetic testing (usually at no charge) after receiving clinical information and ECGs from the patient tested and will perform the test when there is a reasonable chance of finding a mutation in the tested gene. In contrast, the present data originate from the first clinical genetic laboratory that performs the test on a commercial basis without the need for any prerequisite phenotypic data. This probably explains the relatively low yield of positive tests (lower than recent numbers of positive results in research laboratories). The 36% yield of positive results in this cohort also suggests that physicians are at least semi-prudently evaluating the need for the test particularly in light of the high cost. It has been well over a decade since the first LQTS-causative mutations were discovered but still one-third of mutations discovered in this cohort were novel. This highlights one of the major challenges when interpreting the results of genetic testing: distinguishing pathogenic mutations from rare variants that actually have no relationship to the disease. In this particular study, this is made even more difficult as no clinical data are available permitting genotype-phenotype correlations. As this group has previously shown, the availability of clinical phenotype strongly correlates with the likelihood of elucidating a pathogenic mutation.21 Multiple approaches have been used to distinguish between pathogenic and benign rare variants: 1) screening large ethnically-matched control populations to establish variant frequency; 2) examining cosegregation of disease and genetic variant in extended kindreds; 3) analyzing the degree of conservation of the mutated amino acid across species; 4) examining the mutation type and location and 5) performing functional studies. Variants cosegregating in kindreds, absent in matched control populations with a high degree of conservation and demonstrating functional effects, are most likely to be disease-causing. Thus, when these criteria are systematically applied to the novel mutations identified in this study, it is likely that many of the variants constitute ‘background’ genetic noise and are not pathogenic for the LQTS. With increasing availability of genetic testing, distinguishing pathogenic mutations from rare variants is increasingly becoming more important. Consequently, a ‘pathogenicity score’ based on some or all of the elements mentioned above would prove invaluable when interpreting the results of genetic tests. Such an approach has been proposed by a number of groups including the authors of this paper. The authors of the present study, however, should be congratulated as this compendium of novel and rare variants associated with the LQTS and it does provide a useful starting point for further studies of the pathogenesis of these rare diseases.

r m When your heart goes into ventricular fibrillation, it stops umping blood. The resulting lack of oxygen causes ischmia, which becomes progressively more severe until you ie (or, if you are lucky, until someone defibrillates you). he electrical properties of the heart change during the inutes of worsening ischemia, so that ventricular fibrillaion in the first seconds after its onset is not the same rrhythmia as fibrillation several minutes later. The optium technique for defibrillation may also vary depending n how long the heart has been ischemic. Defibrillation by n implantable cardioverter-defibrillator occurs soon after brillation begins, so the shock is applied when ischemia as been present for only a short time. On the other hand, efibrillation by an external defibrillator often happens mintes after fibrillation starts. These two devices (internal and xternal defibrillators) differ not only in their electrode eometry and placement but also in the state of the heart at he time of the shock. Experiments and computer simulations often ignore the hange in fibrillation during these crucial minutes. For intance, when experimentalists place the heart on a Langenorff apparatus, the feedback loop connecting the mechancal pumping of the heart to the electrical state of the cardiac issue is broken: fibrillation no longer leads to ischemia ecause the heart is artificially perfused. Many mathematial models simulate the heart’s electrical behavior using quations whose parameters do not change with time. These odels may be appropriate for analyzing Langendorff exeriments but are less useful for studying fibrillation in an ntact heart. In this issue of Heart Rhythm, Allred et al examine efibrillation in pigs that are not artificially perfused, both mmediately (20 seconds) and much later (7 minutes) after he onset of fibrillation. This paper adds significantly to our nowledge of how fibrillation and defibrillation change with ime. Their study addresses three questions. First, does the electric field (that is, the potential gradint) applied during the shock change with time? The answer o this, the easiest of the three questions, is no. The electric eld is nearly identical if given during the first seconds of brillation or after several minutes. This result is not sur

b Since the initial papers that suggested the presence of riggers for atrial fibrillation (AF) in the pulmonary veins nd described the possibility of curative percutaneous cathter ablation of AF, there has been significant progress in ur understanding of AF and the potential ways in which it ight be ablated. The identification of triggers, substrate, nd the effect of the autonomic nervous system and the ngoing study of approaches to their individual or combined blation has been of great interest in the last few years. he development of new tools for the ablation of more omplex arrhythmias has almost certainly helped in the blation of AF, especially in small-volume units with less xperience. However, success rates remain lower than hose for other supraventricular tachycardias, and the risks ssociated with the ablation of AF are also significantly igher. The risks include not only significant morbidity, but also risk of mortality, with much emphasis being placed on trioesophageal fistula formation. There are also dramatic ifferences in the success rates obtained. Some of this varition undoubtedly relates to operator experience, with the ates in publications and surveys that include smaller volme centers being inferior to the excellent success rates for aroxysmal AF at high-volume centers. In addition, not ll approaches have necessarily given the same success rates hen performed at different centers and by different opertors. Recently, consensus documents have been published ooking at catheter ablation for AF, and it is again clear that ifferent groups propose different approaches. AF is a syndrome with multiple underlying causes, and ts pathogenesis is also multifactorial, although with coniderable overlap in both at points in the disease progresion. It is hardly surprising therefore that not only do these isparate approaches have similar success rates but also that he success rates are not as high as when ablating simpler ubstrates. The challenge going forward is to decide whether a ne-ablation-fits-all strategy with an improved success rate nd lower complication rate can be identified or whether we