Circulation Editors’ Picks

Abstract

HomeCirculationVol. 127, No. 12Circulation Editors’ Picks Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBCirculation Editors’ PicksMost Read Articles in Arrhythmia and Electrophysiology The Editors The Editors Search for more papers by this author Originally published26 Mar 2013https://doi.org/10.1161/CIRCULATIONAHA.113.002294Circulation. 2013;127:e509–e519Sprint Fidelis Lead Fractures in Patients With Cardiac Resynchronization Therapy Devices: Insight From the Resynchronization/Defibrillation for Ambulatory Heart Failure (RAFT) StudySummary: In this multicenter, randomized trial, Sprint Fidelis fractures were found to occur more frequently in the group that received both an implantable cardioverter-defibrillator and cardiac resynchronization therapy than in the group that received only an implantable cardioverter-defibrillator. This is the first study to have adjudicated lead fracture in a blinded fashion, with systematic follow-up in a clinical trial. Our main findings were an overall rate of lead fracture of 1.65%, with a hazard ratio of 2.42 for patients with both an implantable cardioverter-defibrillator and cardiac resynchronization therapy. The only predictor of lead fracture in this population was having undergone both implantation of an implantable cardioverter-defibrillator and cardiac resynchronization therapy. The Fidelis lead issue has provided invaluable information on lead behavior and risks for fracture. The Resynchronization/Defibrillation for Ambulatory Heart Failure (RAFT) study has been able to contribute further information on how cardiac resynchronization therapy influences the risk of fracture related to this lead. The increased risk of fracture in cardiac resynchronization therapy patients should be taken into account when such patients appear for generator change, where the risk for fracture is higher than in a standard implantable cardioverter-defibrillator. Prophylactic revision of the lead in such cases needs to be considered carefully in terms of risks and benefits of this intervention.Conclusions: In this analysis of the RAFT study, patients with an implantable cardioverter-defibrillator (ICD) and cardiac resynchronization therapy were found to have a significantly higher fracture rate than patients with an ICD. This finding needs to be considered when these patients are assessed for possible lead revision at the time of an elective generator replacement.1Mechanism of Loss of Kv11.1 K+ Current in Mutant T421M-Kv11.1–Expressing Rat Ventricular Myocytes: Interaction of Trafficking and GatingSummary: Congenital long QT syndrome type 2 is an inherited arrhythmia disorder characterized by prolonged QT intervals on ECGs in the absence of structural heart disease. Long QT syndrome type 2 is caused by mutations in the KCNH2 (hERG) gene encoding Kv11.1 potassium channels, resulting in reduced repolarizing current (IKr). Long QT syndrome type 2 mutations affect channel function mainly by defective channel protein trafficking to cell membrane or abnormal channel gating. We studied the T421M-Kv11.1 missense mutation identified in a multigenerational long QT syndrome type 2 family with variable penetrance of the mutation phenotype. T421M is localized in the Kv11.1 S1 transmembrane domain. We investigated the disease mechanism by heterologous adenoviral expression of mutant and WT channels in adult rat ventricular myocytes. Compared with wild-type channels, the T421M-Kv11.1 homotetrameric channels have both altered protein trafficking and channel gating properties. When coexpressed, heterotetrameric channels remained trafficking deficient but had wild-type–like gating properties. Thus, the gating properties of heterotetrameric channels do not follow a dominant-negative pattern, whereas the trafficking abnormality does. The lack of a severe dominant-negative effect of mutant α-subunits on the cellular electrophysiology may result in heterotetrameric channels that potentially result in a milder clinical phenotype. Finally, because the proband experienced cardiac arrest triggered by auditory startle, we studied β-adrenergic stimulation of wild-type–Kv11.1 and T421M-Kv11.1 channels in adult rat ventricular myocytes. Wild-type–Kv11.1 and T421M-Kv11.1 channels responded to isoproterenol by increasing current amplitude, suggesting that Kv11.1 channels could be a direct substrate for β-blocker therapy. Our findings may provide new mechanistic insights into disease phenotype and severity.Conclusions: The T421M-Kv11.1 mutation caused a loss of IKv11.1 through interactions of abnormal protein trafficking and channel gating. Furthermore, for coexpressed WT+T421M-Kv11.1 channels, different dominant-negative interactions govern protein trafficking and ion channel gating, and these are likely to be reflected in the clinical phenotype. Our results also show that WT and mutant Kv11.1 channels responded to β-adrenergic stimulation.2Fetal Heart Rate Predictors of Long QT SyndromeSummary: Long QT syndrome (LQTS) may be as common as 1/2500 individuals, yet fewer than 100 cases have been recognized during fetal life. Fetal torsades de pointes and 2° AV block are easily attributed to LQTS. However, these complex arrhythmias are present in only 25% of fetal LQTS; the majority of LQTS fetuses have asymptomatic bradycardia that may not be recognized as an LQTS marker due to its subtle features. The standard obstetric definition of bradycardia is fetal heart rate (FHR) ≤ 110 bpm. To improve recognition of perinatal LQTS we evaluated the FHR/gestational age (GA) relationship of fetal LQTS mutations versus a normal control group. We found GA dependent FHR predictors of LQTS; for example, when compared to a FHR of 110 bpm at any GA, a FHR ≤3rd percentile for GA improves ascertainment of LQTS subjects from 15 to 85%. Fetuses with the lowest FHR tended to have de novo and genetically elusive LQTS mutations, and in addition to bradycardia, also manifested complex LQTS rhythms. Identification of LQTS in the fetus with a heart rate of <3rd also led to diagnosis of LQTS in unsuspecting family members. Thus, postnatal evaluation of individuals with a FHR ≤3rdpercentile for GA improves ascertainment of LQTS both before and after birth.Conclusions: FHR varies by GA in both normal and LQTS fetuses. Postnatal evaluation of neonates with FHR ≤3rd percentile for GA may improve ascertainment of LQTS in fetuses, neonates, and undiagnosed family members.3Rhythm Versus Rate Control Therapy and Subsequent Stroke or Transient Ischemic Attack in Patients With Atrial FibrillationSummary: Despite anticoagulation, stroke remains a complication of atrial fibrillation. Several randomized controlled trials have compared rate and rhythm control approaches in patients with atrial fibrillation and demonstrated a similar impact on mortality, but most trials had inadequate sample size to assess their relative effect on stroke outcome. In the current observational study, we compared the rates of stroke/transient ischemic attack in patients treated with rhythm (n=16 325) or rate (n=41 193) control strategies in a large population-based cohort of patients with recently diagnosed atrial fibrillation. Crude stroke/ transient ischemic attack incidence in the rhythm control group was 1.74 per 100 person-years in comparison with 2.49 in the rate control group (P<0.001). Although at baseline, patients receiving rhythm control therapy had fewer risk factors for stroke in comparison with patients receiving rate control therapy, the association between rhythm control treatment and lower stroke rates remained after multivariate analysis (adjusted hazard ratio, 0.80; 95% confidence interval, 0.74, 0.87) and propensity score analysis (adjusted hazard ratio, 0.77; 95% confidence interval, 0.68, 0.87), which balanced patients’ characteristics between groups. Once stratified by CHADS2 (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, and previous stroke or transient ischemic attack) score, the rhythm control group had a lower stroke risk than the rate control group only for patients with high- and moderate-risk CHADS2 scores. The results of this study provide additional information to guide clinicians’ choice of treatment strategy by considering the outcome of stroke. This study may stimulate future large randomized trials comparing the effectiveness of rhythm versus rate control strategies on the risk of stroke and emphasizes the need for the development of new therapies for atrial fibrillation.Conclusions: In comparison with rate control therapy, the use of rhythm control therapy was associated with lower rates of stroke/transient ischemic attack among patients with atrial fibrillation, in particular, among those with moderate and high risk of stroke.4Survival After Alcohol Septal Ablation for Obstructive Hypertrophic CardiomyopathySummary: The clinical efficacy of alcohol septal ablation for obstructive hypertrophic cardiomyopathy has been demonstrated, but the effects of the procedure on late survival remain uncertain. We examined 177 patients (mean age, 64 years; 68% women) who underwent septal ablation at our institution. The survival of patients who had septal ablation was no different than the expected survival for a comparable general population (8-year estimate, 79%), and similar to that of age- and sex-matched patients who underwent isolated surgical myectomy. The annual incidence of sudden cardiac death was ≈1.3%. This study demonstrates that favorable long-term survival can be achieved in carefully selected patients who undergo septal ablation by experienced operators in a tertiary referral hypertrophic cardiomyopathy center.Conclusions: In this nonrandomized study of carefully selected patients undergoing septal ablation by experienced operators in a tertiary referral hypertrophic cardiomyopathy center, long-term survival was favorable and similar to that of an age- and sex-matched general population, and to patients undergoing surgical myectomy, as well, without an increased risk of sudden cardiac death.5Efficacy and Safety of the Novel Oral Anticoagulants in Atrial Fibrillation: A Systematic Review and Meta-Analysis of the LiteratureSummary: Novel oral anticoagulants, including direct thrombin inhibitors and factor Xa inhibitors, have been proposed as alternatives to vitamin K antagonists for the prevention of stroke and systemic embolism in patients with atrial fibrillation. We conducted a systematic review and a meta-analysis of published and unpublished phase II and III randomized, controlled trials comparing the novel oral anticoagulants with the vitamin K antagonists in patients with atrial fibrillation. We retrieved 12 studies (3 administering dabigatran, 4 administering rivaroxaban, 2 administering apixaban, and 3 administering edoxaban) enrolling >50 000 patients. We found that the novel oral anticoagulants significantly reduced overall mortality, cardiovascular mortality, and stroke or systemic embolism. Furthermore, these drugs showed a trend toward reduced major bleeding, with a significant reduction of intracranial hemorrhage. The novel oral anticoagulants may potentially address some of the limitations of vitamin K antagonists because they have fewer food and drug interactions and a more predictable anticoagulant effect, thus allowing fixed-dose regimens without the need for routine laboratory monitoring. Our meta-analysis also provided robust evidence on the overall clinical benefit of the novel oral anticoagulants, suggesting their cost-effectiveness in the real-life healthcare systems.Conclusions: Novel oral anticoagulants are associated with an overall clinical benefit compared with vitamin K antagonists. Additional research is required to confirm these findings outside the context of randomized trials.6Transient Receptor Potential Canonical-3 Channel–Dependent Fibroblast Regulation in Atrial FibrillationSummary: Atrial fibrillation (AF) is the most common clinical arrhythmia, and its therapy is problematic. There is a need for novel treatment interventions, and mechanistic insights may be helpful in developing such new therapies. Here, we examined the role of a new type of ion channel, the nonselective cation channel TRPC3 (transient receptor potential canonical-3), in AF. TRPC3 can carry a number of ions but may be particularly important as an entry pathway for calcium into nonexcitable cells such as fibroblasts. Tissue fibrosis is produced by an overproduction of extracellular matrix proteins by fibroblasts and is believed to be important in AF. In addition, fibroblasts may contribute to AF via electric interactions with excitable heart cells (cardiomyocytes). We first found that cardiac fibroblasts expressed functional TRPC3 channels, and TRPC3-mediated calcium entry into fibroblasts activated a signaling molecule (extracellular signal-regulated kinase) that induced fibroblast proliferation and differentiation into activated myofibroblasts. We also noted that TRPC3 expression was upregulated in AF patients and 2 experimental AF models. We then studied the role of TRPC3 in atrial remodeling of dogs kept in AF for 7 days by atrial tachypacing. We found that AF increased TRPC3 protein expression and current, although it activated fibroblasts, and that blocking TRPC3 suppressed fibroblast activation and the AF-promoting remodeling caused by AF. We also identified the molecular pathway that leads to TRPC3 upregulation in AF: Downregulation of a TRPC3-suppressing microRNA, miR-26, caused by AF-induced nuclear translocation/regulation by nuclear factor of activated T-lymphocytes (NFAT) in fibroblasts. This work provides novel insights into molecular mechanisms underlying AF, as well as potential new anti-AF targets.Conclusions: TRPC3 channels regulate cardiac fibroblast proliferation and differentiation, likely by controlling the Ca2+ influx that activates extracellular signal-regulated kinase signaling. AF increases TRPC3 channel expression by causing NFAT-mediated downregulation of microRNA-26 and causes TRPC3-dependent enhancement of fibroblast proliferation and differentiation. In vivo, TRPC3 blockade prevents AF substrate development in a dog model of electrically maintained AF. TRPC3 likely plays an important role in AF by promoting fibroblast pathophysiology and is a novel potential therapeutic target.7Use of a Novel Endoscopic Catheter for Direct Visualization and Ablation in an Ovine Model of Chronic Myocardial InfarctionSummary: Substrate mapping of ventricular tachycardia typically uses indirect measures of identifying myocardial scar, including electroanatomic voltage mapping and intracardiac echocardiography. We describe a novel catheter capable of direct endocardial visualization during mapping and irrigated radiofrequency ablation. The catheter contains a small fiberscope capable of directly visualizing the endocardial surface through a clear hood on the catheter tip with a 6.8-mm field of view. Saline is constantly flushed through the catheter to clear blood from the hood and allow visualization of the endocardial surface. Electrograms can be recorded from 4 orthogonal electrodes on the catheter tip; irrigated radiofrequency ablation can be performed via an electrode proximal to the catheter tip that heats the saline irrigant. We tested whether this catheter could visually differentiate among dense scar, border zone, and normal myocardium in an ovine model of chronic myocardial infarction. With the use of image processing techniques, the visual whiteness in the field of view was quantified and correlated well with electrogram measures of scar. Irrigated ablation lesions were delivered and could be observed in both healthy myocardium and myocardial scar. This approach offers a new paradigm in catheter ablation. Advantages include confirmation of catheter contact with the endocardium, direct visualization of anatomic structures such as the papillary muscles and myocardial scar, improved efficacy and safety of catheter ablation through visualization of lesion formation, and the ability to visually confirm contiguity of lesions delivered in a linear fashion during catheter ablation.Conclusions: Visual characteristics of chronic infarct scar in vivo observed with the use of a novel endoscopic catheter correlate with bipolar electrogram voltage. Irrigated radiofrequency lesions in normal endocardial tissue and postinfarction zone can be visualized and quantified with the use of image processing. This technology shows promise for visually based delivery of radiofrequency lesions for the treatment of scar-based ventricular tachycardia.8Phosphoinositide 3-Kinase γ Protects Against Catecholamine-Induced Ventricular Arrhythmia Through Protein Kinase A–Mediated Regulation of Distinct PhosphodiesterasesSummary: Ventricular arrhythmia is a leading cause of sudden death. Malignant ventricular arrhythmias such as ventricular tachycardia can develop in otherwise healthy individuals carrying proarrhythmic mutations and in patients affected by cardiomyopathies such as ischemic heart disease and heart failure. Although the administration of classic antiarrhythmic drugs (ie, β-blockers and amiodarone) and the implantation of cardiac defibrillators constitute a cornerstone of current patient management, only a better understanding of the molecular circuitries underlying ventricular arrhythmogenesis will pave our way toward new frontiers in sudden cardiac death prevention. For this purpose, experimental dissection of the molecular pathways that fine-tune both second messenger signaling and excitation-contraction coupling in cardiomyocytes is paramount. In the present work, using genetically modified mice, we have uncovered that the enzyme phosphoinositide 3-kinase γ (PI3Kγ) is required to maintain a physiological function of important myocardial phosphodiesterases such as phosphodiesterase 3A, 4A, and 4B. Biochemical and functional data indicate that PI3Kγ constitutes a necessary scaffold for these phosphodiesterases because the loss of PI3Kγ leads to abnormal cAMP accumulation, to inappropriate activation of cAMP targets such as L-type calcium channel, and to spontaneous calcium release events in cardiomyocytes. Although in normal hearts the loss of PI3Kγ leads to benign premature ventricular beats on β-adrenergic stimulation, cardiac pressure overload precipitates the development of ventricular tachycardia and rapidly results in substantial mortality. These findings indicate that the β-adrenergic/PI3Kγ/phosphodiesterase signaling hub may constitute a promising molecular target for the development of novel antiarrhythmic therapeutic interventions.Conclusions: PI3Kγ coordinates the coincident signaling of the major cardiac PDE3 and PDE4 isoforms, thus orchestrating a feedback loop that prevents calcium-dependent ventricular arrhythmia.9Ascending-Ramp Biphasic Waveform Has a Lower Defibrillation Threshold and Releases Less Troponin I Than a Truncated Exponential Biphasic WaveformSummary: We demonstrated that an ascending-ramp biphasic shock has a significantly lower defibrillation threshold and causes release of less than half as much troponin I as a truncated exponential biphasic shock at almost the same energy and at a higher peak voltage than the truncated exponential biphasic shock. This result indicates that the shape of the shock waveform, in addition to the peak voltage and energy of the waveform, affects cardiac damage caused by a shock. The results of this study suggest that, in addition to optimizing the shock waveform to decrease the defibrillation threshold, the shock waveform should be optimized to decrease the damage caused by defibrillation. Therefore, it is theoretically possible that the waveform with the lowest defibrillation threshold may not necessarily cause the least damage. Serendipitously, an ascending-ramp first-phase biphasic waveform has both a lower defibrillation threshold energy and a shape that causes less damage than the truncated exponential biphasic waveform. Further investigation is needed to determine whether an ascending ramp biphasic waveform will cause less shock damage to human hearts.Conclusions: The ascending ramp has a significantly lower defibrillation threshold and at ≈30 J causes 58% less troponin I release than the truncated exponential biphasic shock. Therefore, the shock waveform affects both the defibrillation threshold and the amount of cardiac damage.10Implantable Cardioverter-Defibrillators Have Reduced the Incidence of Resuscitation for Out-of-Hospital Cardiac Arrest Caused by Lethal ArrhythmiasSummary: The proportion and incidence of patients with out-of-hospital cardiac arrest (OHCA) that are found in ventricular fibrillation (VF) decreased over the last decades. It used to be well over 70% (incidence, 0.3–0.7/1000 inhabitants) and decreased to 25% to 50% (incidence, 0.1–0.3/1000 inhabitants) in a period of 15 to 20 years. The reason for this worldwide decline in VF is not clear. Possible explanations include a changing morbidity pattern from ischemic heart disease with more chronic heart failure, increased use of β-adrenergic receptor blocking drugs, and later arrival on scene by emergency medical services. We investigated the community impact of implantable cardioverter-defibrillators (ICDs) for primary and secondary prevention by comparing OHCA in the periods 1995 to 1997 when ICD therapy hardly existed to 2005 to 2008 in the Dutch province of North Holland. We took into consideration that if no ICD had been placed, resuscitation for OHCA would have occurred only in part of the patients who received an appropriate ICD shock. The incidence (per 100 000 inhabitants per year) of VF OHCA decreased from 21.1 to 17.4, and non-VF OHCA increased from 12.2 to 19.4, corresponding with a decline of VF OHCA from 63% to 47%. ICD shocks avoided 1.2 VF OHCA per 100 000 inhabitants per year. Thus, successful ICD shocks explained 33% of the decline in VF OHCA. In a sensitivity analysis, the explained decline ranged from 16% to 63%. Part of the decreased proportion of VF OHCA of all OHCA was explained by an even larger (and unexplained) increase in non-VF OHCA. Nevertheless, other factors must play at least an equal role in the explanation for the observed decline in VF OHCA.Conclusions: The incidence of VF OHCA decreased over the last 10 years in North Holland. ICD therapy explained a decrease of 1.2/100 000 inhabitants per year, corresponding with 33% of the observed decline in VF OHCA.11A Comprehensive Evaluation of Rhythm Monitoring Strategies for the Detection of Atrial Fibrillation Recurrence: Insights From 647 Continuously Monitored Patients and Implications for Monitoring After Therapeutic InterventionsSummary: Patient follow-up with either short- or long-duration intermittent rhythm monitoring is significantly inferior to that with continuous rhythm monitoring for the detection of atrial fibrillation (AF) recurrence. Intermittent rhythm monitoring strategies fail to identify AF recurrence in a great proportion of patients at risk. Even with feasible, aggressive intermittent monitoring strategies (such as quarterly 24-hour Holter monitoring), AF recurrence will not be identified in a significant proportion of patients. Because of the low sensitivity of intermittent rhythm monitoring, the results of pharmacological or invasive interventions for AF when evaluated with intermittent monitoring should be considered with caution because chance has an immeasurable effect on the detection of AF recurrence, and thus a great proportion of patients will be misclassified, AF recurrence will be underdiagnosed, and therapeutic success will be overestimated. Novel quantitative and temporal AF characteristics (AF burden, AF density) play a major role in AF recurrence detection with the use of intermittent monitoring strategies and may influence clinical parameters and outcomes in AF patients. For accurate patient management, as well as for the scientific, evidence-based evaluation of AF treatments, continuous rhythm monitoring should be strongly recommended.Conclusions: Intermittent rhythm monitoring (IRM) follow-up is significantly inferior to continuous rhythm monitoring (CM). IRM strategies will not identify AF recurrence in a great proportion of patients at risk. Temporal AF characteristics play a significant role in AF recurrence detection with the use of IRM. For the scientific, evidence-based evaluation of AF treatments, CM should be strongly recommended. Prospective studies are required to evaluate whether CM to guide clinical management can also improve patient outcomes.12Ca2+-Stimulated Adenylyl Cyclase AC1 Generates Efficient Biological Pacing as Single Gene Therapy and in Combination With HCN2Summary: In the United States, ≈300 000 pacemakers are implanted annually, 5% of which result in serious complications requiring surgical revision or other invasive procedures. In addition, electronic pacemakers have limitations such as an inadequate autonomic response, limited battery life, and restrictions with regard to stable lead positioning. These issues may be dealt with in part by the development of biological pacemakers. Within the framework of biological pacing, the AC1-based approach shows potential because it generates highly stable pacemaker function at beating rates of ≈60 bpm and incorporates sensitivity to sympathetic and parasympathetic input. Two important hurdles on the road to clinical application include the demonstration of stable long-term function and the demonstration of safety with regard to both potential proarrhythmia and toxicity. The continued development of electronic pacemakers may obviate the need for biological alternatives, but regardless of whether biological pacemakers find clinical application, their development will continue to increase our understanding of pacemaker function and of cardiac gene therapy.Conclusions: AC1 or HCN2/AC1 overexpression in left bundle branches provides highly efficient biological pacing and greater sensitivity to autonomic modulation than HCN2 alone.13Paradoxical Effect of Increased Diastolic Ca2+ Release and Decreased Sinoatrial Node Activity in a Mouse Model of Catecholaminergic Polymorphic Ventricular TachycardiaSummary: Catecholaminergic polymorphic ventricular tachycardia is a congenital arrhythmogenic disease linked to β-adrenergic–induced ventricular arrhythmias that has a high mortality in children and young adults when untreated. As common features of the catecholaminergic polymorphic ventricular tachycardia phenotype, supraventricular arrhythmias have also been described in catecholaminergic polymorphic ventricular tachycardia patients. The reason why ventricular myocytes exhibit stress-induced hyperactivity (ventricular ectopies and tachycardia) whereas sinoatrial node is often hypoactive (sinus bradycardia) remains elusive. Here, we explored for the first time [Ca2+]i activity of sinoatrial node cells in intact tissues obtained from a mouse bearing the RyR2R4496C catecholaminergic polymorphic ventricular tachycardia mutation. Our results indicate that RyR2R4496C mice manifest a high incidence of sinoatrial node dysrhythmia (pauses) and an impaired positive chronotropic response to β-adrenergic stimulation. In RyR2R4496C sinoatrial node, there is an aberrant Ca2+ homeostasis characterized by an increase in the diastolic Ca2+ release at any time during the diastolic period. This almost continuous and low-grade Ca2+ leakage unloads the sarcoplasmic reticulum, which in turn hampers action potential triggering and decreases the sinus rate. We provide here a mechanistic rationale for sinoatrial node dysfunction in catecholaminergic polymorphic ventricular tachycardia patients. Future work should focus on testing pharmacological approaches to treat dysfunction of heart automaticity using this novel ex vivo physiological preparation.Conclusions: The increased activity of RyR2R4496C in SAN leads to an unanticipated decrease in SAN automaticity by a Ca2+-dependent decrease of ICa,L and sarcoplasmic reticulum Ca2+ depletion during diastole, identifying subcellular pathophysiological alterations contributing to the SAN dysfunction in catecholaminergic polymorphic ventricular tachycardia patients.14Cardiomyocytes Derived From Pluripotent Stem Cells Recapitulate Electrophysiological Characteristics of an Overlap Syndrome of Cardiac Sodium Channel DiseaseSummary: Clinical cardiology could benefit from greater insights into the pathology of cardiomyocytes in inherited cardiac disease. However, the availability of diseased cardiomyocytes is limited by the scarcity of biopsies from patients and the amount of tissue they yield. The advent of induced pluripotent stem cells, through which somatic cells can be genetically reprogrammed into stem cells able to differentiate to cardiomyocytes, now presents opportunities for solving this. However, a remaining issue is the extent to which the phenotype in these cells actually resembles that of cardiomyocytes in the heart itself. Here, we used reprogramming to investigate a cardiac overlap syndrome caused by a mutation in SCN5A, the sodium channel gene. Patients with this mutation (1795insD) can display symptoms of both long-QT syndrome type 3 and Brugada syndrome. We first derived induced pluripotent stem cells from mice with the corresponding SCN5A mutation. The derivative cardiomyocytes had electrophysiological properties similar to primary cardiomyocytes from the same heterozygous mutant mouse and from the embryonic stem cells used to generate it. The mutation resulted in a reduced Na+ current density (Brugada syndrome) and prolonged action potential (long-QT syndrome type 3), demonstrating that stem cell