Journal: Heart Rhythm

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Abstract

Cardiac output and vasodilatation in the vasovagal response: an analysis of the classical papers.

Wieling W, Jardine DL, de Lange FJ, Brignole M, ... Stewart J, Sutton R
The simple faint is secondary to hypotension and bradycardia resulting in transient loss of consciousness. According to Ohm\'s Law applied to the circulation: BP = SVR*CO, hypotension can result from a decrease in SVR (Systemic vascular resistance) or CO (Cardiac output) or both. It is important to understand that when blood pressure (BP) is falling, SVR and CO do not change reciprocally as they do in the steady state. In 1932, Lewis, assuming that decreased SVR alone accounted for hypotension defined "the vasovagal response" along pathophysiological lines to denote the association of vasodilatation with vagal induced bradycardia in simple faint. Studies performed by Barcroft and Sharpey Schafer between 1940 and 1950 used volume-based plethysmography to demonstrate major forearm vasodilatation during extreme hypotension and concluded that the main mechanism for hypotension was vasodilatation. Plethysmographic measurements were intermittent and not frequent enough to capture rapid changes in blood flow during progressive hypotension. However, later investigations by Weissler, Murray and Stevens performed between 1950 and 1970, used invasive beat-to-beat BP measurements and more frequent measurements of CO using the Fick principle. They demonstrated that CO significantly fell before syncope and little vasodilatation occurred until very late in the vasovagal reaction Thus, since the 1970s\', decreasing cardiac output rather than vasodilation has been regarded as the principal mechanism for the hypotension of vasovagal syncope.

Heart Rhythm: 23 Nov 2015; epub ahead of print
Wieling W, Jardine DL, de Lange FJ, Brignole M, ... Stewart J, Sutton R
Heart Rhythm: 23 Nov 2015; epub ahead of print | PMID: 26598322
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Genetic Testing and Genetic Counseling in Patients With Sudden Death Risk Due to Heritable Arrhythmias.

Spoonamore KG, Ware SM
Sudden cardiac death resulting from heritable ventricular arrhythmias is an important cause of mortality, especially in young, healthy individuals. The identification of the genetic basis of Mendelian diseases associated with arrhythmia has allowed the integration of this information into the diagnosis and clinical management of patients and at-risk family members. The rapid expansion of genetic testing options and the increasing complexity involved in the interpretation of results creates unique opportunities and challenges. There is a need for competency to incorporate genetics into clinical management and to provide appropriate family-based risk assessment and information. In addition, disease specific genetic knowledge is required to order and correctly interpret and apply genetic testing results. Importantly, genetic diagnosis has a critical role in the risk-stratification and clinical management of family members. This review summarizes the approach to genetic counseling and genetic testing for inherited arrhythmias and highlights specific genetic principles that apply to long QT syndrome, short QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia.

Heart Rhythm: 18 Nov 2015; epub ahead of print
Spoonamore KG, Ware SM
Heart Rhythm: 18 Nov 2015; epub ahead of print | PMID: 26582592
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Abstract

Cellular Damage, Platelet Activation and Inflammatory Response after Pulmonary Vein Isolation: A Randomized Study Comparing Radiofrequency- with Cryoablation.

Siklódy CH, Arentz T, Minners J, Jesel L, ... Morel O, Trenk D
Background: Experimental data suggest that the use of cryoablation in pulmonary vein isolation (PVI) is associated with less cell damage and less thrombus formation compared to radiofrequency (RF) energy. ObjectiveS: We hypothesized that cryoablation significantly reduces markers of cell damage, platelet activation, and inflammation in patients undergoing pulmonary vein isolation for the treatment of atrial fibrillation (AF). Methods: Sixty patients with symptomatic drug-resistant AF (56±9 years of age, 48 males, 38 with paroxysmal) were randomly assigned to undergo PVI using either an open irrigated tip radiofrequency catheter or a cryoballoon. Markers of cell damage (high sensitive troponin T (hs-TnT), microparticles), platelet activation (platelet reactivity by aggregometry, expression of platelet surface proteins P-selectin and activated GP IIb/IIIa) and inflammatory response (high sensitive C-reactive protein [hs-CRP]) were determined before and up to 48 hours after the procedure. Results: Pulmonary vein isolation resulted in a significant rise in hs-TnT, microparticles, markers of platelet activation and hs-CRP over time with distinct temporal patterns for each parameter. However, after Bonferroni-correction for repeated measurements, there were no significant differences in these parameters between patients treated with cryoablation or radiofrequency energy. Procedure time was significantly shorter in patients treated with the cryoballoon (177±30 vs. 200±46min, P=0.03) with no differences in fluoroscopic time, periprocedural complications or success rate. Conclusions: Cryoablation and radiofrequency energy result in a comparable rise of markers of cell damage, platelet activation and inflammatory response. The data do not support the concept of an improved safety profile for cryoablation in pulmonary vein isolation.

Heart Rhythm: 16 Sep 2011; epub ahead of print
Siklódy CH, Arentz T, Minners J, Jesel L, ... Morel O, Trenk D
Heart Rhythm: 16 Sep 2011; epub ahead of print | PMID: 21920484
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Abstract

Factors Affecting the Degree of QT Prolongation with Drug Challenge in a Large Cohort of Normal Volunteers.

Kannankeril PJ, Norris KJ, Carter S, Roden DM
Background:: The degree of QT prolongation by drug is highly variable and related to risk for polymorphic ventricular tachycardia due to drugs. Objective:: to determine factors that affect the degree of QT prolongation by drugs. Methods:: QT and QTc were measured before and after administration of the QT-prolonging drug ibutilide in 253 normal volunteers aged 18-40 years. Drug effect on QTc prolongation was defined as ΔQTc = QTc after drug minus QTc before drug. Results:: Ibutilide prolonged QT from 396 ± 31 ms to 418 ± 39 ms (P<0.001) and QTc from 406 ± 15 ms to 446 ± 33 ms (P<0.001). The ΔQTc did not correlate with baseline QTc (Pearson correlation 0.016, P = 0.8). Post-drug QTc was correlated weakly with pre-drug QTc (Pearson correlation 0.484, p< 0.001), and strongly with ΔQTc (Pearson correlation 0.882, P < 0.001). ΔQTc was identical for men and women (39 ± 29 ms vs. 39 ± 27 ms, P = 0.9), but displayed significant differences among body mass index categories (P<0.001). Overweight (48 ± 27 ms) and obese (61 ± 31 ms) subjects had significantly more QT prolongation by drug than normal (31 ± 25 ms) or underweight (24 ± 12 ms) subjects. Conclusions:: QT prolongation by ibutilide does not correlate to baseline QTc, and does not differ between men and women. Overweight and obese subjects have greater drug effect on QTc than subjects with normal or low body mass index. These findings have implications for drug-induced long QT syndrome.

Heart Rhythm: 22 Mar 2011; epub ahead of print
Kannankeril PJ, Norris KJ, Carter S, Roden DM
Heart Rhythm: 22 Mar 2011; epub ahead of print | PMID: 21420510
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Abstract

Relationship Between Burden of Premature Ventricular Complexes and Left Ventricular Function.

Baman TS, Lange DC, Ilg KJ, Gupta SK, ... Morady F, Bogun F
Background:: Frequent idiopathic premature ventricular complexes (PVCs) can result in a reversible form of left ventricular dysfunction. The factors resulting in impaired left ventricular function are unclear. Whether a critical burden of PVCs can result in cardiomyopathy has not been determined. Objective:: The objective of this study was to determine a cut-off PVC burden that can result in PVC-induced cardiomyopathy. Methods:: In a consecutive group of 174 patients referred for ablation of frequent, idiopathic PVCs, the PVC burden was determined by 24 hour Holter monitoring, and transthoracic echocardiograms were used to assess left ventricular function. Receiver operator characteristics curves were constructed based on the PVC burden and on the presence or absence of reversible left ventricular dysfunction in order to determine a cut-off PVC burden that is associated with left ventricular dysfunction. Results:: A reduced left ventricular ejection fraction (mean 0.37+/-0.10) was present in 57/174 patients (33%). Patients with a decreased ejection fraction had a mean PVC burden of 33+/-13% as compared to those with normal left ventricular function 13+/-12% (p<0.0001). A PVC burden of >24% best separated the patient population with impaired as compared to preserved left ventricular function (sensitivity 79%, specificity 78%, area under curve: 0.89) The lowest PVC burden resulting in a reversible cardiomyopathy was 10%. In multivariate analysis PVC burden (HR 1.12 CI 1.08-1.16; p<0.01) was independently associated with PVC-induced cardiomyopathy. Conclusion:: A PVC burden of >24% was independently associated with PVC-induced cardiomyopathy.

Heart Rhythm: 29 Mar 2010; epub ahead of print
Baman TS, Lange DC, Ilg KJ, Gupta SK, ... Morady F, Bogun F
Heart Rhythm: 29 Mar 2010; epub ahead of print | PMID: 20348027
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Abstract

Pediatric & Congenital Electrophysiology Society: building an international paediatric electrophysiology organisation.

Cohen M, Sanatani S, Stephenson E, Skinner J, ... Collins KK, Triedman J
The Pediatric and Congenital Electrophysiology Society (PACES) is a non-profit organisation comprised of individuals dedicated to improving the care of children and young adults with cardiac rhythm disturbances. Although PACES is a predominantly North American-centric organisation, international members have been a part of PACES for the last two decades. This year, PACES expanded its North American framework into a broadly expansive international role. On May 12, 2015, paediatric electrophysiology leaders from within the United States of America and Canada met with over 30 international paediatric electrophysiologists from 17 countries and five continents discussing measures to (1) expand PACES\' global vision, (2) address ongoing challenges such as limited resource allocation that may be present in developing countries, (3) expand PACES\' governance to include international representation, (4) promote joint international sessions at future paediatric EP meetings, and (5) facilitate a global multi-centre research consortium. This meeting marked the inception of a formal international collaborative spirit in PACES. This editorial addresses some solutions to breakdown the continental silos paediatric electrophysiologists have practiced within; however, there remain ongoing limitations, and future discussions will be needed to continue to move the PACES global international vision forward.

Heart Rhythm: 18 Apr 2016; epub ahead of print
Cohen M, Sanatani S, Stephenson E, Skinner J, ... Collins KK, Triedman J
Heart Rhythm: 18 Apr 2016; epub ahead of print | PMID: 27090729
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Abstract

Trends in early and late morality in patients undergoing coronary catheterization for myocardial infarction: Implications on observation periods and risk factors to determine ICD candidacy.

Bunch TJ, May HT, Bair TL, Crandall BG, ... Lappe DL, Day JD
Background: Survivors of acute myocardial infarction (MI) are at high risk for death from both sudden cardiac death and progressive heart failure. Objective: We sought to determine mortality trends, identify markers of risk, and determine if outcomes in high risk patients are altered by revascularization during the ICD candidacy observation period. Methods: We included 16,793 patients that presented to the catheterization laboratory for acute management of a MI. All patients had 3 years of follow-up to define short- and long-term mortality. Results: Across the demographics studied there were no significant differences in baseline characteristics over time with exception of an observed decline in patients with an ejection fraction (EF) ≤0.35. Nonetheless, at study closure 16.3% of all cases had an EF≤0.35. There was a gradual increase in use of percutaneous intervention (PCI) and coronary artery bypass (CABG), however, at the end of the study, the highest level of revascularization use was slightly >50%. For the composite, right and left bundle branch block, or QRS >120 the death rates at 1- and 5-years were 31.8% and 46.8%, respectively. These 1- and 5-year mortality rates were increased with an EF≤0.35 (36.0%, 60.2%). Morality in those with EF≤0.35 exceeded 20% in all groups with conduction system disease at 90 days and was not significantly impacted by PCI. Conclusion: The highest risk for death after MI is in patients with an EF≤0.35 and/or conduction system disease. The mortality risk is most pronounced in the early observation period following MI when patients must wait to be considered for an ICD.

Heart Rhythm: 04 Apr 2011; epub ahead of print
Bunch TJ, May HT, Bair TL, Crandall BG, ... Lappe DL, Day JD
Heart Rhythm: 04 Apr 2011; epub ahead of print | PMID: 21457792
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Abstract

Induction of atrial ectopic beats with calcium release inhibition: Local hierarchy of automaticity in the right atrium.

Shinohara T, Joung B, Kim D, Maruyama M, ... Chen PS, Lin SF
Background: Recent evidence indicates that spontaneous sarcoplasmic reticulum (SR) calcium (Ca) release underlies the mechanism of sinoatrial node (SAN) acceleration during beta-stimulation, indicating the importance of the Ca clock in SAN automaticity. Whether or not the same mechanism applies to atrial ectopic pacemakers (AEPs) remains unclear. Objective: The purpose of this study was to assess the mechanism of AEP. Methods: We simultaneously mapped intracellular calcium (Ca(i)) and membrane potential in 12 isolated canine right atria. The late diastolic Ca(i) elevation (LDCAE) was used to detect the Ca clock activity. Pharmacological interventions with isoproterenol (ISO), ryanodine, and ZD7288, a blocker of the I(f) membrane current, were performed. Results: Ryanodine, which inhibits SR Ca release, reduced LDCAE in SAN, resulting in an inferior shift of the pacemaking site. Cycle length increased significantly in a dose-dependent way. In the presence of 3 to 10 mumol/l of ryanodine, ISO infusion consistently induces AEPs from the lower crista terminalis. All ectopic beats continuing over 30 seconds were located at the lower crista terminalis. These AEPs were resistant to ryanodine treatment even at high doses. Subsequent blockade of I(f) inhibited the AEP and resulted in profound bradycardia. Conclusion: Spontaneous SR Ca release underlies ISO-induced increase of superior SAN activity. As compared with SAN, the AEP is less dependent on the Ca clock and more dependent on the membrane clock for its automaticity. AEPs outside the SAN can effectively serve as backup pacemakers when the Ca clock functionality is reduced.

Heart Rhythm: 04 Feb 2010; 7:110-116
Shinohara T, Joung B, Kim D, Maruyama M, ... Chen PS, Lin SF
Heart Rhythm: 04 Feb 2010; 7:110-116 | PMID: 20129292
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Abstract

Single-Sensor System for Spatially-Resolved, Continuous and Multi-Parametric Optical Mapping of Cardiac Tissue.

Lee P, Bollensdorff C, Quinn TA, Wuskell JP, Loew LM, Kohl P
Background:: Simultaneous optical mapping of multiple electrophysiologically-relevant parameters in living myocardium is desirable for integrative exploration of mechanisms underlying heart rhythm generation under normal and pathophysiological conditions. Current multi-parametric methods are technically challenging, usually involving multiple sensors and moving parts, which contributes to high logistic and economic thresholds that prevent easy application of the technique. Objective:: To develop a simple, affordable, and effective method for spatially-resolved, continuous, simultaneous, and multi-parametric optical mapping of the heart, using a single camera. Methods:: We present a new method to simultaneously monitor multiple parameters, using inexpensive off-the-shelf electronic components and no moving parts. The system comprises a single camera, commercially available optical filters and light emitting diodes (LEDs), integrated via microcontroller-based electronics for frame-accurate illumination of the tissue. For proof-of-principle, we illustrate measurement of four parameters, suitable for ratiometric mapping of membrane potential (di-4-ANBDQPQ) and intracellular free calcium (fura-2), in an isolated Langendorff-perfused rat heart during sinus rhythm and ectopy, induced by local electrical or mechanical stimulation. Results:: The pilot-application demonstrates suitability of this imaging approach for heart rhythm research in the isolated heart. In addition, locally induced excitation, whether stimulated electrically or mechanically, gives rise to similar ventricular propagation patterns. Conclusions:: Combining an affordable camera with suitable optical filters and micro-processor controlled LEDs, single-sensor multi-parametric optical mapping can be practically implemented in a simple yet powerful configuration and applied to heart rhythm research. The moderate system complexity and component cost is destined to lower the threshold to broader application of functional imaging, and to ease implementation of more complex optical mapping approaches, such as multi-parametric panoramic imaging. A proof-of-principle application confirmed that although electrically and mechanically induced excitation occur by different mechanisms, their electrophysiological consequences downstream from the point of activation are not dissimilar.

Heart Rhythm: 04 Apr 2011; epub ahead of print
Lee P, Bollensdorff C, Quinn TA, Wuskell JP, Loew LM, Kohl P
Heart Rhythm: 04 Apr 2011; epub ahead of print | PMID: 21459161
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Abstract

Vagal Activity Modulates Spontaneous Augmentation of J Wave Elevation in Patients With Idiopathic Ventricular Fibrillation.

Mizumaki K, Nishida K, Iwamoto J, Nakatani Y, ... Kataoka N, Inoue H
Background: Although J wave elevation in the inferolateral leads could be related to idiopathic ventricular fibrillation (IVF), little is known about the pathophysiologic characteristics of J wave elevation in patients with IVF. Objective: This study aimed to determine the relationship between augmentation of J wave elevation and changes in RR interval or autonomic nervous activities in IVF patients. Methods: Eight IVF patients and 22 controls with J wave elevation (≥0.1 mV) in lead V5 were studied. J wave amplitude was automatically measured in lead CM5 of a digital Holter ECG and the J-RR relationship was determined. Based on analysis of heart rate variability, the relationship between J wave amplitude and ln HF or LF/HF (J-ln HF or J-LF/HF relationship) was also determined. Results: J-RR slope (mm/s) was greater in IVF patients than in controls (3.5±0.7 vs. 2.4±0.8, p<0.01), as was J amplitude (mm) at an RR interval of 1.2 sec (2.8±0.9 vs. 2.0±0.6, p<0.05). J amplitude was correlated positively with ln HF and negatively with LF/HF, and the slopes of both J-ln HF and J-LF/HF regression lines were greater in IVF patients than in controls. During an entire 24-hr period, there was no difference between the two groups in either HF or LF/HF. Nine (82%) of the total 11 episodes of spontaneous VF occurred during 18:00-6:00. Conclusions: In IVF patients as compared with control subjects, J wave elevation was more strongly augmented during bradycardia and was associated with an increase in vagal activity. This could be related to the occurrence of VF predominantly at night in IVF patients.

Heart Rhythm: 23 Sep 2011; epub ahead of print
Mizumaki K, Nishida K, Iwamoto J, Nakatani Y, ... Kataoka N, Inoue H
Heart Rhythm: 23 Sep 2011; epub ahead of print | PMID: 21939630
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Abstract

Cardiac Rhythm Devices in the Pediatric Population: Utilization and Complications.

Czosek RJ, Meganathan K, Anderson JB, Knilans TK, Marino BS, Heaton PC
Background: Cardiac rhythm devices are important in the management of pediatric patients with rhythm abnormalities though factors driving utilization are poorly understood. ObjectiveS: Evaluate utilization trends, complication rates and cost associated with device implantation in the pediatric population. Methods: Device implantation was analyzed using the Kids\' Inpatient Database from 1997-2006. Type of device implantation, patient demographics, hospital characteristics, acute in-hospital complications, cost and length of stay (LOS) were analyzed. Chi-square tests were used to test association between categorical variables and logistic regression analysis was performed to evaluate risk factors associated with complications. Results: There were 5,788 hospitalizations with device implantations. While there was a significant increase in defibrillator implantation, there was no significant increase in the number of pacemaker implantations over this time period. Patient and device-related complications were relatively common in all device cohorts (pacemaker 11.2%, 7.2%; defibrillator 5.9%, 11.5%; and biventricular device 19.4%, 26.7%). Type of complication was dependent on device type. Increased risk of complication was evident in the pacemaker cohort, patients with congenital heart disease, cardiomyopathy, previous cardiac arrest and other heart operations. Patient-related complications increased cost and LOS regardless of patient or procedural characteristics. Device implantation in patients < 5 years old was associated with increased LOS and cost but was not associated with increased risk of complication. Conclusions: Device utilization in pediatrics is increasing due to escalating defibrillator implantation and biventricular pacing. Cost and LOS are significantly increased by patient complications. Reduction in these complications would improve patient care and lower medical costs.

Heart Rhythm: 12 Sep 2011; epub ahead of print
Czosek RJ, Meganathan K, Anderson JB, Knilans TK, Marino BS, Heaton PC
Heart Rhythm: 12 Sep 2011; epub ahead of print | PMID: 21907171
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Abstract

Regional Cooling Facilitates Termination of Spiral-Wave Reentry through Unpinning of Rotors in Rabbit Hearts.

Yamazaki M, Honjo H, Ashihara T, Harada M, ... Kamiya K, Kodama I
Background: Moderate global cooling of myocardial tissue was shown to destabilize 2-dimensional (2-D) reentry and facilitate its termination. Objective: To test the hypothesis that regional cooling destabilizes rotors and facilitates termination of spontaneous and DC-shock-induced subepicardial reentry in isolated, endocardially ablated rabbit hearts. Methods: Fluorescent action potential signals were recorded from 2-D subepicardial ventricular myocardium of Langendorff-perfused rabbit hearts. Regional cooling (by 5.9±1.3°C) was applied to the left ventricular anterior wall using a transparent cooling device (10 mm in diameter). Results: Regional cooling during constant stimulation (2.5 Hz) prolonged the action potential duration (by 36±9%) and slightly reduced conduction velocity (by 4±4%) in the cooled region. Ventricular tachycardias (VTs) induced during regional cooling terminated earlier than those without cooling (control): VTs lasting >30 s were reduced from 17/39 to 1/61. When regional cooling was applied during sustained-VTs (>120 s), 16/33 (48%) sustained-VTs self-terminated in 12.5±5.1 s. VT termination was the result of rotor destabilization, which was characterized by unpinning, drift toward the periphery of the cooled region and subsequent collision with boundaries. The DC-shock intensity required for cardioversion of the sustained-VTs decreased significantly by regional cooling (22.8±4.1 V, n=16 vs. 40.5±17.6 V, n=21). The major mode of reentry termination by DC-shocks was phase resetting in the absence of cooling, whereas unpinning in the presence of cooling. Conclusion: Regional cooling facilitates termination of 2-D reentry through unpinning of rotors.

Heart Rhythm: 15 Aug 2011; epub ahead of print
Yamazaki M, Honjo H, Ashihara T, Harada M, ... Kamiya K, Kodama I
Heart Rhythm: 15 Aug 2011; epub ahead of print | PMID: 21839044
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Abstract

Catheter Ablation of Atrial Fibrillation in Patients with Persistent Left Superior Vena Cava is Associated With Major Intraprocedural Complications.

Wissner E, Tilz R, Konstantinidou M, Metzner A, ... Kuck KH, Ouyang F
Background:: A persistent left superior vena cava (PLSVC) is an uncommon cardiac anomaly. Objective:: This study sought to assess complication rate and procedural outcome in patients with PLSVC referred for catheter ablation of atrial fibrillation (AF). Methods:: Between September 2006 and February 2009, 7 patients referred for circumferential pulmonary vein (PV) isolation (PVI) demonstrated a PLSVC. PVI was confirmed by spiral catheter recording within the respective PVs. Ablation within the PLSVC was performed using an irrigated tip catheter (energy settings: 20 Watts, 43 degrees C, flow rate 17 ml/min) or, alternatively, a cryoballoon catheter (28 mm balloon, 300 sec energy application). Patients were analyzed according to procedural outcome and rate of complications. Results:: Among 7 patients (3 female; mean age 57+/-8 yrs; 2 paroxysmal, 5 persistent AF; structural/congenital heart disease present in 3 patients; mean left atrial [LA] size 43+/-6 mm), 14 ablation procedures were performed. Two major complications (left phrenic nerve injury and cardiac tamponade) occurred in 2/4 patients undergoing PLSVC ablation. Of 4/7 patients undergoing PLSVC ablation, 2 patients necessitated one and 1 patient two redo PLSVC ablation procedures. First-time procedural success rate was 29%; while overall success rate reached 86% after a median follow up period of 621 (339-1289) days. Conclusion:: In patients with ectopic activity from a PLSVC, the ablative strategy should include isolation of the PLSVC as procedural endpoint, although multiple ablation procedures may be necessary to achieve stable SR. Contrary to previous reports complications are common if the PLSVC is targeted for ablation.

Heart Rhythm: 16 Aug 2010; epub ahead of print
Wissner E, Tilz R, Konstantinidou M, Metzner A, ... Kuck KH, Ouyang F
Heart Rhythm: 16 Aug 2010; epub ahead of print | PMID: 20708711
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Abstract

Nonsense-Mediated mRNA Decay Caused by a Frameshift Mutation in a Large Kindred of Type 2 Long QT Syndrome.

Zarraga IG, Zhang L, Stump MR, Gong Q, Vincent GM, Zhou Z
Background: Nonsense and frameshift mutations are common in congenital long QT syndrome type 2 (LQT2). We previously demonstrated that hERG nonsense mutations cause degradation of mutant mRNA by nonsense-mediated mRNA decay (NMD) and are associated with mild clinical phenotypes. The impact of NMD on the expression of hERG frameshift mutations and their phenotypic severity is not clear. Objective: To examine the role of NMD in the pathogenesis of a hERG frameshift mutation, P926AfsX14, identified in a large LQT2 kindred and characterize genotype-phenotype correlations. Methods: Genetic screening was performed among family members. Phenotyping was performed by assessment of ECGs and LQTS-related cardiac events. The functional effect of P926AfsX14 was studied using hERG cDNA and minigene constructs expressed in HEK293 cells. Results: Significant cardiac events occurred in carriers of the P926AfsX14 mutation. When expressed from cDNA, the P926AfsX14 mutant channel was only mildly defective. However, when expressed from a minigene, the P926AfsX14 mutation caused a significant reduction in mutant mRNA, protein, and hERG current. Inhibition of NMD by RNA interference knockdown of up-frameshift protein 1 partially restored expression of mutant mRNA and protein, and led to a significant increase in hERG current in the mutant cells. These results suggest that NMD is involved in the pathogenic mechanism of the P926AfsX14 mutation. Conclusion: Our findings suggest that the hERG frameshift mutation P926AfsX14 primarily results in degradation of mutant mRNA by the NMD pathway rather than production of truncated proteins. When combined with environmental triggers and genetic modifiers, LQT2 frameshift mutations associated with NMD can manifest with a severe clinical phenotype.

Heart Rhythm: 22 Mar 2011; epub ahead of print
Zarraga IG, Zhang L, Stump MR, Gong Q, Vincent GM, Zhou Z
Heart Rhythm: 22 Mar 2011; epub ahead of print | PMID: 21419236
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Genotype-Specific QT Correction for Heart Rate and the Risk of Life Threatening Cardiac Events in Adolescents with the Congenital Long-QT Syndrome.

Barsheshet A, Peterson DR, Moss AJ, Schwartz PJ, ... Zhang L, Goldenberg I
Background:: A prolonged QT interval corrected for heart rate (QTc) is a major risk factor in patients with the long-QT syndrome (LQTS). However, heart rate-related risk in this genetic disorder differs among genotypes. Objective:: We hypothesized that risk-assessment in LQTS patients should incorporate genotype-specific QT correction for heart rate. Methods:: The independent contribution of four repolarization measures (the absolute QT interval, Bazett\'s, Fridericia\'s, and Framingham\'s correction formulae) to the risk of aborted cardiac arrest or sudden cardiac death during adolescence, before and after further adjustment for the RR interval, was assessed in 727 LQT1 and 582 LQT2 patients. Improved QT/RR correction was calculated using a Cox model, dividing the coefficient on log(RR) by that on log(QT). Results:: Multivariate analysis demonstrated that in LQT1 patients 100 msec increments in the absolute QT interval were associated with a 3.3-fold increase in the risk of life-threatening cardiac events (p=0.020), and 100 msec decrements in the RR interval were associated with a further 1.9-fold increase in the risk (p=0.007), whereas in LQT2 patients, resting heart rate was not a significant risk factor (HR=1.11; p=0.51; p-value for heart rate x genotype interaction = 0.036). Accordingly, analysis of an improved QT correction formula showed that patients with the LQT1 genotype required a greater degree of QT correction for heart rate (improved QTc=QT/RR(0.8)) than LQT2 patients (improved QTc=QT/RR(0.2)). Conclusions:: Our findings suggest that risk stratification for life-threatening cardiac events in LQTS patients can be improved by incorporating genotype-specific QT correction for heart rate.

Heart Rhythm: 14 Mar 2011; epub ahead of print
Barsheshet A, Peterson DR, Moss AJ, Schwartz PJ, ... Zhang L, Goldenberg I
Heart Rhythm: 14 Mar 2011; epub ahead of print | PMID: 21397043
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Abstract

Protein Kinase C downregulates IKs by stimulating KCNQ1-KCNE1 potassium channel endocytosis.

Kanda VA, Purtell K, Abbott GW
Background: The slow-activating cardiac repolarization K+ current (IKs), generated by the KCNQ1-KCNE1 potassium channel complex, is controlled via sympathetic and parasympathetic regulation in vivo. Inherited KCNQ1 and KCNE1 mutations predispose to ventricular fibrillation and sudden death, often triggered by exercise or emotional stress. Protein kinase C (PKC), which is activated by α1 adrenergic receptor stimulation, is known to downregulate IKs via phosphorylation of KCNE1 serine 102, but the underlying mechanism has remained enigmatic. We previously showed that KCNE1 mediates dynamin-dependent endocytosis of KCNQ1-KCNE1 complexes. Objective: Determine the potential role of endocytosis in IKs downregulation by PKC. Methods and results: We utilized patch-clamping and fluorescence microscopy to study Chinese Hamster Ovary (CHO) cells co-expressing KCNQ1, KCNE1, and wild-type or dominant-negative mutant (K44A) dynamin 2, , and neonatal mouse ventricular myocytes. The PKC activator phorbol 12-myristate 13-acetate (PMA) decreased IKs density by >60% (p < 0.05) when co-expressed with wild-type dynamin 2 in CHO cells, but had no effect when co-expressed with K44A-dynamin 2. Thus, functional dynamin was required for down-regulation of IKs by PKC activation. PMA increased KCNQ1-KCNE1 endocytosis in CHO cells expressing wild-type dynamin 2, but had no effect on KCNQ1-KCNE1 endocytosis in CHO cells expressing K44A-dynamin 2, determined using Pearson\'s correlation coefficient to quantify endosomal co-localization of KCNQ1 and KCNE1 with internalized fluorescent transferrin. KCNE1-S102A abolished the effect of PMA on IKs currents and endocytosis. Importantly, PMA similarly stimulated endocytosis of endogenous KCNQ1 and KCNE1 in neonatal mouse myocytes. Conclusions: PKC activation downregulates IKs by stimulating KCNQ1-KCNE1 channel endocytosis.

Heart Rhythm: 24 Jun 2011; epub ahead of print
Kanda VA, Purtell K, Abbott GW
Heart Rhythm: 24 Jun 2011; epub ahead of print | PMID: 21699843
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Abstract

Atrioventricular Delay Programming and the Benefit of Cardiac Resynchronization Therapy in MADIT-CRT.

Brenyo A, Kutyifa V, Moss AJ, Mathias A, ... Zareba W, Goldenberg I
Background: The optimal atrioventricular pacing delay (AVD) in cardiac resynchronization therapy (CRT) remains to be determined. Objective: To determine if programming CRT devices to shorter AVD (S-AVD) will improve clinical response secondary to greater reductions in dyssynchrony. Methods: The study population comprised 1,235 patients with left bundle branch block (LBBB) enrolled in MADIT-CRT. We assessed the relationship between AVD and outcomes. Patients programmed to short ([S-AVD] < median value of120 msec; n = 337) vs. longer AVD ([L-AVD] ≥ 120 msec, n = 390) were assessed for the endpoints of HF or death, death alone, and echocardiographic response to the CRT at 1-year follow-up. Outcomes were also compared to the LBBB ICD-only group (n = 508). Results: Multivariate analysis showed that patients programmed to S-AVD experienced a significant 33% (HR 0.67, 95% CI: 0.44 - 0.85, p = 0.037) reduction in the risk of HF or death, and a 47% (HR 0.53, 95% CI: 0.29 - 0.94 p = 0.031) reduction in death alone, compared with those programmed to L-AVD. CRT patients programmed S-AVD and L-AVD experienced respective 63% (HR 0.37, 95% CI: 0.26 - 0.53, p < 0.001) and 46% reductions (HR 0.54, 95% CI: 0.31 - 0.96, p < 0.001) in the risk of HF or death compared to ICD-only patients. At one year of follow-up, S-AVD vs. L-AVD was associated with a greater reduction in LVESV (34.2% vs. 30.8%, p = 0.002) along with a significantly greater improvement in dyssynchrony (22.3% vs. 9.4%, p = 0.036). Conclusions: Our findings indicate that in MADIT-CRT programming the CRT AV delay <120 msec was associated with greater clinical and echocardiographic response to CRT.

Heart Rhythm: 27 May 2013; epub ahead of print
Brenyo A, Kutyifa V, Moss AJ, Mathias A, ... Zareba W, Goldenberg I
Heart Rhythm: 27 May 2013; epub ahead of print | PMID: 23712031
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Abstract

Noninvasive Imaging of Three-dimensional Cardiac Activation Sequence during Pacing and Ventricular Tachycardia.

Han C, Pogwizd SM, Killingsworth CR, He B
Background: Imaging cardiac excitation within ventricular myocardium is important in the treatment of cardiac arrhythmias and might help improve our understanding of arrhythmia mechanisms. Objective: This study aims to rigorously assess the imaging performance of a three-dimensional (3-D) cardiac electrical imaging (3-DCEI) technique with the aid of 3-D intra-cardiac mapping from up to 216 intramural sites during paced rhythm and norepinephrine (NE) induced ventricular tachycardia (VT) in the rabbit heart. Methods: Body surface potentials and intramural bipolar electrical recordings were simultaneously measured in a closed-chest condition in thirteen healthy rabbits. Single-site pacing and dual-site pacing were performed from ventricular walls and septum. VTs and premature ventricular complexes (PVCs) were induced by intravenous NE. Computer tomography images were obtained to construct geometry model. Results: The non-invasively imaged activation sequence correlated well with invasively measured counterparts, with a correlation coefficient of 0.72±0.04, and a relative error of 0.30±0.02 averaged over 520 paced beats as well as 73 NE-induced PVCs and VT beats. All PVCs and VT beats initiated in the subendocardium by a nonreentrant mechanism. The averaged distance from imaged site of initial activation to pacing site or site of arrhythmias determined from intra-cardiac mapping was ~5mm. For dual-site pacing, the double origins were identified when they were located at contralateral sides of ventricles or at the lateral wall and the apex. Conclusion: 3-DCEI can non-invasively delineate important features of focal or multi-focal ventricular excitation. It offers the potential to aid in localizing the origins and imaging activation sequence of ventricular arrhythmias, and to provide noninvasive assessment of the underlying arrhythmia mechanisms.

Heart Rhythm: 14 Mar 2011; epub ahead of print
Han C, Pogwizd SM, Killingsworth CR, He B
Heart Rhythm: 14 Mar 2011; epub ahead of print | PMID: 21397046
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Abstract

The funny current channel HCN4 delineates the developing cardiac conduction system in the chicken heart.

Vicente-Steijn R, Passier R, Wisse LJ, Schalij MJ, ... Groot AC, Jongbloed MR
Background:: Hyperpolarization-activated cyclic nucleotide-gated channel 4(HCN4) in the mouse is expressed in the developing cardiac conduction system (CCS). In the sinoatrial node (SAN), HCN4 is the predominant isoform responsible for the funny current. To date, no data are available on HCN4 expression during chicken CCS development. Objective:: To provide the full-length sequence of Hcn4and describe its expression pattern during development in relation to the CCS in the chicken embryo. Methods:: Hcn4RNA expression was studied by in situ hybridization in sequential chick developmental stages (HH11-HH35) and immunohistochemical stainings were conducted for the myocardial protein cTnI and the cardiac transcription factor Nkx2.5. Results:: We obtained the full-length sequence of Hcn4in chick. Hcn4expression was observed early in development in the primary heart tube. At later stages, expression became restricted to transitional zones flanked by working myocardium , comprising the sinus venosus myocardium where the SAN develops, the atrioventricular canal myocardium, the primary fold (a myocardial zone between the developing ventricles), and the developing outflow tract. Further in development, Hcn4expression was restricted to the SAN, the atrioventricular node, the common bundle, the bundle branches and the internodal and atrioventricular ring myocardium. Conclusion:: We have identified Hcn4 as a marker of the developing CCS in the chick. The primary heart tube expresses Hcn4, which is later restricted to the transitional zones and eventually the elements of the mature CCS. Furthermore, we hypothesize that expression patterns during development may delineate potential arrhythmogenic sites in the adult heart.

Heart Rhythm: 22 Mar 2011; epub ahead of print
Vicente-Steijn R, Passier R, Wisse LJ, Schalij MJ, ... Groot AC, Jongbloed MR
Heart Rhythm: 22 Mar 2011; epub ahead of print | PMID: 21421080
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Abstract

Characterization of Myocardial Scars: Electrophysiological-Imaging Correlates in a Porcine Infarct Model.

Nakahara S, Vaseghi M, Ramirez RJ, Fonseca CG, ... Boyle NG, Shivkumar K
Background: Definition of myocardial scars as identified by electroanatomic mapping is integral to catheter ablation of ventricular tachycardia (VT). Myocardial imaging can also identify scars prior to ablation. However, the relationship between imaging and voltage mapping is not well characterized. Objective: The purpose of this study was to verify the anatomic location and heterogeneity of scars as obtained by electroanatomic mapping with contrast-enhanced MRI (CeMRI) and histopathology, and to characterize the distribution of late potentials in a chronic porcine infarct model. Methods: In-vivo three-dimensional cardiac CeMRI was performed in five infarcted porcine hearts. High-density electroanatomic mapping was used to generate epicardial and endocardial voltage maps. Scar surface area and position on CeMRI were then correlated with voltage maps. Locations of late potentials were subsequently identified. These were classified according to their duration and fractionation. All hearts underwent histopathological examination post mapping. Results: The total dense scar surface area and location on CeMRI correlated to the total epicardial and endocardial surface scar on electroanatomic maps. Electroanatomic mapping (average of 1532 ± 480 points per infarcted porcine) showed fractionated late potentials were more common in dense scars (<0.50 mV) as compared to border zone regions (0.51-1.5 mV), and were more commonly observed on the epicardium. Conclusion: In vivo, CeMRI can identify areas of transmural and non-transmural dense scars. Fractionated late diastolic potentials are more common on the epicardium than the endocardium in dense scar. These findings have implications for catheter ablation of VT and for targeting the delivery of future therapies to scarred regions.

Heart Rhythm: 28 Feb 2011; epub ahead of print
Nakahara S, Vaseghi M, Ramirez RJ, Fonseca CG, ... Boyle NG, Shivkumar K
Heart Rhythm: 28 Feb 2011; epub ahead of print | PMID: 21354335
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Abstract

Double Or Compound Sarcomere Mutations In Hypertrophic Cardiomyopathy: A Potential Link To Sudden Death In The Absence Of Conventional Risk Factors.

Maron BJ, Maron MS, Semsarian C
Background: Risk stratification strategies employing sarcomere gene mutational analysis have proved imprecise in identifying high risk patients with hypertrophic cardiomyopathy (HCM). Additional genetic risk markers that reliably determine which patients are predisposed to sudden death are needed. Objective: Determine whether multiple disease-causing sarcomere mutations can be regarded as markers for sudden death in the absence of other conventional risk factors is unresolved. Methods: Databases of 3 HCM centers were accessed, and 18 probands with 2 disease-causing mutations in genes encoding proteins of the cardiac sarcomere were identified. Results: Severe disease progression or adverse cardiovascular events occurred in 7 of these 18 patients (39%), including 3 patients (ages 31, 37, 57 years) who experienced sudden cardiac arrest, but also were without evidence of conventional HCM risk factors; 2 survived with timely defibrillation and therapeutic hypothermia and one died. These 3 probands carried distinct and heterozygous disease-causing sarcomere mutations (including a man who inherited one mutation independently from each of his parents with HCM) -i.e., double MYBPC3and TNNI3 mutations and compound MYBPC3mutations, as the only predisposing clinical markers evident to potentially explain their unexpected cardiac event. Conclusions: These observations support the emerging hypothesis that double (or compound) mutations detected by genetic testing may confer a gene dosage effect in HCM, predisposing patients to adverse disease progression. In 3 families, multiple sarcomere mutations were associated with a risk of sudden death, even in the absence of conventional risk factors.

Heart Rhythm: 15 Aug 2011; epub ahead of print
Maron BJ, Maron MS, Semsarian C
Heart Rhythm: 15 Aug 2011; epub ahead of print | PMID: 21839045
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Abstract

Atrial Pacing or Ventricular Backup-Only Pacing in Implantable Cardioverter-Defibrillator Patients.

Sweeney MO, Ellenbogen KA, Tang AS, Whellan D, ... Sheldon T, Managed Ventricular Pacing™ versus 40 Pacing (MVP)Trial
Background AND ObjectiveS: To determine whether atrial pacing with ventricular back-up pacing is equivalent to ventricular back-up pacing only in ICD patients. Methods: We randomized 1,030 patients from 84 sites with indications for ICDs, sinus rhythm, and without symptomatic bradycardia to atrial pacing with ventricular back-up at 60 beats/minute (518) or ventricular backup pacing at 40 beats/minute (512) . The primary endpoint was time to death, heart failure (HF) hospitalization (HFH), and HF-related urgent care (HFUC). Results: Follow-up was 2.4 +/- 0.8 years when the trial was stopped for futility. There were 355 endpoint events (103 deaths, 252 HFH/HFUC) in 194 patients favoring ventricular back-up pacing (event-free rate 77.7% vs. 80.3% for atrial pacing at 30 months; hazard ratio 1.14, upper confidence bound 1.59, pre-specified non-inferiority threshold 1.21), therefore equivalence between pacing arms was not demonstrated. Overall HFH/HFUC rates were slightly higher during atrial pacing (event-free rate 85.4% vs. 86.4% for ventricular back-up pacing). Exploratory analyses revealed that the difference in HFH/HFUC rates was largely seen in patients with PR interval = 230 ms. There were no differences between groups for atrial fibrillation, VT/VF, quality of life or echocardiographic measurements. Fewer patients in the atrial pacing group were reported to develop an indication for bradycardia pacing (3.7% vs. 7.3%, p=0.0053). Conclusions: Equivalence between atrial pacing and ventricular back-up pacing only could not be demonstrated.

Heart Rhythm: 05 Aug 2010; epub ahead of print
Sweeney MO, Ellenbogen KA, Tang AS, Whellan D, ... Sheldon T, Managed Ventricular Pacing™ versus 40 Pacing (MVP)Trial
Heart Rhythm: 05 Aug 2010; epub ahead of print | PMID: 20685401
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Abstract

Subcellular heterogeneity of sodium current properties in adult cardiac ventricular myocytes.

Lin X, Liu N, Lu J, Zhang J, ... Fishman GI, Delmar M
Background: Sodium channel α-subunits in ventricular myocytes (VMs) segregate either to the intercalated disc, or to lateral membranes, where they associate with region-specific molecules. Objective: To determine the functional properties of sodium channels as a function of their location in the cell. Methods: Local sodium currents were recorded from adult rodent VMs and Purkinje cells using the cell-attached macropatch configuration. Electrodes were placed either in the cell midsection (M), or cell end (area originally occupied by the intercalated disc; ID). Channels were identified as TTX-sensitive (TTX-S) or TTX-resistant (TTX-R) by application of 100 nM TTX. Results: Average peak-current amplitude was larger in ID than M, and largest at site of contact between attached cells. TTX-S channels were found only in M region of VMs, and not in Purkinje myocytes. TTX-R channels were found in M and ID, but their biophysical properties differed depending on recording location. Sodium current in rat VMs was upregulated by TNF-α. The magnitude of current increase was largest in M, but this difference was abolished by 100 nM TTX. Conclusions: Our data suggest that: a) a large fraction of TTX-R (likely Na(v)1.5) channels in the M region of VMs are inactivated at normal resting potential, leaving most of the burden of excitation to TTX-R channels in the ID; b) cell-cell adhesion increases functional channel density at ID. c) TTX-S (likely non-Na(v)1.5) channels make a minimal contribution to sodium current under control conditions, but represent a functional reserve that can be upregulated by exogenous factors.

Heart Rhythm: 19 Jul 2011; epub ahead of print
Lin X, Liu N, Lu J, Zhang J, ... Fishman GI, Delmar M
Heart Rhythm: 19 Jul 2011; epub ahead of print | PMID: 21767519
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Abstract

Noninvasive Cardiac Activation Imaging of Ventricular Arrhythmias during Drug-induced QT Prolongation in the Rabbit Heart.

Han C, Pogwizd SM, Killingsworth CR, Zhou Z, He B
Background: Imaging myocardial activation from noninvasive body surface potentials promises to aid in both cardiovascular research and clinical medicine. Objective: This study investigates the ability of a noninvasive 3-dimensional cardiac electrical imaging (3DCEI) technique for characterizing the activation patterns of dynamically changing ventricular arrhythmias during drug-induced QT prolongation in rabbit. Methods: Simultaneous body surface potential mapping and 3-dimensional intra-cardiac mapping were performed in a closed-chest condition in eight rabbits. Data analysis was performed on premature ventricular complexes, couplets, and torsades de pointes (TdP) induced during i.v. administration of clofilium and phenylephrine with combinations of various infusion rates. Results: The drug infusion led to significant increase of QT interval (175±7ms to 274±31ms) and rate-corrected QT interval (183±5ms to 262±21ms) during the first dose cycle. All the ectopic beats initiated by a focal activation pattern. The initial beat of TdPs arose at focal site, whereas the subsequent beats were due to focal activity from different sites or two competing focal sites. The imaged results captured the dynamic shift of activation patterns and were in good correlation with the simultaneous measurements with a correlation coefficient of 0.65±0.02 averaged over 111 ectopic beats. Sites of initial activation were localized to be ~5mm. Conclusion: The 3DCEI technique could localize the origin of activation and image activation sequence of TdP during QT prolongation induced by clofilium and phenylephrine in rabbit. It offers the potential to non-invasively investigate the proarrhythmic effects of drug infusion and assess the mechanisms of arrhythmias on a beat-to-beat basis.

Heart Rhythm: 17 Jun 2013; epub ahead of print
Han C, Pogwizd SM, Killingsworth CR, Zhou Z, He B
Heart Rhythm: 17 Jun 2013; epub ahead of print | PMID: 23773986
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Abstract

Electrophysiological Basis for the Antiarrhythmic Actions of Ranolazine.

Antzelevitch C, Burashnikov A, Sicouri S, Belardinelli L
Ranolazine is an FDA-approved anti-anginal agent. Experimental and clinical studies have shown that ranolazine has anti-arrhythmic effects in both ventricles and atria. In the ventricles, ranolazine can suppress arrhythmias associated with acute coronary syndrome, long QT, heart failure, ischemia, and reperfusion. In atria, ranolazine effectively suppresses atrial tachyarrhythmias and fibrillation (AF). Recent studies have shown that the drug may be effective and safe in suppressing AF when used as a pill-in-the pocket approach, even in patients with structurally compromised hearts, warranting further study. The principal mechanism underlying ranolazine\'s antiarrhythmic actions is thought to be primarily via inhibition of late I(Na) in the ventricles, and via use-dependent inhibition of peak I(Na) and I(Kr) in the atria. Short and long term safety of ranolazine has been demonstrated in the clinic, even in patients with structural heart disease. This review summarizes the available data regarding the electrophysiological actions, and anti-arrhythmic properties of ranolazine in preclinical and clinical studies.

Heart Rhythm: 22 Mar 2011; epub ahead of print
Antzelevitch C, Burashnikov A, Sicouri S, Belardinelli L
Heart Rhythm: 22 Mar 2011; epub ahead of print | PMID: 21421082
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Abstract

Positron emission tomography in patients with suspected pacing system infections may play a critical role in difficult cases.

Ploux S, Riviere A, Amraoui S, Whinnett Z, ... Haissaguerre M, Bordachar P
Background: A pacemaker recipient may be recurrently hospitalized with an infection of unknown origin despite detailed investigations. Objective: In the present study, we investigated whether (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET/CT) scanning has a role to play in the identification of pacing material infection, in these difficult cases. Methods: Ten patients presenting with fever of unknown origin despite detailed investigations including transesophageal echocardiography underwent FDG-PET/CT scanning. The identification of increased FDG uptake along a pacing lead prompted the removal of the entire pacing system, whereas in the absence of increased FDG uptake the pacing material was left in place. Forty control pacemaker recipients had FDG-PET/CT scanning performed as part of investigation of malignancy. Results: Among the 40 patients included in the control group, the FDG-PET/CT scanning was normal in 37 (92.5%) patients. In the ten patients who presented with suspected pacing system infections, the FDG-PET/CT scanning showed increased FDG uptake along a lead in six; as a result of this finding they subsequently underwent complete removal of the implanted material. Cultures of the leads were positive in all six patients confirming involvement of the leads in the infectious process. In the other four patients, the pacing system was left in place without objective signs of active lead endocarditis during the follow-up. Conclusion: The present study demonstrates the potential value of FDG-PET/CT scanning in the diagnosis of pacing lead endocarditis in difficult cases. An increased FDG uptake along a lead in this clinical context appears to be a reliable sign of active infection.

Heart Rhythm: 05 Apr 2011; epub ahead of print
Ploux S, Riviere A, Amraoui S, Whinnett Z, ... Haissaguerre M, Bordachar P
Heart Rhythm: 05 Apr 2011; epub ahead of print | PMID: 21463705
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Abstract

Atrial fibrillation is independently associated with senile, vascular, and Alzheimer\'s dementia.

Bunch TJ, Weiss JP, Crandall BG, May HT, ... Lappe DL, Day JD
Background: The aging population has resulted in more patients living with cardiovascular disease, such as atrial fibrillation (AF). Recent focus has been placed on understanding the long-term consequences of chronic cardiovascular disease, such as a potential increased risk of dementia. Objective: This study sought to determine whether there is an association between AF and dementia and whether their coexistence is an independent marker of risk. Methods: A total of 37,025 consecutive patients from the large ongoing prospective Intermountain Heart Collaborative Study database were evaluated and followed up for a mean of 5 years for the development of AF and dementia. Dementia was sub-typed into vascular (VD), senile (SD), Alzheimer\'s (AD), and nonspecified (ND). Results: Of the 37,025 patients with a mean age of 60.6 +/- 17.9 years, 10,161 (27%) developed AF and 1,535 (4.1%) developed dementia (179 VD, 321 SD, 347 AD, 688 ND) during the 5-year follow-up. Patients with dementia were older and had higher rates of hypertension, coronary artery disease, renal failure, heart failure, and prior strokes. In age-based analysis, AF independently was significantly associated with all dementia types. The highest risk was in the younger group (<70). After dementia diagnosis, the presence of AF was associated with a marked increased risk of mortality (VD: hazard ratio [HR] = 1.38, P = .01; SD: HR = 1.41, P = .001; AD: HR = 1.45; ND: HR = 1.38, P <.0001). Conclusion: AF was independently associated with all forms of dementia. Although dementia is strongly associated with aging, the highest risk of AD was in the younger group, in support of the observed association. The presence of AF also identified dementia patients at high risk of death.

Heart Rhythm: 03 Feb 2010; epub ahead of print
Bunch TJ, Weiss JP, Crandall BG, May HT, ... Lappe DL, Day JD
Heart Rhythm: 03 Feb 2010; epub ahead of print | PMID: 20122875
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Abstract

Smoking and Incidence of Atrial Fibrillation: Results from the Atherosclerosis Risk in Communities (ARIC) Study.

Chamberlain AM, Agarwal SK, Folsom AR, Duval S, ... Eberly LE, Alonso A
ObjectiveS:: To determine the association of cigarette smoking with incident AF in a population-based cohort of blacks and whites. Methods:: We determined the risk of incident AF through December 2002 in relation to baseline (1987-1989) smoking status and cigarette-years of smoking in over 15,000 participants of the prospective Atherosclerosis Risk in Communities study. Results:: Over a mean follow-up of 13.1 years, 876 incident AF events were identified. Compared to never smokers, the multivariable-adjusted hazard ratios (HR) for AF were 1.32 (95% CI, 1.10-1.57) in former smokers, 2.05 (95% CI, 1.71-2.47) in current smokers, and 1.58 (95% CI, 1.35-1.85) in ever smokers. In the highest tertile of accumulated smoking amount (>675 cigarette-years), the incidence of AF was 2.10-times greater (95% CI, 1.74-2.53) than those who never smoked. Associations were similar by gender, race, and type of event (AF and atrial flutter), and also when only AF events identified by study exam ECGs were included. Finally, individuals who quit smoking exhibited a trend indicating a slightly lower risk of developing AF (HR, 0.88; 95% CI, 0.65-1.17) compared to those who continued to smoke. Conclusions:: Smoking was associated with the incidence of AF, with more than a 2-fold increased risk of AF attributed to current smoking. In addition, a trend toward a lower incidence of AF appeared among smokers who quit compared to continued smokers.

Heart Rhythm: 22 Mar 2011; epub ahead of print
Chamberlain AM, Agarwal SK, Folsom AR, Duval S, ... Eberly LE, Alonso A
Heart Rhythm: 22 Mar 2011; epub ahead of print | PMID: 21419237
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Abstract

Repetitive Non-Reentrant Ventriculo-Atrial Synchrony: An Under-Recognized Cause of Pacemaker Related Arrhythmia.

Sharma PS, Kaszala K, Tan AY, Koneru JN, ... Ellenbogen KA, Huizar JF
Similar to endless loop tachycardia (ELT), Repetitive Non-Reentrant Ventriculo-Atrial Synchrony (RNRVAS) is a VA synchrony pacemaker mediated arrhythmia. RNRVAS was first described in 1990 and can only occur in the presence of retrograde VA conduction and dual chamber or cardiac resynchronization devices with a tracking (P-synchronous ventricular pacing such as DDD, DDDR) or non-tracking pacing modes that allow AV-sequential pacing (DDI, DDIR). RNRVAS is promoted by 1) high lower rate limit or any feature that allows rapid pacing, 2) long AV intervals or 3) long post-ventricular atrial refractory period (PVARP). In contrast to ELT, RNRVAS is a less well-recognized form of pacemaker-mediated arrhythmia, thus unlike ELT, there are no specific device algorithms to prevent, recognize and terminate RNRVAS. However, RVRNAS has been recently shown to occur frequently. We present a series of cases, some of which were found fortuitously. Due its clinical implications, we propose that algorithms should be developed to prevent, identify and terminate RNRVAS.

Heart Rhythm: 05 Apr 2016; epub ahead of print
Sharma PS, Kaszala K, Tan AY, Koneru JN, ... Ellenbogen KA, Huizar JF
Heart Rhythm: 05 Apr 2016; epub ahead of print | PMID: 27050909
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Abstract

Antiarrhythmic effects of free polyunsaturated fatty acids in an experimental model of LQT2 and LQT3 due to suppression of early afterdepolarizations and reduction of spatial and temporal dispersion of repolarization.

Milberg P, Frommeyer G, Kleideiter A, Fischer A, ... Fehr M, Eckardt L
Background: Torsade de pointes (TdP) are induced by early afterdepolarizations (EADs) in the presence of an increased dispersion of repolarization. Free polyunsaturated fatty acids (PUFAs) have been suggested to influence cardiac repolarization. We investigated the acute antiarrhythmic potential of α-linolenic acid (ALA), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) in a whole-heart model of long QT2 (LQT2)- and long QT3 (LQT3)- syndrome. Methods and results: In 123 Langendorff-perfused rabbit hearts, the I(Kr)-blocking drug erythromycin (E; 300μM) or veratridine (V; 0.5μM), an inhibitor of sodium channel inactivation, significantly increased monophasic ventricular action potentials (MAPs) thereby mimicking LQT2- and LQT3-syndrome. In AV-blocked hearts, eight epi- and endocardial MAPs demonstrated a significant increase in spatial and temporal dispersion. After lowering potassium concentration, E led to EADs and TdP in 44 and 41 of 53 hearts, resp.. Pretreatment with V led to EAD (TdP) in 39 (32) of 43 hearts. Additional treatment with ALA, DHA or EPA (10-20μM) in the LQT2 model, randomly assigned to three groups suppressed EAD in 72% of ALA-treated hearts and in all hearts that were treated with EPA or DHA. This led to a reduction of TdP of 67% (ALA) and to complete abolishment of TdP in all hearts that were treated with EPA or DHA. A comparable finding was seen in V-pretreated hearts. In addition, DHA and EPA significantly shortened MAP duration and reduced spatial and temporal dispersion of repolarization (p<0.01). Conclusion: The present study showed for the first time, that PUFAs are effective in preventing TdP in an experimental model of LQT2- and LQT3-syndrome due to a reversion of AP prolongation, a reduction of spatial and temporal dispersion of repolarization and a suppression of EAD. PUFA effect is stronger in LQT2- than in LQT3-syndrome and the antitorsadogenic effect is more remarkable with DHA and EPA as compared with ALA.

Heart Rhythm: 04 Apr 2011; epub ahead of print
Milberg P, Frommeyer G, Kleideiter A, Fischer A, ... Fehr M, Eckardt L
Heart Rhythm: 04 Apr 2011; epub ahead of print | PMID: 21459164
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Abstract

Inadvertent electrical isolation of the left atrial appendage during catheter ablation of persistent atrial fibrillation.

Chan CP, Wong WS, Pumprueg S, Veerareddy S, ... Morady F, Chugh A
Background: Left atrial appendage (LAA) isolation is rare and may be associated with impaired transport function and thromboembolism. Objective: The purpose of this study was to determine the mechanisms of inadvertent isolation of the LAA during atrial fibrillation (AF) ablation. Methods: This study consisted of 11 patients (ejection fraction 0.43 +/- 0.18, left atrial diameter 51 +/- 8 mm) with persistent AF who had LAA conduction block during a procedure for AF (n = 8) or atrial tachycardia (AT) (n = 3). Results: LAA conduction block occurred during ablation at the Bachmann bundle region in 6 patients, mitral isthmus in 3, LAA base in 2, and coronary sinus in 1. The mean distance from the ablation site to the LAA base was 5.0 +/- 1.9 cm. LAA isolation was transient in all 6 patients in whom LAA conduction was monitored and was permanent in the 4 patients in whom conduction was not monitored during energy delivery. The remaining patient was noted to have LAA isolation during a redo procedure before any ablation. Nine of (82%) the 11 patients have remained arrhythmia-free without antiarrhythmic drugs at mean follow-up of 6 +/- 7 months, and all have continued taking warfarin. Conclusion: Electrical isolation of the LAA may occur during ablation of persistent AF and AT even when the ablation site is remote from the LAA. This likely is due to disruption of the Bachmann bundle and its leftward extension, which courses along the anterior left atrium and bifurcates to surround the LAA. Monitoring of LAA conduction during ablation of persistent AF or AT is important in avoiding permanent LAA isolation.

Heart Rhythm: 04 Feb 2010; 7:173-180
Chan CP, Wong WS, Pumprueg S, Veerareddy S, ... Morady F, Chugh A
Heart Rhythm: 04 Feb 2010; 7:173-180 | PMID: 20129293
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Abstract

Catheter Ablation for Ventricular Tachycardia after failed Endocardial Ablation - Epicardial Substrate or Inappropriate Endocardial Ablation?

Schmidt B, Chun KR, Baensch D, Antz M, ... Ouyang F, Kuck KH
Background :: The substrate of myocardial VT may involve the subepicardial myocardium. Objective:: We aimed to assess the incidence of epicardial substrates in patients with a previously failed endocardial ablation attempt for ventricular tachycardia (VT) as well as safety and effectiveness of epicardial ablation. Methods:: Using an electroanatomical mapping system, endo- and epicardial maps were acquired. Irrigated radiofrequency current ablations of all inducible VTs were performed. Results:: Between 2005 and 2009 fifty-nine patients with or without structural heart disease underwent epicardial VT ablation. Pericardial access failed in 3 of these patients (5%). Of the remaining 56 patients, an epicardial substrate was found in 41 (73%). Overall, acute success was achieved in 46/59 patients (78%) with complete VT abolition in 27 (46%) and partial abolition in 19 (32%). Successful outcomes were the result of endocardial ablation only in 14 patients (24%), epicardial ablation in 21 patients (36%) and endo-/epicardial in 11 patients (19%). Ablation failed to prevent reinduction in 8 patients (13%) and VTs were non-inducible prior to ablation in 5 (8%). Two peri-procedural deaths occurred, one after right ventricular perforation and one due to electromechanical dissociation. In two patients, hepatic bleeding was observed. Recurrence of any VT occurred in 27/57 surviving patients (47%) during a median follow-up of 362 days (q1-q3; 180-468 days). Repeat epicardial mapping was not feasible due to adhesions in 3/12 (25%) patients. Conclusion:: In patients with a previously failed endocardial VT ablation, epicardial mapping reveals a VT substrate in nearly (3/4) of all patients, and epicardial ablation is required for successful VT abolition in more than half of the patients. However, life-threatening complications may occur. Repeat epicardial access was not possible in 25% due to local pericardial adhesions.

Heart Rhythm: 16 Aug 2010; epub ahead of print
Schmidt B, Chun KR, Baensch D, Antz M, ... Ouyang F, Kuck KH
Heart Rhythm: 16 Aug 2010; epub ahead of print | PMID: 20709191
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Abstract

Statin Use and Post-Operative Atrial Fibrillation after Major Non-Cardiac Surgery.

Bhave PD, Goldman LE, Vittinghoff E, Maselli JH, Auerbach A
Background: Although statin lipid-lowering medications likely reduce peri-operative ischemic complications, few data exist to describe statins\' effects on risk for and outcomes of atrial fibrillation following non-cardiac surgery. Objective: To examine the association between treatment with statin medications and clinically significant post-operative atrial fibrillation (POAF) following major non-cardiac surgery. Methods: A retrospective cohort study of patients aged 18 years or older who underwent major non-cardiac surgery between January 1, 2008 and December 31, 2008. Cases of clinically significant POAF were selected using a combination of ICD-9 codes and clinical variables. We defined statin users as those whose pharmacy data included a charge for a statin drug on the day of surgery, the day after surgery, or both. Results: Of 370447 patients, 10957 (3.0%) developed clinically significant POAF; overall, 79871 (21.6%) received a peri-operative statin. Patients receiving statins were generally older (68.8 vs. 61.1 years; P<0.001) and more likely to be receiving a beta-blocker (50.3% vs. 21.6%; P<0.001). Statin use was associated with a lower unadjusted rate of POAF (2.6% vs. 3.0%; P<0.001). After adjustment for patient risk factors and surgery type, odds for POAF remained significantly lower among statin-treated patients (adjusted odds ratio [AOR] 0.79; 95% confidence interval [CI] 0.71-0.87; P<0.001). Statin use was not associated with differences in cost, length of stay, or mortality among patients who developed POAF. Conclusion: Treatment with statin agents appears to be associated with lower risk of clinically significant POAF following major non-cardiac surgery.

Heart Rhythm: 12 Sep 2011; epub ahead of print
Bhave PD, Goldman LE, Vittinghoff E, Maselli JH, Auerbach A
Heart Rhythm: 12 Sep 2011; epub ahead of print | PMID: 21907173
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Abstract

Lone Atrial Fibrillation is Associated with Pectus Excavatum.

Tran NT, Larry Klein J, Paul Mounsey J, Chung EH, ... Pursell I, Gehi AK
Background: Pectus excavatum is a skeletal abnormality which may have cardiac manifestations. Objective: To determine if pectus excavatum is associated with lone atrial fibrillation. Methods: The Pectus Severity Index (PSI) is the ratio of the lateral diameter of the chest to thedistance between sternum and spine on CT scan. A normal PSI is ≤ 2.5 whereas patients withsevere pectus excavatum have a PSI >3.25. We calculated the PSI of 220 consecutive patients withAF who underwent radiofrequency catheter ablation from September 2008 to 2012 and compared this to the PSI of 225 controls without a history of AF undergoing chest CT. Results:: Mean PSI was higher in patients with lone AF (2.72 =/- 0.07) compared to non-lone AF(2.25 +/- 0.03) or controls (2.26 +/- 0.03) (p<0.001). The likelihood of mild, moderate, or severepectus excavatum was higher in lone AF compared to non-lone AF and controls (p<0.001). Patientswith lone AF were over 5 times as likely to have severe pectus excavatum compared to non-lone AF or controls (p<0.001) even after adjustment for potential confounders. Conclusions:: Nearly 2/3 of patients with lone AF have at least mild pectus excavatum and 17%have severe pectus, which is significantly higher than in patients with non-lone AF or controls. Thisassociation suggests a potential genetic or mechanical abnormality may be common to the twodisorders. Our study may provide insight into the pathogenesis of lone AF.3 ABBREVIATIONS: atrial fibrillation (AF), lone atrial fibrillation (lone AF), Pectus Severity Index (PSI),computed tomography (CT), Symptom Mitigation in Atrial Fibrillation Study (SMART Study),University of North Carolina (UNC), hypertension (HTN), coronary artery disease (CAD), heartfailure (CHF), percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG).

Heart Rhythm: 21 May 2013; epub ahead of print
Tran NT, Larry Klein J, Paul Mounsey J, Chung EH, ... Pursell I, Gehi AK
Heart Rhythm: 21 May 2013; epub ahead of print | PMID: 23692892
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Abstract

Catheter Ablation of Ventricular Tachycardia: Lessons Learned from Past Clinical Trials and Implications for Future Clinical Trials.

Pokorney SD, Friedman DJ, Calkins H, Callans DJ, ... Stevenson WG, Al-Khatib SM
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.

Heart Rhythm: 05 Apr 2016; epub ahead of print
Pokorney SD, Friedman DJ, Calkins H, Callans DJ, ... Stevenson WG, Al-Khatib SM
Heart Rhythm: 05 Apr 2016; epub ahead of print | PMID: 27050910
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Abstract

Cardiac Magnetic Resonance T1 Mapping of Left Atrial Myocardium.

Beinart R, Khurram IM, Liu S, Yarmohammadi H, ... Zimmerman SL, Nazarian S
Background: Cardiac magnetic resonance (CMR) T1 mapping is an emerging tool for objective quantification of myocardial fibrosis. Objective: We sought to a) establish the feasibility of left atrial (LA) T1 measurements, b) determine the range of LA T1 values in patients with AF versus healthy volunteers, and c) validate T1 mapping versus LA intra-cardiac electrogram voltage amplitude measures. Methods: CMR imaging at 1.5 Tesla was performed in 51 consecutive patients prior to AF ablation, and in 16 healthy volunteers. T1 measurements were obtained from the posterior LA myocardium using the Modified Look-Locker Inversion-Recovery sequence. Given the established association of reduced electrogram amplitude with fibrosis, intra-cardiac point-by-point bipolar LA voltage measures were recorded for validation of T1 measurements. Results: The median LA T1 relaxation time was shorter in AF patients (387 [IQR 364-428] ms) compared to healthy volunteers (459 [IQR 418-532] ms, P<0.001) and was shorter in AF patients with prior ablation compared to patients without prior ablation (P=0.035). In a generalized estimating equations model, adjusting for data clusters per participant, and age, rhythm during CMR, prior ablation, AF type, hypertension, and diabetes, each 100 ms increase in T1 relaxation time was associated with 0.1 mV increase in intra-cardiac bipolar LA voltage (P=0.025). Conclusion: Measurement of LA myocardium T1 relaxation time is feasible and strongly associated with invasive voltage measures. This methodology may improve the quantification of fibrotic changes in thin walled myocardial tissues.

Heart Rhythm: 05 May 2013; epub ahead of print
Beinart R, Khurram IM, Liu S, Yarmohammadi H, ... Zimmerman SL, Nazarian S
Heart Rhythm: 05 May 2013; epub ahead of print | PMID: 23643513
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Abstract

Cardiac Expression of Skeletal Muscle Sodium Channels Increases Longitudinal Conduction Velocity in the Canine One Week Myocardial Infarction.

Coronel R, Lau DH, Sosunov EA, Janse MJ, ... Robinson RB, Rosen MR
Background: Skeletal muscle sodium channel (Nav1.4) expression in border zone myocardium increases action potential upstroke velocity in depolarized isolated tissue. Because resting membrane potential in the 1 week canine infarct is reduced, we hypothesized that conduction velocity (CV) is greater in Nav1.4 dogs compared to control dogs. Objective: To measure CV in the infarct border zone border in dogs with and without Nav1.4 expression. Methods: Adenovirus was injected in the infarct border zone in 34 dogs. The adenovirus incorporated the Nav1.4- and a green fluorescent protein (GFP) gene (Nav1.4 group, n=16) or only GFP (n=18). After 1 week, upstroke velocity and CV were measured by sequential microelectrode recordings at 4 and 7 mM [K(+)] in superfused epicardial slabs. High density in vivo epicardial activation mapping was performed in a subgroup (8 Nav1.4, 6 GFP) at 3-4 locations in the border zone. Microscopy and antibody staining confirmed GFP or Nav1.4 expression. Results: Infarct sizes were similar between groups (30.6+/-3 % of LV mass, mean+/-SEM). Longitudinal CV was greater in Nav1.4- than in GFP- sites (58.5+/-1.8 vs 53.3+/-1.2 cm/s, 20 and 15 sites, respectively, p<0.05). Transverse CV was not different between the groups. In tissue slabs dV/dt(max) was higher and CV was greater in Nav1.4 than in control at 7 mM [K(+)] (P<0.05). Immunohistochemical Nav1.4 staining was seen at the longitudinal ends of the myocytes. Conclusion: Nav1.4 channels in myocardium surviving 1 week infarction increases longitudinal but not transverse CV, consistent with the increased dV/dt (max) and with the cellular localization of Nav1.4.

Heart Rhythm: 13 Apr 2010; epub ahead of print
Coronel R, Lau DH, Sosunov EA, Janse MJ, ... Robinson RB, Rosen MR
Heart Rhythm: 13 Apr 2010; epub ahead of print | PMID: 20385252
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Abstract

Isolated Septal Substrate for Ventricular Tachycardia in Nonischemic Dilated Cardiomyopathy: Incidence, Characterization and Implications.

Haqqani HM, Tschabrunn CM, Tzou WS, Dixit S, ... Zado ES, Marchlinski FE
Background:: The substrate for ventricular tachycardia (VT) in nonischemic cardiomyopathy (NICM) has a predilection for the basolateral left ventricle (LV) with right bundle branch block (RBBB) VT morphology. Objective:: To describe a unique group of NICM patients with septal VT substrate. Methods and results:: Between 1999 and 2010, 31 of 266 (11.6%) patients with NICM undergoing VT ablation had septal substrate and no lateral involvement: age 59±12 years, ejection fraction 30±14%, heart block in 8 patients. Cardiac magnetic resonance showed septal delayed enhancement in 8/9. Electroanatomic mapping demonstrated bipolar low-voltage (<1.5mV) extending from the basal septum in 22/31 patients. The remaining 9 patients had normal endocardial bipolar voltage but abnormal unipolar septal voltage (<8.3mV) consistent with intramural abnormalities. Epicardial mapping in 14 patients showed no scar in 9 and patchy basal LV summit scar in 5. VTs were mapped to the septal substrate with 62% having RBBB morphology and V(2) precordial transition pattern break in 17% suggesting periseptal exit. After substrate and targeted VT ablation, no VT was inducible in 66% and no "clinical targeted" VT in 86%. Over a mean follow-up of 20±28 months, VT recurred in 10 patients (32%). Conclusions:: Isolated septal VT substrate is uncommon in NICM. Biventricular low-voltage zones extending from the basal septum are characteristic but septal scarring can be entirely intramural as evidenced by unipolar/bipolar electrograms and imaging. Multiple unmappable morphologies are the rule, often requiring several procedures aggressively targeting the septal substrate to achieve moderate long-term VT control.

Heart Rhythm: 11 Mar 2011; epub ahead of print
Haqqani HM, Tschabrunn CM, Tzou WS, Dixit S, ... Zado ES, Marchlinski FE
Heart Rhythm: 11 Mar 2011; epub ahead of print | PMID: 21392586
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Abstract

Management of bacteremia in patients living with cardiovascular implantable electronic devices.

DeSimone DC, Sohail MR
Cardiovascular implantable electronic devices (CIED) have become a critical component in patients with cardiac rhythm disturbances, heart failure, and prevention of sudden cardiac death. However, infection remains a major complication of CIED implantation and is associated with significant morbidity and mortality for device recipients. Early-onset CIED infections frequently originate from generator pocket, secondary to device or pocket contamination at the time of implantation, and may progress to involve device leads or cardiac valves. However, hematogenous seeding of the device leads from a remote source of bacteremia is not infrequent in patients with late-onset CIED infections. While CIED pocket infection can be diagnosed in the majority of cases based on physical findings at the pulse generator site, device lead infection may only manifest with fever and positive blood cultures. However, not every patient with a CIED and positive blood cultures has underlying CIED lead infection. Consequently, management of bacteremia in a CIED recipient without local signs of infection presents a significant challenge. The risk of underlying CIED lead infection in patients presenting with bacteremia depends on several factors including the type of microorganism isolated in blood cultures, duration and source of bacteremia, type of CIED, and the number of device-related procedures. These risk factors must be considered when making decisions regarding need for further diagnostic imaging and whether to retain or remove the device. In this article, we review the published data regarding risk of CIED infection in patients presenting with bacteremia and propose an algorithm for appropriate evaluation and management.

Heart Rhythm: 21 Aug 2016; epub ahead of print
DeSimone DC, Sohail MR
Heart Rhythm: 21 Aug 2016; epub ahead of print | PMID: 27546815
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Abstract

Renal sympathetic denervation for treatment of patients with atrial fibrillation: Reappraisal of the available evidence.

Nammas W, Airaksinen JK, Paana T, Karjalainen PP
Afferent renal sympathetic nerve signaling regulates central sympathetic outflow. In this regard, renal sympathetic denervation has emerged as a novel interventional strategy for treatment of patients with resistant hypertension. Despite the disappointing results of the Simplicity HTN-3 randomized controlled trial, promoters of renal denervation argue that the negative results were due to ineffective denervation technique, and poor patient selection. Yet, long-term \'pathologic\' increase of efferent sympathetic nerve activity is observed in many chronic disease states characterized by sympathetic overactivity, such as arrhythmia, heart failure, insulin resistance, chronic kidney disease, and others. In the current review, we sought to highlight the contemporary evidence on the safety/efficacy of renal denervation in treatment of patients with atrial fibrillation.

Heart Rhythm: 02 Sep 2016; epub ahead of print
Nammas W, Airaksinen JK, Paana T, Karjalainen PP
Heart Rhythm: 02 Sep 2016; epub ahead of print | PMID: 27590432
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Abstract

Follow-up of Patients With New Cardiovascular Implantable Electronic Devices: Is Adherence to the Experts\' Recommendations Associated With Improved Outcomes?

Hess PL, Mi X, Curtis LH, Wilkoff BL, Hegland DD, Al-Khatib SM
Background: A 2008 expert consensus statement recommended an in-person follow-up visit between 2 and 12 weeks after new cardiovascular implantable electronic device (CIED) placement. Objective: To assess outcomes associated with adherence to the experts\' recommendations. Methods: Using data from the National Cardiovascular Data Registry\'s (NCDR®) ICD Registry™ linked to Medicare claims, we studied the association between follow-up within 2-12 weeks after CIED placement between January 1, 2005, and September 30, 2008, and all-cause mortality and risk of readmission within 1 year. Results: Compared with patients who did not receive the recommended follow-up (n=43,060), those who did (n=30,256) were more likely to be older, white, to have received a CRT-D device, to have more advanced heart failure symptoms, and to have non-ischemic dilated cardiomyopathy. In Cox proportional hazards models adjusted for patient demographic and clinical factors, mortality was lower (hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.88-, 0.98; P=0.005) but cardiovascular readmission was higher (HR 1.04, 95% CI 1.01-1.08,P=0.012) among patients who received initial follow-up within 2-12 weeks after CIED, placement compared with those who did not. There was no association between CIED follow-up and readmission for heart failure (HR 1.00, 95% CI 0.96-1.05; P=0.878) or device-related infection (HR 1.22, 95% CI 0.98-1.51; P=0.075). Conclusions: Follow-up within 2-12 weeks after CIED placement was independently associated with improved survival but increased cardiovascular readmission. Quality improvement initiatives designed to increase adherence to experts\' recommendations may be warranted.

Heart Rhythm: 17 Jun 2013; epub ahead of print
Hess PL, Mi X, Curtis LH, Wilkoff BL, Hegland DD, Al-Khatib SM
Heart Rhythm: 17 Jun 2013; epub ahead of print | PMID: 23773989
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Abstract

Myocarditis and ARVC/D: variants or mimics?

Tanawuttiwat T, Sager SJ, Hare JM, Myerburg RJ
Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a disease characterized by fibro-fatty replacement of the right ventricular myocardium, generally considered to be based upon variations in desmosomal genes. However, its pathogenesis is not completely clear since myocarditis and high intensity athletics have both been postulated to contribute to the onset and progression of the disease pattern. We observed a 21-year-old female who presented with fulminant lymphocytic myocarditis, and subsequently fulfilled the diagnostic criteria for ARVC/D by imaging and electrocardiographic characteristics after complete resolution of left ventricular abnormalities associated with myocarditis. Genetic study was however negative for common mutations associated with ARVC/D. Programmed electrical stimulation revealed easily inducible ventricular tachycardia originating from the right ventricular apex, and she received an implantable cardioverter defibrillator. This report supports the hypothesis of a common pathophysiology of ARVC/D associated with desmosomal dysfunction, which can be based upon genetic predisposition or acquired injury.

Heart Rhythm: 17 Jun 2013; epub ahead of print
Tanawuttiwat T, Sager SJ, Hare JM, Myerburg RJ
Heart Rhythm: 17 Jun 2013; epub ahead of print | PMID: 23773988
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Abstract

Synchronous ventricular pacing with direct capture of the atrioventricular conduction system: Functional anatomy, terminology, and challenges.

Mulpuru SK, Cha YM, Asirvatham SJ
Right ventricular apical pacing is associated with an increased incidence of heart failure, atrial fibrillation, and overall mortality. As a result, pacing the ventricles in a manner that closely mimics normal atrioventricular conduction with an intact His-Purkinje system has been explored. Recently, the sustainable benefits of selective His bundle stimulation have been demonstrated and proposed as the preferred method of ventricular stimulation for appropriate patients. Ideally, conduction system pacing should be selective without myocardial capture, overcome distal bundle-branch block when present, and not compromise tricuspid valve function. Contemporary literature on conduction system pacing is confusing largely because of inconsistent terminology and, at times, anatomically inaccurate terms used interchangeably for nonsynonomous anatomic sites. In this review, we discuss the functional anatomy of the atrioventricular conduction access with specific emphasis on terminology, relationship to the membranous septum, tricuspid valve tissue, and proximity to atrial or ventricular myocardium. The potential benefits of each specific site as well as associated unique difficulties with those sites are described.

Heart Rhythm: 06 Aug 2016; epub ahead of print
Mulpuru SK, Cha YM, Asirvatham SJ
Heart Rhythm: 06 Aug 2016; epub ahead of print | PMID: 27498079
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Abstract

THE REVERSE MODE SWITCH ALGORITHM: HOW WELL DOES IT WORK?

Akerström F, Arias MA, Pachón M, Puchol A, Jiménez-López J, Rodríguez-Padial L
BACK GROUND: The performance of the Reverse Mode Switch (RMS) algorithm, aimed at minimizing right ventricular pacing by operating in AAI(R) mode with switch to DDD(R) mode if atrioventricular conduction loss is detected, is not well known. OBJICTIVE: To determine the appropriateness of the RMS episodes available from patient follow-up data at our center. Methods: Patients with the TELIGEN dual-chamber implantable cardioverter defibrillator and the RMS algorithm activated were identified. The RMS episodes with available electrograms (EGM) were analyzed and classified as appropriate (atrioventricular [AV] conduction loss) or inappropriate (non-AV conduction loss) events. Cumulative percentage ventricular pacing (%VP) and amount of premature ventricular complexes (PVC) were recorded. Results: In 21 patients, RMS episodes had occurred in 19 of them with a mean of 527 episodes per month. Of the 172 RMS episodes available for analysis, 27 (16%) were classified as appropriate and 145 (84%) as inappropriate. Almost all (91%) inappropriate RMS episodes were due to PVC and there was a positive correlation between number of total RMS episodes per month and PVCs per month (P<0.0005). Considering patients with only inappropriate RMS episodes (n=11), there was a positive correlation between %VP and number of RMS episodes per month (P<0.05). Conclusion: A large majority of the RMS episodes available for analysis inappropriately triggered switch from AAI(R) to DDD(R) mode due to PVCs. Patients with the RMS algorithm and elevated PVC burden are probably at risk of a high percentage of unnecessary RV pacing.

Heart Rhythm: 03 Jun 2013; epub ahead of print
Akerström F, Arias MA, Pachón M, Puchol A, Jiménez-López J, Rodríguez-Padial L
Heart Rhythm: 03 Jun 2013; epub ahead of print | PMID: 23732226
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Abstract

Ajmaline Attenuates Electrocardiogram Characteristics Of Infero-Lateral Early Repolarization.

Roten L, Derval N, Sacher F, Pascale P, ... Jaïs P, Haïssaguerre M
Background: J waves are the hallmark of both infero-lateral early repolarization (ER) and Brugada syndrome. While ajmaline, a class 1a antiarrhythmic drug, accentuates the J wave in Brugada syndrome, its effect on ER is unreported. Objective: To describe the effect of ajmaline on the electrocardiogram in ER. Methods: We analyzed electrocardiograms before and after administration of intravenous ajmaline (1mg/kg) in 31 patients with ER, 21 patients with Brugada type 1 electrocardiogram (Br) and 22 controls. ER was defined as J point elevation of ≥1 mm with QRS slurring or notching in ≥2 infero-lateral leads (I, aVL, II, III, aVF, V4-V6). Results: Ajmaline decreased mean J wave amplitude in ER group from 0.2±0.15mV at baseline to 0.08±0.09mV (p<0.001). QRS width prolonged significantly in all 3 groups, but prolongation was significantly less in ER group (+21ms) compared to Br group (+36ms; p<0.001) or controls (+28ms; p=0.010). Decrease of mean infero-lateral R wave amplitude was similar in all groups (ER group -0.14mV; Br group -0.11mV; controls -0.13mV; p=ns), but mean infero-lateral S wave amplitude increased significantly less in ER group (ER group +0.14mV; Br group +16 mV; controls +0.20mV; p<0.001). Conclusions: Ajmaline significantly decreases J wave amplitude in ER and prolongs QRS width significantly less than in patients with Brugada type 1 electrocardiogram. This indicates a different pathogenesis for both disorders. The altered terminal QRS vector probably is responsible for the decrease in J wave amplitude in ER, although a specific effect of ajmaline on J waves cannot be excluded.

Heart Rhythm: 14 Sep 2011; epub ahead of print
Roten L, Derval N, Sacher F, Pascale P, ... Jaïs P, Haïssaguerre M
Heart Rhythm: 14 Sep 2011; epub ahead of print | PMID: 21914496
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Abstract

Catheter Ablation of Atrial Fibrillation supported by novel non-fluoroscopic 4D navigation technology.

Rolf S, John S, Gaspar T, Dinov B, ... Piorkowski C, Sommer P
Background: The MediGuide™ Technology (MGT) represents a novel sensor-based electromagnetic 4D navigation system allowing real-time catheter tracking in the environment of pre-recorded x-ray loops. Objective: We now report on our clinical experience in atrial fibrillation (AF) ablation with recently available MGT-enabled ablation catheters. Methods: MGT was used in addition to a conventional 3D mapping system in 80 pts with AF (47 male, age 61±10 yrs., 40 with persistent AF), who underwent circumferential pulmonary vein (PV) isolation, voltage mapping ± substrate modification. Short native RAO/LAO loops were used as background movies for non-fluoroscopic placement of sensor-equipped diagnostic catheters into the coronary sinus and the right ventricle. After single transseptal puncture, selective angiograms of the pulmonary veins were used as background movies for near nonfluoroscopic left atrial (LA) reconstruction. CT registration as well as mapping/ablation was performed using the new open-irrigated MGT-enabled ablation catheter. Results: MGT application was not associated with a change in established workflow. Large parts of the procedure (mean entire duration 167±47 min) could be done without additional fluoroscopy, whereas median residual fluoroscopy duration of 4.6 (interquartile range: 2.9, 7.1) min was mainly used for the acquisition of background loops, transseptal puncture, occasional verification of transseptal sheath position, and manipulation of the circular mapping catheter. Three (4%) minor complications occurred. Conclusions: MGT easily integrates into the workflow of standard AF ablation and allows for high-quality nonfluoroscopic 4D catheter tracking. This results in very low radiation exposure for patients and staff without complicating the workflow of the procedure.

Heart Rhythm: 16 May 2013; epub ahead of print
Rolf S, John S, Gaspar T, Dinov B, ... Piorkowski C, Sommer P
Heart Rhythm: 16 May 2013; epub ahead of print | PMID: 23680898
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Abstract

The Need for and the Challenges of Measuring Renal Sympathetic Nerve Activity.

Kumar Nair GK, Massé S, Asta J, Sevaptisidis E, ... Jackson N, Nanthakumar K
Renal sympathetic denervation (RDN) was primarily developed to treat hypertension, and is potentially a new method for treating arrhythmias. Due to the lack of a standardized protocol to measure renal sympathetic nerve activity, RDN is administered in a blinded manner. This inability to assess efficacy at the time of delivery of treatment may be a large contributor to the ambiguity of RDN outcomes reported in the hypertension literature. The advancement of RDN as a treatment for hypertension or arrhythmias will be hampered by the lack of delivery assessment, a deficiency that the cardiovascular electrophysiology community, with its expertise in recording and mapping, may have a role in addressing and overcoming. The development of endovascular recording of the renal nerve action potentials may provide a useful accessory tool for RDN. Innovation in this area will be crucial, as we as a community reconsider the therapeutic value of RDN.

Heart Rhythm: 24 Jan 2016; epub ahead of print
Kumar Nair GK, Massé S, Asta J, Sevaptisidis E, ... Jackson N, Nanthakumar K
Heart Rhythm: 24 Jan 2016; epub ahead of print | PMID: 26806582
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Abstract

Contemporary Strategies for Risk Stratification and Prevention of Sudden Death with the Implantable Defibrillator in Hypertrophic Cardiomyopathy.

Maron BJ, Maron MS
Hypertrophic cardiomyopathy (HCM) is regarded as the most common non-traumatic cause of sudden death (SD) in young people (including trained athletes). Introduction of implantable cardioverter defibrillators (ICD) to HCM 15 years ago represented a new paradigm for clinical practice and probably the most significant advance in management of this disease. ICDs offer protection against SD by terminating potentially lethal ventricular tachyarrhythmias, (11%/year secondary and 4%/year primary prevention), although implant decisions are weighed against the possibility of device-related complications (5%/year). ICDs have altered the natural history of HCM, creating the opportunity for extended or normal longevity for many patients. However, assessing SD risk and targeting appropriate candidates for prophylactic device therapy can be compounded by unpredictability of the underlying arrhythmogenic substrate, evident by delays ≥10 years between implant and first ICD intervention. Multiple or a single strong risk marker within the clinical profile of an individual HCM patient can justify consideration for a primary prevention ICD when combined with physician judgment and shared decision-making. The role of the mathematical SD risk score proposed by ESC to identify patients who benefit from ICD therapy is incompletely resolved. Contemporary treatment interventions and advanced risk stratification using ≥ 1 conventional markers have served the HCM patient population well, with reduced disease-related mortality rates across all age groups to <1%/year, due largely to the penetration of ICDs into HCM practice. Prevention of SD has now become an integral, albeit challenging, component of HCM management, contributing importantly to its emergence as a contemporary treatable cardiac disease.

Heart Rhythm: 09 Jan 2016; epub ahead of print
Maron BJ, Maron MS
Heart Rhythm: 09 Jan 2016; epub ahead of print | PMID: 26749314
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Abstract

Diagnostic yield in sudden unexplained death and aborted cardiac arrest in the young: The experience of a tertiary referral center in The Netherlands.

van der Werf C, Hofman N, Tan HL, van Dessel PF, ... van Langen IM, Wilde AA
Background: In sudden unexplained death (SUD) in the young (age 1-50 years), cardiologic and genetic examination in surviving relatives may unmask the cause of death in a significant proportion. The causes of aborted cardiac arrest (ACA) in this age group likely are similar to those in sudden cardiac death. However, there is a paucity of recent data on this topic. Objective: The purpose of this study was to gain insight into the yield of current diagnostic strategies used in relatives of SUD victims and in ACA victims aged 1-50 years in our dedicated tertiary referral center. Methods: We studied (1) all consecutive families who presented to the cardiogenetics department for examination because of ?1 first-degree related SUD victim aged 1-50 years and (2) all consecutive ACA victims aged 1-50 years who presented to the cardiogenetics department from 1996 to 2009. Comprehensive cardiologic and genetic examination was performed in both populations. Results: A certain or probable diagnosis was made in 47 (33%) of 140 SUD families, including 45 (96%) cases of inherited cardiac diseases. Long QT syndrome (19%) was the most prevalent diagnosis. In 42 (61%) of 69 ACA victims, the cause of the event was determined (inherited in 31 [74%]). Hypertrophic cardiomyopathy was most prevalent (17%). Conclusion: The yield of the current diagnostic workup in relatives of young SUD victims is 33% and is almost twice as high in young ACA victims. Inherited cardiac diseases are predominantly causative in both groups.

Heart Rhythm: 21 Jul 2010; epub ahead of print
van der Werf C, Hofman N, Tan HL, van Dessel PF, ... van Langen IM, Wilde AA
Heart Rhythm: 21 Jul 2010; epub ahead of print | PMID: 20646679
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Abstract

Substrate Mapping for Unstable Ventricular Tachycardia.

Santangeli P, Marchlinski FE
The primary goal of catheter ablation of scar-related ventricular tachycardia (VT) is the interruption of critical areas of slow conduction responsible for the development and maintenance of the reentrant VT circuit. Most patients with scar-related VT present with unstable arrhythmias that are not amenable to interrogation from multiple sites to define the VT circuit based on the intracardiac activation sequence and the response to entrainment mapping. In order to effectively target unstable VTs, a number of ablation approaches have been described with the aim of targeting the abnormal substrate defined with mapping in sinus or paced rhythm. Some of these strategies (e.g., late potentials and LAVA ablation or scar homogenization) target the entire abnormal substrate harboring abnormal electrograms, defined with a variety of different criteria. Scar dechanneling, linear ablation through sites matching VT with pacing and the core isolation approach focus on more discrete regions within the abnormal substrate that have been proven relevant to the clinical and/or inducible arrhythmias by means of physiological maneuvers, although this does not necessarily translate in less radiofrequency lesions to achieve the procedural endpoint. Observational studies evaluating different substrate-based ablation techniques have reported fairly uniform arrhythmia-free survivals at short- and mid-term follow-up, although direct comparisons between different techniques are lacking. In this article, we will summarize the state-of-the-art different substrate mapping and ablation approaches to target unstable VT with a particular focus on the relative merits and limitations of the described techniques.

Heart Rhythm: 26 Sep 2015; epub ahead of print
Santangeli P, Marchlinski FE
Heart Rhythm: 26 Sep 2015; epub ahead of print | PMID: 26410105
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Abstract

Characteristics of atrial fibrillation cycle length predict restoration of sinus rhythm by catheter ablation.

Di Marco LY, Raine D, Bourke JP, Langley P
Background: Successful termination of atrial fibrillation (AF) during catheter ablation (CA) is associated with arrhythmia-free follow-up. Pre-ablation factors such as mean AF cycle length (AFCL) predict the likelihood of AF termination during ablation but recurring patterns and AFCL stability have not been evaluated. AIM: To investigate novel predictors of acute and postoperative ablation outcomes from intra-cardiac electrograms (EGM): [1] recurring AFCL patterns; [2] localization index (LI) of the instantaneous fibrillatory rate (IFR) distribution. Methods and results: 62 patients with AF (32 paroxysmal AF; 45 men; age 57±10 years), referred for CA were enrolled. 1 minute EGM was recorded from coronary sinus (CS; 5 bipoles) and right atrial appendage (HRA; 2 bipoles). Atrial activations were detected automatically to derive AFCL and IFR [inverse of AFCL] time-series. Recurring AFCL patterns were quantified using recurrence plot indices (RPI): percentage determinism (PD); entropy of determinism (ER); maximum diagonal length (LMAX). AFCL stability was determined by LI. CA outcome predictivity of individual indices was assessed. Terminating AF (T-AF) had higher RPI (p<0.05 in CS7-8) and LI than non-terminating (p<0.005 in CS3-4, p<0.05 in CS5-6, CS7-8, HRA). Arrhythmia-free patients after 3-month follow-up had higher RPI and LI (all p<0.05 in CS7-8). All indices except PD predicted T-AF in CS7-8 (AUC≥0.71, p<0.05; OR ≥4.50). Median AFCL and LI predicted T-AF in HRAD (AUC≥0.75, p<0.05; OR≥7.76). RPI and LI predicted 3-month follow-up (AUC≥0.68, p<0.05; OR ≥4.17) in CS7-8. Conclusions: AFCL recurrence and stability indices could be used in selecting patients more likely to benefit from CA.

Heart Rhythm: 16 Jun 2013; epub ahead of print
Di Marco LY, Raine D, Bourke JP, Langley P
Heart Rhythm: 16 Jun 2013; epub ahead of print | PMID: 23770069
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Abstract

The two incision technique for the implantation of the subcutaneous implantable cardioverter defibrillator.

Knops RE, Olde Nordkamp LR, de Groot JR, Wilde AA
Background: Three incisions in the chest are necessary for the implantation of the entirely subcutaneous implantable defibrillator (S-ICD). The superior parasternal incision is a possible risk for infection and a potential source of discomfort. A less invasive alternative technique of implanting the S-ICD electrode avoids the superior parasternal incision: The two incision technique. Objective: In this prospective cohort study, we sought to evaluate the safety and efficacy of the two incision technique for the implantation of the S-ICD. Methods: Consecutive patients who received a S-ICD between October 2010 and December 2011 were implanted using the two incision technique, which positions the parasternal part of the S-ICD electrode using a standard 11 French peel-away sheath. All patients were routinely evaluated for at least one year for complications and device interrogation at the outpatient clinic. Results: Thirty-nine patients (46% male, mean age 44±15 years) were implanted with a S-ICD using the two incision techniques. During a mean follow-up of 18 months (range 14-27) no dislocations were observed and there was no need for repositioning of either the ICD or the electrode. No serious infections occurred during follow-up except for two superficial wound infections of the pocket incision site. Device function was normal in all patients and no inappropriate sensing occurred related to the implantation technique. Conclusion: The two incision technique is a safe and efficacious alternative for S-ICD implantations and may help to reduce complications. The two incision technique offers physicians a less invasive and simplified implantation procedure of the S-ICD.

Heart Rhythm: 26 May 2013; epub ahead of print
Knops RE, Olde Nordkamp LR, de Groot JR, Wilde AA
Heart Rhythm: 26 May 2013; epub ahead of print | PMID: 23707489
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Abstract

Clinical Impact of the Number of Extrastimuli in Programmed Electrical Stimulation in Patients with Brugada Type 1 Electrocardiogram.

Makimoto H, Kamakura S, Aihara N, Noda T, ... Aiba T, Shimizu W
Background: Use of programmed electrical stimulation (PES) for risk stratification of Brugada syndrome (BrS) is controversial. Objective: To elucidate the role of the number of extrastimuli during PES in BrS patients Methods: Consecutive 108 patients with type 1 electrocardiogram (104 men, mean age 46±12 years, 26 with ventricular fibrillation (VF), 40 with syncope, and 42 asymptomatic) underwent PES with maximum of 3 extrastimuli from the right ventricular apex and outflow tract. Ventricular arrhythmia (VA) was defined as VF or non-sustained polymorphic ventricular tachycardia (PVT) >15 beats. Patients with induced VA by a single extrastimulus or double extrastimuli were assigned to Group-SD, by triple extrastimuli to Group-T, and the remaining patients to Group-N. Results: VA was induced in 81 patients (VF in 71, and PVT in 10), in 4 by a single extrastimulus, 41 by double, and 36 by triple. During 79±48 months of follow-up, 24 patients had VF events. Although overall inducibility of VA was not associated with increased risk of VF (log-rank P=0.78), Group-SD had worse prognosis than Group-T (P=0.004). Kaplan-Meier analysis in patients without prior VF also showed that Group-SD had poorer outcome than Group-T and Group-N (P=0.001). Positive and negative predictive values of VA induction with up to 2 extrastimuli were, respectively, 36% and 87%; better than those with up to 3 (23%, 81%). Conclusions: The number of extrastimuli which induced ventricular arrhythmia served as a prognostic indicator of patients with Brugada type 1 electrocardiogram. Single extrastimulus or double extrastimuli were adequate for PES of Brugada patients.

Heart Rhythm: 23 Sep 2011; epub ahead of print
Makimoto H, Kamakura S, Aihara N, Noda T, ... Aiba T, Shimizu W
Heart Rhythm: 23 Sep 2011; epub ahead of print | PMID: 21939629
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Abstract

Catheter ablation of ventricular tachycardia after left ventricular reconstructive surgery for ischemic cardiomyopathy.

Wijnmaalen AP, Roberts-Thomson KC, Steven D, Klautz RJ, ... Stevenson WG, Zeppenfeld K
Background: After surgical ventricular restoration (SVR) for ischemic cardiomyopathy, ventricular tachycardias (VTs) are an important reason for postoperative morbidity and mortality. Objective: To elucidate the VT substrate, VT characteristics and outcome of radiofrequency catheter ablation (RFCA) in patients with VT after SVR. Methods: Twelve(3%) of 416 patients referred for RFCA for VT after myocardial infarction in three centers had undergone SVR. After induction of VT, left ventricular (LV) electroanatomical mapping was performed. Ablation target sites were identified by entrainment, substrate and/or pace mapping. Results: Four(33%) patients presented within the perioperative period with incessant VT, 8(67%) presented with incessant or recurrent VT late after SVR (VT cycle length 453±102ms). The region of surgical scar was identified by electroanatomical mapping in 11 patients. Twenty-eight VTs (cycle length 384±95ms) were induced. The VT exit was bordering the surgical scar in 20(71%) VTs, of which 15 were at the septal side. All VTs were abolished in 5 patients, in 4 only the clinical VTs were abolished, in 1 re-inducibility was not tested. In 2 patients, ablation failed after which surgical ablation was performed successfully. During follow-up, 3(25%) patients died (non-arrhythmic deaths); all had presented early after SVR. Two(17%) experienced recurrent VT. Conclusion: VT after LV SVR seems to have a bimodal presentation; one third presented with incessant VT in the acute postoperative phase, having a high mortality. Two thirds presented late after SVR; in these patients RFCA is usually effective. Successful ablation sites are frequently located at the border of surgical scars and patch material.

Heart Rhythm: 08 Aug 2011; epub ahead of print
Wijnmaalen AP, Roberts-Thomson KC, Steven D, Klautz RJ, ... Stevenson WG, Zeppenfeld K
Heart Rhythm: 08 Aug 2011; epub ahead of print | PMID: 21820993
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Abstract

Intrinsic left atrial histoanatomy as the basis for reentrant excitation causing atrial fibrillation/flutter in rats.

Matsuyama TA, Tanaka H, Adachi T, Jiang Y, Ishibashi-Ueda H, Takamatsu T
Background: Although the pulmonary veins are accepted as preferential trigger sites for paroxysmal atrial fibrillation/flutter (AF/AFL), the intrinsic basis for reentrant excitation is undetermined in persistent AF/AFL. Objective: To identify histoanatomic substrates for reentrant AF/AFL in rats. Methods: Spatiotemporal patterns of impulse propagation were visualized optically on the posterior surface of the atria in di-4ANEPPS-stained Langendorff-perfused rat heart/lung preparations. The relevant histology was also analyzed. Results: Burst (S1-S2) pacing at the right atrium provoked AF/AFL in 15 of 19 hearts, and most cases developed by organized reentrant excitation through the coronary sinus (CS) and left atrium (LA) roof, with non-organized irregular propagation in 3 cases. The reentrant circuit developed along 2 pathways of propagation: a slower pathway at the LA roof (conduction velocity, 42.4 ± 16.6 cm/s) and a faster pathway along the CS (conduction velocity, 53.3 ± 9.2 cm/s). Upon extra stimulus (S2) after consecutive S1 pacing, the impulse at the roof propagated retrogradely from the CS, resulting in reentrant propagation anchored by the atrial septum and posterior LA. Histologic quantification revealed significantly lower myocardial density in the posterior LA and the septum than elsewhere in the atria. Moreover, myocytes in the LA roof, vs. the CS, were of lower density, more randomly arranged in the direction of conduction, and characterized by more disorganized distribution of connexin 43 over the entire cell membrane, consistent with the slower impulse propagation there. Conclusion: The intrinsic histoanatomic heterogeneity in the LA would constitute a pro-reentrant substrate responsible for perpetuating AF/AFL.

Heart Rhythm: 16 May 2013; epub ahead of print
Matsuyama TA, Tanaka H, Adachi T, Jiang Y, Ishibashi-Ueda H, Takamatsu T
Heart Rhythm: 16 May 2013; epub ahead of print | PMID: 23680896
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Abstract

Endo-Epicardial ablation of Ventricular Arrhythmias in the left ventricle with the Remote Magnetic Navigation System and the 3.5 mm open irrigated magnetic catheter: results from a large single center case-control series.

Di Biase L, Santangeli P, Astudillo V, Conti S, ... Burkhardt JD, Natale A
Introduction:: Remote magnetic navigation (RMN) has been reported as a feasible and safe mapping and ablation system for treatment of ventricular arrhythmias (VAs). However, the reported success rates have been limited with the 4 and 8 mm catheter tips. We report the results in a large series of consecutive patients undergoing radiofrequency (RF) catheter ablation of VAs using the RMN with the 3.5 mm magnetic open irrigated tip catheter (OIC). Methods:: 110 consecutive patients with clinical history of left VA were included in the study. In all cases, an OIC was utilized for mapping and ablation. When ablation with the RMN catheters failed, a manual OIC was used to eliminate the VA. Post ablation pacing maneuvers and isoproterenol were utilized to verify the inducibility of the VAs. Outcomes were compared to a group of 92 consecutive patients undergoing manual ablation by the same operator. Results:: Mapping and ablation with the magnetic OIC were performed in all 110 patients with VA. Ischemic cardiomyopathy was present in 33 (30%), non-ischemic in 14 (13%), and in 63 (57%) patients no structural heart disease was present. Endocardial mapping was performed in all patients, while both endo-epi mapping in 36 (33%) patients. Compared to manual ablation, RMN was associated with longer procedural time (2.9+/-1.2 versus 3.3+/-1.1 hours, p =.004) and RF time (24+/-12 versus 33+/-18 minutes, p=.005) while fluoroscopic time was significantly shorter (35+/-22 versus 26+/-14 minutes, p=.033). During the procedures, cross over to manual ablation was required in 15 patients (14%). At 11.7+/-2.1 months of follow-up in study group and 18.7+/- 3.7 months in manual ablation group, 85% and 86% (p=.817) patients, respectively, were free of VA. Conclusions:: This large series of consecutive patients demonstrates that open irrigation catheter ablation utilizing the RMN is effective for the treatment of left VAs.

Heart Rhythm: 03 May 2010; epub ahead of print
Di Biase L, Santangeli P, Astudillo V, Conti S, ... Burkhardt JD, Natale A
Heart Rhythm: 03 May 2010; epub ahead of print | PMID: 20434589
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Abstract

Increasing time between first diagnosis of atrial fibrillation and catheter ablation adversely affects long-term outcomes.

Jared Bunch T, May HT, Bair TL, Johnson DL, ... Lappe DL, Day JD
Background: Many patients who develop atrial fibrillation (AF) will experience a worsening of their arrhythmia over time. The optimal time to proceed with catheter ablation during the disease course is unknown. Further, it is unknown if delays in treatment will negatively influence outcomes. Methods: A total of 4,535 consecutive patients who underwent an AF ablation procedure that had long-term established care within an integrated health care system were evaluated. Recursive partitioning was used to determine categories associated with changes in risk from the time of first AF diagnosis to first AF ablation: 1:30-180(n=1,152), 2:181-545(n=856), 3:546-1825(n=1,326), 4:>1825(n=1,201) days). Outcomes evaluated include 1 year AF recurrence, stroke, heart failure hospitalization, and death. Results: With increasing time to treatment, surprisingly patients were older (1: 63.7±11.1, 2: 62.6±11.8, 3: 66.4±10.2, 4: 67.6±9.7, p<0.0001) and had more hypertension (1:53.0%, 2:59.0%, 3:53.8%, 4:39.0%, p<0.0001). For each strata of time increase, there was a direct increase of 1 year AF recurrence (1:19.4%, 2: 23.4%, 3:24.9%, 4:24.0%, p-trend = 0.02). After adjustment, clinically significant differences in risk of recurrent AF were found when compared to the 30-180 day time category: 181-545: odd ratio(OR)=1.23, p=0.08; 546-1825: OR=1.27, p=0.02; and >1825: OR=1.25, p=0.05. No differences were observed for 1 year stroke among the groups. Death (1:2.1%, 2:3.9%, 3:5.7%, 4:4.4%, p-trend=0.001) and heart failure hospitalization (1:2.6%, 2:4.1%, 3:5.4%, 4:4.4%, p-trend=0.009) rates at 1 year were higher in the most delayed groups. Conclusions: Delays in treatment with catheter ablation impact procedural success rates independent of temporal changes to the AF subtype at ablation.

Heart Rhythm: 23 May 2013; epub ahead of print
Jared Bunch T, May HT, Bair TL, Johnson DL, ... Lappe DL, Day JD
Heart Rhythm: 23 May 2013; epub ahead of print | PMID: 23702238
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Abstract

Reasons for Failed Ablation for Idiopathic Right Ventricular Outflow Tract Like Ventricular Arrhythmias.

Yokokawa M, Good E, Crawford T, Chugh A, ... Morady F, Bogun F
Background: The right ventricular outflow tract (RVOT) is the most common site of origin of ventricular arrhythmias (VA) in patients with idiopathic VA. A left bundle branch block inferior axis morphology arrhythmia is the hallmark of RVOT arrhythmias. VAs from other sites of origin can mimic RVOT VAs and ablation in the RVOT typically fails for these VAs. The purpose of this study was to analyze reasons for failed ablations of RVOT-like VAs. Methods: Among a consecutive series of 197 patients with an RVOT like Electrocardiographic (ECG) morphology who were referred for ablation, 38 patients (13 men, age: 46±14 years, left ventricular ejection fraction: 47±14%) in whom a prior procedure failed within the RVOT underwent a second ablation procedure. ECG characteristics of the VA were compared to a consecutive series of 50 patients with RVOT VAs. Results: The origin of the VA was identified in 95% of the patients. In 28 of 38 patients (74%) the arrhythmia origin was not in the RVOT. The VA originated from intramural sites (n=8; 21%), the pulmonary arteries (n=7; 18%), the aortic cusps (n=6; 16%), and the epicardium (n=5; 13%). The origin was within the RVOT in 10 patients (26%). In 2 patients (5%), the origin could not be identified despite biventricular, aortic and epicardial mapping. The VA was eliminated in 34/38 patients (89%) with repeat procedures. ECG features of patients with failed RVOT-like arrhythmias were different from the characteristics of RVOT arrhythmias. Conclusions: In patients in whom ablation of a VA with an RVOT like appearance fails, mapping of the pulmonary artery, the aortic cusps, the epicardium, the left ventricular outflow tract and the aortic cusps will help to identify the correct site of origin. The 12 lead ECG is helpful in differentiating these VAs from RVOT VAs.

Heart Rhythm: 23 May 2013; epub ahead of print
Yokokawa M, Good E, Crawford T, Chugh A, ... Morady F, Bogun F
Heart Rhythm: 23 May 2013; epub ahead of print | PMID: 23702237
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Abstract

Resting Heart Rate and Risk of Sudden Cardiac Death in the General Population: Influence of Left Ventricular Systolic Dysfunction and Heart Rate-Modulating Drugs.

Teodorescu C, Reinier K, Uy-Evanado A, Gunson K, Jui J, Chugh SS
Background: Higher levels of resting heart rate (HR) have been associated with sudden cardiac death (SCD) but mechanisms are poorly understood. We hypothesized that severe left ventricular systolic dysfunction (LVSD) and rate-modulating drugs explain the HR-SCD relationship. Objective: We evaluated the relationship between HR, severe LVSD, rate-affecting medications and SCD in the community, using a case-control approach. Methods: From the ongoing Oregon Sudden Unexpected Death Study, SCD cases (n=378) aged ≥35 years and with EKG-documented resting HR, were compared to 378 age- and gender-matched control subjects with coronary artery disease (68±13 years, 69% male). Associations with SCD were assessed using multivariable logistic regression. Results: Mean resting HR was significantly higher among SCD cases compared to controls (7.5bpm difference, p<0.0001). Heart rate was a significant determinant of SCD after adjustment for significant co-morbidities and medications [OR for 10 bpm increase = 1.26; 95% CI (1.14 - 1.38); p<0.0001]. After considering LVSD, resting HR was slightly attenuated but remained significantly associated with SCD (p=0.005). In addition to diabetes, and digoxin as well as pulmonary and renal disease, LVSD was also independently associated with SCD (OR 1.79, 95% CI 1.11-2.87, p=0.02). Conclusion: Contrary to expectations, the significant relationship between increased resting HR and SCD persisted even after adjustment for LVSD and rate-modulating drugs. These findings suggest a potential role for additional, novel interventions/therapies that modulate autonomic tone.

Heart Rhythm: 16 May 2013; epub ahead of print
Teodorescu C, Reinier K, Uy-Evanado A, Gunson K, Jui J, Chugh SS
Heart Rhythm: 16 May 2013; epub ahead of print | PMID: 23680897
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Abstract

Role of Calmodulin Kinase in Catecholaminergic Polymorphic Ventricular Tachycardia.

Napolitano C, Liu N, Priori SG
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited disease causing arrhythmias and sudden death in a structurally normal heart. Ventricular and supraventricular arrhythmias are reproducibly triggered by exercise or acute emotion (i.e. sudden adrenergic activation). Two CPVT variants are known: autosomal dominant caused by mutations in the cardiac ryanodine receptor (RyR2) and autosomal recessive due to calsequestrin mutations (CASQ2). Both RyR2 and CASQ2 have a relevant role in the control of intracellular Ca(2+) fluxes. Thus, CPVT pathogenesis is intrinsically bound to catecholamines and Ca(2+) handling. Cardiac Ca(2+)/calmodulin-dependent protein kinase (CaMKII) is an intracellular mediator of the adrenergic cascade and it specifically modulates Ca(2+) homeostasis. Several lines of evidence suggest that CaMKII not only has a key role in CPVT pathogenesis but is also a promising therapeutic target. Here we will review the available evidence on both these issues and the possible future developments in this area.

Heart Rhythm: 14 Mar 2011; epub ahead of print
Napolitano C, Liu N, Priori SG
Heart Rhythm: 14 Mar 2011; epub ahead of print | PMID: 21397047
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Abstract

A CACNA1C Mutation that Causes a Subset of Timothy Syndrome Phenotypes Correlates.

Hennessey JA, Jiang Y, Miller JD, Stadt HA, ... Kanter R, Pitt GS
Timothy syndrome (TS) is a rare congenital long QT syndrome (LQTS) associated with extracardiac manifestations including craniofacial dysmorphia and dental abnormalities. The locus for TS is CACNA1C, which encodes the CaV1.2 L-type Ca(2+) channel, for which canonical mutations lead to a decrease in voltage-dependent inactivation (VDI). However, a recent report of a patient with LQTS in isolation and a CACNA1C mutation that did not affect VDI raised the question whether altered VDI is necessary for extracardiac phenotypes. In a patient with a maternally inherited microdeletion with a chromosomal translocation who presented with LQTS and associated ventricular tachyarrhythmias (Figure A), a subset of TS phenotypes, and a skeletal myopathy not readily explained by the translocation, we sought to identify a causative mutation for the TS phenotypes.

Heart Rhythm: 10 Nov 2013; 10:1745
Hennessey JA, Jiang Y, Miller JD, Stadt HA, ... Kanter R, Pitt GS
Heart Rhythm: 10 Nov 2013; 10:1745 | PMID: 24210388
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Abstract

Negative Tracheal Pressure During Obstructive Respiratory Events Promotes Atrial Fibrillation by Vagal Activation.

Linz D, Schotten U, Neuberger HR, Böhm M, Wirth K
Background: Obstructive sleep apnea (OSA) causes negative tracheal pressure (NTP) and is associated with atrial fibrillation (AF). Objective: This study aimed to determine the mechanism of atrial electrophysiological changes during tracheal occlusion with or without applied NTP and to evaluate the role of vagal activation, Na(+)/H(+)-exchanger (NHE) and ATP-dependent potassium channels (K(ATP)). Methods: 17 closed-chest pigs were anesthetized with urethane and an endotracheal tube was placed to apply NTP (up to -100 mbar) comparable to clinically observed OSA in patients by a negative pressure device for a time period of 2 minutes. Right atrial refractory periods (AERP) and AF-inducibility were measured transvenously by a monophasic action potential recording and stimulation catheter. Results: All tracheal occlusions with and without applied NTP resulted in comparable increases in blood pressure and hypoxemia. NTP shortened AERP (157.0±2.8 ms to 102.1±6.2 ms, p<0.0001) and enhanced AF-inducibility during AERP-measurements from 0% at baseline to 90% (p<0.00001) during NTP. Release of NTP resulted in a prompt restoration of sinus rhythm and AERP returned to normal. NTP-induced AERP-shortening and AF-inducibility were prevented by atropine or vagotomy. Neither the NHE-blocker cariporide nor the K(ATP)-channel-blocker glibenclamide abolished NTP-induced AERP-shortening. By contrast, tracheal occlusion without applied NTP caused comparable changes in blood gases but did not induce AERP-shortening or AF-inducibility. Conclusion: NTP during obstructive events is a strong trigger for AF compared to changes in blood gases alone. NTP caused AERP-shortening and increased susceptibility to AF mainly by enhanced vagal activation. AERP-shortening was not prevented by K(ATP)-channel-blockade or NHE-blockade.

Heart Rhythm: 04 Apr 2011; epub ahead of print
Linz D, Schotten U, Neuberger HR, Böhm M, Wirth K
Heart Rhythm: 04 Apr 2011; epub ahead of print | PMID: 21457790
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Abstract

Magnetophysiologic and Echocardiographic Comparison of Blocked Atrial Bigeminy and 2:1 Atrioventricular Block in the Fetus.

Wiggins DL, Strasburger JF, Gotteiner N, Cuneo B, Wakai RT
Background: Blocked atrial bigeminy (BAB) and second-degree atrioventricular block with 2:1 conduction block (2:1 AVB) both present as ventricular bradycardia, and can be difficult to distinguish by echocardiography. Since the prognosis and clinical management of these rhythms are very different, an accurate diagnosis is essential. Methods: A retrospective fMCG and pulsed Doppler ultrasound study of ten BAB and seven 2:1 AVB subjects was performed in order to identify parameters that could reliably distinguish BAB from 2:1 AVB. Results: Distinguishing BAB from 2:1 AVB with fMCG was relatively straightforward because in BAB the ectopic P-wave (P\') occurred very early, resulting in a bigeminal (short-long) atrial rhythm. The normalized coupling interval of the ectopic beat (PP\' of blocked beat to PP of conducted beat) was 0.29±0.03. In contrast, echocardiographic assessment of inflow-outflow gave a normalized mechanical coupling interval (AA\'/AA) near 0.5, which made it difficult to distinguish BAB from 2:1 AVB. Heart rate distinguished most BAB and 2:1 AVB subjects (82±5.7 vs. 69±4.2 bpm), but was not a completely reliable indicator. In most subjects, BAB alternated with sinus rhythm or other rhythms, resulting in complex heart rate and rhythm patterns. Conclusion: fMCG can accurately differentiate BAB from 2:1 AVB, based on measurement of PP\' interval and PP\'/PP ratios. Differential diagnosis with pulsed Doppler, however, was more difficult because the mechanical rhythm did not accurately reflect the magnetic rhythm in BAB. fMCG also allows detailed characterization of the complex heart rate and rhythm patterns that commonly accompany BAB.

Heart Rhythm: 25 Apr 2013; epub ahead of print
Wiggins DL, Strasburger JF, Gotteiner N, Cuneo B, Wakai RT
Heart Rhythm: 25 Apr 2013; epub ahead of print | PMID: 23619035
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Abstract

Clinical Significance of Ventricular Tachyarrhythmias in CRT-D Treated Patients.

Kutyifa V, Klein HU, Wang PJ, McNitt S, ... Moss AJ, Zareba W
Background: Data on the outcome of CRT-D patients developing ventricular arrhythmias are limited. ObjectiveS: We aimed to evaluate the prognostic value of ventricular tachycardia (VT) or ventricular fibrillation (VF) episodes by heart rate in patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial - Cardiac Resynchronization Therapy (MADIT-CRT). Methods: Slow VT was defined as VT\'s with heart rate < 200 bpm. Fast VT ≥ 200 bpm and VF (> 250 bpm) were considered as a combined category. Primary end point was heart failure (HF) or death. Secondary end point included all-cause mortality. Results: There were 228 (12.7%) patients with Slow VT, 198 (11.1%) with Fast VT/VF. In time dependent analysis Slow VT was associated with an increased risk of HF/Death in CRT-D patients with LBBB (HR=3.19, 95% CI: 1.83-5.55, p<0.001), but not in ICD patients (HR=1.03, 95% CI: 0.52-2.19, p=0.867, interaction p-value=0.017). CRT-D patients with LBBB and Fast VT or VF doubled their risk of HF/Death as compared to ICD patients (interaction p-value = 0.06). Slow VT events were also predictive of Death in CRT-D patients with LBBB (HR=3.48, 95% CI: 1.66-7.28, p<0.001), but not in ICD patients (interaction p-value = 0.06). Slow VT\'s were highly predictive of subsequent Fast VT/VF (HR=4.33, 95% CI: 3.01-6.24, p<0.001). Conclusion: Slow VT episodes are predictive of subsequent Fast VT/VF. Slow VT and Fast VT/VF episodes in CRT-D patients are associated with an increased risk of subsequent HF/Death. CRT-D treated LBBB patients with slow VT\'s have a significantly higher risk of mortality.

Heart Rhythm: 02 May 2013; epub ahead of print
Kutyifa V, Klein HU, Wang PJ, McNitt S, ... Moss AJ, Zareba W
Heart Rhythm: 02 May 2013; epub ahead of print | PMID: 23639624
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Abstract

Instability of repolarization in LQTS mutation carriers compared to healthy control subjects assessed by vectorcardiography.

Vahedi F, Diamant UB, Lundahl G, Bergqvist G, ... Jensen SM, Bergfeldt L
Background: Potassium channel dysfunction in congenital and acquired forms of long QT syndromes type 1 and 2 (LQT1, LQT2) increases the beat to beat variability of the QT interval. ObjectiveS: Little is, however, known about the variability (instability) of other aspects of ventricular repolarization (VR) in humans and was therefore the topic of this study applying vectorcardiography (VCG). Methods: Beat to beat analysis was performed regarding VCG derived RR, QRS and QT intervals, as well as T vector and T vector loop based parameters during one minute recordings of uninterrupted sinus rhythm at rest in 41 adult LQT1 (n=31) and LQT2 (n=10) mutation carriers and 41 age and sex matched control subjects. The short-term variability (STV) for each parameter, describing the mean orthogonal distance to the line of identity on the Poincaré plot, was calculated. Results: Mutation carriers showed significantly larger (by a factor 2) instability in most VR parameters compared to controls despite higher instantaneous heart rate variability (STVRR) in the control group. The longer the QT interval, the greater was its instability and the instability of VR dispersion measures Tarea (global dispersion) and ventricular gradient (action potential morphology dispersion). Conclusion: A greater instability of most aspects of VR already at rest seems to be a salient feature in both LQT1 and LQT2, which might pave the way for early afterdepolarizations and Torsades de Pointes ventricular tachycardia. In contrast, no signs of increased VR dispersion per se were observed in the mutation carriers.

Heart Rhythm: 05 May 2013; epub ahead of print
Vahedi F, Diamant UB, Lundahl G, Bergqvist G, ... Jensen SM, Bergfeldt L
Heart Rhythm: 05 May 2013; epub ahead of print | PMID: 23643511
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Abstract

Stiff Left Atrial Syndrome Following Catheter Ablation for Atrial Fibrillation: Clinical Characterization, Prevalence and Predictors.

Gibson DN, Di Biase L, Mohanty P, Patel JD, ... Lewis WR, Natale A
Background: There have been no studies of atrial diastolic function following catheter ablation. We observed a few patients with symptomatic left atrial diastolic dysfunction with associated pulmonary hypertension that developed following catheter ablation for atrial fibrillation. Similar findings were described in patients following cardiac surgery and referred to as the "stiff left atrial syndrome". Objective: We prospectively quantify the incidence of patients developing PH associated with diastolic hemodynamic abnormalities of the LA following radiofrequency ablation of atrial fibrillation. and to identify the possible predictors. Methods: Between January 2009 and July 2010, data on 1380 consecutive patients were prospectively collected. Before ablation and at follow up, all patients had an Echocardiogram to assess for the presence of pulmonary hypertension. Patients with no echocardiographic evidence of PH but complaining of unexplained dyspnea with LA diastolic abnormalities were evaluated with right heart catheterization (RHC). Patients were included in the analysis if they developed new or worsening PH post ablation with evidence of LA diastolic dysfunction by RHC or direct LA pressure measurement. All patients were evaluated for pulmonary vein stenosis and excluded if this condition was identified. Results: The mean age was 62±11 (75% male) and non-paroxysmal AF was the predominant arrhythmia (71%). New or worsening PH with associated LA diastolic abnormalities was detected in 19 (1.4%) patients after ablation. The prevalence of PH did not differ between AF types (p=0.612). Compared to patients who did not develop PH, LA scarring (p<0.001), diabetes (p=0.026), and obstructive sleep apnea (OSA, p=0.006) were more frequently observed among those who developed PH. In a multivariable logistic model, pre-procedure LA size < 45mm (OR=6.13, p=0.033), mean LA pressure (OR 1.14, p =0.025), severe LA scarring (OR=4.4, p=0.046), diabetes mellitus (OR=9.5, p=0.004), and obstructive sleep apnea (OR=6.2, p=0.009) were independently associated with the development of PH post ablation. Conclusions: Following RFCAF, PH with left atrial diastolic dysfunction or the so called "Stiff Left Atrial Syndrome" is rare but is a potential complication. Severe LA scarring, LA ≤ 4.5 cm, diabetes mellitus, obstructive sleep apnea and high LA pressure are clinical variables that predict the development of this syndrome. The principal clinical findings include dyspnea, CHF, pulmonary hypertension, and large V waves on PCWP or LA pressure tracings in the absence of mitral regurgitation.

Heart Rhythm: 28 Feb 2011; epub ahead of print
Gibson DN, Di Biase L, Mohanty P, Patel JD, ... Lewis WR, Natale A
Heart Rhythm: 28 Feb 2011; epub ahead of print | PMID: 21354332
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Abstract

Feasibility of Image-Based Simulation to Estimate Ablation Target in Human Ventricular Arrhythmia.

Ashikaga H, Arevalo H, Vadakkumpadan F, Blake RC, ... Trayanova NA, Halperin HR
Background: Previous studies suggest that MRI with late gadolinium enhancement (LGE) may identify slowly conducting tissues in scar-related ventricular tachycardia (VT). Objective: We tested the feasibility of image-based simulation based on LGE to estimate ablation targets in VT. Methods: We conducted a retrospective study in 13 patients who had pre-ablation MRI for scar-related VT ablation. We used image-based simulation to induce VT and estimate target regions according to the simulated VT circuit. The estimated target regions were co-registered with the LGE scar map and the ablation sites from the electroanatomical map in the standard ablation approach. Results: In image-based simulation, VT was inducible in 12 patients (92.3%). All VTs showed macro-reentrant propagation patterns, and the narrowest width of estimated target region that an ablation line should span to prevent VT recurrence was 5.0 3.4 mm. Out of 11 patients who underwent ablation, the results of image-based simulation and the standard approach were consistent in 9 patients (82%), where ablation within the estimated target region was associated with acute success (n=8) and ablation outside the estimated target region was associated with failure (n=1). In one case (9%), the results of image-based simulation and the standard approach were inconsistent, where ablation outside the estimated target region was associated with acute success. Conclusions: The image-based simulation can be used to estimate potential ablation targets of scar-related VT. The image-based simulation may be a powerful noninvasive tool for pre-procedural planning of ablation procedures to potentially reduce the procedure time and complication rates.

Heart Rhythm: 22 Apr 2013; epub ahead of print
Ashikaga H, Arevalo H, Vadakkumpadan F, Blake RC, ... Trayanova NA, Halperin HR
Heart Rhythm: 22 Apr 2013; epub ahead of print | PMID: 23608593
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Abstract

Electrophysiologic Properties of Para-Hisian Atrial Tachycardia.

Iwai S, Badhwar N, Markowitz SM, Stambler BS, ... Scheinman MM, Lerman BB
Background:: Focal atrial tachycardia (AT) originates from preferential sites, including the tricuspid and mitral annuli. AT arising from the atrioventricular annuli is initiated and terminated with programmed stimulation, and is, in general, adenosine- and verapamil-sensitive. Para-Hisian AT arising from the apex of the Triangle of Koch has been considered to be a distinct entity, characterized by unique electrophysiologic properties. Objective:: We sought to more fully delineate the electrophysiologic and electrocardiographic properties of para-Hisian AT in a large series of patients. Methods:: The study population consisted of 38 pts (63 ± 15 yrs; 23 F) with AT from the para-Hisian region. The ATs were focal and originated from the anteroseptal tricuspid annulus, in close proximity to the His bundle recording. Proximity to the His bundle was confirmed by electrogram recordings, fluoroscopy and centrifugal activation pattern on three-dimensional mapping system. Results:: The mean AT cycle length was 421 ± 69 ms. AT was associated with distinct P wave morphology that was significantly narrower than P wave during sinus rhythm. Adenosine (5.0 ± 1.5 mg) terminated AT in 34/35 patients. Intravenous verapamil terminated AT in 3/3 patients; diltiazem terminated AT in 1/1 patient. Catheter ablation was attempted in 30 pts and was successful in 26 (87%). Conclusion:: The para-Hisian region is a source of focal AT, with properties consistent with AT arising circumferentially along the tricuspid and mitral annuli, and should be considered a subset of this broader group of "annular" ATs. The electropharmacologic findings in para-Hisian AT are mechanistically consistent with cyclic AMP-mediated triggered activity.

Heart Rhythm: 14 Mar 2011; epub ahead of print
Iwai S, Badhwar N, Markowitz SM, Stambler BS, ... Scheinman MM, Lerman BB
Heart Rhythm: 14 Mar 2011; epub ahead of print | PMID: 21397044
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Abstract

Repolarizing Cardiac Potassium Channels: Multiple Sites and Mechanisms for CaMKII-Mediated Regulation.

Nerbonne JM
Marked reductions in the densities of the fast, transient voltage-dependent K(+) (Kv) current, I(to,f), and of the inwardly rectifying (Kir) K(+) current, I (K1), are routinely observed in the hypertrophied and failing human heart and in experimental models of pathological cardiac hypertrophy. Attenuation of these prominent repolarizing K(+) currents results in action potential prolongation and increased dispersion of repolarization, both of which are arrhythmogenic. Cardiac hypertrophy and failure are also associated with increased expression and activity of the multifunctional calcium (Ca(2+)) calmodulin (CaM) dependent protein kinase II (CaMKII) and several lines of evidence suggest that CaMKII activation can (directly or indirectly) lead to changes in the functional cell surface expression and the biophysical properties of cardiac I(to,f) and I (K1) channels.

Heart Rhythm: 14 Jan 2011; epub ahead of print
Nerbonne JM
Heart Rhythm: 14 Jan 2011; epub ahead of print | PMID: 21232627
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Abstract

Automated analysis of atrial late gadolinium enhancement imaging correlates with endocardial voltage and clinical outcomes: a two-center study.

Malcolme-Lawes LC, Juli C, Karim R, Bai W, ... Kanagaratnam P, Peters NS
Background: For late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) assessment of atrial scar to guide management and targeting of ablation in AF, an objective, reproducible method of identifying atrial scar is required. Objective: We describe an automated method for operator-independent quantification of LGE that correlates with co-located endocardial voltage and clinical outcomes. Methods: LGE CMR imaging was performed at 2 centres, before and 3 months after pulmonary vein isolation (PVI) for paroxysmal AF (PAF) (N=50). Left atrial (LA) surface scar map was constructed using automated software, expressing intensity as multiples of standard deviation (SD) above blood pool mean. 21 patients underwent endocardial voltage mapping at the time of PVI (11 were redo procedures). Scar maps and voltage maps were spatially registered to the same MRA segmentation. Results: LGE levels of 3, 4 and 5 SD above blood pool intensity were associated with progressively lower bipolar voltages compared to the preceding enhancement level (0.85± 0.33mV, 0.50± 0.22mV and 0.38 ±0.28mV, p=0.002, p<0.001 and p=0.048 respectively).The proportion of atrial surface area classified as scar (i.e. >3 SD above blood pool mean) on pre-ablation scans was greater in patients with post-ablation AF recurrence than those without recurrence (6.6 ± 6.7% vs 3.5 ± 3.0%, p =0.032). LA volume >102ml was associated with a significantly greater proportion of LA scar (6.4± 5.9 vs 3.4± 2.2%, p=0.007). Conclusion: Left atrial scar quantified automatically by a simple objective method correlates with co-located endocardial voltage. Greater pre-ablation scar is associated with LA dilatation and AF recurrence.

Heart Rhythm: 19 May 2013; epub ahead of print
Malcolme-Lawes LC, Juli C, Karim R, Bai W, ... Kanagaratnam P, Peters NS
Heart Rhythm: 19 May 2013; epub ahead of print | PMID: 23685170
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Abstract

Terminating Ventricular Tachyarrhythmias Using Far-Field Low-Voltage Stimuli: Mechanisms and Delivery Protocols.

Rantner LJ, Tice BM, Trayanova NA
Background: Low-voltage termination of VT and atrial fibrillation has shown promising results, however the mechanisms and full range of applications remain unexplored. Objective: This study aimed to elucidate the mechanisms for low-voltage cardioversion and defibrillation, and to develop an optimal low-voltage defibrillation protocol. Methods: We developed a detailed MRI-based computational model of the rabbit right ventricular wall. We applied multiple low-voltage far-field stimuli of various strengths (≤ 1 V/cm) and stimulation rates in VT and VF. Results: Out of the five stimulation rates tested, stimuli applied at 16 or 88% of VT cycle length (CL) were most effective in cardioverting VT, the mechanism being consecutive excitable gap decreases. Stimuli given at 88% of VF CL defibrillated successfully, whereas a faster stimulation rate (16%) often failed because the fast stimuli did not capture enough tissue. In this model, defibrillation threshold (DFT) energy for multiple low-voltage stimuli at 88% VF CL was 0.58% of the DFT energy for a single strong biphasic shock. Based on the simulation results, a novel two-stage defibrillation protocol was proposed. The first stage converted VF into VT by applying low-voltage stimuli at times of maximal excitable gap, capturing large tissue volume and synchronizing depolarization; the second stage terminated VT. The energy required for successful defibrillation using this protocol was 57.42% of the energy for low-voltage defibrillation when stimulating at 88% CL. Conclusion: A novel two-stage low-voltage defibrillation protocol using the excitable gap extent to time multiple stimuli defibrillated VF with the least energy by first converting VF into VT, then terminating VT.

Heart Rhythm: 29 Apr 2013; epub ahead of print
Rantner LJ, Tice BM, Trayanova NA
Heart Rhythm: 29 Apr 2013; epub ahead of print | PMID: 23628521
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Abstract

Atorvastatin for Prevention of Atrial Fibrillation Recurrence Following Pulmonary Veins Isolation: A Double-Blind, Placebo-Controlled, Randomized Trial.

Suleiman M, Koestler C, Lerman A, Lopez-Jimenez F, ... Packer DL, Friedman PA
Background: It is known that statins are effective in preventing atrial fibrillation (AF) in patients undergoing cardiac surgery. ObjectiveS: To evaluate the efficacy of statins in preventing AF recurrence following left atrial ablation. Methods: One hundred twenty-five patients who had no statin indication undergoing catheter ablation due to drug-refractory paroxysmal (n= 90) or persistent (n= 35) AF were randomized in a prospective, double-blind, placebo-controlled trial to receive 80 mg atorvastatin (n=62) or placebo (n=63) for 3 months. The primary end point was freedom from symptomatic AF at 3 months. Secondary endpoints included freedom from any atrial arrhythmia recurrence irrespective of symptoms, quality of life (QoL), and reduction in C-reactive proteins (CRP) Results: At 3 months, 95% of patients in the atorvastatin group were free of symptomatic AF as compared with 93.5% in the placebo group (p=0.75). Similarly, 85% of patients treated in the atorvastatin group remained free of any recurrent atrial arrhythmia vs 88% of patients in the placebo group (p=0.37). The mean CRP levels decreased in the atorvastatin group (mean change -0.75 ± 3; P =0.02) and increased in the placebo group (mean change 2.1±19.9; P=0.48). Mean QoL score improved significantly in both groups (mean change13.14±18.2 in the atorvastatin group and 11.10±17.7 in the placebo group, P=0.53). Conclusion: In patients with no standard indication for statin therapy, treatment with atorvastatin 80 mg per day following AF ablation does not decrease the risk of AF recurrence in the first three months and should not be routinely administered to prevent peri-procedural arrhythmias.

Heart Rhythm: 16 Sep 2011; epub ahead of print
Suleiman M, Koestler C, Lerman A, Lopez-Jimenez F, ... Packer DL, Friedman PA
Heart Rhythm: 16 Sep 2011; epub ahead of print | PMID: 21920481
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Abstract

Brief endocardial surge of Ca2+ transient but monotonic suppression of action potential occurs during acute ischemia in canine ventricular tissue.

Ueyama T, Zipes DP, Lopshire JC, Wu J
Background: Ischemia suppresses action potentials (AP) by elevating interstitial K(+) and activating KATP channels, and alters cytosolic Ca(2+) transients (CaT) via metabolic inhibition. Objective: This study tested the hypothesis that AP and CaT respond to ischemia with different spatiotemporal courses and patterns. Methods: Thirty-four transmural wedges were isolated from canine left ventricular free walls, perfused arterially, and stained with voltage and Ca(2+)-sensitive dyes. Twenty-eight wedges underwent 15 min of arterial occlusion during pacing at a cycle length (PCL) of 300 (n=19) or 600ms (n=9). Six other wedges had sequential reduction of perfusion flow from full to 50%, 25%, and 10% at 300ms PCL. AP and CaT were recorded on the cut-exposed transmural surfaces with an optical mapping system. Results: Although ischemia suppressed APs, it enhanced CaT to 150±10% (more in the endocardium than epicardium) and induced CaT alternans during the first 2 min of arterial occlusion, and then suppressed CaT (PCL: 300ms). Enhancement of CaT (to 159±23%) also occurred during low flow (25%) perfusion (PCL: 300ms). Faster suppression of AP than of CaT occurred with subepicardial preference. After 15 min arterial occlusion, AP and CaT remained in only small regions during 300 ms PCL, but were preserved in most regions during 600ms PCL. Conclusions: Early ischemia induced a surge and alternans in CaT and caused its dissociation from AP both in time course of suppression and in spatial distribution. These results suggested there were different cellular regulatory mechanisms of AP and of CaT in responding to ischemia from arterial occlusion.

Heart Rhythm: 02 Jun 2013; epub ahead of print
Ueyama T, Zipes DP, Lopshire JC, Wu J
Heart Rhythm: 02 Jun 2013; epub ahead of print | PMID: 23727277
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Abstract

Sudden Death in Adult Congenital Heart Disease: Risk Stratification in 2014.

Walsh EP
Arrhythmias and sudden death continue to plague a subset of adult patients with congenital heart disease. Despite investigative efforts spanning many decades, accurate identification of the high-risk patient remains challenging owing to a limited population size, relatively low event rate, and constantly evolving surgical approaches to the various malformations. Furthermore, until recently, most studies of the subject involved single center formats with limited statistical power. The number of adult survivors has now reached a critical size where larger collaborative projects are beginning to generate more objective criteria for assessing risk. This review will provide an update on risk-stratification for several of the major congenital cardiac lesions, and outline the current recommendations for surveillance and management.

Heart Rhythm: 20 Jul 2014; epub ahead of print
Walsh EP
Heart Rhythm: 20 Jul 2014; epub ahead of print | PMID: 25046858
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Abstract

Magnetic versus manual catheter navigation for mapping and ablation of right ventricular outflow tract ventricular arrhythmias: a randomized controlled study.

Zhang F, Yang B, Chen H, Ju W, ... Cao K, Chen M
Background: There has been no randomized controlled study to prospectively compare the performance and clinical outcomes of remote magnetic control (RMC) versus manual catheter control (MCC) during ablation of right ventricular outflow tract (RVOT) ventricular premature complexes (VPC) or tachycardia (VT) Objective: This study prospectively evaluated the efficacy and safety of using either RMC versus MCC for mapping and ablation of RVOT VPC/VT Methods: Thirty consecutive patients with idiopathic RVOT VPC/VT were referred for catheter ablation and randomized into either RMC or MCC group. A non-contact mapping system (NCM) was deployed in the RVOT to identify origins of VPC/VT. Conventional activation and pace-mapping was performed to guide ablation. If ablation performed using one mode of catheter control was acutely unsuccessful, the patient crossed over to the other group. The primary endpoints were patients\' and physicians\' fluoroscopy exposure and times Results: Mean procedural times were similar between RMC and MCC groups. The fluoroscopy exposure and times for both patients and physicians were much lower in RMC group than in the MCC group. Ablation was acutely successful in 14/15 patients in the MCC group and 10/15 in the RMC group. Following cross-over, acute success was achieved in all patients. No major complications occurred in either group. During 22 months of follow-up, RVOT VPC recurred in 2 RMC patients Conclusion: RMC navigation significantly reduces patients\' and physicians\' fluoroscopy times by 50.5 % and 68.6 % respectively when used in conjunction with a NCM to guide ablation of RVOT VPC/VT.

Heart Rhythm: 21 May 2013; epub ahead of print
Zhang F, Yang B, Chen H, Ju W, ... Cao K, Chen M
Heart Rhythm: 21 May 2013; epub ahead of print | PMID: 23692891
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Abstract

Safety and Feasibility of Transseptal Puncture for Atrial Fibrillation Ablation in Patients with Atrial Septal Defect Closure Devices.

Li X, Wissner E, Kamioka M, Makimoto H, ... Kuck KH, Ouyang F
Atrial fibrillation (AF) frequently occurs late after atrial septal defect (ASD) closure. Transseptal puncture (TSP) is critical to successful catheter ablation of AF. In the following, we describe our experience on how to perform TSP in 9 patients with a previously implanted ASD occluder. All patients had a secundum-type ASD, successfully closed with an Amplatzer device in 8 and a Lifetech device in 1 patient. The closure device was implanted at a median of 16 (6-36) months prior to the index procedure. Single or double TSP was performed. Circumferential pulmonary vein isolation (PVI) was completed following successful TSP. In 6 patients with an ASD closure device and a waist diameter of ≤26 mm, double TSP was successful at a site posteroinferior to the implanted device. In the remaining 3 patients, the diameter of the ASD occluder measured 28, 30 and 34 mm, and TSP was performed directly through the posteroinferior portion of the occluder. The puncture site was sequentially dilated using a PCI balloon. Only a single 8.5F long sheath was placed following successful dilatation. PVI was achieved in all patients without complications. In summary, successful TSP can be performed at a site posteroinferior to the ASD closure device if the diameter measures ≤26 mm. In larger devices, direct puncture through the ASD occluder is feasible and safe > 6 months following implantation.

Heart Rhythm: 17 Nov 2013; epub ahead of print
Li X, Wissner E, Kamioka M, Makimoto H, ... Kuck KH, Ouyang F
Heart Rhythm: 17 Nov 2013; epub ahead of print | PMID: 24239844
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Abstract

Forward trafficking of ion channels: What the clinician needs to know.

Smyth JW, Shaw RM
Each heartbeat requires precisely orchestrated action potential propagation through the myocardium, achieved by coordination of about 1 million ion channels on the surface of each cardiomyocyte. Specific ion channels must occur within discrete subdomains of the sarcolemma to exert their electrophysiological effects with highest efficiency (e.g., voltage-gated Ca(2+) channels at T-tubules and gap junctions at intercalated discs). Regulation of ion channel movement to their appropriate membrane subdomain is an exciting research frontier with opportunity for novel therapeutic manipulation of ion channels in the treatment of heart disease. Although much research has generally focused on internalization and subsequent degradation of ion channels, the field of forward trafficking of de novo ion channels from the cell interior to the sarcolemma has now emerged as a key regulatory step in cardiac electrophysiological function. In this brief review, we provide an overview of the current understanding of the cellular biology governing the forward trafficking of ion channels.

Heart Rhythm: 12 Jul 2010; epub ahead of print
Smyth JW, Shaw RM
Heart Rhythm: 12 Jul 2010; epub ahead of print | PMID: 20621620
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Abstract

Pulmonary vein isolation in cases of difficult catheter lacement: A new pacing maneuver to demonstrate complete isolation of the veins.

Alonso-Martín C, Rodríguez Font E, Guerra JM, Viñolas Prat X
Background: Pulmonary vein electrical isolation is the main goal of atrial fibrillation ablation. To ensure electrical isolation of the pulmonary veins, entrance and exit block should be demonstrated. However, this is sometimes challenging due to the complex anatomy of the pulmonary vein area and the anatomical variations that may preclude the correct position of the commonly used circular multielectrode catheter inside the veins. Objective: The present work describes a new pacing maneuver useful to demonstrate complete isolation of ipsilateral veins in cases of difficult catheter placement. Methods and results: Three representative cases illustrate the usefulness of the maneuver either at the right or left pulmonary veins. After circumferential ablation of ipsilateral veins, the circular catheter is positioned in one vein and the ablation catheter in the other ipsilateral vein. When local capture in one vein can be demonstrated while pacing from the other vein and no conduction to the atria is observed, isolation of both veins can be assured. Conclusion: This novel maneuver might be of help to assess complete isolation of the pulmonary veins in cases of difficult circular catheter placement.

Heart Rhythm: 28 Apr 2013; epub ahead of print
Alonso-Martín C, Rodríguez Font E, Guerra JM, Viñolas Prat X
Heart Rhythm: 28 Apr 2013; epub ahead of print | PMID: 23623799
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Abstract

Resetting and Entrainment of Reentrant Ventricular Tachycardia Associated with Myocardial Infarction.

Josephson ME, Almendral J, Callans DJ
Resetting and entrainment are specific responses to programmed stimulation that are useful in determining the mechanism of ventricular tachycardia (VT), localizing critical components of a reentrant circuit to guide ablation, determine how antiarrhythmic drugs affect the tachycardia, and developing antitachycardia pacing modalities. While resetting have certain things in common, they differ significantly in the ability to characterize the properties of VT. Only resetting, which is the interaction of a single extrastimulus with the tachycardia can characterize the properties of the VT itself. Entrainment assesses the effect of overdrive pacing on a reset circuit, not the VT itself. The terms for these techniques are often incorrectly used interchangeably. The current review details the characteristics and uses of both stimulation techniques.

Heart Rhythm: 30 Mar 2014; epub ahead of print
Josephson ME, Almendral J, Callans DJ
Heart Rhythm: 30 Mar 2014; epub ahead of print | PMID: 24681116
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How do Sex Hormones Modify Arrhythmogenesis in Long-QT Syndrome? - Sex Hormone Effects on Arrhythmogenic Substrate and Triggered Activity.

Odening KE, Koren G
Gender differences in cardiac repolarization and the arrhythmogenic risk of patients with inherited and acquired long-QT syndromes are well appreciated clinically. Enhancing our knowledge of the mechanisms underlying these differences is critical to improve our therapeutic strategies for preventing sudden cardiac death in such patients. This review summarizes the effects of sex hormones on the expression and function of ion channels that control cardiac cell excitation and repolarization as well as key proteins that regulate Ca(2+) dynamics at the cellular level. Moreover, it examines the role of sex hormones in modifying the dynamic spatiotemporal (regional and transmural) heterogeneities in action potential duration (e.g., the arrhythmogenic substrate) and the susceptibility to (sympathetic) triggered activity at the tissue, organ, and whole-animal levels. Finally, it explores the implications of these effects on the management of LQTS patients.

Heart Rhythm: 22 Jun 2014; epub ahead of print
Odening KE, Koren G
Heart Rhythm: 22 Jun 2014; epub ahead of print | PMID: 24954242
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Abstract

Expanding Role of SK Channels in Cardiac Electrophysiology.

Mahida S
The small conductance calcium-activated potassium channels (SK channels) are an important group of potassium selective ion channels. SK channels display more pronounced expression in the atrium relative to the ventricle. Current evidence relating to the functional role of SK channels in the atria is conflicting and whether these channels contribute to atrial repolarization under physiological circumstances is a matter of debate. Multiple studies have however reported that SK channels are important mediators of proarrhythmogenic electrical remodelling in the atria. In keeping with their expression profile, SK channels do not appear to play a prominent role in ventricular repolarization. SK channels represent potentially attractive therapeutic targets for atrial fibrillation (AF). A number of pharmacological modulators of SK channels have been tested in animal models of AF. However, these studies have also demonstrated inconsistent results and have raised important questions regarding the proarrhythmogenic potential of SK channel modulation. These findings have important implications for drug development. This review summarizes the role of the SK channels in cardiac electrophysiology and discusses the potential role of these channels as therapeutic targets.

Heart Rhythm: 30 Mar 2014; epub ahead of print
Mahida S
Heart Rhythm: 30 Mar 2014; epub ahead of print | PMID: 24681007
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Abstract

Combined Blockade of Early And Late Activated Atrial Potassium Currents Suppresses Atrial Fibrillation in a Pig Model of Obstructive Apnea.

Linz D, Schotten U, Neuberger HR, Böhm M, Wirth K
Background: Negative tracheal pressure (NTP) during tracheal obstruction in obstructive apnea increases vagal tone and causes pronounced shortening of the atrial effective refractory period (AERP) thereby perpetuating atrial fibrillation (AF). The role of different atrial potassium channels under those conditions has not been investigated. Objective: This study aimed to evaluate the atrial effects of blockade of the late activated potassium current (I(Kr)) by sotalol, of blockade of the early activated potassium currents (I(Kur)/I(to)) by AVE0118 and of the multichannel blocker amiodarone during tracheal occlusions with applied NTP. Methods: 21 pigs were anesthetized and an endotracheal tube was placed to apply NTP (up to -100 mbar) comparable to clinically observed obstructive sleep apnea for 2 minutes. Right AERP and AF-inducibility were measured transvenously by a monophasic action potential recording and stimulation catheter. Results: Tracheal occlusion with applied NTP caused pronounced AERP-shortening. AF was inducible during all NTP-maneuvers. Neither blockade of I(Kr) by sotalol, nor blockade of I(Kur)/I(to) by AVE0118 nor amiodarone affected NTP-induced AERP-shortening although they prolonged the AERP during normal breathing. Atropine given after amiodarone completely inhibited NTP-induced AERP-shortening. The combined blockade of I(Kr) and I(Kur)/I(to) by sotalol plus AVE0118, however, attenuated NTP-induced AERP-shortening and AF-inducibility independent of the order of administration. Conclusion: The atrial proarrhythmic effect of NTP simulating obstructive apneas is difficult to inhibit by class III antiarrhythmic drugs. Neither amiodarone nor blockade of I(Kr) or I(Kur)/I(to) attenuated NTP-induced AERP-shortening. However, the combined blockade of I(Kur)/I(to) and I(Kr) suppressed NTP-induced AERP-shortening.

Heart Rhythm: 19 Jul 2011; epub ahead of print
Linz D, Schotten U, Neuberger HR, Böhm M, Wirth K
Heart Rhythm: 19 Jul 2011; epub ahead of print | PMID: 21767520
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Abstract

Associations Between the CHADS 2 Score, Atrial Substrate Properties and Outcome of Catheter Ablation in the Patients with Paroxysmal Atrial Fibrillation.

Chao TF, Cheng CC, Lin WS, Tsao HM, ... Wu TJ, Chen SA
Background:: The CHADS(2) score is used for the risk stratification of strokes in patients with atrial fibrillation (AF). Objective:: This study aimed to investigate the associations between the CHADS(2) score, atrial substrate and outcome of catheter ablation in patients with paroxysmal AF. Methods:: A total of 247 paroxysmal AF patients who received catheter ablation were enrolled. The patients were divided into 3 groups according to their CHADS(2) score (group 1: score 0, group 2: score 1-2, and group 3: score 3-6). The bi-atrial substrate properties and outcome of catheter ablation were analyzed. Results:: The CHADS(2) scores in these 3 groups were 0 (group 1), 1.24 ± 0.48 (group 2) and 3.60 ± 0.83 (group 3), respectively. The left atrial voltage became lower (group 1 versus 2 versus 3 = 2.08 ± 0.73 mV versus 1.80 ± 0.81 mV versus 1.06 ± 0.69 mV) and the activation time longer (group 1 versus 2 versus 3 = 93.4 ± 17.7 msec versus 101.9 ± 21.2 msec versus 112.2 ± 21.7 msec) while the CHADS(2) score increased. During a follow up of 17.3 ± 7.0 months, 23.1% of the study population suffered from recurrences. The recurrence rates of these 3 groups were 13.0% (group 1), 27.6% (group 2) and 45.9% (group 3), respectively. The groups of different CHADS(2) scores remained as the independent predictor of recurrence in the multivariate analysis. Conclusions:: A high CHADS(2) score was associated with different left atrial substrate properties and a poor outcome after catheter ablation of paroxysmal AF.

Heart Rhythm: 15 Mar 2011; epub ahead of print
Chao TF, Cheng CC, Lin WS, Tsao HM, ... Wu TJ, Chen SA
Heart Rhythm: 15 Mar 2011; epub ahead of print | PMID: 21402172
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Abstract

Ganglionated Plexi Ablation vs Linear Ablation in Patients Undergoing Pulmonary Vein Isolation for Persistent/Longstanding Persistent Atrial Fibrillation: A Randomized Comparison.

Pokushalov E, Romanov A, Katritsis DG, Artyomenko S, ... Mittal S, Steinberg JS
Background: The optimal ablation technique for persistent and longstanding persistent atrial fibrillation (AF) is unclear. Both linear lesions (LL) and ganglionated plexi (GP) ablation have been used, in addition to pulmonary vein isolation (PVI), but no direct comparison of the two methods exists. Methods: Two hundred sixty four consecutive patients with persistent/longstanding persistent AF were randomly assigned to 2 different ablation schemes: PVI+LL (n=132) and PVI+GP ablation (n=132). Consistent sinus rhythm (SR) off antiarrhythmic drug was assessed after follow-up of at least 3 years with the use of an implanted monitoring device (IMD). Results: All procedural endpoints were acutely achieved. At 12 months following a single procedure, 47% of patients treated with PVI+LL were in SR compared to 54% of patients treated with PVI+GP (p=0.29). At 3 years, 34% of patients with PVI+LL and 49% of patients with PVI+GP maintained SR (p=0.035). Atrial flutter was more frequent in PVI+LL than in PVI+GP ablation group (18% versus 6%, P=0.002). After a second procedure in 78 patients of the PVI+LL group and 55 patients of the PVI+GP group, the long-term overall success rate was 52% and 68%, respectively (p=0.006). Conclusions: PVI+GP ablation confers superior clinical results with less ablation-related left atrial flutter and reduced AF recurrence compared to PVI+LL at 3 years of follow-up.

Heart Rhythm: 22 Apr 2013; epub ahead of print
Pokushalov E, Romanov A, Katritsis DG, Artyomenko S, ... Mittal S, Steinberg JS
Heart Rhythm: 22 Apr 2013; epub ahead of print | PMID: 23608592
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Abstract

Mapping of Cardiac Electrical Activation with Electromechanical Wave Imaging: An in silico-in vivo Reciprocity Study.

Provost J, Gurev V, Trayanova N, Konofagou EE
Background: Electromechanical Wave Imaging (EWI) is an entirely non-invasive, ultrasound-based imaging method capable of mapping the electromechanical activation sequence of the ventricles in vivo. Given the broad accessibility of ultrasound scanners in the clinic, the application of EWI could constitute a flexible surrogate for the 3D electrical activation. Objective: The purpose of this report is to reproduce the electromechanical wave (EW) using an anatomically-realistic electromechanical model, and establish the capability of EWI to map the electrical activation sequence in vivo when pacing from different locations. Methods: EWI was performed in one canine during pacing from three different sites. A high-resolution dynamic model of coupled cardiac electromechanics of the canine heart was used to predict the experimentally recorded electromechanical wave. The simulated 3D electrical activation sequence was then compared with the experimental EW. Results: The electrical activation sequence and the EW were highly correlated for all pacing sites. The relationship between the electrical activation and the EW onset was found to be linear with a slope of 1.01 to 1.17 for different pacing schemes and imaging angles. Conclusions: The accurate reproduction of the EW in simulations indicates that the model framework is capable of accurately representing the cardiac electromechanics and thus testing new hypotheses. The one-to-one correspondence between the electrical activation sequence and the EW indicates that EWI could be used to map the cardiac electrical activity. This opens the door for further exploration of the technique in assisting in the early detection, diagnosis and treatment monitoring of rhythm dysfunction.

Heart Rhythm: 27 Dec 2010; epub ahead of print
Provost J, Gurev V, Trayanova N, Konofagou EE
Heart Rhythm: 27 Dec 2010; epub ahead of print | PMID: 21185403
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Abstract

The Use Of A Radiofrequency Needle Improves The Safety And Efficacy Of Transseptal Puncture For Atrial Fibrillation Ablation.

Winkle RA, Mead RH, Engel G, Patrawala RA
Background: Atrial fibrillation (AF) ablation requires transseptal puncture to gain entry to the LA. On rare occasions, LA entry cannot be achieved or cardiac perforation results in pericardial tamponade. ObjectiveS: To compare a new radiofrequency (RF) transseptal needle to the standard needle. METHOD: We evaluated 1550 AF ablations in 1167 patients. We compared 975 transseptal punctures done using a standard needle to 575 done using a new electrode tipped needle attached to a RF perforation generator. Results: The rate of failure to cross the atrial septum was lower for the RF needle (1/575 (0.17%) vs.12/ 975 (1.23%), P = 0.039) and there were fewer pericardial tamponades with the RF needle (0/ 575 (0.00%) vs. 9/975 (0.92%), P = 0.031). Multivariate analysis showed the RF needle use was the only variable associated with a lower incidence of tamponade (P = 0.04). Since the RF needle was used later in our series, we examined our 975 standard needle punctures over time for evidence of improved operator experience that might explain the superior RF results. For the standard needle, there was no trend for improved septal crossing rates (P = 0.794) or fewer tamponades (P = 0.456) with more operator experience. Instrumentation time was shorter for the RF needle (27.1 ± 10.9 vs. 36.4 ± 17.7 minutes, P < 0.0001). Conclusions: Our data suggest that the RF needle is superior to the standard transseptal needle. It results in shorter instrumentation times, a greater efficacy in transseptal crossing and fewer episodes of pericardial tamponade.

Heart Rhythm: 24 Jun 2011; epub ahead of print
Winkle RA, Mead RH, Engel G, Patrawala RA
Heart Rhythm: 24 Jun 2011; epub ahead of print | PMID: 21699841
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Abstract

Antiarrhythmic use from 1991 to 2007: Insights from the Canadian Registry of Atrial Fibrillation (CARAF I and II).

Andrade JG, Connolly SJ, Dorian P, Green M, ... Talajic M, Kerr CR
Background -: Traditionally, the pharmacologic management of atrial fibrillation (AF), the most common sustained cardiac arrhythmia, has been dichotomized into control of ventricular rate or the reestablishment and maintenance of sinus rhythm. Objective -: The purpose of this study was to evaluate the use of rate-controlling drugs, and antiarrhythmic drugs (AAD) in the Canadian Registry of Atrial Fibrillation (CARAF) over a 16-year period from 1991 through 2007. METHODS -: 1,400 patients with new-onset paroxysmal AF who were enrolled in CARAF were included in this analysis. We assessed trends in ventricular rate-controlling medication use (digoxin, beta-blockers, and calcium channel blockers) and AAD (class IA, IC and III antiarrhythmics) at baseline and follow-up visits as well as by calendar year. RESULTS -: AAD use increased initially from 1991 to 1994 (peak use 42.5%) before steadily declining. Sotalol use decreased (27% to 6%) while amiodarone use increased (1.6% to 17.9%). Rate-controlling medication use decreased from 1991 to 1995 (54.1% to 34.1%) due to declining digoxin use (62.9% to 16.3%). After 1999, there was a continued rise in rate-controlling medication use (peak use 52.5% in 2007) due to increased beta-blocker use (17% to 45.7%). Calcium channel blockers use changed little over the duration of the study. CONCLUSION -: The management of AF has undergone significant shifts since 1990, reflecting the influence of drug development, prevailing belief systems, the impact of large clinical trials and evidence-based recommendations. Monitoring of pharmacotherapy trends will provide insight into the "real-world" application evidence-based guidelines, as well as allow the opportunity to identify deficiencies and improve patient care.

Heart Rhythm: 30 Apr 2010; epub ahead of print
Andrade JG, Connolly SJ, Dorian P, Green M, ... Talajic M, Kerr CR
Heart Rhythm: 30 Apr 2010; epub ahead of print | PMID: 20430112
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Abstract

Rationale and Objectives for ECG Screening in Infancy.

Philip Saul J, Schwartz PJ, Ackerman MJ, Triedman JK
Electrocardiographic (ECG) screening of infants and children who may be at risk for sudden cardiac death is controversial, and both rational and emotional arguments have often been given similar weights. The authors each have direct experience in this field, but have different backgrounds and have expressed divergent views on this topic. We attempted to build consensus among ourselves based on the available facts, in hopes of providing an unbiased review of the relevant science and policy issues in favor of or against ECG screening in infants and children. This report presents our shared view on this medically and societally important topic. The long QT syndrome (LQTS) satisfies several criteria that may make ECG screening worthwhile: it is not rare (~1 in 2,000 births); ECG diagnosis is feasible and can be used to trigger appropriate genetic testing; it causes approximately 10% of cases of sudden infant death syndrome as well as deaths in childhood and later in life, and effective treatments are available. By stimulating cascade screening of family members, diagnosis of affected infants may also prompt identification of asymptomatic but affected individuals. Neonatal screening is cost-effective using conventional criteria, and with a QTc cutoff of 460 ms in two different ECGs the number of false positives is estimated to be low (~1 in 1,000). It is our conclusion that parents of newborn children should be informed about LQTS, a life-threatening but very treatable disease of significant prevalence that may be diagnosed by a simple ECG.

Heart Rhythm: 19 Sep 2014; epub ahead of print
Philip Saul J, Schwartz PJ, Ackerman MJ, Triedman JK
Heart Rhythm: 19 Sep 2014; epub ahead of print | PMID: 25239430
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Abstract

Left Ventricular Epicardial Electrogram Recordings in Idiopathic Ventricular Fibrillation with Inferior and Lateral Early Repolarization.

Nakagawa K, Nagase S, Morita H, Ito H
We report the first case of idiopathic ventricular fibrillation (VF) with inferior and lateral early repolarization (ER) in which left ventricular (LV) epicardial electrogram recording was performed. The patient was a 42-year-old male with inferior and lateral ER on ECG and an episode of VF. In electrophysiological study, we recorded prominent J waves and potentials after the QRS complex at the epicardium of lateral LV, but not within the endocardium at the opposite area. These features were accentuated on pilsicainide administration but diminished on constant atrial pacing and isoproterenol administration. The epicardial J wave almost coincided with the ER on ECG. Atrial pacing and isoproterenol diminished ER; however, pilsicainide also diminished ER with accentuated S wave in lead V4. This might be due to the transmural or far-field conduction delay causing the J wave to merge with the S wave. VF was induced with programmed stimulation only from lateral LV epicardium. The epicardial myocardium of the LV might contribute to arrhythmogenesis in this patient.

Heart Rhythm: 03 Nov 2013; epub ahead of print
Nakagawa K, Nagase S, Morita H, Ito H
Heart Rhythm: 03 Nov 2013; epub ahead of print | PMID: 24184784
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2015 ACC/AHA/HRS Advanced Training Statement on Clinical Cardiac Electrophysiology (A Revision of the ACC/AHA 2006 Update of the Clinical Competence Statement on Invasive Electrophysiology Studies, Catheter Ablation, and Cardioversion).

Zipes DP, Calkins H, Williams ES, Halperin JL
The document was approved by the American College of Cardiology Board of Trustees in August 2015 and Executive Committee in September 2015, the American Heart Association Science Advisory and Coordinating Committee in August 2015 and Executive Committee in September 2015, and by the Heart Rhythm Society Board of Trustees in August 2015. For the purpose of transparency, disclosure information for the ACC Board of Trustees, the board of the convening organization of this document, is available at: http://www.acc.org/about-acc/leadership/officers-and-trustees. The American College of Cardiology requests that this document be cited as follows: Zipes DP, Calkins H, Daubert JP, Ellenbogen KA, Field ME, Fisher JD, Fogel RI, Frankel DS, Gupta A, Indik JH, Kusumoto FM, Lindsay BD, Marine JE, Mehta LS, Mendes LA, Miller JM, Munger TM, Sauer WH, Shen WK, Stevenson WG, Su WW, Tracy CM, Tsiperfal A. ACC/AHA/HRS advanced training statement on clinical cardiac electrophysiology (a revision of the ACC/AHA 2006 update of the clinical competence statement on invasive electrophysiology studies, catheter ablation, and cardioversion). J Am Coll Cardiol 20XX; XX:xxx-xx. This article is copublished in Circulation: Arrhythmia and Electrophysiology and HeartRhythm Journal. Copies: This document is available on the World Wide Web sites of the American College of Cardiology (www.acc.org), American Heart Association (http://myamericanheart.org), and Heart Rhythm Society (www.hrsonline.org). For copies of this document, please contact Elsevier Inc. Reprint Department, fax (212) 633-3820, email [email protected] Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of the American College of Cardiology. Requests may be completed online via the Elsevier site (http://www.elsevier.com/about/policies/author-agreement/obtaining-permission).

Heart Rhythm: 21 Sep 2015; epub ahead of print
Zipes DP, Calkins H, Williams ES, Halperin JL
Heart Rhythm: 21 Sep 2015; epub ahead of print | PMID: 26392325
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This program is still in alpha version.