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1.  A Common Missense Variant in the Neuregulin1 Gene is associated with Both Schizophrenia and Sudden Cardiac Death 
Background
Both schizophrenia and epilepsy have been linked to increased risk of sudden cardiac death (SCD). We hypothesized that DNA variants within genes previously associated with schizophrenia and epilepsy may contribute to an increased risk of SCD.
Objective
To investigate the contribution to SCD susceptibility of DNA variants previously implicated in schizophrenia and epilepsy.
Methods
From the ongoing Oregon Sudden Unexpected Death Study, comparisons were performed among 340 SCD cases presenting with ventricular fibrillation and 342 controls. We tested for association between 17 SNPs mapped to 14 loci previously implicated in schizophrenia and epilepsy using logistic regression, assuming additive, dominant and recessive genetic models.
Results
The minor allele of the non-synonymous SNP rs10503929 within the Neuregulin 1 gene (NRG1) was associated with SCD under all three investigated models, with the strongest association for the recessive genetic model (recessive P=4.01×10−5, OR= 4.04; additive P=2.84×10−7, OR= 1.9 and dominant P=9.01×10−6, OR= 2.06). To validate our findings, we further explored the association of this variant in the Harvard Cohort SCD study. The SNP rs10503929 was associated with an increased risk of SCD under the recessive genetic model (P=0.0005, OR= 2.7). This missense variation causes a methionine to threonine change and functional effects are currently unknown.
Conclusions
The observed association between a schizophrenia-related NRG1 variant and SCD may represent the first evidence of coexisting genetic susceptibility between two conditions that have an established clinical overlap. Further investigation is warranted to explore the molecular mechanisms of this variant in the pathogenesis of SCD.
doi:10.1016/j.hrthm.2013.03.020
PMCID: PMC3692570  PMID: 23524320
sudden cardiac death; association study; genetics; schizophrenia; epilepsy; neuregulin-1
2.  Inhibition of Platelet-Derived Growth Factor-AB Signaling Prevents Electromechanical Remodeling of Adult Atrial Myocytes that Contact Myofibroblasts 
Background
Persistent atrial fibrillation (PAF) results in electromechanical and structural remodeling by mechanisms that are poorly understood. Myofibroblast proliferation and fibrosis is a major source of structural remodeling in PAF. Myofibroblasts also interact with atrial myocytes via direct physical contact and release of signaling molecules that may contribute to remodeling.
Objective
To determine whether myofibroblasts contribute to atrial myocyte electromechanical remodeling via direct physical contact and platelet-derived growth factor (PDGF) signaling.
Methods and Results
Myofibroblasts and myocytes from adult sheep atria were co-cultured for 24 hours. Myocytes making contact with myofibroblasts demonstrated significant reduction (p≤0.05) in L-type calcium (ICa,L) peak current density, shortening of action potential duration (APD)and reduction in calcium transients. These effects were blocked by pre-treatment with neutralizing PDGF-AB antibody (N-ab). Heterocellular contact also severely disturbed the localization of the L-type calcium channel. Exposure of adult sheep atrial myocytes to 1ng/ml recombinant PDGF-AB peptide for 24 hours reduced both APD50 and APD80 (p≤0.05). Peak ICa,L was reduced as well. Pretreatment with N-ab prevented these effects. Finally, while control atrial myocytes did not respond 1:1 to pacing frequencies >3 Hz, atrial myocytes from hearts that were tachypaced for 2 months and normal myocytes treated with PDGF-AB for 24 hrs could be paced at 10 Hz.
Conclusion
In addition to leading to fibrosis, atrial myofibroblasts contribute to electromechanical remodeling of myocytes via direct physical contact and release of PDGF-AB, which may be a factor in PAF induced remodeling.
doi:10.1016/j.hrthm.2013.03.014
PMCID: PMC3692578  PMID: 23499624
arrhythmia; electrophysiology; ion channels; atrial fibrillation; PDGF; calcium channel
3.  Effect of Wenxin Keli and Quinidine to Suppress Arrhythmogenesis in an Experimental Model of Brugada Syndrome 
Background
Wenxin Keli (WK), a Chinese herb extract, is reported to be effective in the treatment of atrial and ventricular cardiac arrhythmias. Recent studies suggest that WK inhibits the transient outward current (Ito).
Objective
The present study examines the effectiveness of WK, alone and in combination with quinidine, to suppress arrhythmogenesis in an experimental model of Brugada syndrome (BrS).
Methods and Results
Action potential and ECG recordings were obtained from epicardial and endocardial sites of coronary-perfused canine right ventricular wedge preparations. The Ito agonist NS5806 (10–15 μM) was used to pharmacologically mimic a genetic predisposition to BrS. The Ito agonist induced Phase 2 reentry (P2R) in 13/19 preparations and polymorphic ventricular tachycardia (pVT) in 11/19 wedge preparations. WK (10g/L) suppressed P2R and pVT in 100% (3/3) of preparations. A lower concentration of WK (5g/L) suppressed P2R in 60% (3/5) and pVT in 50% (2/4), but in combination with a low concentration of quinidine (5 μM) was 100% effective in suppressing P2R and pVT. Quinidine alone suppressed P2R and pVT in 60% (3/5) and 50% (2/4), respectively and in combination with WK (5g/L) suppressed P2R and pVT by 80% (4/5) and 75% (3/4), respectively. WK reduced Ito, ICa and contractility in single cardiomyocytes, but dose-dependently increased contractility in intact wedge preparations, an effect mimicked by tyramine.
Conclusions
Our data provide support for the hypothesis that Wenxin Keli, particularly in combination with quinidine, effectively suppresses arrhythmogenesis in an experimental model of BrS via inhibition of Ito and indirect adrenergic sympathomimetic effects.
doi:10.1016/j.hrthm.2013.03.011
PMCID: PMC3702731  PMID: 23499631
Transient outward potassium channel current; positive inotropic effect; cardiac arrhythmias; sudden cardiac death
4.  Regulation of the SK3 channel by MicroRNA-499 - potential role in atrial fibrillation 
BACKGROUND
MicroRNAs are important regulators of gene expression, including those involving electrical remodeling in atrial fibrillation (AF). Recently, KCNN3, the gene that encodes the small conductance calcium-activated potassium channel 3 (SK3), was found to be strongly associated with AF.
OBJECTIVES
This study sought to evaluate the changes in atrial myocardial microRNAs in patients with permanent AF and to determine the role of microRNA on the regulation of cardiac SK3 expression.
METHODS
Atrial tissue obtained during cardiac surgery from patients (4 sinus rhythm and 4 permanent AF) was analyzed by microRNA arrays. Potential targets of microRNAs were predicted by software programs. The effects of specific microRNAs on target gene expression were evaluated in HL-1 cells from a continuously proliferating mouse hyperplastic atrial cardiomyocyte cell line. Interactions between microRNAs and targets were further evaluated by luciferase reporter assay and by Argonaute pull-down assay.
RESULTS
Twenty one microRNAs showed significant, greater than two-fold changes in AF. miR-499 was upregulated by 2.33 fold (P<0.01) in AF atria, whereas SK3 protein expression was down-regulated by 46% (P<0.05). Transfection of miR-499 mimic in HL-1 cells resulted in the downregulation of SK3 protein expression, while that of miR-499 inhibitor upregulated SK3 expression. Binding of miR-499 to the 3′UTR of KCNN3 was confirmed by luciferase reporter assay and by the enhanced presence of SK3 mRNA in Argonaute pulled-down microRNA-induced silencing complexes (mRISC) after transfection with miR-499.
CONCLUSION
Atrial miRNA-499 is significantly upregulated in AF, leading to SK3 downregulation and possibly contributing to the electrical remodeling in AF.
doi:10.1016/j.hrthm.2013.03.005
PMCID: PMC3710704  PMID: 23499625
atrial fibrillation; microRNA; SK3 channel; electrical remodeling; small-conductance calcium-activated potassium channel
6.  Ventricular fibrillation associated with complete right bundle branch block 
BACKGROUND
A substantial number of patients with idiopathic ventricular fibrillation (IVF) present with no specific electrocardiographic (ECG) findings.
OBJECTIVE
To evaluate complete right bundle branch block (RBBB) in patients with IVF.
METHODS
Patients with IVF showing complete RBBB were included in the present study. Structural and primary electrical diseases were excluded, and provocation tests were performed to exclude the presence of spastic angina or Brugada syndrome (BrS). The prevalence of complete RBBB and the clinical and ECG parameters were compared either in patients with IVF who did not show RBBB or in the general population and age and sex comparable controls with RBBB.
RESULTS
Of 96 patients with IVF, 9 patients were excluded for the presence of BrS. Of 87 patients studied, 10 (11.5%) patients showed complete RBBB. None had structural heart diseases, BrS, or coronary spasms. The mean age was 44 ± 15 years, and 8 of 10 patients were men. Among the ECG parameters, only the QRS duration was different from that of the other patients with IVF who did not show complete RBBB. Ventricular fibrillation recurred in 3:2 in the form of storms, which were well suppressed by isoproterenol. Complete RBBB was found less often in control subjects (1.37%; P < .0001), and the QRS duration was more prolonged in patients with IVF: 139 ± 10 ms vs 150 ± 14 ms (P = .0061).
CONCLUSIONS
Complete RBBB exists more often in patients with IVF than in controls. A prolonged QRS complex suggests a conduction abnormality. Our findings warrant further investigation of the role of RBBB in the development of arrhythmias in patients with IVF.
doi:10.1016/j.hrthm.2013.03.013
PMCID: PMC3770839  PMID: 23499623
Sudden death; Idiopathic ventricular fibrillation; Right bundle branch block; Electrocardiogram; Brugada syndrome
7.  Antiarrhythmic effects of the highly selective late sodium channel current blocker GS-458967 
Heart rhythm : the official journal of the Heart Rhythm Society  2013;10(7):10.1016/j.hrthm.2013.03.023.
BACKGROUND
Previous studies have shown that late sodium channel current (INa) blockers such as ranolazine can exert antiarrhythmic effects by suppressing early and delayed after-depolarization (EAD and DAD)-induced triggered activity.
OBJECTIVE
To evaluate the electrophysiological properties of GS-458967 (GS967), a potent and highly selective late INa blocker, in canine Purkinje fibers (PFs) and pulmonary vein (PV) and superior vena cava (SVC) sleeve preparations.
METHODS
Transmembrane action potentials were recorded from canine PFs and PV and SVC sleeve preparations by using standard microelectrode techniques. The rapidly activating delayed rectifier potassium channel current blocker E-4031 (2.5–5 μM) and the late INa agonist ATX-II (10 nM) were used to induce EADs in PFs. Isoproterenol (1 μM), high calcium ([Ca2+]o = 5.4 mM), or their combination was used to induce DADs and triggered activity.
RESULTS
In PFs, GS967 (10–300 nM) caused a significant concentration-dependent reduction in action potential duration without altering the maximum rate of rise of the action potential upstroke, action potential amplitude, or resting membrane potential at any rate studied (basic cycle lengths of 1000, 500, and 300 ms) or concentration evaluated (n = 5; P < .05). GS967 (30–100 nM) abolished EADs and EAD-induced triggered activity elicited in PFs by exposure to E-4031 (n = 4) or ATX-II (n = 4). In addition, GS967 reduced or abolished DADs and suppressed DAD-induced triggered activity elicited in PFs (n = 4) and PV (n = 4) and SVC (n = 3) sleeve preparations by exposure to isoproterenol, high calcium, or their combination.
CONCLUSIONS
Our data suggest that the selective inhibition of late INa with GS967 can exert antiarrhythmic effects by suppressing EAD- and DAD-mediated extrasystolic activity in PFs and PV and SVC sleeve preparations.
doi:10.1016/j.hrthm.2013.03.023
PMCID: PMC3836836  PMID: 23524321
Antiarrhythmic drugs; Electrophysiology; Pharmacology; Late sodium current; Ranolazine
9.  Pro-arrhythmic Effect of Blocking the Small Conductance Calcium Activated Potassium Channel in Isolated Canine Left Atrium 
Background
Small conductance calcium activated potassium channels (SKCa) are voltage insensitive and are activated by intracellular calcium. Genome wide association studies revealed that a variant of SKca is associated with lone atrial fibrillation (AF) in humans. Roles of SKca in atrial arrhythmias remain unclear.
Objective
The purpose of this study was to determine roles of SKCa in atrial arrhythmias.
Methods
Optical mapping using isolated canine left atrium was performed. The optical action potential duration (APD) and induction of arrhythmia were evaluated before and after the addition of specific SKCa blockers, Apamin or UCL-1684.
Results
SKCa blockade significantly increased APD80 (188±19 ms vs 147±11ms, p< 0.001). The pacing cycle length (PCL) thresholds to induce 2:2 alternans and wave breaks were prolonged by SKCa blockade. Increased APD heterogeneity was observed following SKCa blockade, as measured by the difference between maximum and minimum APD (39±4ms vs 26±5ms, p<0.05), by standard deviation (12.43±2.36ms vs 7.49±1.47ms, p<0.001), or by coefficient of variation (6.68±0.97% vs 4.90±0.84%, p<0.05). No arrhythmia was induced at baseline by S1–S2 protocol. After SKCa blockade, 4 out of 6 atria developed arrhythmia.
Conclusion
Blockade of SKCa promotes arrhythmia and prolongs the PCL threshold of 2:2 alternans and wave breaks in the canine left atrium. The proarrhythmic effect could be attributed to the increased APD heterogeneity in the canine left atrium. This study provides supportive evidence of GWAS studies showing association of KCNN3 and lone AF
doi:10.1016/j.hrthm.2013.01.033
PMCID: PMC3663880  PMID: 23376397
Atrial arrhythmia; SKCa; action potential duration; repolarization; optical mapping
10.  Low-Level Vagus Nerve Stimulation Upregulates Small Conductance Calcium Activated Potassium Channels in the Stellate Ganglion 
Background
Small conductance calcium activated potassium (SK) channels are responsible for afterhyperpolarization that suppresses nerve discharges.
Objectives
To test the hypotheses that low-level vagus nerve stimulation (LL-VNS) leads to the upregulation of SK2 proteins in the LSG.
Methods
Six dogs (Group 1) underwent 1-wk LL-VNS of the left cervical vagus nerve. Five normal dogs (Group 2) were used as control. SK2 protein levels were examined by western blotting. The ratio between SK2 and glyceraldehydes-3-phosphate-dehydrogenase (GAPDH) levels was used as an arbitrary unit (AU).
Results
We found higher SK2 expression in Group 1 (0.124 ± 0.049 AU) than Group 2 (0.085 ± 0.031 AU, P < 0.05). Immunostaining showed that the density of nerve structures stained with SK2 antibody was also higher in Group 1 (11,546 ± 7,271 μm2/mm2) than in Group 2 (5,321 ± 3,164 μm2/mm2, P < 0.05). There were significantly more ganglion cells without immunoreactivity to TH in Group 1 (11.4 ± 2.3%) than Group 2 (4.9 ± 0.7%; P < 0.05). The TH-negative ganglion cells mostly stained positive for choline acetyltransferase (ChAT) (95.9 ± 2.8% in Group 1 and 86.1 ± 4.4% in Group 2, P = 0.10). Immunofluorescence confocal microscopy revealed a significant decrease in the SK2 staining in the cytosol but an increase in the SK2 staining on the membrane of the ganglion cells in Group 1 compared to Group 2.
Conclusion
Left LL-VNS results in the upregulation of SK2 proteins, increased SK2 protein expression in the cell membrane and the increased TH-negative (mostly ChAT-positive) ganglion cells in the LSG. These changes may underlie the antiarrhythmic efficacy of LL-VNS in ambulatory dogs.
doi:10.1016/j.hrthm.2013.01.029
PMCID: PMC3671581  PMID: 23357541
Autonomic nervous system; Vagus nerve stimulation; Stellate ganglion; Small conductance calcium activated potassium channel; Western blot
11.  Arrhythmia Risk Stratification based on QT Interval Instability 
Background
Experimental studies have demonstrated that unstable repolarization dynamics is a risk factor of arrhythmia. We have recently developed an algorithm to detect QT interval (QTI) instability from the clinical ECG. In this study we developed a clinical arrhythmia risk stratification index based on the detection of QTI instability.
Methods
Intracardiac electrocardiograms were recorded at rest in 114 patients with implanted ICDs. Patients were followed up until appropriate ICD therapy or death occurred, whichever came first. Each recording was divided into 1-min episodes (minECGs); the instability in QTI dynamics, if any, of each minECG was detected with our algorithm. An arrhythmia risk index termed QTI instability index (QTII) was defined as the number of minECGs with unstable QTI dynamics normalized by the number of minECGs with premature activations (PA). The performance of QTII in arrhythmia risk stratification was examined with survival analysis, and was compared with other risk indices, such as mean RR interval (RRI), the standard deviation of RRI and QTI, and the frequency of PA. We hypothesized that the index QTII, which account for multiple risk factors and their interdependence, perform better than indices quantifying individual arrhythmia risk factors in the stratification of arrhythmia risk.
Results
The results of survival analysis show that QTII outperformed all other studied indices in arrhythmia risk stratification and was the only independent indicator of arrhythmia propensity in a multivariate survival model.
Conclusion
QTII is a promising arrhythmia risk stratification index.
doi:10.1016/j.hrthm.2013.02.014
PMCID: PMC3703156  PMID: 23416373
arrhythmia; implantable cardioverter-defibrillator; QT interval electrocardiography; risk stratification; sudden death
12.  A Clinical Feasibility Study of Atrial and Ventricular Electromechanical Wave Imaging 
Background
Cardiac Resynchronization Therapy (CRT) and atrial ablation currently lack a noninvasive imaging modality for reliable treatment planning and monitoring. Electromechanical Wave Imaging (EWI) is an ultrasound-based method that has previously been shown to be capable of noninvasively and transmurally mapping the activation sequence of the heart in animal studies by estimating and imaging the electromechanical wave, i.e., the transient strains occurring in response to the electrical activation, at both very high temporal and spatial resolution.
Objective
Demonstrate the feasibility of noninvasive transthoracic EWI for mapping the activation sequence during different cardiac rhythms in humans.
Methods
EWI was performed in CRT patients with a left bundle-branch block (LBBB), during sinus rhythm, left-ventricular pacing, and right-ventricular pacing and in atrial flutter (AFL) patients before intervention and correlated with results from invasive intracardiac electrical mapping studies during intervention. Additionally, the feasibility of single-heartbeat EWI at 2000 frames/s, is demonstrated in humans for the first time in a subject with both AFL and right bundle-branch-block.
Results
The electromechanical activation maps demonstrated the capability of EWI to localize the pacing sites and characterize the LBBB activation sequence transmurally in CRT patients. In AFL patients, the propagation patterns obtained with EWI were in agreement with results obtained from invasive intracardiac mapping studies.
Conclusion
Our findings demonstrate the potential capability of EWI to aid in monitoring and follow-up of patients undergoing CRT pacing therapy and atrial ablation with preliminary validation in vivo.
doi:10.1016/j.hrthm.2013.02.028
PMCID: PMC4005774  PMID: 23454060
Ablation; Arrhythmias; Noninvasive Imaging; Pacing
13.  Survival Benefit of Primary Prevention Implantable Cardioverter-Defibrillator Therapy After Myocardial Infarction: Does Time to Implant Matter? 
Background
Whether there is an optimal time to place an implantable cardioverter-defibrillator (ICD) more than 40 days after myocardial infarction (MI) in guideline-eligible patients is unknown.
Objective
To evaluate the impact of time from MI to randomization on mortality, re-hospitalizations, and complications.
Methods
Individual data on patients enrolled in 9 primary and secondary prevention ICD trials were provided. Clinical trials were eligible for the current analysis if they enrolled patients with an MI more than 40 days prior to randomization to primary prevention ICD therapy versus usual care: MADIT-I, MUSTT, MADIT-II, and SCD-HeFT.
Results
ICD recipients died less frequently than non-recipients at 5 years across all subgroups of time from MI to randomization. In unadjusted Cox proportional hazards regression, a survival benefit was evident in most subgroups. Adjusted Bayesian Weibull survival modeling yielded hazard ratio (HR) 0.50, 95% posterior credible interval [PCI] 0.20–1.25 41–180 days after MI; HR 0.98, 95% PCI 0.37–2.37 181–365 days after MI; HR 0.22, 95% PCI 0.07–0.59 >1–2 years after MI; HR 0.42, 95% PCI 0.17–0.90 >2–5 years after MI; HR 0.55, 95% PCI 0.25–1.15 >5–10 years after MI; and HR 0.48, 95% PCI 0.20–1.02 > 10 years after MI. There was no evidence of an interaction between time from MI and all-cause mortality, re-hospitalizations, or complications.
Conclusions
In this meta-analysis, there was scant evidence that the efficacy of primary prevention ICD therapy and no evidence that the risks of re-hospitalizations or complications are dependent on time to implantation more than 40 days after MI.
doi:10.1016/j.hrthm.2013.02.011
PMCID: PMC4037291  PMID: 23416381
implantable cardioverter-defibrillator; sudden cardiac death; myocardial infarction; heart failure
15.  Mutation and Gender Specific Risk in Type-2 Long QT Syndrome 
Background
Men and women with type-2 long QT syndrome (LQT2) exhibit time-dependent differences in the risk for cardiac events. We hypothesized that data regarding the location of the disease-causing mutation in the KCNH2 channel may affect gender-specific risk in LQT2
Objectives
To risk stratify LQT2 patients for life-threatening cardiac events based on clinical and genetic information.
Methods
The risk for life-threatening cardiac events from birth through age 40 (comprising aborted cardiac arrest [ACA] or sudden cardiac death [SCD]) years was assessed among 1,166 LQT2 males (n=490) and females (n=676) by the location of the LQTS-causing mutation in the KCNH2 channel (pre-specified in the primary analysis as pore-loop vs. nonpore-loop).
Results
During follow-up, the cumulative probability of life-threatening cardiac events years was significantly higher among LQT2 women (26%) as compared with men (14%; p<0.001). Multivariate analysis showed that the risk for life-threatening cardiac events was not significantly different between women with and without pore-loop mutations (HR=1.20; p=0.33). In contrast, men with pore-loop mutations displayed a significant >2-fold higher risk of a first ACA or SCD as compared with those with nonpore-loop mutations (HR=2.18; p=0.01). Consistently, women experienced a high rate of life-threatening events regardless of mutation-location (pore-loop: 35%, nonpore-loop: 23%), whereas in men the rate of ACA or SCD was high among those with pore-loop mutations (28%) and relatively low among those with nonpore-loop mutations (8%).
Conclusion
Combined assessment of clinical and mutation-specific data can be used for improved risk stratification for life-threatening cardiac events in type-2 long QT syndrome.
doi:10.1016/j.hrthm.2011.03.049
PMCID: PMC4028036  PMID: 21440677
long-QT syndrome; pore-loop mutations; sudden cardiac death; gender
16.  CARDIAC MRI SCAR PATTERNS DIFFER BY GENDER IN AN IMPLANTABLE CARDIOVERTER DEFIBRILLATOR AND CARDIAC RESYNCHRONIZATION COHORT 
Background
Recent meta-analyses suggest that the effectiveness of cardiac devices may differ between genders. Compared to men, women may not benefit as much from implantable defibrillators (ICDs), yet benefit more from cardiac resynchronization therapy (CRT). Myocardial scar burden is associated with increased incidence of appropriate ICD shocks but decreased response to CRT and may explain gender differences in device benefit.
Objective
To test the hypothesis that the extent of myocardial scar is less in women than men.
Methods
In 235 patients referred for primary prevention ICDs who underwent cardiac magnetic resonance imaging, we compared scar size by gender. Analyses were performed for all patients (ICD cohort) and those receiving biventricular pacemakers (CRT subgroup).
Results
In the ICD cohort, women (vs. men) had a higher prevalence of non-ischemic cardiomyopathy (NICM, 64% vs. 39%, p<0.001) which accounted for a smaller overall scar burden (0.5% vs 13%, p<0.01). Likewise, in the CRT subgroup, the higher prevalence of NICM in women (83% vs. 46%, p=0.01) also contributed to a smaller scar size (0 vs 13%, p<0.01). Women also had significantly less scarring of the inferolateral LV wall.
Conclusions
In a cohort of patients undergoing clinically indicated ICD and CRT, women had less myocardial scar than men. This difference was primarily driven by a higher prevalence of NICM in women. These findings may have important implications for the future study of gender disparities in ICD and CRT outcomes.
doi:10.1016/j.hrthm.2013.01.003
PMCID: PMC3636172  PMID: 23313802
Cardiac Magnetic Resonance Imaging; Implantable Cardioverter-Defibrillators; Cardiac Resynchronization Therapy; Gender
17.  Inhibition of CaMKII Phosphorylation of RyR2 Prevents Inducible Ventricular Arrhythmias in Mice with Duchenne Muscular Dystrophy 
Background
Ventricular tachycardia (VT) is the second most common cause of death in patients with Duchenne muscular dystrophy (DMD). Recent studies have implicated enhanced sarcoplasmic reticulum (SR) Ca2+ leak via ryanodine receptors (RyR2) as a cause of VT in the mdx mouse model of DMD. However, the signaling mechanisms underlying induction of SR Ca2+ leak and VT are poorly understood.
Objective
To test whether enhanced CaMKII phosphorylation of RyR2 underlies SR Ca2+ leak and induction of VT in mdx mice.
Methods
Programmed electrical stimulation (PES) was performed on anesthetized mice, and confocal imaging of calcium release events in isolated ventricular myocytes.
Results
PES revealed inducible VT in mdx mice, which was inhibited by CaMKII inhibition or mutation S2814A in RyR2. Myocytes from mdx mice exhibited more Ca2+ sparks and Ca2+ waves compared with wild type (WT) mice, in particular at faster pacing rates. Arrhythmogenic Ca2+ waves were inhibited by CaMKII but not PKA inhibition. Moreover, mutation S2814A but not S2808A in RyR2 suppressed spontaneous Ca2+ waves in myocytes from mdx mice.
Conclusion
CaMKII blockade and genetic inhibition of RyR2-S2814 phosphorylation prevent VT induction in a mouse model of DMD. In ventricular myocytes from mdx mice, spontaneous Ca2+ sparks and Ca2+ waves can be suppressed by CaMKII inhibition or mutation S2814A in RyR2. Thus, inhibition of CaMKII-induced SR Ca2+ leak might be a new strategy to prevent arrhythmias in patients with DMD without heart failure.
doi:10.1016/j.hrthm.2012.12.016
PMCID: PMC3605194  PMID: 23246599
Cardiac arrhythmias; Ca2+/calmodulin kinase II; mouse model; ryanodine receptor; Duchenne muscular dystrophy; ventricular tachycardia
19.  Sympathetic nerve fibers and ganglia in canine cervical vagus nerves: Localization and quantitation 
Background
Cervical vagal nerve (CVN) stimulation may improve left ventricular ejection fraction in patients with heart failure.
Objectives
To test the hypothesis that sympathetic structures are present in the CVN and to describe the location and quantitate these sympathetic components of the CVN.
Methods
We performed immunohistochemical studies of the CVN from 11 normal dogs and simultaneously recorded stellate ganglion nerve activity, left thoracic vagal nerve activity, and subcutaneous electrocardiogram in 2 additional dogs.
Results
A total of 28 individual nerve bundles were present in the CVNs of the first 11 dogs, with an average of 1.87 ± 1.06 per dog. All CVNs contain tyrosine hydroxylase-positive (sympathetic) nerves, with a total cross-sectional area of 0.97 ± 0.38 mm2. The sympathetic nerves were nonmyelinated, typically located at the periphery of the nerve bundles and occupied 0.03%–2.80% of the CVN cross-sectional area. Cholineacetyltransferase-positive nerve fibers occupied 12.90%–42.86% of the CVN cross-sectional areas. Ten of 11 CVNs showed tyrosine hydroxylase and cholineacetyltransferase colocalization. In 2 dogs with nerve recordings, we documented heart rate acceleration during spontaneous vagal nerve activity in the absence of stellate ganglion nerve activity.
Conclusions
Sympathetic nerve fibers are invariably present in the CVNs of normal dogs and occupy in average up to 2.8% of the cross-sectional area. Because sympathetic nerve fibers are present in the periphery of the CVNs, they may be susceptible to activation by electrical stimulation. Spontaneous activation of the sympathetic component of the vagal nerve may accelerate the heart rate.
doi:10.1016/j.hrthm.2012.12.015
PMCID: PMC3758134  PMID: 23246597
Cervical vagus nerves; Sympathetic nerves; Ganglion cells; Heart failure; Vagal nerve stimulation
20.  Noninvasive electrocardiographic mapping to guide ablation of outflow tract ventricular arrhythmias 
Heart Rhythm  2014;11(4):587-594.
Background
Localizing the origin of outflow tract ventricular tachycardias (OTVT) is hindered by lack of accuracy of electrocardiographic (ECG) algorithms and infrequent spontaneous premature ventricular complexes (PVCs) during electrophysiological studies.
Objectives
To prospectively assess the performance of noninvasive electrocardiographic mapping (ECM) in the pre-/periprocedural localization of OTVT origin to guide ablation and to compare the accuracy of ECM with that of published ECG algorithms.
Methods
Patients with symptomatic OTVT/PVCs undergoing clinically indicated ablation were recruited. The OTVT/PVC origin was mapped preprocedurally by using ECM, and 3 published ECG algorithms were applied to the 12-lead ECG by 3 blinded electrophysiologists. Ablation was guided by using ECM. The OTVT/PVC origin was defined as the site where ablation caused arrhythmia suppression. Acute success was defined as abolition of ectopy after ablation. Medium-term success was defined as the abolition of symptoms and reduction of PVC to less than 1000 per day documented on Holter monitoring within 6 months.
Results
In 24 patients (mean age 50 ± 18 years) recruited ECM successfully identified OTVT/PVC origin in 23/24 (96%) (right ventricular outflow tract, 18; left ventricular outflow tract, 6), sublocalizing correctly in 100% of this cohort. Acute ablation success was achieved in 100% of the cases with medium-term success in 22 of 24 patients. PVC burden reduced from 21,837 ± 23,241 to 1143 ± 4039 (P < .0001). ECG algorithms identified the correct chamber of origin in 50%–88% of the patients and sublocalized within the right ventricular outflow tract (septum vs free-wall) in 37%–58%.
Conclusions
ECM can accurately identify OTVT/PVC origin in the left and the right ventricle pre- and periprocedurally to guide catheter ablation with an accuracy superior to that of published ECG algorithms.
doi:10.1016/j.hrthm.2014.01.013
PMCID: PMC4067940  PMID: 24440381
CT, computed tomographic; EF, ejection fraction; ECG, electrocardiographic; ECM, electrocardiographic mapping; EPS, electrophysiological study; LV, left ventricular/ventricle; LVOT, left ventricular outflow tract; OTVT, outflow tract ventricular tachycardia; PVC, premature ventricular complex; PVS, programmed ventricular stimulation; RV, right ventricular/ventricle; RVOT, right ventricular outflow tract; VT, ventricular tachycardia; Ventricular tachycardia; Premature ventricular complex; Outflow tract tachycardia
21.  Sudden infant death syndrome: Do ion channels play a role? 
doi:10.1016/j.hrthm.2008.07.028
PMCID: PMC3940066  PMID: 18823823
Sudden infant death syndrome; Long QT syndrome; Ion channels; Genetics; QT interval; Electrocardiogram
22.  Prevalence of early-onset atrial fibrillation in congenital long QT syndrome 
BACKGROUND
The prevalence of atrial fibrillation (AF) in the young (age <50 years) is 0.1%, or 1:1,000 persons. Mutations in KCNQ1-, KCNH2-, and KCNA5-encoded potassium channels and SCN5A-encoded sodium channels have been reported in familial AF. A mechanism of atrial torsade has been suggested to occur in patients with congenital long QT syndrome (LQTS).
OBJECTIVE
The purpose of this study was to determine the prevalence of AF in patients with congenital LQTS.
METHODS
History of documented AF was sought from two independent cohorts. One cohort consisted of 252 consecutive patients (146 females and 106 males, average age at diagnosis 23 ± 16 years, QTc 465 ± 51 ms) with genetically proven LQTS seen at Mayo’s LQTS Clinic. The second cohort consisted of 205 consecutive patients (133 females and 72 males, average age at testing 23 ± 16 years, QTc 479 ± 51 ms) with a positive FAMILION genetic test (PGxHealth) for LQTS.
RESULTS
Early-onset AF was documented in 8 (1.7%) of 457 patients, including 6 (2.4%) of 252 patients seen at Mayo and 2 (1%) of 205 patients with a positive FAMILION test. Five (2.4%) of 211 patients with LQT1-susceptibility mutations had documented AF, compared to 0 of 174 patients with LQT2, 1 of 59 patients with LQT3, 1 of 1 patient with Andersen-Tawil syndrome, and 1 of 34 patients with multiple mutations. The average age at diagnosis of AF of the six patients evaluated at Mayo was 24.3 years (range 4–46 years). Early-onset AF (age <50 years) was significantly more common in patients with LQTS compared to population-based prevalence statistics (P <.001, relative risk 17.5).
CONCLUSION
Compared to the background prevalence of 0.1%, early-onset AF was observed in almost 2% of patients with genetically proven LQTS and should be viewed as an uncommon but possible LQT-related dysrhythmia. Clinical complaints of palpitations warrant thorough assessment in patients with LQTS.
doi:10.1016/j.hrthm.2008.02.007
PMCID: PMC3940082  PMID: 18452873
Atrial fibrillation; Long QT syndrome; Tachyarrhythmias; Ion channels
23.  Fusion During Entrainment Of Orthodromic Reciprocating Tachycardia Is Enhanced For Basal Pacing Sites But Diminished When Pacing Near Purkinje System Endpoints 
Background
In the EP lab, orthodromic atrioventricular reciprocating tachycardia (ORT) can be distinguished from atrial tachycardia and atrioventricular node (AVN) reentry tachycardia by identifying orthodromic and antidromic wavefront fusion during ventricular overdrive pacing (VOP). Previous work has shown that basal VOP near the accessory pathway (AP) increases the likelihood of observing fusion; however, in a third of cases, fusion is not appreciable regardless of VOP location.
Objective
We sought to explore the hypothesis that pacing near His-Purkinje system (PS) endpoints reduces fusion quality, which may explain non-responsive ORT patients.
Methods
In a novel computer model of ORT, simulations were performed with a variety of AP locations and pacing sites; results were analyzed to assess factors influencing fusion quality in pseudo-ECG signals.
Results
Entrainment by basal VOP near the AP was more likely to produce fusion visible on simulated ECGs compared to entrainment by apical VOP, but this advantage was dramatically diminished when the pacing site was also near PS endpoints. Prediction of fusion quality based on AP proximity alone was dramatically improved when corrected to penalize for PS proximity.
Conclusion
These results suggest that basal VOP near the AP and far from the PS is optimal; this could be tested in patients. A denser basal ramification of PS fibers is known to exist in a minority of human hearts; our findings indicate that this unusual PS configuration is a plausible explanation for ORT cases where fusion is never observed in spite of entrainment by basal VOP near the AP.
doi:10.1016/j.hrthm.2012.11.021
PMCID: PMC3587662  PMID: 23207137
Orthodromic atrioventricular reciprocating tachycardia; Purkinje system; ventricular overdrive pacing
24.  Remodeling of the cardiac sodium channel, Connexin43 and Plakoglobin at the intercalated disk in patients with arrhythmogenic cardiomyopathy 
Background
Arrhythmogenic cardiomyopathy (AC) is tightly associated with desmosomal mutations in the majority of patients. Arrhythmogenesis in AC patients is likely related to remodeling of cardiac gap junctions and increased levels of fibrosis. Recently, using experimental models, we also identified sodium channel dysfunction secondary to desmosomal dysfunction. The aim of the present study was to assess the immunoreactive signal levels of the sodium channel protein NaV1.5, as well as Connexin43 and Plakoglobin, in myocardial specimens obtained from AC patients.
Methods
Left and right ventricular free wall (LVFW/RVFW) post-mortem material was obtained from 5 AC patients and 5 age and sex-matched controls. RV septal biopsies (RVSB) were taken from another 15 AC patients. All patients fulfilled the 2010 revised Task Force Criteria for AC diagnosis. Immunohistochemical analyses were performed using antibodies against Connexin43 (Cx43), Plakoglobin, NaV1.5, Plakophilin-2 and N-Cadherin.
Results
N-Cadherin and Desmoplakin immunoreactive signals and distribution were normal in AC patients compared to control. Plakophilin-2 signals were unaffected unless a PKP2 mutation predicting haploinsufficiency was present. Distribution was unchanged compared to control. Immunoreactive signal levels of PKG, Cx43 and NaV1.5 were disturbed in 74%, 70% and 65% of the patients, respectively.
Conclusions
Reduced immunoreactive signal of PKG, Cx43 and NaV1.5 at the intercalated disks can be observed in a large majority of the patients. Decreased levels of Nav1.5 might contribute to arrhythmia vulnerability and, in the future, potentially could serve as a new clinically relevant tool for risk assessment strategies.
doi:10.1016/j.hrthm.2012.11.018
PMCID: PMC3608196  PMID: 23178689
25.  Risk of Life Threatening Cardiac Events among Patients with Long QT Syndrome and Multiple Mutations 
Background
Patients with long QT syndrome (LQTS) who harbor multiple mutations (i.e. ≥ 2 mutations in ≥ 1 LQTS-susceptibility gene) may experience increased risk for life-threatening cardiac events.
Objectives
The present study was designed to compare the clinical course of LQTS patients with multiple mutations to those with a single mutation.
Methods
The risk for life-threatening cardiac events (comprising aborted cardiac arrest, implantable defibrillator shock, or sudden cardiac death) from birth through age 40 years, by the presence of multiple vs. single mutations, was assessed among 403 patients from the LQTS Registry.
Results
Patients with multiple mutations (n = 57) exhibited a longer QTc at enrollment compared with those with a single mutation (mean ± SD: 506 ± 72 vs. 480 ± 56 msec, respectively; p = 0.003) and had a higher rate of life threatening cardiac events during follow-up (23% vs. 11%, respectively; p < 0.001). Consistently, multivariate analysis demonstrated that patients with multiple mutations had a 2.3-fold (p = 0.015) increased risk for life threatening cardiac events as compared to patients with a single mutation. The presence of multiple mutations in a single LQTS gene was associated with a 3.2-fold increased risk for life threatening cardiac events (p = 0.010) whereas the risk associated with multiple mutation status involving > 1 LQTS gene was not significantly different from the risk associated with a single mutation (HR 1.7, p = 0.26).
Conclusions
LQTS patients with multiple mutations have a greater risk for life-threatening cardiac events as compared to patients with a single mutation.
doi:10.1016/j.hrthm.2012.11.006
PMCID: PMC3690288  PMID: 23174487
Aborted cardiac arrest; Long QT syndrome; Mutation; Risk factor; Sudden cardiac death

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