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.
To investigate the contribution to SCD susceptibility of DNA variants previously implicated in schizophrenia and epilepsy.
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.
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.
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.
sudden cardiac death; association study; genetics; schizophrenia; epilepsy; neuregulin-1
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.
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.
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.
arrhythmia; electrophysiology; ion channels; atrial fibrillation; PDGF; calcium channel
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).
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.
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.
Transient outward potassium channel current; positive inotropic effect; cardiac arrhythmias; sudden cardiac death
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.
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.
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.
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.
Atrial miRNA-499 is significantly upregulated in AF, leading to SK3 downregulation and possibly contributing to the electrical remodeling in AF.
atrial fibrillation; microRNA; SK3 channel; electrical remodeling; small-conductance calcium-activated potassium channel
catheter ablation; ventricular septal puncture; mechanical valves; VT
A substantial number of patients with idiopathic ventricular fibrillation (IVF) present with no specific electrocardiographic (ECG) findings.
To evaluate complete right bundle branch block (RBBB) in patients with IVF.
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.
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).
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.
Sudden death; Idiopathic ventricular fibrillation; Right bundle branch block; Electrocardiogram; Brugada syndrome
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.
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.
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.
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.
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.
Antiarrhythmic drugs; Electrophysiology; Pharmacology; Late sodium current; Ranolazine
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.
The purpose of this study was to determine roles of SKCa in atrial arrhythmias.
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.
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.
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
Atrial arrhythmia; SKCa; action potential duration; repolarization; optical mapping
Small conductance calcium activated potassium (SK) channels are responsible for afterhyperpolarization that suppresses nerve discharges.
To test the hypotheses that low-level vagus nerve stimulation (LL-VNS) leads to the upregulation of SK2 proteins in the LSG.
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).
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.
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.
Autonomic nervous system; Vagus nerve stimulation; Stellate ganglion; Small conductance calcium activated potassium channel; Western blot
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.
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.
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.
QTII is a promising arrhythmia risk stratification index.
arrhythmia; implantable cardioverter-defibrillator; QT interval electrocardiography; risk stratification; sudden death
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.
Demonstrate the feasibility of noninvasive transthoracic EWI for mapping the activation sequence during different cardiac rhythms in humans.
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.
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.
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.
Ablation; Arrhythmias; Noninvasive Imaging; Pacing
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.
To evaluate the impact of time from MI to randomization on mortality, re-hospitalizations, and complications.
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.
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.
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.
implantable cardioverter-defibrillator; sudden cardiac death; myocardial infarction; heart failure
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
To risk stratify LQT2 patients for life-threatening cardiac events based on clinical and genetic information.
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).
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%).
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.
long-QT syndrome; pore-loop mutations; sudden cardiac death; gender
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.
To test the hypothesis that the extent of myocardial scar is less in women than men.
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).
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.
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.
Cardiac Magnetic Resonance Imaging; Implantable Cardioverter-Defibrillators; Cardiac Resynchronization Therapy; Gender
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.
To test whether enhanced CaMKII phosphorylation of RyR2 underlies SR Ca2+ leak and induction of VT in mdx mice.
Programmed electrical stimulation (PES) was performed on anesthetized mice, and confocal imaging of calcium release events in isolated ventricular myocytes.
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.
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.
Cardiac arrhythmias; Ca2+/calmodulin kinase II; mouse model; ryanodine receptor; Duchenne muscular dystrophy; ventricular tachycardia
Cervical vagal nerve (CVN) stimulation may improve left ventricular ejection fraction in patients with heart failure.
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.
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.
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.
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.
Cervical vagus nerves; Sympathetic nerves; Ganglion cells; Heart failure; Vagal nerve stimulation
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.
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.
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.
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%.
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.
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
Sudden infant death syndrome; Long QT syndrome; Ion channels; Genetics; QT interval; Electrocardiogram
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).
The purpose of this study was to determine the prevalence of AF in patients with congenital LQTS.
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.
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).
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.
Atrial fibrillation; Long QT syndrome; Tachyarrhythmias; Ion channels
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.
We sought to explore the hypothesis that pacing near His-Purkinje system (PS) endpoints reduces fusion quality, which may explain non-responsive ORT patients.
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.
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.
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.
Orthodromic atrioventricular reciprocating tachycardia; Purkinje system; ventricular overdrive pacing
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.
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.
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.
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.
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.
The present study was designed to compare the clinical course of LQTS patients with multiple mutations to those with a single mutation.
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.
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).
LQTS patients with multiple mutations have a greater risk for life-threatening cardiac events as compared to patients with a single mutation.
Aborted cardiac arrest; Long QT syndrome; Mutation; Risk factor; Sudden cardiac death