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Myocardial scars harbor areas of slow conduction and display abnormal electrograms. Pace-mapping at these sites can generate a 12-lead electrocardiogram morphological match to a targeted ventricular tachycardia (VT), and in some instances, multiple exit morphologies can result. At times, this can also result in the initiation of VT, termed pace-mapped induction (PMI). We hypothesized that in patients undergoing catheter ablation of VT, scar substrates with multiple exit sites (MES) identified during pace-mapping have improved freedom from recurrent VT and PMI of VT predicts successful sites of termination during ablation.
Methods and Results
High-density mapping was performed in all subjects to delineate scar (0.5-1.5mV). Sites with abnormal electrograms (EGMs) were tagged, stimulated (bipolar 10 mA at 2 ms), and targeted for ablation. MES was defined as more than one QRS morphology from a single pacing site. Pace-mapped induction (PMI) was defined as initiation of VT during pace-mapping (400-600ms).
In a two-year period, 44 consecutive patients with scar-mediated VT underwent mapping and ablation. MES were observed during pace-mapping in 25 patients (57%). At 9 months, 74% patients who exhibited MES during pace-mapping had no recurrence of VT compared to 42% of those without MES observed (p=0.024), with an overall freedom from VT of 61%. Thirteen patients (30%) demonstrated PMI and termination of VT was seen in 95% (18/19) of sites where ablation was performed.
During pace-mapping, EGMs that exhibit MES and PMI may be specific for sites critical to reentry. These functional responses hold promise for identifying important sites for catheter ablation of VT.
PMCID: PMC4334590  PMID: 22333344
2.  Loss-of-Function of hNav1.5 by ZASP1-D117N Associated with Intraventricular Conduction Disturbances in Left Ventricular Noncompaction 
Defects of cytoarchitectural proteins can cause left ventricular noncompaction (LVNC), which is often associated with conduction system diseases. We have previously identified a p.D117N mutation in the LDB3-encoding Z-band Alternatively Spliced PDZ motif gene (ZASP) in a patient with LVNC and conduction disturbances. We sought to investigate a role of p.D117N mutation in the LBD3 NM_001080114.1 isoform (ZASP1-D117N) in the regulation of cardiac sodium channel (Nav1.5) that plays an important role in the cardiac conduction system.
Methods and Results
Effects of ZASP1-wt and ZASP1-D117N on Nav1.5 were studied in HEK-293 cells and neonatal rat cardiomyocytes (NRCMs). Patch-clamp study demonstrated that ZASP1-D117N significantly attenuated INa by 27% in HEK-293 cells and by 32% in NRCMs. In addition, ZASP1-D117N rightward shifted the voltage-dependent activation and inactivation in both systems. In silico simulation using Luo-Rudy phase 1 model demonstrated that altered Nav1.5 function can reduce cardiac conduction velocity by 28% compared to the control. Pull-down assays showed that both wt and ZASP1-D117N can complex with Nav1.5 and telethonin/T-Cap, which required intact PDZ domains. Immunohistochemical staining in NRCMs demonstrates that ZASP1-D117N did not significantly disturb the Z-line structure. Disruption of cytoskeletal networks with ML-7 and cytochalasin D abolished the effects of ZASP1-D117N on the Nav1.5.
ZASP1 can form protein complex with telethonin/T-Cap and Nav1.5. The LVNC-specific ZASP1 mutation can cause loss-of-function of Nav1.5 without significant alteration of the cytoskeletal protein complex. Our study suggests that electrical remodeling can occur in LVNC subject due to a direct effect of mutant ZASP on Nav1.5.
PMCID: PMC4331025  PMID: 22929165
ZASP; sodium channel; cardiac conduction disturbance; left ventricular noncompaction
3.  Percutaneous Left Ventricular Assist Devices in Ventricular Tachycardia Ablation 
Data on relative safety, efficacy, and role of different percutaneous left ventricular assist devices for hemodynamic support during the ventricular tachycardia (VT) ablation procedure are limited.
Methods and Results
We performed a multicenter, observational study from a prospective registry including all consecutive patients (N=66) undergoing VT ablation with a percutaneous left ventricular assist devices in 6 centers in the United States. Patients with intra-aortic balloon pump (IABP group; N=22) were compared with patients with either an Impella or a TandemHeart device (non-IABP group; N=44). There were no significant differences in the baseline characteristics between both the groups. In non-IABP group (1) more patients could undergo entrainment/activation mapping (82% versus 59%; P=0.046), (2) more number of unstable VTs could be mapped and ablated per patient (1.05±0.78 versus 0.32±0.48; P<0.001), (3) more number of VTs could be terminated by ablation (1.59±1.0 versus 0.91±0.81; P=0.007), and (4) fewer VTs were terminated with rescue shocks (1.9±2.2 versus 3.0±1.5; P=0.049) when compared with IABP group. Complications of the procedure trended to be more in the non-IABP group when compared with those in the IABP group (32% versus 14%; P=0.143). Intermediate term outcomes (mortality and VT recurrence) during 12±5-month follow-up were not different between both groups. Left ventricular ejection fraction ≤15% was a strong and independent predictor of in-hospital mortality (53% versus 4%; P<0.001).
Impella and TandemHeart use in VT ablation facilitates extensive activation mapping of several unstable VTs and requires fewer rescue shocks during the procedure when compared with using IABP.
PMCID: PMC4329420  PMID: 24532564
catheter ablation; intra-aortic balloon pumping; tachycardia; ventricular
4.  The Interrelationship between Electrocardiographic Left Ventricular Hypertrophy and QT Prolongation as Predictors of Increased Risk of Mortality in the General Population 
Prolonged-QT commonly coexists in the electrocardiogram (ECG) with left ventricular hypertrophy (ECG-LVH). However, it is unclear to what extent QT prolongation coexisting with ECG-LVH can explain the prognostic significance of ECG-LVH, and whether prolonged-QT coexisting with ECG-LVH should be considered as an innocent consequence of ECG-LVH.
Methods and Results
The study population consisted of 7506 participants (mean age 59.4±13.3 years, 49% whites, 47% males) from the US Third National Health and Nutrition Examination Survey (NHANES-III). ECG-LVH was defined by Cornell voltage criteria. Prolonged heart rate-adjusted QT (prolonged-QTa) was defined as QTa ≥ 460 ms in women or 450 ms in men. Cox proportional hazards analysis was used to calculate the hazard ratios (HR) with 95% confidence intervals (CI) for the risk of all-cause mortality for various combinations of ECG-LVH and prolonged-QTa. ECG-LVH was present in 4.2% (n=312) of the participants, of whom 16.4% had prolonged-QTa. In a multivariable adjusted model and compared to the group without ECG-LVH or prolonged-QTa, mortality risk was highest in the group with concomitant ECG-LVH and prolonged-QTa (HR (95% CI): 1.63(1.12, 2.36)), followed by isolated ECG-LVH (1.48 (1.24, 1.77)), and then isolated prolonged-QTa (1.27 (1.12, 1.46)). In models with similar adjustment where ECG-LVH and prolonged-QTa were entered as two separate variables and subsequently additionally adjusted for each other, the mortality risk was essentially unchanged for both variables.
Although prolonged-QT commonly coexists with LVH, both are independent markers of poor prognosis. Concomitant presence of prolonged-QT and ECG-LVH carries a higher risk than either predictor alone.
PMCID: PMC4314284  PMID: 24762807
Prolonged-QTa; Left Ventricular Hypertrophy; Mortality; NHANES
5.  [No title available] 
PMCID: PMC3951442  PMID: 24429494
6.  [No title available] 
PMCID: PMC4001739  PMID: 24382411
7.  [No title available] 
PMCID: PMC4086672  PMID: 24363354
8.  [No title available] 
PMCID: PMC4292880  PMID: 23443619
9.  Differences in Repeating Patterns of Complex Fractionated Left Atrial Electrograms in Longstanding Persistent Atrial Fibrillation as Compared With Paroxysmal Atrial Fibrillation 
Complex fractionated atrial electrograms (CFAE) are morphologically more uniform in persistent longstanding as compared with paroxysmal atrial fibrillation (AF). It was hypothesized that this may result from a greater degree of repetitiveness in CFAE patterns at disparate left atrial (LA) sites in longstanding AF.
Methods and Results
CFAEs were obtained from recording sites outside the 4 pulmonary vein (PV) ostia and at a posterior and an anterior LA site during paroxysmal and longstanding persistent AF (10 patients each, 120 sequences total). To quantify repetitiveness in CFAE, the dominant frequency was measured from ensemble spectra using 8.4-second sequences, and repetitiveness was calculated by 2 novel techniques: linear prediction and Fourier reconstruction methods. Lower prediction and reconstruction errors were considered indicative of increasing repetitiveness and decreasing randomness. In patients with paroxysmal AF, CFAE pattern repetitiveness was significantly lower (randomness higher) at antral sites outside PV ostia as compared with LA free wall sites (P<0.001). In longstanding AF, repetitiveness increased outside the PV ostia, especially outside the left superior PV ostium, and diminished at the LA free wall sites. The result was that in persistent AF, there were no significant site-specific differences in CFAE repetitiveness at the selected LA locations used in this study. Average dominant frequency magnitude was 5.32±0.29 Hz in paroxysmal AF and higher in longstanding AF, at 6.27±0.13 Hz (P<0.001), with the frequency of local activation approaching a common upper bound for all sites.
In paroxysmal AF, CFAE repetitiveness is low and randomness high outside the PVs, particularly the left superior PV. As evolution to persistent longstanding AF occurs, CFAE repetitiveness becomes more uniformly distributed at disparate sites, possibly signifying an increasing number of drivers from remote PVs.
PMCID: PMC4279955  PMID: 21536597
atrial fibrillation; CFAE; dominant frequency; ensemble average; linear prediction
10.  “Cardiac KATP” 
PMCID: PMC4275794  PMID: 22203659
Editorials; atrial fibrillation; conduction; ion channels or ion channel; ischemia; ventricular arrhythmia
11.  A Connexin 40 Mutation Associated with a Malignant Variant of Progressive Familial Heart Block Type-1 
Progressive familial heart block type I (PFHBI) is a hereditary arrhythmia characterized by progressive conduction disturbances in the His-Purkinje system. PFHBI has been linked to genes such as SCN5A that influence cardiac excitability, but not to genes that influence cell-to-cell communication. Our goal was to explore whether nucleotide substitutions in genes coding for connexin proteins would associate with clinical cases of PFHBI and if so, to establish a genotype-cell phenotype correlation for that mutation.
Methods and Results
We screened 156 probands afflicted with PFHBI. In addition to 12 sodium channel mutations, we found a germline GJA5 (connexin40; Cx40) mutation (Q58L) in an afflicted family. Heterologous expression of Cx40-Q58L in connexin-deficient neuroblastoma cells resulted in marked reduction of junctional conductance (Cx40-WT: 22.2±1.7 nS, n=14; Cx40-Q58L: 0.56±0.34 nS, n=14; p<0.001) and diffuse localization of immunoreactive proteins in the vicinity of the plasma membrane without formation of gap junctions. Heteromeric co-transfection of Cx40-WT and Cx40-Q58L resulted in homogenous distribution of proteins in the plasma membrane rather than in membrane plaques in about 50% of cells; well-defined gap junctions were observed in other cells. Junctional conductance values correlated with the distribution of gap junction plaques.
Mutation Cx40-Q58L impairs gap junction formation at cell-cell interfaces. This is the first demonstration of a germline mutation in a connexin gene that associates with inherited ventricular arrhythmias, and emphasizes the importance of Cx40 in normal propagation in the specialized conduction system.
PMCID: PMC4274644  PMID: 22247482
heart block; genes; ion channels; sudden death; gap junctions
12.  Spatial Profiles of Electrical Mismatch Determine Vulnerability to Conduction Failure across a Host-Donor Cell Interface 
Circulation. Arrhythmia and electrophysiology  2013;6(6):10.1161/CIRCEP.113.001050.
Electrophysiological mismatch between host cardiomyocytes and donor cells can directly affect the electrical safety of cardiac cell therapies; however, the ability to study host-donor interactions at the microscopic scale in situ is severely limited. We systematically explored how action potential (AP) differences between cardiomyocytes and other excitable cells modulate vulnerability to conduction failure in vitro.
Methods and Results
AP propagation was optically mapped at 75 µm resolution in micropatterned strands (n=152) in which host neonatal rat ventricular myocytes (NRVMs; AP duration (APD)=153.2±2.3 ms, conduction velocity (CV)=22.3±0.3 cm/s) seamlessly interfaced with genetically engineered excitable donor cells expressing inward rectifier potassium (Kir2.1) and cardiac sodium (Nav1.5) channels with either weak (CV=3.1±0.1 cm/s) or strong (CV=22.1±0.4 cm/s) electrical coupling. Selective prolongation of engineered donor cell APD (from 31.9–139.1 ms) by low dose BaCl2 generated a wide range of host-donor repolarization time (RT) profiles with maximum gradients (∇RTmax) of 5.5–257 ms/mm. During programmed stimulation of donor cells, the vulnerable time window (VW) for conduction block across the host-donor interface most strongly correlated with ∇RTmax. Compared to well-coupled donor cells, the interface composed of poorly-coupled cells significantly shortened the RT profile width by 19.7% and increased ∇RTmax and VW by 22.2% and 19%, respectively. Flattening the RT profile by perfusion of 50 µmol/L BaCl2 eliminated coupling-induced differences in vulnerability to block.
Our results quantify how the degree of electrical mismatch across a cardiomyocyte-donor cell interface affects vulnerability to conduction block with important implications for the design of safe cardiac cell and gene therapies.
PMCID: PMC3877650  PMID: 24235268
cell transplantation; action potential; conduction; gap junctions; optical mapping; cell therapy; heart failure; dispersion; conduction block
13.  Impact of Nonischemic Scar Features on Local Ventricular Electrograms and Scar-Related Ventricular Tachycardia Circuits in Patients with Nonischemic Cardiomyopathy 
Circulation. Arrhythmia and electrophysiology  2013;6(6):10.1161/CIRCEP.113.000159.
The association of local electrogram features with scar morphology and distribution in nonischemic cardiomyopathy (NICM) has not been investigated. We aimed to quantify the association of scar on late-gadolinium enhanced cardiac magnetic resonance (LGE-CMR) with local electrograms and ventricular tachycardia (VT) circuit sites in patients with NICM.
Methods and Results
Fifteen patients with NICM underwent LGE-CMR before VT ablation. The transmural extent and intramural types (endocardial, mid-wall, epicardial, patchy, transmural) of scar were measured in LGE-CMR short axis planes. Electro-anatomic map (EAM) points were registered to LGE-CMR images. Myocardial wall thickness, scar transmurality, and intramural scar types were independently associated with electrogram amplitude, duration, and deflections in linear mixed effects multivariable models, clustered by patient. Fractionated and isolated potentials were more likely to be observed in regions with higher scar transmurality (P<0.0001 by ANOVA) and in regions with patchy scar (versus endocardial, mid wall, epicardial scar, P<0.05 by ANOVA). Most VT circuit sites were located in scar with >25% scar transmurality.
Electrogram features are associated with scar morphology and distribution in patients with NICM. Prior knowledge of electrogram image associations may optimize procedural strategies including the decision to obtain epicardial access.
PMCID: PMC3884514  PMID: 24235267
ventricular tachycardia; nonischemic cardiomiopathy; cardiac magnetic resonance imaging; electrophysiology mapping
14.  Impact of Local Ablation on Inter-Connected Channels within Ventricular Scar: Mechanistic Implications for Substrate Modification 
The extent to which channels within scar are inter-connected is not known. The objective of the study was to evaluate the impact of local ablation of LPs on adjacent and remote areas of slow conduction with simultaneous multipolar mapping.
Methods and Results
Analysis was performed on consecutive patients referred for ablation of scar-mediated VT with double ventricular access. Ablation was performed targeting the earliest of LPs visualized on the multipolar catheter and the impact on later LPs was recorded. In 21 patients, a multipolar catheter placed within scar visualized spatially distinct LPs. Among 39 RF applications, ablation at earlier LPs had an effect on neighboring and remote LPs in 31 (80%), with delay in 8 (21%), partial elimination in 9 (23%), and complete elimination in 14 (36%). The mean distance where an ablation impact was detected was 17.6±14.7mm (range 2mm-50mm). Among all patients, 9.7±7.8 RF applications were delivered to homogenize the targeted scar region with a mean number of 23±12 LPs targeted.
Ablation can eliminate neighboring and remote areas of slow conduction, suggesting that channels within scar are frequently inter-connected. This is the first mechanistic demonstration to show that ablation can modify electrical activity in regions of scar outside of the known radius of an RF lesion. The targeting of relatively earlier LPs can expedite scar homogenization without the need for extensive ablation of all LPs.
PMCID: PMC3977176  PMID: 24162832
ablation; ventricular tachycardia; mapping; late potential
15.  Long-Duration Ventricular Fibrillation Exhibits 2 Distinct Organized States 
Previous studies showed that endocardial activation during long-duration ventricular fibrillation (VF) exhibits organized activity. We identified and quantified the different types of organized activity.
Methods and Results
Two 64-electrode basket catheters were inserted, respectively, into the left ventricle and right ventricle of dogs to record endocardial activation from the endocardium during 7 minutes of VF (controls, n=6). The study was repeated with the KATP channel opener pinacidil (n=6) and the calcium channel blocker flunarizine (n=6). After 2 minutes of VF without drugs, 2 highly organized left ventricular endocardial activation patterns were observed: (1) ventricular electric synchrony pattern, in which endocardial activation arose focally and either had a propagation sequence similar to sinus rhythm or arose near papillary muscles, and (2) stable pattern, in which activation was regular and repeatable, sometimes forming a stable re-entrant circuit around the left ventricular apex. Between 3 and 7 minutes of VF, the percent of time ventricular electric synchrony was present was control=25%, flunarizine=24% (P=0.44), and pinacidil=0.1% (P<0.001) and the percent of time stable pattern was present was control=71%, flunarizine=48% (P<0.001), and pinacidil=56% (P<0.001). The remainder of the time, nonstable re-entrant activation with little repeatability was present.
After 3 minutes, VF exhibits 2 highly organized endocardial activation patterns 96% of the time, one potentially arising focally in the Purkinje system that was prevented with a KATP channel opener but not a calcium channel blocker and the other potentially arising from a stable re-entrant circuit near the apical left ventricular endocardium.
PMCID: PMC3982786  PMID: 24243784
arrhythmias; cardiac; ventricular fibrillation
16.  Screening Entire Health System ECG Databases to Identify Patients at Increased Risk of Death 
Current methods to identify patients at higher risk for sudden cardiac death, primarily left ventricular ejection fraction (LVEF) ≤35%, miss ∼80% of patients who die suddenly. We tested the hypothesis that patients with elevated QRS scores (index of myocardial scar) and wide QRS-T angles (index abnormal depolarization-repolarization relationship) have high 1-year all-cause mortality and could be further risk-stratified with clinical characteristics.
Methods and Results
We screened all 12-lead ECGs (∼50,000 patients) over 6 months at 2 large hospital systems and analyzed clinical characteristics and 1-year mortality. Patients with ECGs obtained in hospital areas with known high mortality rates were excluded. At one hospital, QRS score ≥5 and QRS-T angle ≥105° identified 8.0% of patients and was associated with an odds ratio (OR) of 2.79 [95% confidence interval 2.10-3.69] for 1-year mortality compared to patients below both ECG thresholds (13.9% vs. 5.5% death rate). LVEF was >35% in 82% of the former group of patients and addition of ECG measures to LVEF increased the discrimination of death risk (p<0.0001). At the second hospital, the OR was 2.42 [1.95-3.01] for 1-year mortality (8.8% vs. 3.8%). Adjustment for patient characteristics eliminated inter-hospital differences. Multivariable adjusted OR combining data from both hospitals was 1.53 [1.28-1.83]. Increasing heart rate and chronic renal impairment further predicted mortality.
Screening hospital ECG databases with QRS scoring and QRS-T angle analysis identifies patients with high 1-year all-cause mortality and predominantly preserved LVEF. This approach may represent a widely-available method to identify patients at increased risk of death.
PMCID: PMC3992472  PMID: 24122522
electrocardiography; screening; arrhythmia; fibrosis; death; myocardial scar
17.  Selective Targeting of Gain-of-function KCNQ1 Mutations Predisposing to Atrial Fibrillation 
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in adults. We hypothesized that gain-of-function KCNQ1 mutations previously associated with familial AF have distinct pharmacological properties that may enable targeted inhibition.
Methods and Results
Wild-type (WT) KCNQ1 or the familial AF mutation KCNQ1-S140G were heterologously co-expressed with KCNE1 to enable electrophysiological recording of the slow delayed rectifier current (IKs) and investigation of pharmacological effects of the IKs selective blocker HMR-1556. Co-expression of KCNQ1-S140G with KCNE1 generated potassium currents (S140G-IKs) that exhibited greater sensitivity to HMR-1556 than WT-IKs. Enhanced HMR-1556 sensitivity was also observed for another gain-of-function AF mutation, KCNQ1-V141M. Heteromeric expression of KCNE1 with both KCNQ1-WT and KCNQ1-S140G generated currents (HET-IKs) with gain-of-function features including larger amplitude, a constitutively active component, hyperpolarized voltage dependence of activation, and extremely slow deactivation. A low concentration of HMR-1556, which had little effect on WT-IKs but was capable of inhibiting the mutant channel, reduced both instantaneous and steady-state HET-IKs to levels that were not significantly different from WT-IKs and attenuated use-dependent accumulation of the current. In cultured adult rabbit left atrial myocytes, expression of S140G-IKs shortened action potential duration (APD) compared to WT-IKs. Application of HMR-1556 mitigated S140G-IKs -induced APD shortening and did not alter APD in cells expressing WT-IKs.
The enhanced sensitivity of KCNQ1 gain-of-function mutations for HMR-1556 suggests the possibility of selective therapeutic targeting and, therefore, our data illustrates a potential proof-of-principal for genotype-specific treatment of this heritable arrhythmia.
PMCID: PMC3892565  PMID: 24006450
arrhythmia; atrial fibrillation; antiarrhythmic drug; potassium channels; genetics
18.  Frequency Analysis of Atrial Action Potential Alternans: A Sensitive Clinical Index of Individual Propensity to Atrial Fibrillation 
Few clinical indices identify the propensity of patients to atrial fibrillation (AF) when not in AF. Repolarization alternans has been shown to indicate AF vulnerability, but is limited in its sensitivity to detect changes in action potential duration (APD), that may be subtle. We hypothesized that spectral analysis would be a more sensitive and robust marker of action potential (AP) alternans and thus a better clinical index of individual propensity to AF than APD alternans.
Methods and Results
In 31 patients (12 persistent AF, 15 paroxysmal AF, 4 controls with no AF), we recorded left (n=27) and right (n=6) atrial monophasic APs during incremental pacing from cycle length (CL) 500 ms (120 bpm) to AF onset. Alternans was measured by APD and spectral analysis. At baseline pacing [median CL 500 (IQR 500,500) ms], APD alternans was detected in only 7/27 AF patients (no controls), while spectral AP alternans was detected in 18/27 AF patients (no controls; p=0.003); AP alternans was more prevalent in persistent than paroxysmal AF, and absent in controls (p=0.018 APD, p=0.042 spectral). Spectral AP alternans magnitude at baseline was highest in persistent AF, with modest rate-dependent amplification, then in paroxysmal AF, with marked rate-dependence, and was undetectable in controls until just before induced AF.
Spectral AP alternans near baseline rates can identify patients with, versus those without, clinical histories and pathophysiological substrates for AF. Future studies should examine whether the presence of spectral AP alternans during sinus rhythm may obviate the need to actually demonstrate AF, such as on ambulatory ECG monitoring.
PMCID: PMC3897260  PMID: 23995250
alternans; action potential; atrial fibrillation; spectral analysis; action potential duration
19.  Sinoatrial Node Reentry in a Canine Chronic Left Ventricular Infarct Model: The Role of Intranodal Fibrosis and Heterogeneity of Refractoriness 
Reentrant arrhythmias involving the sinoatrial node (SAN), namely, SAN reentry, remain one of the most intriguing enigmas of cardiac electrophysiology. The goal of the present study was to elucidate the mechanism of SAN micro-reentry in canine hearts with post myocardial infarction (MI) structural remodeling.
Methods and Results
In vivo, Holter monitoring revealed ventricular arrhythmias and SAN dysfunctions in post left ventricular MI (6–15 wks) dogs (n=5) compared to control dogs (n=4). In vitro, high resolution near-infrared optical mapping of intramural SAN activation was performed in coronary perfused atrial preparations from MI (n=5) and controls (n=4). Both SAN macro- (slow-fast; 16–28 mm) and micro-reentries (1–3 mm) were observed in 60% of the MI preparations during moderate autonomic stimulation (acetylcholine (0.1 µM) or isoproterenol (0.01-0.1 µM)) after termination of atrial tachypacing (5–8 Hz), a finding not seen in controls. The autonomic stimulation induced heterogeneous changes in the SAN refractoriness; thus, competing atrial and/or SAN pacemaker waves could produce unidirectional blocks and initiate intranodal micro-reentries. The micro-reentry pivot waves were anchored to the longitudinal block region and produced both tachycardia and paradoxical bradycardia (due to exit block), despite an atrial ECG morphology identical to regular sinus rhythm. Intranodal longitudinal conduction blocks coincided with interstitial fibrosis strands that were exaggerated in the MI SAN pacemaker complex (fibrosis density 37±7% MI vs. 23±6% control, P<0.001).
Both tachy- and bradyarrhythmias can result from SAN micro-reentries. Post-infarction remodeling, including increased intranodal fibrosis and heterogeneity of refractoriness, provides substrates for SAN reentry.
PMCID: PMC3904863  PMID: 23960214
sinoatrial node; sinoatrial node reentry; autonomic stimulation; optical mapping; myocardial infarction
20.  The Unfolded Protein Response Regulates Cardiac Sodium Current in Systolic Human Heart Failure 
Human heart failure (HF) increases alternative mRNA splicing of the SCN5A cardiac Na+ channel, generating variants encoding truncated, nonfunctional channels that are trapped in the endoplasmic reticulum. In this work, we tested whether truncated Na+ channels activate the unfolded protein response (UPR), contributing to SCN5A electrical remodeling in HF.
Methods and Results
UPR and SCN5A were analyzed in human ventricular systolic HF tissue samples and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Cells were exposed to angiotensin II (AngII) and hypoxia, known activators of abnormal SCN5A mRNA splicing, or were induced to overexpress SCN5A variants. UPR effectors, PERK, calreticulin, and CHOP, were increased in human HF tissues. Induction of SCN5A variants with AngII or hypoxia or the expression of exogenous variants induced the UPR with concomitant downregulation of Na+ current. PERK activation destabilized SCN5A and, surprisingly, Kv4.3 channel mRNAs but not TRPM7 channel mRNA. PERK inhibition prevented the loss of full-length SCN5A and Kv4.3 mRNA levels resulting from expressing Na+ channel mRNA splice variants.
UPR can be initiated by Na+ channel mRNA splice variants and is involved in the reduction of cardiac Na+ current during human HF. Since the effect is not entirely specific to the SCN5A transcript, the UPR may play an important role in downregulation of multiple cardiac genes in HF.
PMCID: PMC3909518  PMID: 24036084
sodium channels; heart failure; human; SCN5A; PERK; splicing variants
21.  Both Hypothyroidism and Hyperthyroidism Increase Atrial Fibrillation Inducibility in Rats 
Evidence indicates that cardiac hypothyroidism may contribute to heart failure (HF) progression. It is also known that HF is associated with an increased risk of atrial fibrillation (AF). While it is established that hyperthyroidism increases AF incidence, the effect of hypothyroidism on AF is unclear. This study investigated the effects of different thyroid hormone levels, ranging from hypothyroidism to hyperthyroidism on AF inducibility in thyroidectomized rats.
Methods and Results
Thyroidectomized rats with serum confirmed hypothyroidism 1 month after surgery were randomized into hypothyroid (n=9), euthyroid (n=9) and hyperthyroid (n=9) groups. Rats received placebo, 3.3mg L-thyroxine (T4), or 20 mg T4 pellets (60 day release form) for 2 months, respectively. At the end of treatment, hypothyroid, euthyroid and hyperthyroid status was confirmed. Hypothyroid animals showed cardiac atrophy and reduced cardiac systolic and diastolic function, while hyperthyroid rats exhibited cardiac hypertrophy and increased cardiac function. Hypothyroidism and hyperthyroidism produced opposite electrophysiological changes in heart rates and atrial effective refractory period, but both significantly increased AF susceptibility. AF incidence was 78% in hypothyroid, 67% in hyperthyroid, and the duration of induced AF was also longer, compared with 11% in the euthyroid group (all p<0.05). Hypothyroidism increased atrial interstitial fibrosis, but connexin 43 was not affected.
Both hypothyroidism and hyperthyroidism lead to increased AF vulnerability in a rat thyroidectomy model. Our results stress that normal thyroid hormone levels are required to maintain normal cardiac electrophysiology and prevent cardiac arrhythmias and AF.
PMCID: PMC3973490  PMID: 24036190
thyroid hormones; atrial fibrillation; arrhythmia; electrophysiology
22.  Arrhythmia Phenotype during Fetal Life Suggests LQTS Genotype: Risk Stratification of Perinatal Long QT Syndrome 
Fetal arrhythmias characteristic of long QT syndrome (LQTS) include torsades de pointes (TdP) and/or 2° atrioventricular block (AVB), but sinus bradycardia, defined as fetal heart rate <3% for gestational age, is most common. We hypothesized that prenatal rhythm phenotype might predict LQTS genotype and facilitate improved risk stratification and management.
Method and Results
Records of subjects exhibiting LQTS fetal arrhythmias were reviewed. Fetal echocardiograms, neonatal ECG, and genetic testing were evaluated. We studied 43 subjects exhibiting fetal LQTS arrhythmias: TdP ± 2° AVB (Group 1, n=7), isolated 2° AVB (Group 2, n=4) and sinus bradycardia (Group 3, n=32). Mutations in known LQTS genes were found in 95% of subjects tested. SCN5A mutations occurred in 71% of Group 1 while 91% of subjects with KCNQ1 mutations were in Group 3. Small numbers of subjects with KCNH2 mutations (n=4) were scattered in all 3 groups. Age at presentation did not differ among groups, and most subjects (n=42) were live born with gestational ages of 37.5±2.8 wks (mean±SD). However, those with TdP were typically delivered earlier. Prenatal treatment in Group 1 terminated (n=2) or improved (n=4) TdP. The neonatal QTc (mean±SE) of Group 1 (664.7±24.9) was longer than neonatal QTc in both Group 2 (491.2±27.6, p=0.004) and Group 3 (483.1±13.7, p<0.001). Despite medical and pacemaker therapy, postnatal cardiac arrest (n=4) or sudden death (n=1) was common among subjects with fetal/neonatal TdP.
Rhythm phenotypes of fetal LQTS have genotype-suggestive features which, along with QTc duration, may risk stratify perinatal management.
PMCID: PMC4151528  PMID: 23995044
long QT syndrome; fetal; arrhythmia; torsade de pointes; atrioventricular block; sinus bradycardia
23.  Effect of mental challenge induced by movie clips on action potential duration in normal human subjects independent of heart rate 
Mental stress and emotion have long been associated with ventricular arrhythmias and sudden death in animal models and humans. The effect of mental challenge on ventricular action potential duration (APD) in conscious healthy humans has not been reported.
Methods and Results
Activation recovery intervals (ARI) measured from unipolar electrograms as a surrogate for APD (n=19) were recorded from right and left ventricular endocardium during steady state pacing while subjects watched an emotionally charged film clip. To assess the possible modulating role of altered respiration on APD, the subjects then repeated the same breathing pattern they had during the stress, but without the movie clip. Haemodynamic parameters (mean, systolic, and diastolic blood pressure, and rate of pressure increase) and respiration rate increased during the stressful part of the film clip (p=0.001). APD decreased during the stressful parts of the film clip, eg for global RV ARI at end of film clip 193.8ms (SD 14) vs 198.0ms (SD13) during the matched breathing control (end film LV 199.8ms (SD16) vs control 201.6ms (SD15), p=0.004. Respiration rate increased during the stressful part of the film clip (by 2 breaths/minute), and was well matched in the respective control period without any haemodynamic or ARI changes.
Our results document for the first time direct recordings of the effect of a mental challenge protocol on ventricular action potential duration in conscious humans. The effect of mental challenge on APD was not secondary to emotionally-induced altered respiration or heart rate.
PMCID: PMC4143747  PMID: 24833641
Mental Challenge; Action Potential Duration; Activation Recovery Interval; Arrhythmia
24.  Long-Term Frequency Gradients during Persistent Atrial Fibrillation in Sheep are Associated with Stable Sources in the Left Atrium 
Dominant frequencies (DFs) of activation are higher in the atria of patients with persistent than paroxysmal atrial fibrillation (AF) and left-to-right atrial (LA-to-RA) DF gradients have been identified in both. However, whether such gradients are maintained as long-term persistent AF is established remains unexplored. We aimed at determining in-vivo the time-course in atrial DF values from paroxysmal to persistent AF in sheep, and test the hypothesis that a LA-to-RA DF difference is associated with LA drivers in persistent AF.
Methods and Results
AF was induced using RA tachypacing (N=8). Electrograms were obtained weekly from a RA lead and a loop recorder (ILR) implanted near the LA. DFs were determined for 5-sec-long electrograms (QRST subtracted) during AF in-vivo and in ex-vivo optical mapping. Underlying structural changes were compared to weight-matched controls (N=4). Following the first AF episode, DF increased gradually over a 2-week period (7±0.21 to 9.92±0.31 Hz, N=6, p<0.05). During 9–24 weeks of AF the DF values on the ILR were higher than the RA (10.6±0.08 vs. 9.3±0.1 Hz, respectively; N=7, p<0.0001). Subsequent optical mapping confirmed a DF gradient from posterior LA-to-RA (9.1±1.0 to 6.9±0.9 Hz. p<0.05) and demonstrated patterns of activation compatible with drifting rotors in the posterior LA (PLA). Persistent AF sheep showed significant enlargement of the PLA compared to controls.
In the sheep transition from paroxysmal to persistent AF shows continuous LA-to-RA DF gradients in-vivo together with enlargement of the PLA, which harbors the highest frequency domains and patterns of activation compatible with drifting rotors.
PMCID: PMC4121987  PMID: 23051840
atrial fibrillation; electrophysiology mapping; remodeling; dominant frequency; rotors
25.  A Novel Method for Determining the Phase of T-Wave Alternans: Diagnostic and Therapeutic Implications 
Circulation. Arrhythmia and electrophysiology  2013;6(4):10.1161/CIRCEP.113.000114.
T-wave alternans (TWA) has been implicated in the pathogenesis of ventricular arrhythmias and sudden cardiac death (SCD). However, in order to effectively estimate and suppress TWA, the phase of TWA must be accurately determined.
Methods and Results
We developed a method that computes the beat-by-beat integral of the T-wave morphology, over time points within the T-wave with positive alternans. Then, we estimated the signed derivative of the T-wave integral sequence which allows the classification of each beat to a binary phase index. In animal studies, we found that this method was able to accurately identify the T-wave phase in artificially induced alternans (p<0.0001). The coherence of the phase increased consistently after acute ischemia induction in all body-surface and intracardiac leads (p<0.0001). Also, we developed a phase resetting detection algorithm that enhances the diagnostic utility of TWA. We further established an algorithm that employs the phase of TWA in order to deliver appropriate polarity pacing pulses (all interventions compared to baseline, p<0.0001 for alternans voltage; p<0.0001 for Kscore), to suppress TWA. Finally, we demonstrated that using the phase of TWA we can suppress spontaneous TWA during acute ischemia; 77.6% for alternans voltage (p<0.0001) and 92.5% for Kscore (p<0.0001).
We developed a method to quantify the temporal variability of the TWA phase. This method is expected to enhance the utility of TWA in predicting ventricular arrhythmias and SCD and raises the possibility of using upstream therapies to abort a ventricular tachyarrhythmia prior to its onset.
PMCID: PMC3845209  PMID: 23884196
alternans; arrhythmia (heart rhythm disorders); pacing; implantable cardioverter-defibrillator

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