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1.  Apamin Sensitive Potassium Current Modulates Action Potential Duration Restitution and Arrhythmogenesis of Failing Rabbit Ventricles 
Background
Apamin-sensitive K currents (IKAS) are upregulated in heart failure (HF). We hypothesize that apamin can flatten action potential duration restitution (APDR) curve and reduce ventricular fibrillation (VF) duration in failing ventricles.
Methods and Results
We simultaneously mapped membrane potential and intracellular Ca (Cai) in 7 rabbits hearts with pacing-induced HF and in 7 normal hearts. A dynamic pacing protocol was used to determine APDR at baseline and after apamin (100 nM) infusion. Apamin did not change APD80 in normal ventricles, but prolonged APD80 in failing ventricles at either long (≥300 ms) or short (≤170 ms) pacing cycle length (PCL), but not at intermediate PCL. The maximal slope of APDR curve was 2.03 [95% CI, 1.73 to 2.32] in failing ventricles and 1.26 [95% CI, 1.13 to 1.40] in normal ventricles at baseline (p=0.002). After apamin administration, the maximal slope of APDR in failing ventricles decreased to 1.43 [95% CI, 1.01 to 1.84] (p=0.018) whereas no significant changes were observed in normal ventricles. During VF in failing ventricles, the number of phase singularities (baseline vs apamin, 4.0 vs 2.5), dominant frequency (13.0 Hz vs 10.0 Hz), and VF duration (160 s vs 80 s) were all significantly (p<0.05) decreased by apamin.
Conclusions
Apamin prolongs APD at long and short, but not at intermediate PCL in failing ventricles. IKAS upregulation may be antiarrhythmic by preserving the repolarization reserve at slow heart rate, but is proarrhythmic by steepening the slope of APDR curve which promotes the generation and maintenance of VF.
doi:10.1161/CIRCEP.111.000152
PMCID: PMC3678988  PMID: 23420832
ventricular fibrillation; optical mapping; experimental models heart failure; electrophysiology
2.  Trans-fatty acid consumption and heart rate variability in two separate cohorts of older and younger adults 
Background
Trans-fatty acid (TFA) consumption is associated with risk of coronary heart disease, and trans-18:2, but not trans-18:1, in red blood cells membranes has been associated with sudden cardiac arrest. Abnormal heart rate variability (HRV) reflects autonomic dysfunction and predicts cardiac death. Relationships between TFA consumption and HRV remain under-studied. We determined whether total TFA consumption, as well as trans-18:1 and trans-18:2 TFA consumption, were independently associated with HRV in two independent cohorts in the US and Portugal.
Methods and Results
In two independent cohorts of older US adults (Cardiovascular Health Study ([CHS], age=72±5yrs, 1989/1995) and young Portuguese adults (Porto, age=19±2yrs, 2008/2010), we assessed habitual TFA intake by food frequency questionnaires in CHS (separately estimating trans-18:1 and trans-18:2) and multiple 24-hour recalls in Porto (estimating total TFA only, which in a subset correlated with circulating trans-18:2, but not trans-18:1, suggesting that we captured the former). HRV was assessed using 24-hour Holters in CHS (N=1,076) and repeated short-term (5-min) ECGs in Porto (N=160). We used multivariate-adjusted linear regression to relate TFA consumption to HRV cross-sectionally (CHS, Porto) and longitudinally (CHS). In CHS, higher trans-18:2 consumption was associated with lower 24-hour standard-deviation-of-all-normal-to-normal-intervals (SDNN) both cross-sectionally (−12%, 95%CI=6–19%, p=0.001) and longitudinally (−15%, 95%CI=4–25 %, p= 0.009), and lower 24-hour SDANN and SDNN-index (p<0.05 each). Higher trans-18:1 consumption in CHS was associated with more favorable 24-hour HRV, in particular time-domain indices (SDNN, SDANN, SDNN-index; p<0.05 each). In Porto, each higher SD TFA consumption was associated with 4% lower 5-min SDNN (95%CI=1–8%, p=0.04), and 7% lower 5-min rMSSD (95%CI=1–13%, p=0.04).
Conclusions
Trans-18:2 consumption is associated with specific, less favorable indices of HRV in both older and young adults. Trans-18:1 consumption is associated with more favorable HRV indices in older adults. Our results support the need to investigate potential HRV related mechanisms whereby trans-18:2 may increase arrhythmic risk.
doi:10.1161/CIRCEP.111.966259
PMCID: PMC3967844  PMID: 22772898
Electrophysiology; trans-fatty acids; heart rate variability; nutrition
3.  Videoscopic Left Cardiac Sympathetic Denervation for Patients With Recurrent Ventricular Fibrillation/Malignant Ventricular Arrhythmia Syndromes Besides Congenital Long-QT Syndrome 
Background
Treatment options for patients with recurrent ventricular arrhythmias refractory to pharmacotherapy and ablation are minimal. Although left cardiac sympathetic denervation (LCSD) is well established in long-QT syndrome, its role in non-long-QT syndrome arrhythmogenic channelopathies and cardiomyopathies is less clear. Here, we report our single-center experience in performing LCSD in this setting.
Methods and Results
In this institutional review board-approved study, we retrospectively reviewed the electronic medical records of all patients (N=91) who had videoscopic LCSD at our institution from 2005 to 2011. Data were analyzed for the subset (n=27) who were denervated for an underlying diagnosis other than autosomal dominant or sporadic long-QT syndrome. The spectrum of arrhythmogenic disease included catecholaminergic polymorphic ventricular tachycardia (n=13), Jervell and Lange-Nielsen syndrome (n=5), idiopathic ventricular fibrillation (n=4), left ventricular noncompaction (n=2), hypertrophic cardiomyopathy (n=1), ischemic cardiomyopathy (n=1), and arrhythmogenic right ventricular cardiomyopathy (n=1). Five patients had LCSD because of high-risk assessment and β-blocker intolerance, none of whom had a sentinel breakthrough cardiac event at early follow-up. Among the remaining 22 previously symptomatic patients who had LCSD as secondary prevention, all had an attenuation in cardiac events, with 18 having no breakthrough cardiac events so far and 4 having experienced ≥1 post-LCSD breakthrough cardiac event.
Conclusions
LCSD may represent a substrate-independent antifibrillatory treatment option for patients with life-threatening ventricular arrhythmia syndromes other than long-QT syndrome. The early follow-up seems promising, with a marked reduction in the frequency of cardiac events postdenervation.
doi:10.1161/CIRCEP.112.971754
PMCID: PMC3912558  PMID: 22787014
catecholaminergic polymorphic ventricular tachycardia; sudden cardiac arrest; ventricular fibrillation; left cardiac sympathetic denervation; denervation
4.  Increased Left Ventricular Mass as a Predictor of Sudden Cardiac Death: Is it Time to put it to the Test? 
doi:10.1161/CIRCEP.112.974931
PMCID: PMC3596001  PMID: 23424223
Sudden Cardiac Death; Left Ventricular Hypertrophy; Implantable Cardioverter Defibrillator; Ventricular Tachycardia; Ventricular Fibrillation
5.  Dilated Cardiomyopathy 
doi:10.1161/CIRCEP.111.962050
PMCID: PMC3603701  PMID: 23022708
arrhythmia (Heart Rhythm Disorders); cardiomyopathy; genetics
6.  Follow-up of Patients with New Cardiovascular Implantable Electronic Devices: Are Experts’ Recommendations Implemented in Routine Clinical Practice? 
Background
A 2008 expert consensus statement outlined the minimum frequency of follow-up of patients with cardiovascular implantable electronic devices (CIEDs).
Methods and Results
We studied 38,055 Medicare beneficiaries who received a new CIED between January 1, 2005, and June 30, 2009. The main outcome measure was variation of follow-up by patient factors and year of device implantation. We determined the number of patients who were eligible for and attended an in-person CIED follow-up visit within 2 to 12 weeks, 0 to 16 weeks, and 1 year after implantation. Among eligible patients, 42.4% had an initial in-person visit within 2 to 12 weeks. This visit was significantly more common among white patients than black patients and patients of other races (43.0% vs 36.8% vs 40.5%; P < .001). Follow-up within 2 to 12 weeks improved from 40.3% in 2005 to 55.1% in 2009 (P < .001 for trend). The rate of follow-up within 0 to 16 weeks was 65.1% and improved considerably from 2005 to 2009 (62.3% to 79.6%; P < .001 for trend). Within 1 year, 78.0% of the overall population had at least 1 in-person CIED follow-up visit.
Conclusions
Although most Medicare beneficiaries who received a new CIED between 2005 and 2009 did not have an initial in-person CIED follow-up visit within 2 to 12 weeks after device implantation, the rate of initial follow-up improved appreciably over time. This CIED follow-up visit was significantly more common in white patients than patients of other races.
doi:10.1161/CIRCEP.112.974337
PMCID: PMC3640354  PMID: 23264436
cardiac resynchronization therapy; implantable cardioverter-defibrillator; pacemakers; outcomes research
7.  Early Risk of Mortality after Coronary Artery Revascularization in Patients with Left Ventricular Dysfunction and Potential Role of the Wearable Cardioverter Defibrillator 
Background
Implantable cardioverter defibrillator (ICD) implantation for prevention of sudden cardiac death is typically deferred for 90 days after coronary revascularization, but mortality may be highest early after cardiac procedures in patients with ventricular dysfunction. We determined mortality risk in post-revascularization patients with left ventricular ejection fraction (LVEF) ≤35% and compared survival to those discharged with a wearable cardioverter defibrillator (WCD).
Methods and Results
Hospital survivors after surgical (CABG) or percutaneous (PCI) revascularization with LVEF≤35% were included from Cleveland Clinic and national WCD registries. Kaplan-Meier, Cox proportional hazards, propensity score-matched survival and hazard function analyses were performed. Early mortality hazard was higher among 4149 patients discharged without a defibrillator compared to 809 with WCDs (90-day mortality post-CABG 7% vs. 3%, p=0.03; post-PCI 10% vs. 2%, p<0.0001). WCD use was associated with adjusted lower risks of long-term mortality in the total cohort (39%, p<0.0001) and both post-CABG (38%, p=0.048) and post-PCI (57%, p<0.0001) cohorts (mean follow-up 3.2 years). In propensity-matched analyses, WCD use remained associated with lower mortality (58% post-CABG, p=0.002; 67% post-PCI, p<0.0001). Mortality differences were not attributable solely to therapies for ventricular arrhythmia. Only 1.3% of the WCD group had a documented appropriate therapy.
Conclusions
Patients with LVEF≤35% have higher early compared to late mortality after coronary revascularization, particularly after PCI. As early hazard appeared less marked in WCD users, prospective studies in this high risk population are indicated to confirm whether WCD use as a bridge to LVEF improvement or ICD implantation can improve outcomes after coronary revascularization.
doi:10.1161/CIRCEP.112.973552
PMCID: PMC3676862  PMID: 23275233
survival; coronary revascularization; left ventricular dysfunction; percutaneous coronary intervention; wearable defibrillator
8.  Myocardial Structural Associations with Local Electrograms: A Study of Post-Infarct Ventricular Tachycardia Pathophysiology and Magnetic Resonance Based Non-Invasive Mapping 
Background
The association of scar on late-gadolinium enhancement cardiac magnetic resonance (LGE-CMR) with local electrograms on electroanatomic mapping (EAM) has been investigated. We aimed to quantify these associations to gain insights regarding LGE-CMR image characteristics of tissues and critical sites that support post-infarct ventricular tachycardia (VT).
Methods and Results
LGE-CMR was performed in 23 patients with ischemic cardiomyopathy before VT ablation. Left ventricular wall thickness and post-infarct scar thickness were measured in each of 20 sectors per LGE-CMR short-axis plane. EAM points were retrospectively registered to the corresponding LGE-CMR images. Multivariable regression analysis, clustered by patient, revealed significant associations between left ventricular wall thickness, post infarct scar thickness, and intramural scar location on LGE-CMR, and local endocardial electrogram bipolar/unipolar voltage, duration, and deflections on EAM. Antero-posterior and septal/lateral scar localization was also associated with bipolar and unipolar voltage. Anti-arrhythmic drug use was associated with electrogram duration. Critical sites of post-infarct VT were associated with >25% scar transmurality and slow conduction sites with >40 msec stimulus-QRS time were associated with >75% scar transmurality.
Conclusions
Critical sites for maintenance of post-infarct VT are confined to areas with >25% scar transmurality. Our data provides insights into the structural substrates for delayed conduction and VT, and may reduce procedural time devoted to substrate mapping, overcome limitations of invasive mapping due to sampling density, and enhance magnetic resonance based ablation by feature extraction from complex images.
doi:10.1161/CIRCEP.112.970699
PMCID: PMC3581804  PMID: 23149263
ischemic heart disease; magnetic resonance imaging; mapping; ventricular tachycardia; late gadolinium enhancement
9.  Translational Research in Atrial Fibrillation: A Quest for Mechanistically Based Diagnosis and Therapy 
doi:10.1161/CIRCEP.111.970335
PMCID: PMC3535065  PMID: 23022707
ablation; arrhythmia (mechanisms); atrial fibrillation; electrophysiology mapping; imaging
10.  Mechanisms for Human Atrial Fibrillation Initiation: Clinical and Computational Studies of Repolarization Restitution and Activation Latency 
Circulation. Arrhythmia and electrophysiology  2012;5(6):10.1161/CIRCEP.111.969022.
Background
Mechanisms of atrial fibrillation (AF) initiation are incompletely understood. We hypothesized that rate-dependent changes (restitution) in action potential duration (APD) and activation latency are central targets for clinical interventions that induce AF. We tested this hypothesis using clinical experiments and computer models.
Methods and Results
In 50 patients (20 persistent, 23 paroxysmal AF, 7 controls), we used monophasic action potential catheters to define left atrial APD restitution, activation latency and AF incidence from premature extrastimuli. Isoproterenol (n=14), adenosine (n=10), or rapid pacing (n=36) were then initiated to determine impact on these parameters. Compared with baseline in AF patients, isoproterenol and rapid pacing decreased activation latency (64±14vs 31±13 vs 24±14 ms, p<0.05), steepened maximum APD restitution slope (0.8±0.7 vs 1.7±0.5 vs 1.1±0.5, p<0.05), and increased AF incidence (12% vs 64% vs 84%, p<0.05). Conversely, adenosine shortened APD (p<0.05), yet increased activation latency (86±27 ms, p=0.002) so that maximum APD restitution slope did not steepen (1.0±0.5, p=NS) and AF incidence was unchanged (10%, p=NS). In controls, no intervention steepened APD restitution or initiated AF. Computational modeling revealed that isoproterenol steepened APD restitution by increased ICaL and decreased activation latency via enhanced IKr inactivation, while rapid pacing steepened APD restitution via increased IK1.
Conclusions
Steep APD restitution is a common pathway for AF initiation by isoproterenol and tachycardia, via reduced activation latency that enables engagement of steep APD restitution at rapid rates. Modeling suggests AF initiation from each intervention uses distinct ionic mechanisms. This insight may help design interventions to prevent AF.
doi:10.1161/CIRCEP.111.969022
PMCID: PMC3833353  PMID: 23027797
action potentials; atrial fibrillation; computers; electrophysiology; pacing
12.  Identification and Acute Targeting of Gaps in Atrial Ablation Lesion Sets using a Real Time MRI System 
Background
Radiofrequency ablation is routinely used to treat cardiac arrhythmias, but gaps remain in ablation lesion sets, as there is no direct visualization of ablation related changes. In this study we describe using a real time MRI (RT-MRI) system to acutely identify and target gaps leading to a complete and transmural ablation in the atrium.
Methods and Results
A swine model was used for these studies (n=12). Ablation lesions with a gap were created in the atrium using fluoroscopy and an electro-anatomical system in the first group (n=5). The animal was then moved to a 3 Tesla MRI system where high-resolution late gadolinium enhancement (LGE) MRI was used to identify the gap. Using a RT-MRI catheter navigation and visualization system the gap area was ablated in the MR scanner. In a second group (n=7) ablation lesions with varying gaps in between were created under RT-MRI guidance and gap lengths determined using LGE MR images were correlated with gap length measured from gross pathology. Gaps up to 1.0 mm were identified using gross pathology and 1.4 mm using LGE MRI. Using a RT-MRI system with active catheter navigation gaps can be targeted acutely, leading to lesion sets with no gaps. The correlation coefficient (R2) between gap length identified using MRI and gross pathology was 0.95.
Conclusions
Real time MRI system can be used to identify and acutely target gaps in atrial ablation lesion sets. Acute targeting of gaps in ablation lesion sets can potentially lead to significant improvement in clinical outcomes.
doi:10.1161/CIRCEP.112.973164
PMCID: PMC3691079  PMID: 23071143
ablation; magnetic resonance imaging; atrial fibrillation arrhythmia; real time MRI; real-time imaging
13.  The Electrocardiographic PR Interval and Adverse Outcomes in Older Adults: the Health, Aging and Body Composition Study 
Background
The electrocardiographic PR interval increases with aging, differs by race, and is associated with atrial fibrillation (AF), pacemaker implantation and all-cause mortality. We sought to determine the associations between PR interval and heart failure, AF, and mortality in a biracial cohort of older adults.
Methods and results
The Health, Aging, and Body Composition (Health ABC) Study is a prospective, biracial cohort. We employed multivariable Cox proportional hazards models to examine PR interval (hazard ratios expressed per standard deviation (SD) increase) and 10-year risks of heart failure, AF, and all-cause mortality. Multivariable models included demographic, anthropometric, and clinical variables in addition to established cardiovascular risk factors. We examined 2722 Health ABC participants (age 74±3 years, 51.9% women, and 41% black). We did not identify significant effect modification by race for the outcomes studied. Following multivariable adjustment, every SD increase (29 ms) in PR interval was associated with a 13% greater 10-year risk of heart failure (95% confidence interval [CI], 1.02 to 1.25) and a 13% increased risk of incident AF (95% CI, 1.04 to 1.23). PR interval >200 ms was associated with a 46% increased risk of incident heart failure (95% CI, 1.11 to 1.93). PR interval was not associated with increased all-cause mortality.
Conclusions
We identified significant relations of PR interval to heart failure and AF in older adults. Our findings extend prior investigations by examining PR interval and associations with adverse outcomes in a biracial cohort of older men and women.
doi:10.1161/CIRCEP.112.975342
PMCID: PMC3613778  PMID: 23243193
PR interval; epidemiology; heart failure; atrial fibrillation; mortality; aging
14.  Extra-Cardiac Neural Remodeling in Humans with Cardiomyopathy 
Background
Intra-myocardial nerve sprouting after myocardial infarction is associated with ventricular arrhythmias (VAs). Whether human stellate ganglia remodel in association with cardiac pathology is unknown. The purpose of this study was to determine whether cardiac pathology is associated with remodeling of the stellate ganglia in humans.
Methods and Results
Left stellate ganglia (LSG) were collected from patients undergoing sympathetic denervation for intractable ventricular arrhythmias, and from cadavers, along with intact hearts. Clinical data on patients and cadaveric subjects were reviewed. We classified ganglia from normal; scarred; and non-ischemic cardiomyopathic hearts without scar as NL (n=3); SCAR (n=24); and NICM (n=7), respectively. Within LSG, neuronal size, density, fibrosis, synaptic density and nerve sprouting were determined. Nerve density and sprouting were also quantified in cadaveric hearts. Mean neuronal size in NL, SCAR, and NICM groups were; 320±4μm2, 372±10μm2,and 435±10μm2 (p=0.002). No significant differences in neuronal density and fibrosis were present between the groups. Synaptic density in SCAR and NICMganglia were 57.8±11.2um2/ mm2 (p=0.039) and 44.5±7.9um2/ mm2 (p=0.084) respectively, compared to the NL, 17.8±7um2/ mm2 (overall p=0.162). There were no significant differences in LSG nerve sprouting or myocardial nerve density between the groups.
Conclusions
Neuronal hypertrophy withinLSGis associated with chronic cardiomyopathy in humans. Ganglionic and myocardial nerve sprouting and nerve density were not significantly different. These changes may be related to increased cardiac sympathetic signaling and VAs. Further studies are needed to determine the electrophysiologic consequences of extra-cardiac neuronal remodeling in humans.
doi:10.1161/CIRCEP.112.972836
PMCID: PMC3529182  PMID: 22923270
cardiomyopathy; nervous system; autonomic; nervous system; sympathetic; ventricular arrhythmia
15.  Predictors of Sustained Ventricular Arrhythmias in Cardiac Resynchronization Therapy 
Background
Patients undergoing cardiac resynchronization therapy (CRT) are at high risk for ventricular arrhythmias and risk stratification in this population remains poor.
Methods and Results
This study followed 269 patients (LVEF < 35%, QRS > 120ms, NYHA III/IV) undergoing CRT with defibrillator (CRT-D) for 553±464 days after CRT-D implantation to assess for independent predictors of appropriate device therapy for ventricular arrhythmias (VAs). Baseline medication use, medical comorbidities, and echocardiographic parameters were considered. The 4-year incidence of appropriate device therapy was 36%. A Cox proportional hazard model identified left ventricular end systolic diameter (LVESD) > 61mm as an independent predictor in the entire population (HR 2.66, p = 0.001). Those with LVESD > 61mm had a 51% 3-year incidence of VA compared to a 26% incidence among those with a less dilated ventricle (p = 0.001). Among patients with LVESD ≤61mm, multivariate predictors of appropriate therapy were absence of beta-blocker therapy (HR 6.34, p<0.001, LVEF < 20% (HR 4.22, p <0.001), and history of sustained VA (2.97, p = 0.013). Early (<180d after implant) shock therapy was found to be a robust predictor of heart failure hospitalization (HR 3.41, p < 0.004) and mortality (HR 5.16 p < 0.001.)
Conclusions
Among CRT-D patients, LVESD > 61mm is powerful predictor of ventricular arrhythmias and further risk stratification of those with less dilated ventricles can be achieved based on assessment of EF, history of sustained VA, and absence of beta-blocker therapy.
doi:10.1161/CIRCEP.112.971101
PMCID: PMC3766722  PMID: 22787010
Cardiomyopathy; tachyarrhythmias; heart failure; pacemakers; risk factors
16.  Mechanism-based facilitated maturation of human pluripotent stem cell-derived cardiomyocytes 
Background
Human embryonic stem cells (hESCs) can be efficiently and reproducibly directed into cardiomyocytes (CMs) using stage-specific induction protocols. However, their functional properties and suitability for clinical and other applications have not been evaluated.
Methods and Results
Here we showed that CMs derived from multiple pluripotent human stem cell lines (hESC: H1, HES2) and types (induced pluripotent stem cell or iPSC) using different in vitro differentiation protocols (embryoid body formation, endodermal induction, directed differentiation) commonly displayed immature, pro-arrhythmic action potential (AP) properties such as high-degree of automaticity, depolarized resting membrane potential (RMP), Phase 4- depolarization and delayed after-depolarization (DAD). Among the panoply of sarcolemmal ionic currents investigated (INa+/ICaL2+/IKr+/INCX+/If+/Ito+/IK1-/IKs-), we pinpointed the lack of the Kir2.1-encoded inwardly rectifying K+ current (IK1) as the single mechanistic contributor to the observed immature electrophysiological properties in hESC-CMs. Forced expression of Kir2.1 in hESC-CMs led to robust expression of Ba2+-sensitive IK1 and more importantly, completely ablated all the pro-arrhythmic AP traits, rendering the electrophysiological phenotype indistinguishable from the adult counterparts. These results provided the first link of a complex developmentally arrested phenotype to a major effector gene, and importantly, further led us to develop a biomimetic culturing strategy for enhancing maturation.
Conclusions
By providing the environmental cues that are missing in conventional culturing method, this approach did not require any genetic or pharmacological interventions. Our findings can facilitate clinical applications, drug discovery and cardiotoxicity screening by improving the yield, safety and efficacy of derived CMs.
doi:10.1161/CIRCEP.111.973420
PMCID: PMC3757253  PMID: 23392582
human embryonic stem cells; cardiomyocytes; maturation; electrophysiology; arrhythmogenicity
17.  Panoramic Electrophysiological Mapping but not Electrogram Morphology Identifies Stable Sources for Human Atrial Fibrillation 
Background
The foundation for successful arrhythmia ablation is the mapping of electric propagation to identify underlying mechanisms. In atrial fibrillation (AF), however, mapping is difficult so that ablation has often targeted electrogram features, with mixed results. We hypothesized that wide field-of-view (panoramic) mapping of both atria would identify causal mechanisms for AF and allow interpretation of local electrogram features, including complex fractionated atrial electrograms (CFAE).
Methods and Results
Contact mapping was performed using biatrial multipolar catheters in 36 AF subjects (29 persistent). Stable AF rotors (spiral waves) or focal sources were seen in 35 of 36 cases and targeted for ablation (focal impulse and rotor modulation) before pulmonary vein isolation. In 31 of 36 subjects (86.1%), AF acutely terminated (n=20; 16 to sinus rhythm) or organized (n=11; 19±8% slowing) with 2.5 minutes focal impulse and rotor modulation (interquartile range, 1.0–3.1) at one source, defined as the primary source. Subjects exhibited 2.1±1.0 concurrent AF sources of which the primary, by phase mapping, precessed in limited areas (persistent 2.5±1.7 versus paroxysmal 1.7±0.5 cm2; P=0.30). Notably, source regions showed mixed electrogram amplitudes and CFAE grades that did not differ from surrounding atrium (P=NS). AF sources were not consistently surrounded by CFAE (P=0.67).
Conclusions
Stable rotors and focal sources for human AF were revealed by contact panoramic mapping (focal impulse and rotor modulation mapping), but not by electrogram footprints. AF sources precessed within areas of ≈2 cm2, with diverse voltage characteristics poorly correlated with CFAE. Most CFAE sites lie remote from AF sources and are not suitable targets for catheter ablation of AF.
doi:10.1161/CIRCEP.111.977264
PMCID: PMC3746540  PMID: 23392583
atrium; contact panoramic mapping; electrophysiology; fibrillation; focal sources; FIRM ablation; human; rotors
18.  In Situ Confocal Imaging in Intact Heart Reveals Stress-Induced Ca2+ Release Variability in a Murine CPVT Model of RyR2R4496C+/− Mutation 
Background
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is directly linked to mutations in proteins (e.g., RyR2R4496C) responsible for intracellular Ca2+ homeostasis in the heart. However, the mechanism of Ca2+ release dysfunction underlying CPVT has only been investigated in isolated cells but not in the in situ undisrupted myocardium.
Methods and Results
We investigated in situ myocyte Ca2+ dynamics in intact Langendorff perfused hearts (ex vivo) from wildtype (WT) and RyR2R4496C+/− mice using laser scanning confocal microscopy. We found that myocytes from both WT and RyR2R4496C+/− hearts displayed uniform, synchronized Ca2+ transients. Ca2+ transients from beat to beat were comparable in amplitude with identical activation and decay kinetics in WT and RyR2R4496C+/− hearts, suggesting that excitation-contraction (EC) coupling between the sarcolemmal Ca2+ channels and mutated RyR2R4496C+/− channels remains intact under baseline resting conditions. Upon adrenergic stimulation, RyR2R4496C+/− hearts exhibited a high degree of Ca2+ release variability (CRV). The varied pattern of Ca2+ release was absent in single isolated myocytes, independent of cell cycle length, synchronized among neighboring myocytes, and correlated with CPVT. A similar pattern of action potential variability, which was synchronized among neighboring myocytes, was also revealed under adrenergic stress in intact hearts but not in isolated myocytes.
Conclusions
Our studies using in situ confocal imaging approach suggest that mutated RyR2s are functionally normal at rest but display a high degree of CRV upon intense adrenergic stimulation. CRV is a Ca2+ release abnormality resulting from electrical defects rather than the failure of the Ca2+ release response to action potentials in mutated ventricular myocytes. Our data provide important insights into Ca2+ release and electrical dysfunction in an established model of CPVT.
doi:10.1161/CIRCEP.111.969733
PMCID: PMC3421047  PMID: 22722659
arrhythmia (mechanisms); calcium; catecholaminergic polymorphic ventricular tachycardia; sarcoplasmic reticulum; ryanodine receptors
19.  Effect of SkM1 Sodium Channels Delivered Via a Cell Platform on Cardiac Conduction and Arrhythmia Induction 
Background
In depolarized myocardial infarct epicardial border zones (EBZ), the cardiac sodium channel is largely inactivated, contributing to slow conduction and reentry. We have demonstrated that adenoviral delivery of the skeletal muscle sodium channel SkM1 to EBZ normalizes conduction and reduces induction of ventricular tachycardia/fibrillation (VT/VF). We now studied the impact of canine mesenchymal stem cells (cMSC) in delivering SkM1.
Methods and Results
cMSC were isolated and transfected with SkM1. Co-culture experiments showed cMSC/SkM1, but not cMSC alone, maintained fast conduction at depolarized potentials. We studied 3 groups in the canine 7d infarct: sham, cMSC and cMSC/SkM1. In vivo EBZ electrograms were broad and fragmentedin sham, narrower in cMSC and narrow and unfragmented in cMSC/SkM1 (P<0.05). During programmed electrical stimulation (PES) of EBZ, QRS duration in cMSC/SkM1 was shorter than in cMSC and sham (P<0.05). PES-induced VT/VFwas equivalent in all groups (P>0.05).
Conclusions
cMSC provide efficient, effective delivery of SkM1 current. The interventions performed (cMSC or cMSC/SkM1) were neither antiarrhythmic nor proarrhythmic. Comparing outcomes with cMSC/SkM1 and viral gene delivery highlights the criticality of the delivery platform to SkM1 antiarrhythmic efficacy.
doi:10.1161/CIRCEP.111.969907
PMCID: PMC3427660  PMID: 22722661
arrhythmia; gene therapy; myocardial infarction; Na+ channels; cardiac conduction; cell therapy
20.  Predictive Value of Beat-to-Beat QT Variability Index across the Continuum of Left Ventricular Dysfunction: Competing Risks of Non-cardiac or Cardiovascular Death, and Sudden or Non-Sudden Cardiac Death 
Background
The goal of this study was to determine the predictive value of beat-to-beat QT variability in heart failure (HF) patients across the continuum of left ventricular dysfunction.
Methods and Results
Beat-to-beat QT variability index (QTVI), heart rate variance (LogHRV), normalized QT variance (QTVN), and coherence between heart rate variability and QT variability have been measured at rest during sinus rhythm in 533 participants of the Muerte Subita en Insuficiencia Cardiaca (MUSIC) HF study (mean age 63.1±11.7; males 70.6%; LVEF >35% in 254 [48%]) and in 181 healthy participants from the Intercity Digital Electrocardiogram Alliance (IDEAL) database. During a median of 3.7 years of follow-up, 116 patients died, 52 from sudden cardiac death (SCD). In multivariate competing risk analyses, the highest QTVI quartile was associated with cardiovascular death [hazard ratio (HR) 1.67(95%CI 1.14-2.47), P=0.009] and in particular with non-sudden cardiac death [HR 2.91(1.69-5.01), P<0.001]. Elevated QTVI separated 97.5% of healthy individuals from subjects at risk for cardiovascular [HR 1.57(1.04-2.35), P=0.031], and non-sudden cardiac death in multivariate competing risk model [HR 2.58(1.13-3.78), P=0.001]. No interaction between QTVI and LVEF was found. QTVI predicted neither non-cardiac death (P=0.546) nor SCD (P=0.945). Decreased heart rate variability (HRV) rather than increased QT variability was the reason for increased QTVI in this study.
Conclusions
Increased QTVI due to depressed HRV predicts cardiovascular mortality and non-sudden cardiac death, but neither SCD nor excracardiac mortality in HF across the continuum of left ventricular dysfunction. Abnormally augmented QTVI separates 97.5% of healthy individuals from HF patients at risk.
doi:10.1161/CIRCEP.112.970541
PMCID: PMC3432262  PMID: 22730411
ECG; ejection fraction; heart failure; sudden death; QT variability
21.  Epicardial Adipose Tissue and Neural Mechanisms of Atrial Fibrillation 
doi:10.1161/CIRCEP.112.974956
PMCID: PMC3438902  PMID: 22895598
atrial fibrillation; Editorials; inflammation; nervous system, autonomic
22.  Repolarization Changes Underlying Long-Term Cardiac Memory Due to Right Ventricular Pacing: Noninvasive Mapping with ECGI 
Background
Cardiac memory refers to the observation that altered cardiac electrical activation results in repolarization changes that persist after the restoration of a normal activation pattern. Animal studies, however, have yielded disparate conclusions both regarding the spatial pattern of repolarization changes in cardiac memory and the underlying mechanisms. This study was undertaken to produce three dimensional images of the repolarization changes underlying long-term cardiac memory in humans.
Methods and Results
Nine adult subjects with structurally normal hearts and dual-chamber pacemakers were enrolled in the study. Non-invasive electrocardiographic imaging (ECGI) was used before and after one month of ventricular pacing to reconstruct epicardial activation and repolarization patterns. Eight subjects exhibited cardiac memory in response to ventricular pacing. In all subjects, ventricular pacing resulted in a prolongation of the activation recovery interval (a surrogate for action potential duration) in the region close to the site of pacemaker-induced activation from 228.4±7.6 ms during sinus rhythm to 328.3±6.2 ms during cardiac memory. As a consequence, increases are observed in both apical-basal and right-left ventricular gradients of repolarization resulting in a significant increase in the dispersion of repolarization.
Conclusions
These results demonstrate that electrical remodeling in response to ventricular pacing in human subjects results in action potential prolongation near the site of abnormal activation and a marked dispersion of repolarization. This dispersion of repolarization is potentially arrhythmogenic and, intriguingly, was less evident during continuous RV pacing, suggesting the novel possibility that continuous RV pacing at least partially suppresses pacemaker-induced cardiac memory.
doi:10.1161/CIRCEP.112.970491
PMCID: PMC3445629  PMID: 22772896
action potentials; pacemakers; remodeling; T wave memory; cardiac memory
23.  Long QT Syndrome: From Genetics to Management 
doi:10.1161/CIRCEP.111.962019
PMCID: PMC3461497  PMID: 22895603
arrhythmia (Heart Rhythm Disorders); beta-blockers; death, sudden; genetics; long-QT syndrome
24.  Size and Ionic Currents of Unexcitable Cells Coupled to Cardiomyocytes Distinctly Modulate Cardiac Action Potential Shape and Pacemaking Activity in Micropatterned Cell Pairs 
Background
Cardiac cell therapies can yield electrical coupling of unexcitable donor cells to host cardiomyocytes with functional consequences that remain unexplored.
Methods and Results
We micropatterned cell pairs consisting of a neonatal rat ventricular myocyte (NRVM) coupled to an engineered HEK293 cell expressing either connexin-43 (Cx43 HEK) or Kir2.1 and connexin-43 (Kir2.1+Cx43 HEK). The NRVM-HEK contact length was fixed yielding a coupling strength of 68.9±9.7 nS, while HEK size was systematically varied. With increase in Cx43 HEK size, NRVM maximal diastolic potential (MDP) was reduced from −71.7±0.6 mV in single NRVMs to −35.1±1.3 mV in pairs with HEK:NRVM cell surface area ratio of 1.7±0.1, while action potential upstroke ((dVm/dt)max) and duration (APD) decreased to 1.6±0.7 % and increased to 177±32% of the single NRVM values, respectively (N=21 cell pairs). Pacemaking occurred in all NRVM-Cx43 HEK pairs with cell surface area ratios of 1.1-1.9. In contrast, NRVMs coupled with Kir2.1+Cx43 HEKs of increasing size had similar MDPs, exhibited no spontaneous activity, and showed gradual decrease in APD (N=23). Furthermore, coupling single NRVMs to a dynamic clamp model of HEK cell ionic current reproduced the cardiac MDPs and pacemaking rates recorded in cell pairs, while reproducing changes in (dVm/dt)max and APD required coupling to a HEK model that also included cell membrane capacitance.
Conclusions
Size and ionic currents of unexcitable cells electrically coupled to cardiomyocytes distinctly affect cardiac action potential shape and initiation with important implications for the safety of cardiac cell and gene therapies.
doi:10.1161/CIRCEP.111.969329
PMCID: PMC3506117  PMID: 22679057
ion channels; cardiac cell therapy; gap junctions; micropatterning; passive cell
25.  Contribution of Fibrosis and the Autonomic Nervous System to Atrial Fibrillation Electrograms in Heart Failure 
Background
Fibrotic and autonomic remodeling in heart failure (HF) increase vulnerability to atrial fibrillation (AF). Since AF electrograms (EGMs) are thought to reflect underlying structural substrate, we sought to: a) determine differences in AF-EGMs in normal versus HF atria and b) assess how fibrosis and nerve-rich fat contribute to AF-EGM characteristics in HF.
Methods and Results
AF was induced in 20 normal dogs by vagal stimulation and in 21 HF dogs (subjected to 3 weeks of rapid ventricular pacing at 240/min). AF-EGMs were analyzed for dominant frequency (DF), organizational index (OI), fractionation intervals (FI) and Shannon's entropy (ShEn). In 8 HF dogs, AF-EGM correlation with underlying fibrosis/fat/nerves was assessed. In HF, compared to normals, a) DF was lower and OI/FI/ShEn were greater. DF/FI were more heterogeneous in HF. %fat was greater, and fibrosis and fat more heterogeneously distributed in the posterior left atrium (PLA) than left atrial appendage (LAA). DF/OI correlated closely with %fibrosis. Heterogeneity of DF/FI correlated with heterogeneity of fibrosis. Autonomic blockade caused a greater change in DF/FI/ShEn in the PLA than LAA, with the decrease in ShEn correlating with %fat.
Conclusions
The amount and distribution of fibrosis in the HF atrium appears to contribute to slowing and increased organization of AF-EGMs, while the nerve-rich fat in the HF-PLA is positively correlated with AF-EGM entropy. By allowing for improved detection of regions of dense fibrosis and high autonomic nerve density in the HF atrium, these findings may help enhance the precision and success of substrate-guided ablation for AF.
doi:10.1161/CIRCEP.111.970095
PMCID: PMC3607299  PMID: 22722658
atrium; fibrillation; heart failure; nervous system; autonomic; fibrosis

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