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1.  The subcutaneous ICD—current evidence and challenges 
The subcutaneous implantable cardioverter-defibrillator (S-ICD) represents an exciting development in ICD technology. It has relative advantages over traditional transvenous systems, particularly for young patients in whom the lifetime risk of device-related complications may be deemed to be unacceptably high. While data relating to device longevity and long term safety profile is yet to be accrued, several recent studies have demonstrated good clinical efficacy comparable to transvenous ICDs. Indeed, new techniques have also been developed to simplify the S-ICD implantation procedure and attempts have been made to address challenges pertaining to T-wave oversensing to reduce the delivery of inappropriate shocks. The impact of inappropriate shocks and lack of anti-tachycardia pacing (ATP) function are not only contentious matters, but also have important implications for patients in whom the S-ICD would be suitable. It is envisaged that subsequent models of this device will be less cumbersome, with the possibility that an entirely leadless pacemaker-defibrillator will one day be possible. Although the S-ICD may not completely replace transvenous devices in its current form, evidence suggests that it is a viable alternative particularly in preventing sudden cardiac death in non-pacing dependent patients.
PMCID: PMC4278039  PMID: 25610802
Subcutaneous implantable cardioverter-defibrillator (S-ICD); sudden cardiac death
2.  The investigation of sudden arrhythmic death syndrome (SADS)—the current approach to family screening and the future role of genomics and stem cell technology 
SADS is defined as sudden death under the age of 40 years old in the absence of structural heart disease. Family screening studies are able to identify a cause in up to 50% of cases-most commonly long QT syndrome (LQTS), Brugada and early repolarization syndrome, and catecholaminergic polymorphic ventricular tachycardia (CPVT) using standard clinical screening investigations including pharmacological challenge testing. These diagnoses may be supported by genetic testing which can aid cascade screening and may help guide management. In the current era it is possible to undertake molecular autopsy provided suitable samples of DNA can be obtained from the proband. With the evolution of rapid sequencing techniques it is possible to sequence the whole exome for candidate genes. This major advance offers the opportunity to identify novel causes of lethal arrhythmia but also poses the challenge of managing the volume of data generated and evaluating variants of unknown significance (VUS). The emergence of induced pluripotent stem cell technology could enable evaluation of the electrophysiological relevance of specific ion channel mutations in the proband or their relatives and will potentially enable screening of idiopathic ventricular fibrillation survivors combining genetic and electrophysiological studies in derived myocytes. This also could facilitate the assessment of personalized preventative pharmacological therapies. This review will evaluate the current screening strategies in SADS families, the role of molecular autopsy and genetic testing and the potential applications of molecular and cellular diagnostic strategies on the horizon.
PMCID: PMC3771072  PMID: 24062688
sudden death; screening; ion channel; stem cell; SADS
3.  Bridging the gap between computation and clinical biology: validation of cable theory in humans 
Introduction: Computerized simulations of cardiac activity have significantly contributed to our understanding of cardiac electrophysiology, but techniques of simulations based on patient-acquired data remain in their infancy. We sought to integrate data acquired from human electrophysiological studies into patient-specific models, and validated this approach by testing whether electrophysiological responses to sequential premature stimuli could be predicted in a quantitatively accurate manner.
Methods: Eleven patients with structurally normal hearts underwent electrophysiological studies. Semi-automated analysis was used to reconstruct activation and repolarization dynamics for each electrode. This S2 extrastimuli data was used to inform individualized models of cardiac conduction, including a novel derivation of conduction velocity restitution. Activation dynamics of multiple premature extrastimuli were then predicted from this model and compared against measured patient data as well as data derived from the ten-Tusscher cell-ionic model.
Results: Activation dynamics following a premature S3 were significantly different from those after an S2. Patient specific models demonstrated accurate prediction of the S3 activation wave, (Pearson's R2 = 0.90, median error 4%). Examination of the modeled conduction dynamics allowed inferences into the spatial dispersion of activation delay. Further validation was performed against data from the ten-Tusscher cell-ionic model, with our model accurately recapitulating predictions of repolarization times (R2 = 0.99).
Conclusions: Simulations based on clinically acquired data can be used to successfully predict complex activation patterns following sequential extrastimuli. Such modeling techniques may be useful as a method of incorporation of clinical data into predictive models.
PMCID: PMC3761165  PMID: 24027527
conduction velocity restitution; computational modeling; action potential duration; patient specific modeling; cardiac arrhythmia
4.  Is CRT pro-arrhythmic? A comparative analysis of the occurrence of ventricular arrhythmias between patients implanted with CRTs and ICDs 
Aim and Hypothesis: Despite the proven symptomatic and mortality benefit of cardiac resynchronization therapy (CRT), there is anecdotal evidence it may be pro-arrhythmic in some patients. We aimed to identify if there were significant differences in the incidence of ventricular arrhythmias (VAs) in patients undergoing CRT-D and implantable cardioverter-defibrillators (ICD) implantation for primary prevention indication. We hypothesized that CRT is unlikely to be pro-arrhythmic based on the positive mortality and morbidity data from large randomized trials.
Methods and Results: A retrospective analysis of device therapies for VA in a primary prevention device cohort was performed. Patients with ischemic (IHD) and non-ischemic (DCM) cardiomyopathy and ICD or CRT+ICD devices (CRT-D) implanted between 2005 and 2007 without prior history of sustained VA were included for analysis. VA episodes were identified from stored electrograms and defined as sustained (VT/VF) if therapy [anti-tachycardia pacing (ATP) or shocks] was delivered or non-sustained (NSVT) if not. Of a total of 180 patients, 117 (68% male) were in the CRT-D group, 42% IHD, ejection fraction (EF) 24.5 ± 8.2% and mean follow-up 23.9 ± 9.8 months. 63 patients (84% male) were in the ICD group, 60% IHD, EF 27.7 ± 7.2% and mean follow-up 24.6 ± 10.8 months. Overall, there was no significant difference in the incidence of VA (35.0 vs. 38.1%, p = 0.74), sustained VT (21.3 vs. 28.5%, p = 0.36) or NSVT (12.8 vs. 9.5%, p = 0.63) and no significant difference in type of therapy received for VT/VF: ATP (68 vs. 66.6%, p = 0.73) and shocks (32 vs. 33.3%, p = 0.71) between the CRT-D and ICD groups, respectively.
Conclusion: In patients with cardiomyopathy receiving CRT-D and ICDs for primary prophylaxis, there was no significant difference in the incidence of VA. From this single center retrospective analysis, there is no evidence to support cardiac resynchronization causing pro-arrhythmia.
PMCID: PMC4166112  PMID: 25278901
cardiac resynchronization therapy; ICD; heart failure; ventricular arrhythmia
5.  Dynamic Conduction and Repolarisation Changes in Early Arrhythmogenic Right Ventricular Cardiomyopathy versus Benign Outflow Tract Ectopy Demonstrated by High Density Mapping & Paced Surface ECG Analysis 
PLoS ONE  2014;9(7):e99125.
The concealed phase of arrhythmogenic right ventricular cardiomyopathy (ARVC) may initially manifest electrophysiologically. No studies have examined dynamic conduction/repolarization kinetics to distinguish benign right ventricular outflow tract ectopy (RVOT ectopy) from ARVC's early phase. We investigated dynamic endocardial electrophysiological changes that differentiate early ARVC disease expression from RVOT ectopy.
22 ARVC (12 definite based upon family history and mutation carrier status, 10 probable) patients without right ventricular structural anomalies underwent high-density non-contact mapping of the right ventricle. These were compared to data from 14 RVOT ectopy and 12 patients with supraventricular tachycardias and normal hearts. Endocardial & surface ECG conduction and repolarization parameters were assessed during a standard S1-S2 restitution protocol.
Definite ARVC without RV structural disease could not be clearly distinguished from RVOT ectopy during sinus rhythm or during steady state pacing. Delay in Activation Times at coupling intervals just above the ventricular effective refractory period (VERP) increased in definite ARVC (43±20 ms) more than RVOT ectopy patients (36±14 ms, p = 0.03) or Normals (25±16 ms, p = 0.008) and a progressive separation of the repolarisation time curves between groups existed. Repolarization time increases in the RVOT were also greatest in ARVC (definite ARVC: 18±20 ms; RVOT ectopy: 5±14, Normal: 1±18, p<0.05). Surface ECG correlates of these intracardiac measurements demonstrated an increase of greater than 48 ms in stimulus to surface ECG J-point pre-ERP versus steady state, with an 88% specificity and 68% sensitivity in distinguishing definite ARVC from the other groups. This technique could not distinguish patients with genetic predisposition to ARVC only (probable ARVC) from controls.
Significant changes in dynamic conduction and repolarization are apparent in early ARVC before detectable RV structural abnormalities, and were present to a lesser degree in probable ARVC patients. Investigation of dynamic electrophysiological parameters may be useful to identify concealed ARVC in patients without disease pedigrees by using endocardial electrogram or paced ECG parameters.
PMCID: PMC4094482  PMID: 25014132
6.  Early Experience with the Subcutaneous ICD 
Current Cardiology Reports  2014;16(8):516.
The Subcutaneous Internal Cardiac Defibrillator (S-ICD) represents a major advance in the care of patients who have an indication for an internal cardiac defibrillator without pacing indications. Its main advantage is that it can deliver a shock to cardiovert ventricular arrhythmias utilising a tunnelled subcutaneous lead, negating the risks associated with conventional transvenous systems. Initial studies have shown comparable efficacy in cardioversion of induced and spontaneous ventricular tachycardia (VT) and ventricular fibrillation (VF) when compared to conventional transvenous systems. In addition, inappropriate shocks occurred in a similar percentage of patients to conventional ICD studies. Complication rates are low and relate largely to localised wound infections, treated successfully with antibiotics. The long term efficacy of the device is yet to be ascertained, however, a randomised trial & prospective registries are currently in progress to enable direct comparison with transvenous ICDs. This article summarises the early clinical experience and trials in the implantation of the S-ICD.
PMCID: PMC4119251  PMID: 24994568
Internal cardiac defibrillator; Sudden cardiac death; Ventricular arrhythmia; Defibrillation; Subcutaneous ICD
7.  Worldwide experience with a totally subcutaneous implantable defibrillator: early results from the EFFORTLESS S-ICD Registry 
European Heart Journal  2014;35(25):1657-1665.
The totally subcutaneous implantable-defibrillator (S-ICD) is a new alternative to the conventional transvenous ICD system to minimize intravascular lead complications. There are limited data describing the long-term performance of the S-ICD. This paper presents the first large international patient population collected as part of the EFFORTLESS S-ICD Registry.
Methods and results
The EFFORTLESS S-ICD Registry is a non-randomized, standard of care, multicentre Registry designed to collect long-term, system-related, clinical, and patient reported outcome data from S-ICD implanted patients since June 2009. Follow-up data are systematically collected over 60-month post-implant including Quality of Life. The study population of 472 patients of which 241 (51%) were enrolled prospectively has a mean follow-up duration of 558 days (range 13–1342 days, median 498 days), 72% male, mean age of 49 ± 18 years (range 9–88 years), 42% mean left ventricular ejection fraction. Complication-free rates were 97 and 94%, at 30 and 360 days, respectively. Three hundred and seventeen spontaneous episodes were recorded in 85 patients during the follow-up period. Of these episodes, 169 (53%) received therapy, 93 being for Ventricular Tachycardia/Fibrillation (VT/VF). One patient died of recurrent VF and severe bradycardia. Regarding discrete VT/VF episodes, first shock conversion efficacy was 88% with 100% overall successful clinical conversion after a maximum of five shocks. The 360-day inappropriate shock rate was 7% with the vast majority occurring for oversensing (62/73 episodes), primarily of cardiac signals (94% of oversensed episodes).
The first large cohort of real-world data from an International patient S-ICD population demonstrates appropriate system performance with clinical event rates and inappropriate shock rates comparable with those reported for conventional ICDs. Clinical trial registration URL: Unique identifier NCT01085435.
PMCID: PMC4076663  PMID: 24670710
Subcutaneous ICD; Ventricular arrhythmias; Cardiac arrest; Primary prevention; Secondary prevention
8.  Heart Rate Recovery in Patients With Hypertrophic Cardiomyopathy 
The American Journal of Cardiology  2014;113(6):1011-1017.
Recovery in heart rate (HR) after exercise is a measure of autonomic function and a prognostic indicator in cardiovascular disease. The aim of this study was to characterize heart rate recovery (HRR) and to determine its relation to cardiac function and morphology in patients with hypertrophic cardiomyopathy (HC). We studied 18 healthy volunteers and 41 individuals with HC. All patients underwent clinical assessment and transthoracic echocardiography. Continuous beat-by-beat assessment of HR was obtained during and after cardiopulmonary exercise testing using finger plethysmography. HRR and power spectral densities were calculated on 3 minutes of continuous RR recordings. Absolute HRR was lower in patients than that in controls at 1, 2, and 3 minutes (25.7 ± 8.4 vs 35.3 ± 11.0 beats/min, p <0.001; 36.8 ± 9.4 vs 53.6 ± 13.2 beats/min, p <0.001; 41.2 ± 12.2 vs 62.1 ± 14.5 beats/min, p <0.001, respectively). HRR remained lower in patients at 2 and 3 minutes after normalization to peak HR. After normalization to the difference in HR between peak exercise and rest, HRR was significantly impaired in individuals with obstructive HC at 3 minutes compared with controls. HR at 3 minutes correlated with peak left ventricular outflow tract gradient (B 0.154 beats/min/mm Hg, confidence interval 0.010 to 0.299, p = 0.037) and remained a significant predictor of HRR after multivariable analysis. Spectral analysis showed a trend toward an increased low-frequency to high-frequency ratio in patients (p = 0.08) suggesting sympathetic predominance. In conclusion, HRR is impaired in HC and correlates with the severity of left ventricular outflow tract gradient. Prospective studies of the prognostic implications of impaired HRR in HC are warranted.
PMCID: PMC4038954  PMID: 24461767
9.  Electrophysiological abnormalities precede overt structural changes in arrhythmogenic right ventricular cardiomyopathy due to mutations in desmoplakin-A combined murine and human study 
European Heart Journal  2012;33(15):1942-1953.
Anecdotal observations suggest that sub-clinical electrophysiological manifestations of arrhythmogenic right ventricular cardiomyopathy (ARVC) develop before detectable structural changes ensue on cardiac imaging. To test this hypothesis, we investigated a murine model with conditional cardiac genetic deletion of one desmoplakin allele (DSP ±) and compared the findings to patients with non-diagnostic features of ARVC who carried mutations in desmoplakin.
Methods and results
Murine: the DSP (±) mice underwent electrophysiological, echocardiographic, and immunohistochemical studies. They had normal echocardiograms but delayed conduction and inducible ventricular tachycardia associated with mislocalization and reduced intercalated disc expression of Cx43. Sodium current density and myocardial histology were normal at 2 months of age. Human: ten patients with heterozygous mutations in DSP without overt structural heart disease (DSP+) and 12 controls with supraventricular tachycardia were studied by high-density electrophysiological mapping of the right ventricle. Using a standard S1–S2 protocol, restitution curves of local conduction and repolarization parameters were constructed. Significantly greater mean increases in delay were identified particularly in the outflow tract vs. controls (P< 0.01) coupled with more uniform wavefront progression. The odds of a segment with a maximal activation–repolarization interval restitution slope >1 was 99% higher (95% CI: 13%; 351%, P= 0.017) in DSP+ vs. controls. Immunostaining revealed Cx43 mislocalization and variable Na channel distribution.
Desmoplakin disease causes connexin mislocalization in the mouse and man preceding any overt histological abnormalities resulting in significant alterations in conduction–repolarization kinetics prior to morphological changes detectable on conventional cardiac imaging. Haploinsufficiency of desmoplakin is sufficient to cause significant Cx43 mislocalization. Changes in sodium current density and histological abnormalities may contribute to a worsening phenotype or disease but are not necessary to generate an arrhythmogenic substrate. This has important implications for the earlier diagnosis of ARVC and risk stratification.
PMCID: PMC3409421  PMID: 22240500
Arrhythmia; Conduction; ARVC; Repolarization; Desmosome; Desmoplakin
10.  Anger, Emotion, and Arrhythmias: from Brain to Heart 
Strong emotion and mental stress are now recognized as playing a significant role in severe and fatal ventricular arrhythmias. The mechanisms, although incompletely understood, include central processing at the cortical and brain stem level, the autonomic nerves and the electrophysiology of the myocardium. Each of these is usually studied separately by investigators from different disciplines. However, many are regulatory processes which incorporate interactive feedforward and feedback mechanisms. In this review we consider the whole as an integrated interactive brain–heart system.
PMCID: PMC3196868  PMID: 22022314
anger; emotion; brain–heart system; mental stress
11.  A novel desmocollin-2 mutation reveals insights into the molecular link between desmosomes and gap junctions 
Heart Rhythm  2011;8(5):711-718.
Cellular adhesion mediated by cardiac desmosomes is a prerequisite for proper electric propagation mediated by gap junctions in the myocardium. However, the molecular principles underlying this interdependence are not fully understood.
The purpose of this study was to determine potential causes of right ventricular conduction abnormalities in a patient with borderline diagnosis of arrhythmogenic right ventricular cardiomyopathy.
To assess molecular changes, the patient's myocardial tissue was analyzed for altered desmosomal and gap junction (connexin43) protein levels and localization. In vitro functional studies were performed to characterize the consequences of the desmosomal mutations.
Loss of plakoglobin signal was evident at the cell junctions despite expression of the protein at control levels. Although the distribution of connexin43 was not altered, total protein levels were reduced and changes in phosphorylation were observed. The truncation mutant in desmocollin-2a is deficient in binding plakoglobin. Moreover, the ability of desmocollin-2a to directly interact with connexin43 was abolished by the mutation. No pathogenic potential of the desmoglein-2 missense change was identified.
The observed abnormalities in gap junction protein expression and phosphorylation, which precede an overt cardiac phenotype, likely are responsible for slow myocardial conduction in this patient. At the molecular level, altered binding properties of the desmocollin-2a mutant may contribute to the changes in connexin43. In particular, the newly identified interaction between the desmocollin-2a isoform and connexin43 provides novel insights into the molecular link between desmosomes and gap junctions.
PMCID: PMC3085091  PMID: 21220045
Cardiomyopathy; Conduction; Connexin43; Desmocollin-2; Desmoglein-2; Desmosome; Functional studies; Gap junction; Mutation; Plakoglobin; ARVC, arrhythmogenic right ventricular cardiomyopathy; Cx43, connexin43; DAPI, 4′,6-diamidino-2-phenylindole; DSC2, desmocollin-2; DSG2, desmoglein-2; DSP, desmoplakin; GFP, green fluorescent protein; GST, glutathione-S-transferase; ICS, intracellular cadherin segment; PG, plakoglobin; PKP2, plakophilin-2; RV, right ventricle; YFP, yellow fluorescent protein
12.  Factors determining heterogeneity in coronary collateral development: A clinical perspective 
Experimental & Clinical Cardiology  2002;7(2-3):120-127.
The mechanisms responsible for collateral development have attracted considerable attention in cellular and molecular research because these vessels have the capacity to protect against myocardial infarction and reduce exercise-induced ischemia. This has led to a number of phase I trials employing angiogenic peptides, genes and cell transplantation. However, there are significant differences in the degree of collateral development among patients even with similar patterns of coronary disease. Understanding the factors responsible for this heterogeneity has important implications for the efficacy of future therapeutic strategies. Therefore, this review will examine these factors from the clinical perspective integrating the clinical evidence with recent molecular and cellular studies. The role of specific pharmacological agents and novel investigational strategies will be discussed.
PMCID: PMC2719174  PMID: 19649235
Angiogenesis; Coronary collaterals; Ischemia; Myocardial infarction

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