The role of genetic testing in the prevention, diagnosis, and prognosis of sudden cardiac arrest in children.

Background: Determining the pathogenesis of sudden cardiac arrest (SCA) in children is crucial for its management and prognosis. Our aim is to analyze the role of broad genetic testing in the prevention, diagnosis, and prognosis of SCA in Children. Methods: ECG, 12-lead holter, exercise testing, cardiac imaging, familial study, and genetic testing were used to study 29 families, in whom a child experienced SCA. Results: After a thorough clinical and genetic evaluation a positive diagnosis was reached in 24/29 (83%) families. Inherited channelopathies (long QT syndrome and catecholaminergic polymorphic ventricular tachycardia) were the most prevalent 20/29 (69%) diagnosis, followed by cardiomyopathy 3/29 (10%). Broad genetic testing was positive in 17/24 (71%) cases. Using the Mann-Whitney test, we found that genetic testing (effect size = 0.625, p = 0.003), ECG (effect size = 0.61, p = 0.009), and exercise test (effect size = 0.63, p = 0.047) had the highest yield in reaching the final diagnosis. Genetic testing was the only positive test available for five (17%) families. Among 155 family members evaluated through cascade screening, 73 (47%) had a positive clinical evaluation and 64 (41%) carried a pathologic mutation. During 6 ± 4.8 years of follow-up, 58% of the survived children experienced an arrhythmic event. Of nine family members who had an ICD implant for primary prevention, four experienced appropriate ICD shock. Conclusions: The major causes of SCA among children are genetic etiology, and genetic testing has a high yield. Family screening has an additional role in both the diagnosis and preventing of SCA.

Elevated thrombin generation levels in the left atrial appendage in patients with atrial fibrillation.

Background: Atrial Fibrillation (AF) is the most common sustained tachi-arrhythmia. Thrombus formation in the left atrial appendage (LAA) increases the risk of stroke and systemic embolism in patients with AF. Objectives: The aim of this study was to compare thrombin generation in the LAA to the LA among patients with AF. Methods: A cross-sectional study of consecutive patients with AF undergoing pulmonary veins catheter ablation. Blood samples from the femoral vein (FV), right atrium (RA), left atrium (LA), and LAA were collected during the catheter ablation procedures. Thrombin generation was assessed by a Calibrated Automated Thrombogram. The LAA-calibrated automated thrombogram parameters were compared with the RA, LA, and FV. Results: A total of 47 consecutive patients were enrolled in the study. The endogenous thrombin potential and peak height were significantly higher in the LAA compared with the LA, the mean differences and 95% CI between the LA and LAA were -378.9 (-680.5, -77.2) (nM∗min) and -66.7 (-119.6, -13.8) (nM) in the endogenous thrombin potential and peak height respectively. Conclusion: In patients with AF undergoing catheter ablation, the LAA demonstrated increased thrombin generation compared with the LA. This finding might contribute to the understanding of why the LAA is more predisposed to thrombus formation than the LA. Clinical Trials Registration: NCT03795883.

Non-ischemic sudden cardiac arrest: Role of 12 lead Holter, family screening and genetic testing.

OBJECTIVE AND BACKGROUND: To evaluate the diagnostic and prognostic yield of a comprehensive protocol involving clinical and broad genetic testing in consecutive sudden cardiac arrest (SCA) population. Determining the pathogenesis of non-ischemic SCA is crucial for management and SCA prevention in other family members METHODS: Families with unexplained non-ischemic SCA event underwent rigorous clinical and genetic protocol after referral to our inherited arrhythmia clinic, during 2011-2017. RESULTS: One hundred and four index cases, 29 ± 16 years, and 421 family members were studied. After a thorough evaluation, diagnosis was made in 80 (77%) of families. The most prevalent 47/104 (45%) diagnosis was inherited channelopathy. The genetic test was positive, in 37 /69 (54%) of patients. Using the Mann Whitney test, we found that electrocardiography (ECG) (effect size 0.5, p < .001), 12 lead Holter (effect size 0.33, p = .001) and family screening (effect size 0.4, p = .001) had the highest yield in reaching the final diagnosis. Family screening, genetic testing, and cardiac MRI were the exclusive modalities for final diagnosis in 14%, 9%, and 2% of families, respectively. Among 421 family members evaluated through cascade screening, 127 (30%), were diagnosed and medically treated. Nine family members from 25 (40%) patients who underwent implantable cardioverter defibrillator (ICD) implantation have experienced appropriate ICD shock. CONCLUSIONS: A rigorous, systematic protocol in a specialized inherited arrhythmia clinic has a high diagnostic and prognostic yield. ECG, 12 lead Holter and family screening significantly increased the diagnostic yield. In nine families, without genetic testing, the diagnosis would have been missed.

Arrhythmic burden among asymptomatic patients with ischemic cardiomyopathy and an implantable cardioverter-defibrillator.

BACKGROUND: The clinical benefit of primary prevention implantable cardioverter-defibrillator (ICD) therapy in asymptomatic patients (New York Heart Association [NYHA] functional class I) with ischemic cardiomyopathy and left ventricular dysfunction is continually disputed. OBJECTIVE: The purpose of this study was to evaluate the incidence of ventricular arrhythmias, mortality rates, and appropriate device therapies by NYHA class in a prospective national ICD registry. METHODS: The study comprised 1670 consecutive patients with ischemic cardiomyopathy who were implanted with a primary prevention ICD and enrolled in the prospective national Israeli ICD Registry from 2010. The risk for clinical and arrhythmic events was assessed by NYHA class. RESULTS: Asymptomatic patients (NYHA I) composed 19% of the study cohort. Comparison according to NYHA class showed that the highest mortality rate was in the NYHA III-IV group vs NYHA I and NYHA II (10.5% vs 5.4% and 5.8%, respectively; log rank P = .003). Conversely, cumulative incidence of appropriate ICD therapies, corrected for death as a competing risk, were higher among patients with NYHA I (11% vs 7%; P = .021). In a multivariate model, NYHA I vs ≥II remained independently associated with a significant 2-fold risk for appropriate ICD therapy (hazard ratio 2.03; 95% confidence interval 1.28-3.24). CONCLUSION: Our findings indicate that patients with ischemic cardiomyopathy without heart failure symptoms have a higher risk of appropriate ICD therapy compared with symptomatic patients after adjustment for the competing risk of death, suggesting possible incremental benefit of primary ICD implantation in this population.

Acute Kidney Injury After Primary Angioplasty: Is Contrast-Induced Nephropathy the Culprit?

BACKGROUND: Acute kidney injury (AKI) following primary percutaneous coronary intervention (pPCI) is frequently interpreted as contrast-induced AKI but may result from other insults. We aimed to determine the causal association of contrast material exposure and the incidence of AKI following pPCI using a control group of propensity score-matched patients with ST-segment-elevation myocardial infarction who were not exposed to contrast material. METHODS AND RESULTS: We studied 2025 patients with ST-segment-elevation myocardial infarction who underwent pPCI and 1025 patients receiving fibrinolysis or no reperfusion who were not exposed to contrast material during the first 72 hours of hospital stay (control group). AKI was defined as creatinine of ≥0.5 mg/dL or >25% rise within 72 hours. AKI rates were similar in the pPCI and control groups (10.3% versus 12.1%, respectively; P=0.38). Propensity score matching resulted in 931 matched pairs with PCI and no PCI, with balanced baseline covariates (standardized difference <0.1). Among propensity score-matched patients, AKI rates were not significantly different with and without PCI (8.6% versus 10.9%, P=0.12). In the pPCI cohort, independent predictors of AKI included age ≥70 years, insulin-treated diabetes mellitus, diuretic therapy, anterior infarction, baseline estimated glomerular filtration rate, and variables related to the presence of pump failure (higher Killip class, intra-aortic balloon pump use) and reduced left ventricular ejection fraction but not contrast material dose. A risk score based on the PCI cohort had similar discriminatory capacity for AKI in the control group (C statistic 0.81±0.02 and 0.78±0.02, respectively; P=0.26). CONCLUSIONS: The development of AKI in patients with ST-segment-elevation myocardial infarction undergoing pPCI is mainly related to older age, baseline estimated glomerular filtration rate, heart failure, and hemodynamic instability. Risk for AKI is similar among ST-segment-elevation myocardial infarction patients with and without contrast material exposure.

Impact of computed tomography image and contact force technology on catheter ablation for atrial fibrillation.

AIM: To investigate the impact of using computed tomography (CT) and contact force (CF) technology on recurrence of atrial tachyarrhythmia after atrial fibrillation (AF) ablation. METHODS: This non-randomized study included 2 groups of patients. All patients had symptomatic recurrent paroxysmal or persistent AF and were treated with at least 1 anti arrhythmic medication or intolerant to medication. The first group included 33 patients who underwent circumferential pulmonary veins isolation (PVI) for AF during 2012 and 2013 guided by CT image integration (Cartomerge, Biosense Webster, Diamond Bar, CA, United States) of left atrium and pulmonary veins into an electroanatomic mapping (EAM) system (CT group) using standard irrigated radiofrequency catheter (ThermoCool, Carto, Biosense Webster, Diamond Bar, CA, United States) or irrigated catheter with integrated CF sensor (Smart Touch, Carto, Biosense Webster, Diamond Bar, CA, United States). The second group included immediately preceding 32 patients who had circumferential PVI by standard irrigated catheter (ThermoCool) using only EAM (Carto) system (EAM group). Linear lesions were performed according to the discretion of operator. RESULTS: Sex, age, and persistent AF were not different between groups. PVI was achieved in all patients in both groups. Linear ablations including cavo-tricuspid isthmus and or roof line ablation were not different between groups. Free of atrial tachyarrhythmia during follow-up of 24 mo was significantly higher among CT group compared to EAM group (81% vs 55%; respectively; P = 0.027). When 11 patients from CT group who had ablation using Smart Touch catheter were excluded, the difference between CT group and EAM became non significant (73% vs 55%; respectively; P = 0.16). Sub analysis of CT group showed that patients who had ablation using Smart Touch catheter tend to be more free of atrial tachyarrhythmia compared to patients who had ablation using standard irrigated catheter during follow-up (100% vs 73%; respectively; P = 0.07). Major complications (pericardial effusion, cerebrovascular accident/transient ischemic attack, vascular access injury requiring intervention) did not occurred in both groups. CONCLUSION: These preliminary results suggest that CT image integration and CF technology may reduce the recurrence of atrial tachyarrhythmia after catheter ablation for AF.

Outflow tract ventricular arrhythmia originating from the aortic cusps: our approach for challenging ablation.

BACKGROUND: Ablation of outflow flow ventricular arrhythmia (VA) originating from aortic cusps can be challenging. The aim of this study was to describe our approach for this ablation. METHODS: All patients with outflow VA suspected to originate from aortic cusps according to ECG or after failed ablation from right ventricular outflow tract (RVOT) underwent cardiac CT and radiofrequency ablation. CT image of aortic cusps and coronary arteries was integrated into electroanatomic mapping system by point (left main ostium)-based registration. Ablation was performed at the earliest activation site. RESULTS: Ten patients were included in this case cohort. The ablation catheter was easily maneuvered above and below the aortic valve after registration. Two patients who had previous failed ablation of RVOT focus had successful ablation at right coronary cusp (RCC) and at left coronary cusp (LCC). A patient who had previous failed ablations of RVOT and LCC focuses had successful ablation at RCC-LCC junction. A patient who had previous failed ablation at LCC had successful ablation at RCC-LCC junction. Three patients had successful ablation at RCC-LCC junction, and one patient at LCC. One patient had successful ablation at anterior interventricular vein-great cardiac vein junction. One patient had successful ablation at non-coronary cusp. During follow-up (12-30 months), one patient had recurrence of VA controlled by flecainide. The remaining patients were free of VA without medications. CONCLUSIONS: Catheter ablation of VA originating from aortic cusps is safe and effective. CT image integration into electroanatomic mapping system can be helpful in this challenging ablation.

Heart failure in patients with diabetes undergoing primary percutaneous coronary intervention.

INTRODUCTION: Diabetes mellitus is associated with increased risk after acute coronary syndromes. Primary percutaneous coronary intervention is the most effective method of reperfusion for acute ST-elevation myocardial infarction and can limit the ischaemic damage to the left ventricle. However, there are few data on the impact of diabetes mellitus on the risk of heart failure following primary percutaneous coronary intervention. METHODS: We studied 958 ST-elevation myocardial infarction patients treated with primary percutaneous coronary intervention, of whom 263 (27.5%) had diabetes mellitus, with 67 (7.0%) treated with insulin. The primary end points of the study were re-admission for heart failure. Secondary end points were all-cause mortality and recurrent infarctions. The follow-up period was 5 years after hospital discharge. RESULTS: The cumulative incidence of re-admission for heart failure was 8.4%, 15.2% and 26.7% in patients without diabetes mellitus, non-insulin-treated and insulin-treated diabetes mellitus, respectively. Compared with patients without diabetes mellitus, the adjusted hazard ratio for heart failure was 1.95 (95% confidence intervals 1.30-2.93) and 3.09 (95% confidence intervals 1.71-5.60) in non-insulin-treated and insulin-treated diabetes mellitus, respectively. The corresponding hazard ratios for mortality were 1.03 (95% confidence intervals 0.68-1.55) and 2.04 (95% confidence intervals 1.22-3.42), respectively. There was a J-shaped association between fasting glucose levels in the acute phase and risk of mortality (P=0.0001) and a direct association with heart failure (P=0.03). CONCLUSION: Despite modern treatment of ST-elevation myocardial infarction and high levels of guideline-based medical care, diabetes mellitus had an independent adverse effect on the risk of re-admissions for heart failure, which was particularly high among insulin-treated patients.

Left Cardiac Sympathetic Denervation in Patients with CASQ2-Associated Catecholaminergic Polymorphic Ventricular Tachycardia.

BACKGROUND: Left cardiac sympathetic denervation (LCSD) was reported to be effective in patients with intractable ryanodine receptor mutation-associated catecholaminergic polymorphic ventricular tachycardia (CPVT). OBJECTIVES: To report our experience with LCSD in calsequestrin (CASQ2) mutation-associated CPVT. METHODS: LCSD was performed in three patients with CASQ2 mutation-associated CPVT with symptoms and exercise-induced ventricular arrhythmia despite high dose beta-blocker RESULTS: None of them experienced symptoms or exercise-induced ventricular arrhythmia after LCSD. However, all had recurrence of symptoms and/or exercise-induced ventricular arrhythmia after 6 months (6-18 months). CONCLUSIONS: LCSD conferred short-term suppression but less than optimal long-term suppression of exercise-induced ventricular arrhythmia among CASQ2-associated CPVT patients.

Clinical characteristics and outcomes of elderly patients treated with an implantable cardioverter-defibrillator or cardiac resynchronization therapy in a real-world setting: data from the Israeli ICD Registry.

BACKGROUND: Elderly patients are underrepresented in clinical trials of device therapy. OBJECTIVE: To provide real-world data regarding outcomes associated with device-based therapy in a large cohort of elderly patients enrolled in the Israeli ICD Registry. METHODS: Between July 2010 and June 2012, a total of 2807 consecutive patients undergoing implanted cardioverter-defibrillator/cardiac resynchronization therapy-defibrillator (ICD/CRT-D) implantation were prospectively enrolled in the Israeli ICD Registry. For the present analysis, patients were categorized into 3 age groups: ≤60 years (n = 1378 [49%]), 61-75 years (n = 863 [31%]), and >75 years (n = 566 [20%]). RESULTS: Elderly patients (>75 years of age) had more comorbid conditions and were more likely to undergo CRT-D implantation (all P < .01). However, the rate of device-related complications associated with surgical reinterventions at 1 year was <3% regardless of age (P = .70 for the comparison among the 3 age groups). Multivariate analysis showed that the risk of heart failure or death and of appropriate ICD therapy for ventricular arrhythmias was significantly increased with increasing age among patients who received an ICD. In contrast, the age-related increase in the risk of all end points was attenuated among patients who received CRT-D devices (all P values for age-by-device-type interactions are <.05). CONCLUSIONS: In a real-world scenario, elderly patients (>75 years of age) comprise approximately 20% of the ICD/CRT-D recipients and experience a device reintervention rate similar to that of their younger counterparts. Our data suggest that the association between advanced age and adverse clinical outcomes is attenuated in elderly patients implanted with CRT-D devices.

Ablation of idiopathic ventricular fibrillation triggered by ventricular premature beat originating from myocardium of right ventricle: Case report.

We report a case of a 55-year-old woman with idiopathic ventricular fibrillation (VF) who suffered from recurrent implantable cardioverter-defibrillator shocks triggered by short coupled ventricular premature beat (VPB). This VPB was mapped and ablated from the myocardium of right ventricle close to the lateral tricuspid annulus. .

Modeling of arrhythmogenic right ventricular cardiomyopathy with human induced pluripotent stem cells.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a primary heart muscle disorder resulting from desmosomal protein mutations. ARVC is characterized pathologically by fibrofatty infiltration and clinically by arrhythmias and sudden cardiac death. We aimed to establish a patient-/disease-specific human induced pluripotent stem cell (hiPSC) model of ARVC. METHODS AND RESULTS: Dermal fibroblasts were obtained from 2 patients with ARVC with plakophilin-2 (PKP2) mutations, reprogrammed to generate hiPSCs, coaxed to differentiate into cardiomyocytes (CMs), and then compared with healthy control hiPSC-derived CMs (hiPSC-CMs). Real-time polymerase chain reaction showed a significant decrease in the expression of PKP2 in the ARVC-hiPSC-CMs. Immunostainings revealed reduced densities of PKP2, the associated desmosomal protein plakoglobin, and the gap-junction protein connexin-43. Electrophysiological assessment demonstrated prolonged field potential rise time in the ARVC-hiPSC-CMs. Transmission electron microscopy identified widened and distorted desmosomes in the ARVC-hiPSC-CMs. Clusters of lipid droplets were identified in the ARVC-CMs that displayed the more severe desmosomal pathology. This finding was associated with upregulation of the proadipogenic transcription factor peroxisome proliferator-activated receptor-γ. Exposure of the cells to apidogenic stimuli augmented desmosomal distortion and lipid accumulation. The latter phenomenon was prevented by application of a specific inhibitor of glycogen synthase kinase 3ß (6-bromoindirubin-3'-oxime). CONCLUSIONS: This study highlights the unique potential of the hiPSC technology for modeling inherited cardiac disorders in general and ARVC specifically. The hiPSC-CMs were demonstrated to recapitulate the ARVC phenotype in the dish, provide mechanistic insights into early disease pathogenesis, and provide a unique platform for drug discovery and testing in this disorder.

Flecainide therapy suppresses exercise-induced ventricular arrhythmias in patients with CASQ2-associated catecholaminergic polymorphic ventricular tachycardia.

BACKGROUND: Calsequestrin-associated catecholaminergic polymorphic ventricular tachycardia (CPVT2) can cause sudden death in young individuals in response to stress. Beta-blockers are the mainstay medical treatment for patients with CPVT2. However, they do not prevent syncope and sudden death in all patients. Flecainide was reported to reduce exercise-induced ventricular arrhythmias (EIVA) in patients with ryanodine receptor-associated CPVT. The role of flecainide in CPVT2 is not known. OBJECTIVE: To summarize our experience in combining flecainide and beta-blockers in high-risk patients with CPVT2. METHODS: All patients with CPVT2 (10 patients) who have high-risk features (syncope, EIVA, or appropriate implantable cardioverter-defibrillator [ICD] shocks) despite beta-blockers with or without calcium channel blockers were treated with a combination of flecainide and beta-blockers. Exercise test was done before and after beginning treatment with flecainide. RESULTS: All patients had EIVA and 4 had appropriate ICD shocks before flecainide treatment. EIVA-included frequent ventricular premature beats and or ventricular tachycardia during the exercise test while on high dose of beta-blockers with or without calcium channel blockers before treatment with flecainide. After combination therapy with flecainide and beta-blockers, EIVA were suppressed completely in all patients. During follow-up of 15.5 ± 10.4 months (range 2-29 months), 8 patients were free of symptoms and free of arrhythmias. Two patients had 1 VT storm episode with recurrent ICD shocks despite repeated normal stress test. CONCLUSIONS: Flecainide can completely prevent ventricular arrhythmia during exercise and partially prevent recurrent ICD shocks in high-risk patients with CPVT2.

Importance of ventricular tachycardia storms not terminated by implantable cardioverter defibrillators shocks in patients with CASQ2 associated catecholaminergic polymorphic ventricular tachycardia.

In this study, the clinical and implantable cardioverter-defibrillator (ICD)-related follow-up of patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) with homogenous missense mutations in CASQ2 was summarized. Patients were followed in a pediatric cardiology clinic and an ICD clinic. All patients were treated with high-dose ß blockers. ICDs were recommended for patients who remained symptomatic despite medical treatment. Twenty-seven patients were followed for 1 to 15 years (median 9). Twenty patients (74%) were symptomatic at diagnosis; 13 (65%) remained symptomatic after treatment with high-dose ß blockers and thus were advised to receive ICDs. Eight of these patients refused ICDs, and eventually 6 (75%) died suddenly. Four of the 5 patients who received ICDs had ventricular tachycardia storms treated but not terminated by recurrent ICD shocks. These ventricular tachycardia storms (2 episodes in 2 patients and 1 episode in 2 patient) terminated spontaneously after finishing the programmed ICD shocks, without degeneration to ventricular fibrillation. None of the patients who received ICDs died. In conclusion, patients with CASQ2-associated CPVT should be recommended to receive ICDs to prevent sudden death when medical therapy is not effective. These patients may have recurrent ventricular tachycardia storms treated but not terminated by recurrent ICD shocks, without degeneration to ventricular fibrillation.

Patient safety and outcomes from live case demonstrations of interventional cardiology procedures.

OBJECTIVES: The goal of this study was to examine the safety and results of interventional procedures performed during the broadcast of live case demonstrations. BACKGROUND: Professional meetings using live case demonstrations to present cutting-edge technology are considered a valuable educational resource. There is an ongoing discussion on whether patients who are treated during live case demonstrations are exposed to a higher risk. METHODS: Between 1998 and 2010, 101 patients were treated during live transmissions from a single center in 15 invasive-cardiology conferences. Technical success was defined as the ability to effectively perform the planned procedure without any major complication. The primary endpoint of the study was the composite occurrence of death, myocardial infarction, or stroke. RESULTS: The interventional procedures included coronary (n=66), carotid (n=15), peripheral (n=1), valvular (n=2), congenital heart disease (n=12), and complex electrophysiological mapping and ablation interventions (n=7). In 4 cases, the intended procedure was not done. The procedure was technically successful in 95%. In 5 cases, the procedure was unsuccessful because of the inability to cross a chronic total occlusion. There were no deaths during the hospital stay, and the composite primary endpoint occurred in 2 patients: a minor stroke following an atrial fibrillation ablation and a rise in serum troponin levels after percutaneous coronary intervention. These results were no different from those of 66 matched controls who underwent procedures performed by the same operators but not as live case demonstrations (relative risk: 0.32; 95% confidence interval: 0.02 to 3.62, p=0.62). CONCLUSIONS: In this consecutive series of interventional cardiology procedures that were performed by expert operators during live demonstration courses, the procedural and 30-day clinical outcomes were similar to those found in daily practice and to those that have been reported in the contemporary published data. These results suggest that broadcasting live case demonstrations in selected patients from selected centers may be safe.

Iatrogenic intra-atrial macro-reenterant tachycardia following transcatheter closure of atrial septal defect treated by radiofrequency ablation.

Percutaneous closure of an atrial septal defect (ASD) has been established as a safe and effective alternative to surgical management. We describe a case of a 41-year-old patient in whom an Amplatzer septal occluder device was used to close a moderately large ASD and who subsequently developed incessant intra-atrial macro-reenterant tachycardia. The tachycardia was terminated by radiofrequency ablation guided by electroanatomical mapping.

Modelling the long QT syndrome with induced pluripotent stem cells.

The ability to generate patient-specific human induced pluripotent stem cells (iPSCs) offers a new paradigm for modelling human disease and for individualizing drug testing. Congenital long QT syndrome (LQTS) is a familial arrhythmogenic syndrome characterized by abnormal ion channel function and sudden cardiac death. Here we report the development of a patient/disease-specific human iPSC line from a patient with type-2 LQTS (which is due to the A614V missense mutation in the KCNH2 gene). The generated iPSCs were coaxed to differentiate into the cardiac lineage. Detailed whole-cell patch-clamp and extracellular multielectrode recordings revealed significant prolongation of the action-potential duration in LQTS human iPSC-derived cardiomyocytes (the characteristic LQTS phenotype) when compared to healthy control cells. Voltage-clamp studies confirmed that this action-potential-duration prolongation stems from a significant reduction of the cardiac potassium current I(Kr). Importantly, LQTS-derived cells also showed marked arrhythmogenicity, characterized by early-after depolarizations and triggered arrhythmias. We then used the LQTS human iPSC-derived cardiac-tissue model to evaluate the potency of existing and novel pharmacological agents that may either aggravate (potassium-channel blockers) or ameliorate (calcium-channel blockers, K(ATP)-channel openers and late sodium-channel blockers) the disease phenotype. Our study illustrates the ability of human iPSC technology to model the abnormal functional phenotype of an inherited cardiac disorder and to identify potential new therapeutic agents. As such, it represents a promising paradigm to study disease mechanisms, optimize patient care (personalized medicine), and aid in the development of new therapies.

Circadian pattern of life-threatening ventricular arrhythmia in patients with sleep-disordered breathing and implantable cardioverter-defibrillators.

BACKGROUND: Sleep-disordered breathing (SDB) has been associated with various benign cardiac arrhythmias occurring during sleep. OBJECTIVE: The purpose of this study was to demonstrate that SDB contributes to the development of life-threatening ventricular arrhythmias in patients with an established arrhythmic substrate. METHODS: We prospectively studied the association between SDB and timing of life-threatening ventricular arrhythmic events in 45 patients with an implantable cardioverter-defibrillator (ICD). SDB was defined as an apnea-hypopnea index (AHI) >10 events/hour based on an overnight sleep study. The primary outcome measure was appropriate ICD therapy, defined as antitachycardia pacing or shock for ventricular tachycardia or ventricular fibrillation during 1-year follow-up. RESULTS: SDB was present in 26 (57.8%) patients. Appropriate ICD therapies were higher among patients with SDB (73% vs 47%, P = .02). Logistic regression identified SDB as a predictor of any appropriate ICD therapy (odds ratio 4.4, 95% confidence interval 1.4-15.3, P = .01). The risk for ventricular arrhythmias was higher in patients with SDB solely due to an increase in events occurring between midnight and 6 AM (odds ratio 5.6, 95% confidence interval 2.0-15.6, P = .001) with no discernible effect on appropriate ICD therapy during nonsleeping hours (odds ratio 0.7, 95% confidence interval 0.2-2.3, P = .61). CONCLUSION: Patients with an ICD and SDB have a striking increase in the onset of life-threatening ventricular arrhythmic events during sleeping hours. These findings provide a rationale for SDB screening in patients with appropriate ICD therapy if device interrogation reveals a predominance of nocturnal onset of arrhythmias.

Long-term outcome of atrial synchronous mode pacing in patients with atrioventricular block using a single lead.

BACKGROUND: Current guidelines suggest the use of atrial synchronous mode (VDD) pacemakers in patients with atrioventricular (AV) block and normal sinus node function. However VDD mode is being used much less than expected. The objectives of our study were to evaluate the efficacy of VDD pacing in long-term follow-up and to find risk factors for VDD loss. METHODS: We retrospectively evaluated all patients with VDD pacemakers who were implanted in our center between 1995 and 2007. RESULTS: During the study period, 123 consecutive patients with AV block (51% men, age 62 +/- 17.8 years) received a VDD pacemaker. Mean follow up duration was 4.5 +/- 3.2 years. At the last follow up visit, 21 patients (21.6%) lost their original VDD mode and were programmed to ventricular-based pacing (VVIR) (undersensing, 11; chronic AF, 7; SND, 3). In 28 patients, VDD mode was restored or maintained by increasing atrial sensitivity. No episodes of atrial oversensing were observed. In multivariate analysis history of paroxysmal AF (p = 0.007, odds ratio 36.6, 95% confidence interval 2.7-493.7) and p wave lower than 1 mv during the follow up (p = 0.021, odds ratio 7, 95% confidence interval 1.3-36.7), were found risk factors to VDD loss. CONCLUSIONS: VDD pacing has good long-term performance. Absence of paroxysmal AF history predicts maintenance of VDD pacing mode. Taking into account that no atrial oversensing was observed, our recommendation is to increase atrial sensitivity when P wave amplitude declines to less than 1 mv.