Faculty Bibliography

Early repolarization, Brugada syndrome, and pathologic J waves have been described for decades, but only recently experimental and clinical data have allowed reconciliation of Brugada and Early Repolarization under the common definition of J-wave syndromes. The concept was derived from studies showing, in both conditions, the presence of transmural dispersion of repolarization, localized conduction abnormalities, and abnormal transition between QRS and ST segment on electrocardiogram. Although several clinical studies have addressed the clinical presentation and epidemiology of J-wave syndromes, relevant knowledge gaps exist. Incomplete pathophysiologic understanding and uncertain electrocardiographic definitions limit effective risk stratification. Here, we review the current knowledge and recommendations for diagnosis and clinical management of these arrhythmogenic disorders.

BACKGROUND:Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a familial arrhythmogenic syndrome characterized by sudden death. There are several genetic forms of CPVT associated with mutations in genes encoding the cardiac ryanodine receptor (RyR2) and its auxiliary proteins including calsequestrin (CASQ2) and calmodulin (CaM). It has been suggested that impairment of the ability of RyR2 to stay closed (ie, refractory) during diastole may be a common mechanism for these diseases. Here, we explore the possibility of engineering CaM variants that normalize abbreviated RyR2 refractoriness for subsequent viral-mediated delivery to alleviate arrhythmias in non-CaM-related CPVT. METHODS AND RESULTS/RESULTS:To that end, we have designed a CaM protein (GSH-M37Q; dubbed as therapeutic CaM or T-CaM) that exhibited a slowed N-terminal Ca dissociation rate and prolonged RyR2 refractoriness in permeabilized myocytes derived from CPVT mice carrying the CASQ2 mutation R33Q. This T-CaM was introduced to the heart of R33Q mice through recombinant adeno-associated viral vector serotype 9. Eight weeks postinfection, we performed confocal microscopy to assess Ca handling and recorded surface ECGs to assess susceptibility to arrhythmias in vivo. During catecholamine stimulation with isoproterenol, T-CaM reduced isoproterenol-promoted diastolic Ca waves in isolated CPVT cardiomyocytes. Importantly, T-CaM exposure abolished ventricular tachycardia in CPVT mice challenged with catecholamines. CONCLUSIONS:Our results suggest that gene transfer of T-CaM by adeno-associated viral vector serotype 9 improves myocyte Ca handling and alleviates arrhythmias in a calsequestrin-associated CPVT model, thus supporting the potential of a CaM-based antiarrhythmic approach as a therapeutic avenue for genetically distinct forms of CPVT.

PURPOSE OF REVIEW/OBJECTIVE:The current article provides a concise summary of the possibilities and limitations of genotype-based risk stratification of cardiac arrhythmias. We will outline the most important findings of the recent years in the light of their chronological and conceptual development. RECENT FINDINGS/RESULTS:Genotype-phenotype association studies in families with single-gene disorders as well as in the general population led to the discovery of several DNA variants significantly associated with the risk of sudden death or life-threatening arrhythmias. In genetic (monogenic) diseases, the disease-causing mutations modulate the risk of events and response to antiarrhythmic therapy according to the specific gene involved, to their position of the mutation and to their functional effects. These causal relationships have been quite well characterized in the case of long QT syndrome but are still less defined in the case of other inherited conditions. Quantitatively, the risk associated with a single genetic variant is large for DNA variants that cause monogenic inherited arrhythmias. Much different is the case of more common variants associated with the risk of arrhythmias in the general population as they are generally associated with a small effect size. SUMMARY/CONCLUSIONS:Genetic profiling identifies arrhythmogenic risk even if a complete picture allowing high-granularity risk stratification is yet to come.

BACKGROUND:Detailed information on the profile of patients with Brugada syndrome (BrS) presenting their first arrhythmic event (AE) after prophylactic implantation of an implantable cardioverter-defibrillator (ICD) is limited. OBJECTIVES/OBJECTIVE:The objectives of this study were (1) to compare clinical, electrocardiographic, electrophysiological, and genetic profiles of patients who exhibited their first documented AE as aborted cardiac arrest (group A) with profiles of those in whom the AE was documented after prophylactic ICD implantation (group B) and (2) to characterize group B patients' profile using the class II indications for ICD implantation established by HRS/EHRA/APHRS expert consensus statement in 2013. METHODS:A survey of 23 centers from 10 Western and 4 Asian countries enabled data collection of 678 patients with BrS who exhibited their AE (group A, n = 426; group B, n = 252). RESULTS:The first AE occurred in group B patients 6.7 years later than in group A (mean age 46.1 ± 13.3 years vs 39.4 ± 15.1 years; P < .001). Group B patients had a higher incidence of family history of sudden cardiac death and SCN5A mutations. Of the 252 group B patients, 189 (75%) complied with the HRS/EHRA/APHRS indications whereas the remaining 63 (25%) did not. CONCLUSION/CONCLUSIONS:Patients with BrS with the first AE documented after prophylactic ICD implantation exhibited their AE at a later age with a higher incidence of positive family history of sudden cardiac death and SCN5A mutations as compared with those presenting with aborted cardiac arrest. Only 75% of patients who exhibited an AE after receiving a prophylactic ICD complied with the 2013 class II indications, suggesting that efforts are still required for improving risk stratification.

BACKGROUND:Long QT syndrome (LQTS) is a common inheritable arrhythmogenic disorder, often secondary to mutations in the KCNQ1, KCNH2, and SCN5A genes. The disease is characterized by a prolonged ventricular repolarization (QTc interval) that confers susceptibility to life-threatening arrhythmic events (LAEs). OBJECTIVES/OBJECTIVE:This study sought to create an evidence-based risk stratification scheme to personalize the quantification of the arrhythmic risk in patients with LQTS. METHODS:Data from 1,710 patients with LQTS followed up for a median of 7.1 years (interquartile range [IQR]: 2.7 to 13.4 years) were analyzed to estimate the 5-year risk of LAEs based on QTc duration and genotype and to assess the antiarrhythmic efficacy of beta-blockers. RESULTS:The relationship between QTc duration and risk of events was investigated by comparison of linear and cubic spline models, and the linear model provided the best fit. The 5-year risk of LAEs while patients were off therapy was then calculated in a multivariable Cox model with QTc and genotype considered as independent factors. The estimated risk of LAEs increased by 15% for every 10-ms increment of QTc duration for all genotypes. Intergenotype comparison showed that the risk for patients with LQT2 and LQT3 increased by 130% and 157% at any QTc duration versus patients with LQT1. Analysis of response to beta-blockers showed that only nadolol reduced the arrhythmic risk in all genotypes significantly compared with no therapy (hazard ratio: 0.38; 95% confidence interval: 0.15 to 0.93; p = 0.03). CONCLUSIONS:The study provides an estimator of risk of LAEs in LQTS that allows a granular estimate of 5-year arrhythmic risk and demonstrate the superiority of nadolol in reducing the risk of LAEs in LQTS.

OBJECTIVE:In this work, we propose an ontology-driven approach to identify events and their attributes from episodes of care included in medical reports written in Italian. For this language, shared resources for clinical information extraction are not easily accessible. MATERIALS AND METHODS/METHODS:The corpus considered in this work includes 5432 non-annotated medical reports belonging to patients with rare arrhythmias. To guide the information extraction process, we built a domain-specific ontology that includes the events and the attributes to be extracted, with related regular expressions. The ontology and the annotation system were constructed on a development set, while the performance was evaluated on an independent test set. As a gold standard, we considered a manually curated hospital database named TRIAD, which stores most of the information written in reports. RESULTS:The proposed approach performs well on the considered Italian medical corpus, with a percentage of correct annotations above 90% for most considered clinical events. We also assessed the possibility to adapt the system to the analysis of another language (i.e., English), with promising results. DISCUSSION AND CONCLUSION/CONCLUSIONS:Our annotation system relies on a domain ontology to extract and link information in clinical text. We developed an ontology that can be easily enriched and translated, and the system performs well on the considered task. In the future, it could be successfully used to automatically populate the TRIAD database.

Aims/UNASSIGNED:CMR) permits a comprehensive evaluation of stable coronary artery disease (CAD). We sought to assess whether, in a large contemporaneous population receiving optimal medical therapy, CMR independently predicts prognosis beyond conventional cardiovascular risk factors (RF). Methods/UNASSIGNED:We performed a single centre, observational prospective study that enrolled 465 CAD patients (80% males; 63±11 years), optimally treated with ACE-inhibitors/ARB, aspirin, and statins (76-85%). Assessments included conventional evaluation (clinical history, atherosclerosis RF, electrocardiography, and echocardiography) and a comprehensive CMR with LV dimensions/function, late gadolinium enhancement (LGE), and stress perfusion CMR (SPCMR). Results/UNASSIGNED:During a median follow-up of 62 months (IQR 23-74) there were 50 deaths and 92 major adverse cardiovascular events (MACE). CMR variables improved multivariate model prediction power of mortality and MACE over traditional RF alone (F-test p<0.05 and p<0.001, respectively). LGE was an independent prognostic factor of mortality (hazard ratio [95% CI]: 3.4 [1.3-8.8]); moreover, LGE (3.3 [1.7-6.3]) and SPCMR (2.1 [1.4-3.2]) were the best predictors of MACE. Conclusion/UNASSIGNED:LGE is an independent noninvasive marker of mortality in the long term in patients with stable CAD and optimized medical therapy. Furthermore, LGE and SPCMR independently predict MACE beyond conventional risk stratification.

BACKGROUND:Short QT syndrome (SQTS) is a rare and life-threatening arrhythmogenic syndrome characterized by abbreviated repolarization. Hydroquinidine (HQ) prolongs the QT interval in SQTS patients, although whether it reduces cardiac events is currently unknown. OBJECTIVES/OBJECTIVE:This study investigated whether long-term treatment with HQ reduces the occurrence of life-threatening arrhythmic events (LAE) (cardiac arrest or sudden cardiac death) in SQTS patients. METHODS:In this cohort study on consecutive SQTS patients, 2 analyses were performed: 1) a matched-period analysis for the occurrence of LAE in 17 SQTS patients who received long-term HQ; and 2) a comparison of the annual incidence of LAE off- and on-HQ in 16 SQTS patients who survived a cardiac arrest. RESULTS:A total of 17 patients (82% male, age 29 ± 3 years, QTc before treatment 331 ± 3 ms) received HQ therapy (584 ± 53 mg/day). Therapy was stopped in 2 cases (12%) due to gastrointestinal intolerance, and 15 patients continued treatment for 6 ± 1 year. QTc prolongation was observed in all patients (by 60 ± 6 ms; p < 0.001). We compared the occurrence of LAE during 6 ± 1 years before and after HQ, observing that patients on HQ experienced a reduction in both the rate of LAE from 40% to 0% (p = 0.03) and the number of LAE per patient from 0.73 ± 0.3 to 0 (p = 0.026). Furthermore, the annual rate of LAE in the 16 patients with a previous cardiac arrest dropped from 12% before HQ to 0 on therapy (p = 0.028). CONCLUSIONS:We demonstrated for the first time that treatment with HQ was associated with a lower incidence of LAE in SQTS patients. These data point to the importance that quinidine, that in several countries has been removed from the market, remains available worldwide for patients with SQTS. In the present study, therapy with HQ has been proven to be safe, with a relatively low rate of side effects.

Cardiovascular disease-related deaths frequently arise from arrhythmias, but treatment options are limited due to perilous side effects of commonly used antiarrhythmic drugs. Cardiac rhythmicity strongly depends on cardiomyocyte Ca²⁺ handling and prevalent cardiac diseases are causally associated with perturbations in intracellular Ca²⁺ handling. Therefore, intracellular Ca²⁺ transporters are lead candidate structures for novel and safer antiarrhythmic therapies. Mitochondria and mitochondrial Ca²⁺ transport proteins are important regulators of cardiac Ca²⁺ handling. Here we evaluated the potential of pharmacological activation of mitochondrial Ca²⁺ uptake for the treatment of cardiac arrhythmia. To this aim,we tested substances that enhance mitochondrial Ca²⁺ uptake for their ability to suppress arrhythmia in a murine model for ryanodine receptor 2 (RyR2)-mediated catecholaminergic polymorphic ventricular tachycardia (CPVT) in vitro and in vivo and in induced pluripotent stem cell-derived cardiomyocytes from a CPVT patient. In freshly isolated cardiomyocytes of RyR2^R4496C/WT mice efsevin, a synthetic agonist of the voltage-dependent anion channel 2 (VDAC2) in the outer mitochondrial membrane, prevented the formation of diastolic Ca²⁺ waves and spontaneous action potentials. The antiarrhythmic effect of efsevin was abolished by blockade of the mitochondrial Ca²⁺ uniporter (MCU), but could be reproduced using the natural MCU activator kaempferol. Both mitochondrial Ca²⁺ uptake enhancers (MiCUps), efsevin and kaempferol, significantly reduced episodes of stress-induced ventricular tachycardia in RyR2^R4496C/WT mice in vivo and abolished diastolic, arrhythmogenic Ca²⁺ events in human iPSC-derived cardiomyocytes.