Faculty Bibliography

BACKGROUND: Short QT syndrome (SQTS) is a rare inheritable arrhythmia, associated with atrial and ventricular fibrillations, caused by mutations in six cardiac ion channel genes with high penetrance. However, genotype-specific clinical differences between SQTS patients remain to be elucidated. METHODS AND RESULTS: We screened five unrelated Japanese SQTS families, and identified three mutations in KCNH2 and KCNQ1. A novel mutation KCNH2-I560T, when expressed in COS-7 cells, showed a 2.5-fold increase in peak current density, and a positive shift (+14mV) of the inactivation curve compared with wild type. Computer simulations recapitulated the action potential shortening and created an arrhythmogenic substrate for ventricular fibrillation. In another family carrying the mutation KCNQ1-V141M, affected members showed earlier onset of manifestation and frequent complications of bradyarrhythmia. To determine genotype-specific phenotypes in SQT1 (KCNH2), SQT2 (KCNQ1), and other subtypes SQT3-6, we analyzed clinical variables in 65 mutation-positive patients among all the 132 SQTS cases previously reported. The age of manifestation was significantly later in SQT1 (SQT1: 35+/-19years, n=30; SQT2: 17+/-25years, n=8, SQT3-6: 19+/-15years, n=15; p=0.011). SQT2 exhibited a higher prevalence of bradyarrhythmia (SQT2: 6/8, 75%; non-SQT2: 5/57, 9%; p<0.001) and atrial fibrillation (SQT2: 5/8, 63%; non-SQT2: 12/57, 21%; p=0.012). Of 51 mutation-positive individuals from 16 SQTS families, nine did not manifest short QT, but exhibited other ECG abnormalities such as atrial fibrillation. The resulting penetrance, 82%, was lower than previously recognized. CONCLUSION: We propose that SQTS patients may exhibit different clinical manifestations depending upon their genotype.

Today the ECG is still, over 100 years after its invention (Willem Einthoven 1903), the most commonly used diagnostic procedure in clinical cardiology. In recent years, we have accumulated knowledge that has significantly expanded the diagnostic possibilities of ECG, through the recognition of patterns associated with a number of primary electrical diseases of the myocardium, the so-called inherited arrhythmogenic diseases. These clinical entities are caused by gene mutations that determine a substrate leading to the onset of life-threatening rhythm disturbances. The study of ECG abnormalities in these diseases showed characteristic phenotypic traits, which in combination with information derived from molecular genetics, have allowed using the ECG as a prognostic tool as well as a diagnostic test. The assessment of genotype-phenotype correlations in inherited arrhythmogenic diseases has allowed to advance the idea of the ECG as an inheritable trait. Such heritable quantitative traits are potentially related to the risk of sudden death in the general population, which is known to have a familial predisposition. This article summarizes the pathophysiology and phenotypic manifestation of the main arrhythmogenic diseases. Also shown are current possibilities and limitations of the use of a simple and low-cost technology, not only as a tool for diagnosis but also as a tool to identify prognostic markers. We will show how, rather surprisingly, the ECG often allows extracting the most important information for appropriate risk classification and clinical management.

BACKGROUND: The burden of sudden unexplained death in sub-Saharan Africa is unknown. AIM: The aim of this study is to establish the epidemiology of sudden cardiac death in Cameroon. METHODS: The Douala sudden unexplained death (Douala-SUD) study is a prospective, multiple-source, community-based surveillance of all cases of unexpected death (< 24hours from onset of symptoms) occurring in victims aged>15 years. After approval from institutional boards, all deaths occurring in residents of four areas of Douala city will be checked for circumstances of death and past medical history. Subjects who die naturally will be further investigated. Unexpected death victims will be checked for detailed demographic, clinical, electrocardiographic, echocardiographic and biological records. Autopsy background and genetic analysis (postmortem or in first relatives if the young victim is aged<40 years) will be performed as far as possible. Finally, the use of cardiopulmonary resuscitation efforts during the timeframe of sudden cardiac arrest will also be evaluated. CONCLUSION: The Douala-SUD study will provide comprehensive, contemporary data on the epidemiology of sudden unexplained and cardiac death in sub-Saharan Africa and will help in the development of strategies to prevent and manage cardiac arrest in Cameroon as well as in other sub-Saharan countries.

BACKGROUND: -Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disorder characterized by sudden cardiac death in children. Drug therapy is still insufficient to provide full protection from cardiac arrest and the use of the implantable defibrillator in the pediatric population is limited by side effects. There is therefore a rational to explore the curative potential of gene therapy for this disease. We investigated the efficacy and durability of viral gene transfer of Calsequestrin 2 (CASQ2) wild type gene in a CPVT knock-in mice model carrying the CASQ2R33Q/R33Q (R33Q) mutation. METHODS AND RESULTS: -We engineered an Adeno-Associated Viral vector serotype 9 (AAV9) containing cDNA of CASQ2 wild type (AAV9-CASQ2) plus GFP to infect: 1) newborn R33Q mice studied by in vivo and in vitro protocols at 6, 9 and 12 months to investigate the ability of the infection to prevent the disease; 2) adult R33Q mice studied after 2 months to assess if the AAV9-CASQ2 delivery could revert the CPVT phenotype. In both protocols we observed the restoration of physiological expression and interaction of CASQ2, Junctin and Triadin, the rescue of electrophysiological and ultrastructural abnormalities in Calcium Release Units present in R33Q mice and the lack of life-threatening arrhythmias. CONCLUSIONS: -Our data demonstrate that viral gene transfer of wild type CASQ2 into the heart of R33Q mice prevents and reverts severe manifestations of CPVT and this curative effect lasts for one year after a single injection of the vector thus posing the rationale for the design of a clinical trial.

BACKGROUND: The estimated rate of sudden cardiac death (SCD) in Western countries ranges from 300,000 to 400,000 annually, which represents 0.36 to 1.28 per 1 000 inhabitants in Europe and the United States. The burden of SCD in Africa is unknown. Our aim is to assess the epidemiology of SCD in Africa. METHODS: The Pan-Africa SCD study is a prospective, multicentre, community-based registry monitoring all cases of cardiac arrest occurring in victims over 15 years old. We will use the definition of SCD as 'witnessed natural death occurring within one hour of the onset of symptoms' or 'unwitnessed natural death within 24 hours of the onset of symptoms'. After approval from institutional boards, we will record demographic, clinical, electrocardiographic and biological variables of SCD victims (including survivors of cardiac arrest) in several African cities. All deaths occurring in residents of districts of interest will be checked for past medical history, circumstances of death, and autopsy report (if possible). We will also analyse the employment of resuscitation attempts during the time frame of sudden cardiac arrest (SCA) in various patient populations throughout African countries. CONCLUSION: This study will provide comprehensive, contemporary data on the epidemiology of SCD in Africa and will help in the development of strategies to prevent and manage cardiac arrest in this region of the world.

OBJECTIVE: We explored whether subclinical alterations of sarcoplasmic reticulum (SR) Ca2+ release through cardiac ryanodine receptors (RyR2) aggravate cardiac remodeling in mice carrying a human RyR2R4496C+/- gain-of-function mutation in response to pressure overload. BACKGROUND: RyR2 dysfunction causes increased diastolic SR Ca2+ release associated with arrhythmias and contractile dysfunction in inherited and acquired cardiac diseases, such as catecholaminergic polymorphic ventricular tachycardia (CPVT) and heart failure (HF). METHODS: Functional and structural properties of wild-type (WT) and CPVT-associated RyR2R4496C+/- hearts were characterized under conditions of pressure overload induced by transverse aortic constriction (TAC). RESULTS: WT and RyR2R4496C+/- hearts had comparable structural and functional properties at baseline. After TAC, RyR2R4496C+/- hearts responded with eccentric hypertrophy, substantial fibrosis, ventricular dilatation and reduced fractional shortening, ultimately resulting in overt HF. RyR2R4496C+/--TAC cardiomyocytes showed increased incidence of spontaneous SR Ca2+ release events, reduced Ca2+ transient peak amplitude and SR Ca2+ content as well as reduced SR Ca2+-ATPase2a and increased Na+/Ca2+-exchange protein expression. HF phenotype in RyR2R4496C+/--TAC mice was associated with increased mortality due to pump failure, but not tachyarrhythmic events. RyR2-stabilizer K201 markedly reduced Ca2+ spark frequency in RyR2R4496C+/--TAC cardiomyocytes. Mini-osmotic pump infusion of K201 prevented deleterious remodeling and improved survival in RyR2R4496C+/--TAC mice. CONCLUSIONS: The combination of subclinical congenital alteration of SR Ca2+ release and pressure overload promotes eccentric remodeling and HF death in RyR2R4496C+/- mice, and pharmacological RyR2 stabilization prevents this deleterious interaction. These findings imply potential clinical relevance for patients with acquired or inherited gain-of-function of RyR2-mediated SR Ca2+ release.

OBJECTIVES: This study intends to gain further insights into the natural history, the yield of familial and genetic screening, and the arrhythmogenic mechanisms in the largest cohort of short QT syndrome (SQTS) patients described so far. BACKGROUND: SQTS is a rare genetic disorder associated with life-threatening arrhythmias, and its natural history is incompletely ascertained. METHODS: Seventy-three SQTS patients (84% male; age, 26 +/- 15 years; corrected QT interval, 329 +/- 22 ms) were studied, and 62 were followed for 60 +/- 41 months (median, 56 months). RESULTS: Cardiac arrest (CA) was the most frequent presenting symptom (40% of probands; range, <1 month to 41 years). The rate of CA was 4% in the first year of life and 1.3% per year between 20 and 40 years; the probability of a first occurrence of CA by 40 years of age was 41%. Despite the male predominance, female patients had a risk profile superimposable to that of men (p = 0.49). The yield of genetic screening was low (14%), despite familial disease being present in 44% of kindreds. A history of CA was the only predictor of recurrences at follow-up (p < 0.0000001). Two patterns of onset of ventricular fibrillation were observed and were reproducible in patients with multiple occurrences of CA. Arrhythmias occurred mainly at rest. CONCLUSIONS: SQTS is highly lethal; CA is often the first manifestation of the disease with a peak incidence in the first year of life. Survivors of CA have a high CA recurrence rate; therefore, implantation of a defibrillator is strongly recommended in this group of patients.

Up to 14,500 young individuals die suddenly every year in Europe of cardiac pathologies. The majority of these tragic events are related to a group of genetic defects that predispose the development of malignant arrhythmias (inherited arrhythmogenic diseases [IADs]). IADs include both cardiomyopathies (hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy) and channelopathies (long QT syndrome, short QT syndrome, Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia). Every time an IAD is identified in a patient, other individuals in his/her family may be at risk of cardiac events. However; if a timely diagnosis is made, simple preventative measures may be applied. Genetic studies play a pivotal role in the diagnosis of IADs and may help in the management of patients and their relatives.