Sequenom MassARRAY approach in the arrhythmogenic right ventricular cardiomyopathy post-mortem setting: clinical and forensic implications.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare cardiac disease characterized by myocardial fibrofatty replacement, which can lead to sudden death. Previous studies have described a reduction of plakoglobin (PKG) protein at the level of intercalated disks as the hallmark of ARVC. The main objective of this study was to investigate the involvement of desmosome mutations in the histological phenotype of ARVC. We performed a genetic analysis of ARVC cases, and histological characterization of ARVC heart tissue samples. We genetically analyzed 48 ARVC cases distributed into two groups: 42 human tissue heart samples with conclusive diagnoses of ARVC after post-mortem examination; and six DNA samples from peripheral blood of living patients who were clinically diagnosed. Sequenom MassARRAY analysis revealed three ARVC-associated variants in three patients in 42 tissue samples (7.14 %). Three individuals carried one single pathogenic mutation, p.R811S _PKP2, p.S824L_DSC2, and p.T526M_PKP2 in postmortem samples. In the living patients group, Sequenom MassARRAY revealed no mutation, however, later Sanger sequencing analysis identified three ARVC mutations in 2/6 patients not included in the Sequenom design. In post-mortem tissue samples we performed immunohistochemical labeling for desmosomal proteins and Connexin 43. This study revealed that PKP2 carriers present either absent or clearly reduced PKG immunolabeling, while the DSC2 carrier showed PKG immunolabeling similar to control samples. Immunolabeling for Cx43 did not show any differences compared to controls. The present Sequenom MassARRAY design is a useful tool for post-mortem genetic diagnosis of ARVC. Plakoglobin reduction occurs at intercalated disks, while other desmosome proteins and Cx43 remain unaltered.

An enigmatic case of cardiac death in an 18-years old girl.

We report a case of unusual and unexplained cardiac death in an 18-years old female patient with congenital neurosensorial deafness. The fatal event was characterized by an initial syncopal episode, associated with a wide QRS tachycardia (around 110 bpm) but stable hemodynamic conditions. The patient, however, subsequently developed severe hypotension and progressive bradyarrhythmias until asystole and lack of cardiac response to resuscitation maneuvers and ventricular pacing.

High-density substrate mapping in Brugada syndrome: combined role of conduction and repolarization heterogeneities in arrhythmogenesis.

BACKGROUND: Two principal mechanisms are thought to be responsible for Brugada syndrome (BS): (1) right ventricular (RV) conduction delay and (2) RV subepicardial action potential shortening. This in vivo high-density mapping study evaluated the conduction and repolarization properties of the RV in BS subjects. METHODS AND RESULTS: A noncontact mapping array was positioned in the RV of 18 BS patients and 20 controls. Using a standard S(1)-S(2) protocol, restitution curves of local activation time and activation recovery interval were constructed to determine local maximal restitution slopes. Significant regional conduction delays in the anterolateral free wall of the RV outflow tract of BS patients were identified. The mean increase in delay was 3-fold greater in this region than in control (P=0<0.001). Local activation gradient was also maximally reduced in this area: 0.33+/-0.1 (mean+/-SD) mm/ms in BS patients versus 0.51+/-0.15 mm/ms in controls (P<0.0005). The uniformity of wavefront propagation as measured by the square of the correlation coefficient, r(2), was greater in BS patients versus controls (0.94+/-0.04 versus 0.89+/-0.09 [mean+/-SD]; P<0.05). The odds ratio of BS hearts having any RV segment with maximal restitution slope >1 was 3.86 versus controls. Five episodes of provoked ventricular tachycardia arose from wave breaks originating from RV outflow tract slow-conduction zones in 5 BS patients. CONCLUSIONS: Marked regional endocardial conduction delay and heterogeneities in repolarization exist in BS. Wave break in areas of maximal conduction delay appears to be critical in the initiation and maintenance of ventricular tachycardia. These data indicate that further studies of mapping BS to identify slow-conduction zones should be considered to determine their role in spontaneous ventricular arrhythmias.

Role of genetic testing in arrhythmogenic right ventricular cardiomyopathy/dysplasia.

In a cohort of patients with confirmed or suspected arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D), genetic testing is useful in confirming the diagnosis, particularly in individuals who do not completely fulfil Task Force criteria for the disease, thereby also enabling the adoption of preventive measures in family members. Due to the high percentage of novel mutations that are expected to be identified in ARVC/D, the use of genetic screening technology based on the identification of known mutations seems to have very restricted value. Our results support that the presence of certain genetic variations could play a role in the final phenotype of patients with ARVC/D, where single and compound mutation carriers would have more symptomatic forms of the disease and the polymorphism P366L could be associated to a more benign phenotype.

Lamotrigine induced Brugada-pattern in a patient with genetic epilepsy associated with a novel variant in SCN9A.

BACKGROUND: A 30-year-old man presented with intellectual disability associated with epilepsy. The epilepsy was initially treated with sodium valproate and since he was 28 years-old with lamotrigine. With the addition of lamotrigine, a pattern of Brugada syndrome appeared on the electrocardiogram. The family history was positive for epilepsy from the mothers side, who had never been treated with lamotrigine. OBJECTIVE: Determine the genetic cause of the intellectual disability, epilepsy and Brugada syndrome of the patient and try to establish a possible correlation between the genetic background and the Brugada syndrome pattern under lamotrigine treatment. METHODS: A standard karyotype, array comparative genomic hybridization and two different NGS panels have done to the index case to identify the genetic causes of the intellectual disability, epilepsy and Brugada syndrome pattern. RESULTS: Genetic analyses in the family identified a de novo duplication of 1.3 Mb in 8p21.3 as well as two novel heterozygous rare variants in SCN9A and AKAP9 genes, both inherited from the mother. CONCLUSION: We hypothesize that in this family the SCN9A variant was responsible for the epileptic syndrome. In addition, given that SCN9A is lightly expressed in the heart tissue, we postulate that this SCN9A variant, alone or in combination with AKAP9 variant, might be responsible for the Brugada pattern when challenged by lamotrigine.

Dominant-negative effect of a mutant cardiac troponin T on cardiac structure and function in transgenic mice.

Hypertrophic cardiomyopathy (HCM) is a disease of sarcomeric proteins. The mechanism by which mutant sarcomeric proteins cause HCM is unknown. The leading hypothesis proposes that mutant sarcomeric proteins exert a dominant-negative effect on myocyte structure and function. To test this, we produced transgenic mice expressing low levels of normal or mutant human cardiac troponin T (cTnT). We constructed normal (cTnT-Arg92) and mutant (cTnT-Gln92) transgenes, driven by a murine cTnT promoter, and produced three normal and five mutant transgenic lines, which were identified by PCR and Southern blotting. Expression levels of the transgene proteins, detected using a specific antibody, ranged from 1 to 10% of the total cTnT pool. M-mode and Doppler echocardiography showed normal left ventricular dimensions and systolic function, but diastolic dysfunction in the mutant mice evidenced by a 50% reduction in the E/A ratio of mitral inflow velocities. Histological examination showed cardiac myocyte disarray in the mutant mice, which amounted to 1-15% of the total myocardium, and a twofold increase in the myocardial interstitial collagen content. Thus, the mutant cTnT-Gln92, responsible for human HCM, exerted a dominant-negative effect on cardiac structure and function leading to disarray, increased collagen synthesis, and diastolic dysfunction in transgenic mice.

A transgenic rabbit model for human hypertrophic cardiomyopathy.

Certain mutations in genes for sarcomeric proteins cause hypertrophic cardiomyopathy (HCM). We have developed a transgenic rabbit model for HCM caused by a common point mutation in the beta-myosin heavy chain (MyHC) gene, R400Q. Wild-type and mutant human beta-MyHC cDNAs were cloned 3' to a 7-kb murine beta-MyHC promoter. We injected purified transgenes into fertilized zygotes to generate two lines each of the wild-type and mutant transgenic rabbits. Expression of transgene mRNA and protein were confirmed by Northern blotting and 2-dimensional gel electrophoresis followed by immunoblotting, respectively. Animals carrying the mutant transgene showed substantial myocyte disarray and a 3-fold increase in interstitial collagen expression in their myocardia. Mean septal thicknesses were comparable between rabbits carrying the wild type transgene and their nontransgenic littermates (NLMs) but were significantly increased in the mutant transgenic animals. Posterior wall thickness and left ventricular mass were also increased, but dimensions and systolic function were normal. Premature death was more common in mutant than in wild-type transgenic rabbits or in NLMs. Thus, cardiac expression of beta-MyHC-Q(403) in transgenic rabbits induced hypertrophy, myocyte and myofibrillar disarray, interstitial fibrosis, and premature death, phenotypes observed in humans patients with HCM due to beta-MyHC-Q(403).

Familial dilated cardiomyopathy: A multidisciplinary entity, from basic screening to novel circulating biomarkers.

Idiopathic dilated cardiomyopathy has become one of the most prevalent inherited cardiomyopathies over the past decades. Genetic screening of first-degree relatives has revealed that 30-50% of the cases have a familial origin. Similar to other heart diseases, familial dilated cardiomyopathy is characterized by a high genetic heterogeneity that complicates family studies. Cli'nical screening, 12-lead electrocardiogram and transthoracic echocardiogram are recommended for patients and first-degree family members. Magnetic resonance also needs to be considered. Genetic technologies have become fundamental for the clinical management of this disease. New generation sequencing methods have made genetic testing feasible for extensive panels of genes related to the disease. Recently, new imaging modalities such as speckle-tracking, strain and strain rate or magnetic resonance, and circulating biomarkers such as non-coding RNAs, have emerged as potential strategies to help cardiologists in their clinical practice. Imaging, genetic and blood-based techniques should be considered together in the evaluation and testing of familial dilated cardiomyopathy. Here, we discuss the current procedures and novel approaches for the clinical management of familial dilated cardiomyopathy.

Brugada syndrome: a decade of progress.

The Brugada syndrome has gained wide recognition throughout the world and today is believed to be responsible for 4% to 12% of all sudden deaths and approximately 20% of deaths in patients with structurally normal hearts. The incidence of the disease is on the order of 5 per 10 000 inhabitants and, apart from accidents, is the leading cause of death of men under the age of 50 in regions of the world where the inherited syndrome is endemic. This minireview briefly summarizes the progress made over the past decade in our understanding of the clinical, genetic, cellular, ionic, and molecular aspects of this disease.

Ionic mechanisms responsible for the electrocardiographic phenotype of the Brugada syndrome are temperature dependent.

The Brugada syndrome is a major cause of sudden death, particularly among young men of Southeast Asian and Japanese origin. The syndrome is characterized electrocardiographically by an ST-segment elevation in V1 through V3 and a rapid polymorphic ventricular tachycardia that can degenerate into ventricular fibrillation. Our group recently linked the disease to mutations in SCN5A, the gene encoding for the alpha subunit of the cardiac sodium channel. When heterologously expressed in frog oocytes, electrophysiological data recorded from the Thr1620Met missense mutant failed to adequately explain the electrocardiographic phenotype. Therefore, we sought to further characterize the electrophysiology of this mutant. We hypothesized that at more physiological temperatures, the missense mutation may change the gating of the sodium channel such that the net outward current is dramatically augmented during the early phases of the right ventricular action potential. In the present study, we test this hypothesis by expressing Thr1620Met in a mammalian cell line, using the patch-clamp technique to study the currents at 32 degrees C. Our results indicate that Thr1620Met current decay kinetics are faster when compared with the wild type at 32 degrees C. Recovery from inactivation was slower for Thr1620Met at 32 degrees C, and steady-state activation was significantly shifted. Our findings explain the features of the ECG of Brugada patients, illustrate for the first time a cardiac sodium channel mutation of which the arrhythmogenicity is revealed only at temperatures approaching the physiological range, and suggest that some patients may be more at risk during febrile states.

Modulation of I(Kr) inactivation by mutation N588K in KCNH2: a link to arrhythmogenesis in short QT syndrome.

OBJECTIVE: Short QT syndrome (SQTS) is characterized by ventricular arrhythmias and sudden death. One form of SQTS is caused by mutation N588K in human ether-a-go-go-related gene (HERG). In this study we sought to determine the potential role of N588K in arrhythmias. METHODS: We measured the characteristics of HERG current generated by wild-type (WT) KCNH2 and the N588K mutant channel expressed in mammalian TSA201 cells. RESULTS: Whole-cell patch-clamp recordings of WT HERG currents showed the usual rapid onset of inactivation (rectification) at potentials more positive than +10 mV. In contrast, N588K currents rectified at potentials over +80 mV. Over the physiological range of potentials, N588K currents do not inactivate. During an action potential clamp, WT currents displayed a "hump" like waveform with slow activation kinetics and a rapid increase during phase 3 repolarization. In contrast, N588K currents were proportional to the amplitude of the action potential and displayed a dome-like configuration and a much larger current during the initial phases in the ventricle. Purkinje cell action potentials display a more negative phase 2 repolarization than the ventricle and elicited much smaller WT and N588K currents of similar amplitudes. CONCLUSIONS: Physiologically the N588K mutation abolishes rectification of HERG currents and specifically increases I(Kr) in the ventricle with minimal effects on the Purkinje fiber action potential duration. Such preferential prolongation may explain the separation of the T and U waves observed in the ECG of SQTS patients and lead to re-excitation of the ventricle endocardium.

Sodium channel blockers identify risk for sudden death in patients with ST-segment elevation and right bundle branch block but structurally normal hearts.

BACKGROUND: A mutation in the cardiac sodium channel gene (SCN5A) has been described in patients with the syndrome of right bundle branch block, ST-segment elevation in leads V1 to V3, and sudden death (Brugada syndrome). These electrocardiographic manifestations are transient in many patients with the syndrome. The present study examined arrhythmic risk in patients with overt and concealed forms of the disease and the effectiveness of sodium channel blockers to unmask the syndrome and, thus, identify patients at risk. METHODS AND RESULTS: The effect of intravenous ajmaline (1 mg/kg), procainamide (10 mg/kg), or flecainide (2 mg/kg) on the ECG was studied in 34 patients with the syndrome and transient normalization of the ECG (group A), 11 members of 3 families in whom a SCN5A mutation was associated with the syndrome and 8 members in whom it was not (group B), and 53 control subjects (group C). Ajmaline, procainamide, or flecainide administration resulted in ST-segment elevation and right bundle branch block in all patients in group A and in all 11 patients with the mutation in group B. A similar pattern could not be elicited in the 8 patients in group B who lacked the mutation or in any person in group C. The follow-up period (37+/-33 months) revealed no differences in the incidence of arrhythmia between the 34 patients in whom the phenotypic manifestation of the syndrome was transient and the 24 patients in whom it was persistent (log-rank, 0.639). CONCLUSIONS: The data demonstrated a similar incidence of potentially lethal arrhythmias in patients displaying transient versus persistent ST-segment elevation and right bundle branch block, as well as the effectiveness of sodium channel blockers to unmask the syndrome and, thus, identify patients at risk.

Novel cardiac troponin T mutation as a cause of familial dilated cardiomyopathy.

BACKGROUND: Familial dilated cardiomyopathy (FDCM) and hypertrophic cardiomyopathy (FHCM) are the 2 most common forms of primary cardiac muscle diseases. Studies indicate that mutations in sarcomeric proteins are responsible for FHCM and suggest that mutations in cytoskeletal proteins cause FDCM. Evidence is evolving, however, that such conclusions are premature. METHODS AND RESULTS: A novel missense mutation in the cardiac troponin T gene was identified by direct sequencing and confirmed by endonuclease restriction analysis in a large family with FDCM that we had previously mapped to chromosome 1q32. The mutation substitutes tryptophan for a highly conserved amino acid, arginine, at amino acid residue 141 (Arg141Trp). The mutation occurs within the tropomyosin-binding domain of cardiac troponin T and alters the charge of the residue. This mutation cosegregates with the disease, being present in all 14 living affected individuals. The mutation was not found in 100 normal control subjects. Clinical features were congestive heart failure with premature deaths. The age of onset and severity of the disease are highly variable, with incomplete penetrance. Because 15 mutations in troponin T are known to cause FHCM, 219 probands with FHCM were screened, and none had the mutation. CONCLUSIONS: Thus, the novel cardiac troponin T mutation Arg141Trp is responsible for FDCM in our family. Because several mutations in troponin T have already been recognized to be responsible for FHCM, it appears that the phenotype, whether it be hypertrophy or dilatation, is determined by the specific mutation rather than the gene.

The Brugada Syndrome.

In 1992 a syndrome was described consisting of syncopal episodes and/or (resuscitated) sudden death in patients with a structurally normal heart and a characte ristic electrocardiogram (ECG) displaying a pattern resembling a right bundle branch block with ST segment elevation in leads V1 to V3. The disease is genetically determined with an autosomal dominant pattern of transmission in 50% of the familial cases. Several different mutations have been identified affecting the structure, function and trafficking of the sodium channel. The syndrome is ubiquitous. Its incidence and prevalence are difficult to estimate, but this disease may cause 4 to 10 sudden deaths per 10,000 inhabitants per year representing the most frequent cause of natural death in males younger than 50 in South Asia. The disease has been linked to the sudden infant death syndrome (SIDS) and to the sudden unexpected death syndrome (SUDS) by showing that the electrocardiogram and mutations are the same as in Brugada syndrome. The diagnosis is easily made by means of the ECG when it is typical. There exist, however, patients with concealed and intermittent electrocardiographic forms that make the diagnosis difficult. The ECG can be modulated by changes in autonomic balance, body temperature, glucose level and the administration of antiarrhythmic, neuroleptic and antimalaria drugs. Beta adrenergic stimulation normalizes the ECG. Loss of the action potential dome in right ventricular epicardium but not in endocardium underlies the ST segment elevation. Electrical heterogeneity within right ventricular epicardium leads to the development of closely coupled extrasystoles via phase 2 reentry that precipitate ventricular ,fibrillation. Antiarrhythmic drugs do not prevent sudden death in symptomatic or asymptomatic individuals. Implantation of an automatic cardioverter-defibrillator is the only currently proven effective therapy. Patients with frequent electrical storms may even need cardiac transplantation as last resort.

A common mutation in methylenetetrahydrofolate reductase gene is not a major risk of coronary artery disease or myocardial infarction.

A common mutation (C677-->T) in methylenetetrahydrofolate (MTHFR) gene, involved in the metabolism of homocysteine, has been suggested to play a role in increasing cardiovascular disease risk. We determined the frequency of C677-->T genotypes and alleles in 155 Caucasian patients with angiographically documented coronary artery disease (CAD) and in 155 age and sex matched normal Caucasian individuals. DNA was extracted from the blood and genotypes were determined by polymerase chain reaction, restriction mapping with HinfI and gel electrophoresis. The distribution of MTHFR C677-->T genotypes followed the Hardy-Weinberg equilibrium. The distribution of MTHFR genotypes and the frequency of alleles were similar in cases and controls. The TT genotype was present in 8% of controls as compared to 6% of cases (P = 0.50, OR = 0.82; 95% CI: 0.34-1.96). The frequency of T allele was also similar in patients with CAD compared with controls (0.29 vs. 0.33; P = 0.29). There was also no significant association between C677-->T genotypes and the risk of myocardial infarction. In a subgroup of 44 cases and 89 controls who had no conventional risk factors for CAD (hyperlipidemia, hypertension, diabetes mellitus, and smoking), the frequency of TT genotype was similar (11% vs. 8%, respectively, P = 0.71, OR: 0.67, 95% CI: 0.20-2.23). Thus, the MTHFR TT genotype is not a major genetic risk factor for predisposition to CAD and its thrombotic complications in this population.

A prospective study of paraoxonase gene Q/R192 polymorphism and severity, progression and regression of coronary atherosclerosis, plasma lipid levels, clinical events and response to fluvastatin.

Human serum paraoxonase (PON1) is a high-density lipoprotein (HDL)-associated enzyme that is responsible for the protective effect of HDL against oxidation of low-density lipoprotein (LDL). PON1 has a Glu to Arg polymorphism at codon 192 (CGA-->CAA) which is designated R/Q192. The R/Q192 polymorphism has been associated with coronary artery disease (CAD) in several, but not all, case-control studies. We prospectively studied the association of the Q/R192 genotypes with the severity, progression and regression of CAD, plasma lipid levels, clinical events and response to treatment with fluvastatin in a well-characterized cohort. Genotypes were determined by polymerase chain reaction (PCR) and restriction mapping with AlwI enzyme in 356 subjects in the Lipoprotein and Coronary Atherosclerosis Study (LCAS). Fasting plasma lipids were measured and quantitative coronary angiograms were obtained at baseline and 2.5 years following randomization to fluvastatin or placebo. A total of 177 (50%), 142 (40%) and 37 (10%) subjects had Q/Q, Q/R and R/R genotypes, respectively. Baseline and final plasma levels of HDL, LDL, triglyceride and other lipoproteins, lesion-specific minimum lumen diameters (MLD), mean MLD, number of coronary lesions and total occlusions at baseline and follow-up and clinical event rates were not significantly different among the genotypes. There was no genotype-treatment interaction with respect to plasma lipid levels and angiographic indices of CAD. The Q/R192 variants of PON1 are not associated with severity, progression or regression of coronary atherosclerosis, plasma lipid levels, clinical events, or response to treatment with fluvastatin. Thus, the Q/R192 polymorphism is not a major risk factor in susceptibility to CAD in the LCAS population.

Lipoprotein lipase gene mutations, plasma lipid levels, progression/regression of coronary atherosclerosis, response to therapy, and future clinical events. Lipoproteins and Coronary Atherosclerosis Study.

Mutations in human lipoprotein lipase (LPL) gene are potential risk factors for susceptibility to coronary artery disease (CAD). The objectives of this study were to determine the influence LPL mutations Asn291Ser and Ser447Ter on plasma lipid levels, regression and progression of CAD, clinical events rate, and response to fluvastatin therapy in the Lipoprotein and Coronary Atherosclerosis Study (LCAS) population. LCAS is a double blind, randomized, placebo-controlled study designed to test the influence of fluvastatin on progression or regression of CAD. The Asn291Ser and Ser447Ter genotypes were determined by polymerase chain reaction (PCR) and restriction enzyme digestion. Fasting plasma lipid profiles were measured and quantitative coronary angiography was performed at baseline and 2.5 years following randomization. Fatal and non-fatal cardiovascular events during the follow-up period were recorded. A total of 4% (14/363) and 18% (62/352) of the subjects had the Asn291Ser and Ser447Ter mutations, respectively. Overall, there was no statistically association between the Asn291Ser and Ser447Ter mutations and the baseline or final mean plasma levels of lipids, number of coronary lesions, total occlusions, the mean minimal lumen diameter (MLD) stenoses and the clinical events rate. However, patients with the Ser447Ter variant had a slightly higher baseline high density lipoprotein-cholesterol (HDL-C) level (46.2 +/- 12 vs 43.2 +/- 11, P = 0.057), less increase in plasma HDL levels in response to fluvastatin therapy (3 vs 11%, P = 0.056) and a higher cardiovascular events rate (23 vs 13%, P = 0.056). Thus, the Ser447Ter variant had a modest influence on plasma HDL levels and the rate of cardiovascular events. These changes were of borderline statistical significance. Neither the Ser447Ter nor the Asn291Ser mutation had a major impact on susceptibility to CAD, progression or regression of CAD, clinical events rate or response to fluvastatin therapy in LCAS population.

Role of molecular biology in identifying individuals at risk for sudden cardiac death.

Cardiology has participated in the new developments in molecular biology and the impact of the Human Genome Project. In these last few years, we have observed how the research in human physiology and journal publications have been focusing on the most basic molecular level. Clinicians have likely been having trouble keeping up with the new developments and, more importantly, with the highly publicized discoveries trying to discern what is research and what can already be applied at the bedside. Molecular biology has just started, and there is no doubt that it will have a tremendous impact in the diagnosis, prevention, and therapy of most diseases, including sudden death and cardiac arrhythmia. In the last few years, we have seen new data in the field of genetics and arrhythmia that are already shaping our approach to an inherited disease. Routine clinical tests are not yet available, mainly due to the lack of sufficiently powerful technology, but with the pace of evolution at this turn of the millennium, we can certainly assume that such testing is just a matter of time.

Sudden death in high-risk family members: Brugada syndrome.

Brugada syndrome (an electrocardiographic pattern of right bundle branch block, ST segment elevation in leads V1 to V3, and sudden death) is genetically determined and caused by mutations in the cardiac ion channels. The mode of inheritance of the disease is autosomal dominant in half of familial forms. Sudden death may, however, occur from a variety of causes in relatives and patients with this syndrome. Twenty-five Flemish families with this syndrome with a total of 334 members were studied. Affected members were recognized by means of the typical electrocardiogram of the syndrome, either occurring spontaneously or after the intravenous administration of antiarrhythmic drugs. Sudden deaths in these families were classified as related or not to the syndrome by analysis of the data at the time of the event, mode of inheritance of the disease, and data provided by survivors. Of the 25 families with the syndrome, 18 were symptomatic (at least 1 sudden death related to the syndrome) and 7 were asymptomatic (no sudden deaths related to the syndrome). In total, there were 42 sudden cardiac deaths (12% incidence). Twenty-four sudden deaths were related to the syndrome and all happened in symptomatic families. Eighteen sudden deaths (43% of total sudden deaths) were not related to the syndrome (9 cases) or were of unclear cause (9 cases). Three of them occurred in 2 asymptomatic families and the remaining 15 in 5 symptomatic families. A total of 24 of the 50 affected members (47%) and 18 of the 284 unaffected members (6%) had aborted sudden death. This difference in the incidence of sudden death was statistically significant (p <0.0001). Patients with aborted sudden death caused by the syndrome were younger than patients with sudden death of other or unclear causes (38 +/- 4 years vs 59 +/- 3 years respectively; p = 0.0003). In families at high risk of sudden death because of genetically determined diseases, the main cause of sudden death remains the disease itself. However, almost half of sudden deaths are caused by unrelated diseases or from unclear causes. Accurate classification of the causes of sudden death is mandatory for appropriate analysis of the causes of death when designing preventive treatments.

Use of the prophylactic implantable cardioverter defibrillator for patients with normal hearts.

About 10-20% of patients dying suddenly and unexpectedly do not have structural heart disease. The major causes of sudden death in this population are acute ischemia, the syndrome of right bundle branch block, and ST-elevation from V1 to V3, the long QT-syndrome, and the Wolff-Parkinson-While syndrome. In some patients, none of these syndromes can be recognized and ventricular fibrillation is classified as idiopathic. There are good preventive and therapeutic methods against acute ischemia and there are also curative treatments for the Wolff-Parkinson-White syndrome. Patients with idiopathic ventricular fibrillation cannot be recognized beforehand. However, there are electrocardiographic and genetic markers for the Brugada syndrome and the long QT syndrome. It is, therefore, justified to discuss the possible role of the prophylactic defibrillator to prevent sudden death in these 2 syndromes for which no effective treatment exists. Patients with Brugada syndrome have a high incidence of sudden death, and prophylactic defibrillators are indicated in patients with inducible arrhythmias at electrophysiologic study, irrespective of symptoms. On the contrary, the incidence of sudden death in the long QT syndrome is very low, making prophylactic defibrillator implantation not cost-effective.