Sudden cardiac death is a common outcome of several

Transcription

1 Sudden Cardiac Death Sudden Cardiac Death and Genetic Ion Channelopathies Long QT, Brugada, Short QT, Catecholaminergic Polymorphic Ventricular Tachycardia, and Idiopathic Ventricular Fibrillation Carlo Napolitano, MD, PhD; Raffaella Bloise, MD; Nicola Monteforte, MD; Silvia G. Priori, MD, PhD Sudden cardiac death is a common outcome of several cardiac disorders such as acute myocardial ischemia, myocardial infarction, and heart failure. However, 5% to 15% of cardiac arrest victims fail to show evidence of structural abnormalities at autopsy. 1 3 In 1997, a panel of experts defined sudden death in the absence of an identifiable cause as idiopathic ventricular fibrillation (IVF): IVF is the terminology that best acknowledges our current inability to identify a causal relationship between the clinical circumstance and the arrhythmia. 4 In the same article, the requirements for the diagnosis of IVF were identified on the basis of the clinical tools available at the time. In 1992, using the phenotypes observed in the IVF registry, we advanced the hypothesis that IVF could be the manifestation of concealed forms of arrhythmogenic disorders 5 exacerbated by appropriate triggers. A few years later, the discovery of the genes of long-qt syndrome (LQTS) 6 8 and the detection of incomplete penetrance 9 supported this early hypothesis. Incomplete penetrance and variable expressivity in inherited arrhythmogenic disorders imply that the distinctive ECG patterns that characterize these disorders may be concealed. 10 Interestingly, however, the absence of the ECG markers of the disease is not an indicator of favorable outcome, as demonstrated by the evidence that the incidence of cardiac arrest in LQTS patients with normal QTc during the first 40 years of life is 4%, ie, 0.1%/y. 11,12 In the last 15 years, the results of mutation screening in sudden unexplained death syndrome or sudden infant death syndrome, the so-called molecular autopsy, have been reported in several studies (Table 1) Although the yield of molecular autopsy reported by different studies is highly variable, ranging from 4% to 30%, it is sufficient to prove the concept that ion channel mutations may underlie IVF and that a positive genetic test may allow the extension of genotyping to family members of those affected to reduce additional deaths in the family. Channelopathies Associated With Prolonged Repolarization LQTS: Definition and Pathophysiology LQTS is defined as an arrhythmogenic disorder in the structurally normal heart presenting with QT prolongation that is often associated with peculiar ST-T wave morphology, syncope, and sudden death. 10 Some genetic variants of the disease are associated with more complex phenotype, including extracardiac manifestations. LQTS forms with multiorgan involvement are the recessive Jervell and Lange Nielsen syndrome, characterized by QT prolongation and congenital deafness; the Andersen-Tawil syndrome, which manifests with QT prolongation associated with facial dysmorphisms and hypokalemic periodic paralysis; and the Timothy syndrome, which shows marked QT prolongation, syndactyly, paroxysmal hypoglycemia, atrioventricular block, congenital heart defects, developmental disorders/ autism spectrum disorders, reduced immune response, and life-threatening arrhythmias (see Reference 10 for a review). The number of genes known to cause LQTS has steadily increased (Table 2) over the last 15 years. However, even after extended screening, mutations in the first 3 genes identified in the early 1990s (KCNQ1, KCNH2, and SCN5A) still account for the vast majority (80% 90%) of patients. Thus, most of the recently identified genes are actually responsible for a small percentage of patients. Therefore, it is difficult to collect enough information to interpret the role of mutations identified in these minor genes. 21 Interestingly, the genes associated with LQTS encode for either the macromolecular complex-forming ion channels (ie, and subunits) or their regulatory peptides. Mutations lead to QT interval prolongation either by impairing repolarizing currents (loss of function) or by increasing depolarizing currents (gain of function). Because different genes may participate in the same function, it turns out that multiple genetic variants may affect the same ionic current. For example, the potassium current I Ks is reduced in patients who carry mutations in 3 genes: KCNQ1, KCNE1, and AKAP9, which encode the subunit and the subunit of the channel that conducts I Ks and encodes for a regulatory protein involved in the adrenergic signaling that activates I Ks (Table 2 and Figure 1). Clinical Manifestations and Management LQTS diagnosis should be considered in all patients presenting with QTc 440 milliseconds in male patients and From Molecular Cardiology, IRCCS Fondazione Salvatore Maugeri, Pavia, Italy (C.N., R.B., N.M., S.G.P.); Cardiovascular Genetics Program, Leon H. Charney Division of Cardiology, New York University School of Medicine, New York (C.N., S.G.P.); and Department of Molecular Medicine, University of Pavia, Pavia, Italy (S.G.P.). Correspondence to Silvia G. Priori, Molecular Cardiology, IRCCS Salvatore Maugeri Foundation, Via Maugeri 10/10a, Pavia, Italy. silvia.priori@fsm.it (Circulation. 2012;125: ) 2012 American Heart Association, Inc. Circulation is available at DOI: /CIRCULATIONAHA

2 2028 Circulation April 24, 2012 Table 1. Molecular Autopsy in Idiopathic Ventricular Fibrillation Study Cohort Cases, n Autopsy/Toxicology Negative, n (%) Genes Analyzed SUDS (1 40 y), unselected (62) KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, KCNJ2 SUDS ( 20 y), consecutive, retrospective SUDS ( 45 y), consecutive, retrospective SUDS ( 45 y), consecutive, retrospective SIDS ( 1 y), retrospective SIDS ( 1 y), consecutive, retrospective SIDS ( 1 y) consecutive, unselected (5)* Segments of KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2 Identified Mutations, n (%) 5 (15 of autopsy negative) 2 (31 of autopsy negative) Reference (100; enrolling criteria) RyR2, selected exons 7 (14) (100; enrolling criteria) KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, KCNJ2, target analysis of ANK2 (10 exons) and CACNA1C (exon 8A) 93 (n 45 SIDS, n 48 possible SIDS) 93 (100; autopsy and toxicology negative) (100; autopsy negative) 252 SIDS (55), 61 (24) borderline SIDS (20) 16 SCN5A 2 (2.1) 17 KCNQ1, KCHH2, SCN5A 5 (11.9) 18 KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, KCNJ2, CAV3 26 (13) 19 SIDS ( 1 y), retrospective (100) KCNQ1, KCNH2, KCNE1, KCNE2 4 (4.3) 20 SUDS indicates sudden unexplained death syndrome; SIDS, sudden infant death syndrome. *Two cases with normal autopsy excluded for evidence of Wolff-Parkinson-White syndrome. Same cohort as in study 3. Screening performed on SIDS and borderline SIDS only. 460 milliseconds in female patients. Except for the Timothy syndrome and rare SCN5A mutations, 22 the presence of structural abnormalities and of acquired causes of QT prolongation should be excluded. Given the presence of incomplete penetrance and QT variability, exercise stress testing, Table 2. Genes Involved in the Long-QT Syndrome Variant Gene Protein Effect of Mutations LQT1 KCNQ1 KvLQT1 Reduced I Ks LQT2 KCNH2 HERG Reduced I Kr LQT3 SCN5A Nav1.5 Increased I Na LQT4 ANK2 Ankyrin B Reduced membrane expression of Na and Ca 2 channels LQT5 KCNE1 MinK Reduced I Ks LQT6 KCNE2 MiRP Reduced I Kr LQT7, Andersen syndrome LQT8, Timothy syndrome KCNJ2 Kir2.1 Reduced outward I K1 CACNA1c Cav1.2 Increased I Ca LQT9 CAV3 Cardiac caveolin gene LQT10 SCN4B Sodium channel 4 subunit Increased I Na resulting from altered gating kinetic Reduced subunit expression causing increased I Na LQT11 AKAP9 Yotiao Impaired I Ks activation by catecholamines LQT12 SNTA1 Syntrophin Reduced NaV1.5 nitrosylation and increased current LQT13 KCNJ5 Kir3.4/GIRK4 Reduced I KAch, acetylcholine-dependent potassium current Holter monitoring, and pharmacological challenge may be useful as diagnostic tests Once diagnosis is established, -blocker therapy is recommended. LQT1 patients respond very well to -blockers 26,27 ; interestingly, lack of compliance is the most important cause of events occurring during antiadrenergic treatment in LQT1. 27 Compared with LQT1 patients, LQT2 and LQT3 patients have a higher recurrence rate of arrhythmic events while on therapy. 26 The implantation of an implantable cardioverter-defibrillator (ICD) may be considered on evidence of -blocker failure and in selected high-risk individuals. Additionally, left cardiac sympathetic denervation may be an option to reduce the number of recurrences in highly symptomatic patients. 28 Genetic testing is useful to guide clinical management of mutation carriers in 1 of the 3 most common genes: KCNQ1, KCNH2, and SCN5A. Each of these genetic variants has a distinguishing morphology of the ST-T wave complex, a typical trigger for arrhythmic events, and a variable response to -blockers. 10 QT interval duration is the most powerful risk factor ( 500-millisecond QT threshold is considered a robust indicator of high-risk), but genotype information independently supports better clinical management. QTc is indeed modulated by genotype and sex; female patients with LQT2 and male patients with LQT3 with QTc 500 milliseconds are at highest risk of cardiac events between birth and 40 years of age in the absence of therapy. 29 More recent evidence suggests that dissection of additional features of the mutation (such as its position and biophysical effects) might be associated with differential risk of cardiac events (Table 3) Although genotype-phenotype correlations are useful, interindividual variability exists and must be taken into account in the assessment of any given patient or family. Incomplete penetrance and variable expressivity are indeed common in LQTS 10 and may be explained by different causes: multiple

3 Napolitano et al Genetics and Mechanisms of Ion Channelopathies 2029 Figure 1. Cartoon illustrating the genes associated with inherited arrhythmogenic diseases grouped by ion channel/function. SR indicates sarcoplasmic reticulum; VT, ventricular tachycardia. mutations (compound or double heterozygosity), modulating coding single-nucleotide polymorphisms in the same gene (cis or trans) harboring the primary mutation, and different genetic combinations of subject-specific pools of single-nucleotide polymorphisms affecting the QT interval33,34 (Figure 2). Table 3. Genotype-Phenotype Correlation in the Long-QT Syndrome ECG Pattern, Clinical Presentation LQT1 Overall, the integration of genotype information with clinical variables has produced improved risk stratification schemes. LQTS is the best example of successful genotypesupported clinical management. It is clear, however, that the identification of mutations in rare genetic variants (eg, LQT4 to LQT13) provides a marginal contribution to diagnosis and even less to risk stratification.21 We believe that this observation questions the need for screening all patients on all the Risk Factors for Events Broad T wave Exercise, swimming Impaired QT adaptation during tachycardia Cytoplasmic loop mutations (vs other localizations) Incomplete penetrance ( 60%), especially at rest Dominant negative mutations (vs haploinsufficiency) High effectiveness of -blockers LQT2 LQT3 Flat, notched T waves Acute emotions, loud nose, sudden awakening Usually normal QT adaptation at fast rates Pore region mutations (vs other localizations) Reduced -blocker effectiveness (vs LQT1) Female sex Straight ST segment, narrow T wave Rest, sleep Reduced -blocker effectiveness (vs LQT1) Male sex Figure 2. Risk stratification in long-qt syndrome (LQTS) including sex; QTc duration; LQT1, LQT2, and LQT3 genotype; and the NOS1AP genotype as a genetic modifier of the underlying main genetic defect.34

4 2030 Circulation April 24, 2012 Table 4. Genes Involved in Inherited Arrhythmias Phenotype Variant Gene Protein Functional Defect Brugada syndrome BrS1 SCN5A Cardiac sodium channel subunit (Nav1.5) Loss of function, reduced Na current BrS2 GPD1-L Glycerol-6-phosphate-dehydrogenase Loss of function, reduced Na current BrS3 CACNA1c L-type calcium channel subunit (Cav1.2) Loss of function, reduced Ca 2 current BrS4 CACNB2 L-type calcium channel 2 subunit Loss of function, reduced Ca 2 current BrS5 SCN1B Cardiac sodium channel 1 subunit Loss of function, reduced Na current BrS6 KCNE3 Transient outward current subunit Gain of function, increased K I to current BrS7 SCN3B Cardiac sodium channel 3 subunit Loss of function, reduced Na current BrS8 MOG1 Nucleocytoplasmic and microtubule transport Loss of function, reduced Na current BrS9 KCNE5 Transient outward current subunit Gain of function, increased K I to current BrS10 KCND3 I to potassium channel (Kv4.3) Gain of function, increased K I to current Short-QT syndrome SQTS1 KCNH2 I Kr potassium channel subunit (HERG) Gain of function, increased outward K current SQTS2 KCNQ1 I Ks potassium channel subunit (KvLQT1) Gain of function, increased outward K current SQTS3 KCNJ2 I K1 potassium channel (Kir2.1) Gain of function, increased outward K current SQTS4 CACNA1c L-type calcium channel subunit (Cav1.2) Loss of function, reduced Ca 2 current SQTS5 CACNB2 L-type calcium channel 2 subunit Loss of function, reduced Ca 2 current SQTS6 CACNA2D1 L-type calcium channel 1 subunit Loss of function, reduced Ca 2 current Catecholaminergic VT CPVT1 RyR2 Cardiac ryanodine receptor (RyR2) Gain of function, diastolic Ca 2 release from SR CPVT2 CASQ2 Cardiac calsequestrin (CASQ2) Loss of SR Ca 2 buffering capacity VT indicates ventricular tachycardia; SR, sarcoplasmic reticulum. known genes, with the exception of specific malignant cases, and raises the possibility that, by limiting genetic testing to the better-characterized genes, we could reduce costs and decrease the percentage of mutations interpreted as being variants of unknown significance. 21 Pharmacological Therapy Based on Mechanisms The evidence of incomplete effectiveness of -blockers has stimulated the search for alternative therapeutic strategies. The so-called gene-specific therapies are centered on the idea that it is possible to counteract the biophysical effects of a mutation with the use of targeted drugs. Although bench work has suggested several plausible corrective approaches, only a few have become part of clinical management. Potassium supplements shorten QT interval by increasing the repolarizing potassium current I Kr that is inversely regulated by the concentration of extracellular potassium. This approach has been proposed for LQT2, although it has the potential to shorten QT interval in all patients with at least 1 KCNH2 wild-type (functional) allele. Mexiletine was shown in cellular models of LQT3 to normalize action potential duration. 35 When tested in LQT3 patients, a shortening of QT interval was found in some of the mutation carriers. Of note, the effectiveness of mexiletine may be mutation specific 36 and may even cause further QT prolongation. 37 Thus, its use should be weighted and monitored very carefully. Channelopathies Associated With Abbreviated Repolarization and Conduction Defects As outlined in the previous section, LQTS is caused by a loss-of-function mutation in a channel that conducts a repolarizing current and a gain-of-function mutation in a channel that carries a depolarizing current. When the opposite effects occur, mutations cause completely different diseases such as Brugada syndrome (BrS), short-qt syndrome, early repolarization syndrome, sinus node dysfunction, and progressive conduction defects. Combinations of the above-mentioned phenotypes (eg, BrS plus conduction defect or BrS plus short QT interval) may also occur in the so-called overlap syndromes. 10 BrS: Definition and Pathophysiology BrS is characterized by ST-segment elevation with coved morphology in the right precordial leads and complete or incomplete right bundle-branch block. This ECG pattern is intermittent and may be unmasked by pharmacological challenge with sodium channel blockers such as procainamide, flecainide, ajmaline, or pilsicainide. The onset of ventricular arrhythmias causes the occurrence of syncope and may lead to sudden death, usually at rest. Known triggers for arrhythmic events are fever and the consumption of large meals; the latter has been related to glucose-induced insulin secretion that might enhance ST-segment elevation. 38 The electrophysiological mechanisms of BrS are still not completely known. It has been suggested that the arrhythmogenic substrate is due to the altered balance of inward and outward currents that is too much in favor of the latter in the early action potential phases (mainly during phase 1, loss of action potential dome), particularly in the epicardial layers. This selective action potential shortening increases transmural dispersion and favors reentry. 39 Ten different genes causally linked to BrS have been reported (Table 4). Loss-of-function mutations of SCN5A (BrS1), the gene encoding for the cardiac sodium channel, were the first to be identified, and this gene is currently the only BrS key gene. 21 Reduced sodium current and a BrS phenotype can be also due to mutations in SCN5A-regulating genes: GPD1-L, SCN1B, and SCN3B (Table 4). 40,41 Loss-of-

5 Napolitano et al Genetics and Mechanisms of Ion Channelopathies 2031 Figure 3. Absolute and annual event rate in the major Brugada syndrome registries. function mutations in the CACNA1c and CACNB2 genes encoding for the and subunits of the cardiac calcium channel can also cause BrS and may represent the second most frequent cause of the disease. 42 Overall, no more than 30% of the genetic tests sent to genotyping facilities turn out positive for a disease-causing mutation. 21 Management and Role of Genetics Management of BrS is based on the use of ICD in selected high-risk individuals. No drug has been definitely proven effective in reducing the cardiac arrest burden. It is therefore clear that risk assessment is a key issue in this condition to tailor the use of ICD therapy. Recent data in large series of patients confirmed our initial observation 43 that the disease is less aggressive than initially thought and showed an annual incidence of cardiac arrest between 1%/y and 2%/y 44,45 (Figure 3). Of note, the event rate is time dependent with events peaking in the third to fourth decade of life (Figure 4). The presence of a spontaneous type 1 ECG (ie, no need for drug challenge to make the diagnosis) together with history of syncope consistently identifies subjects who warrant an ICD. Additional risk factors may be represented by QRS fragmentation 45,46 and short ventricular refractory period, but this evidence awaits confirmation. Inducibility of ventricular tachycardia/ventricular fibrillation at programmed electric stimulation has been a matter Figure 4. Relative percentage of symptomatic Brugada syndrome patients by age clusters showing a peak of incidence in the third and fourth decades of life (data from the Pavia Brugada syndrome registry). of debate for several years, and the most recent large series and controlled studies dismiss its predictive role. 44,45 Genotype-phenotype correlation is scanty in BrS. It has been reported that SCN5A mutations are associated with a high incidence of conduction abnormalities 47 and that those leading to truncated proteins might be more malignant 48 ; the carriers of CACNA1C mutations may have an abbreviated repolarization. 42 At present however, there is no robust algorithm to link BrS genotype with either a specific phenotype or a distinctive risk profile. As a consequence, genetic testing cannot guide therapeutic decisions. We believe that, analogous to LQTS, the practice of unsupervised genetic screening of all known genes is a nontrivial pitfall. Indeed, adopting systematic screening of new genes before there is adequate knowledge to establish whether a mutation is truly causative for the disease may lead to the impossibility of using the results for clinical purposes. The appropriateness of this practice may require a reappraisal. 21 Pharmacological Therapy Based on Mechanisms The experimental observation that agents that inhibit the transient outward current (I Na and I to ) can restore the action potential dome in the epicardium and be antiarrhythmic by preventing the phase 2 reentry poses some rationale for the use of quinidine (a nonspecific I to blocker) to treat BrS patients. 49 Based on encouraging preliminary data, clinical trials are ongoing to test the value of quinidine to prevent sudden cardiac death in BrS ( identifier, NCT ). Several other pharmacological approaches have been proposed, but none has found clinical applicability so far. 50 Short-QT Syndrome Short-QT syndrome is described as a disorder characterized by abbreviated QT interval, ventricular and atrial arrhythmias, and sudden cardiac death. There have been 70 short-qt syndrome cases reported worldwide, with the mean QTc value in the entire population of 310 milliseconds (The upper limit set by the majority of groups is between 340 and 350 milliseconds). Symptomatic (sudden death or cardiac arrest) individuals, accounting for 25% of the total, tend to present with shorter QTc (average, 300 milliseconds). 51 Mutations in 6 genes have been identified (Table 4 and Figure 1), but they account for only a few families each. The proportion of patients with short QT who are successfully genotyped is unknown, and no single gene accounts for 5% of cases. Therefore, the value of genetic testing in the syndrome is limited and does not bear prognostic implications. 52 Data on a limited cohort of patients suggest that carriers of KCNH2 mutations may present with shorter QT interval. 52 Risk stratification and management of short-qt syndrome are still ill defined. Analogous to other inherited channelopathies, it is likely that the severity of the ECG phenotype is related to prognosis (ie, the shorter the QT intervals, the higher the risk). Quinidine can normalize the QT interval, but its long-term efficacy is not proven. Therefore, an ICD is the only way to prevent sudden death.

6 2032 Circulation April 24, 2012 Figure 5. Top, Flecainide abolished triggered activity induced by isoproterenol (Iso) but not delayed afterdepolarizations in the catecholaminergic polymorphic ventricular tachycardia mouse model RyR2-R4496C in a reversible manner (arrows indicate field stimulation). The inhibition of triggered activity is likely due to reduced excitability, as depicted in the graphs on the bottom, which show the lowest current required to induce an action potential before and after flecainide. Flecainide significantly increased the threshold for current induced action potential. 61 Channelopathies Associated With Abnormal Calcium Handling Catecholaminergic polymorphic ventricular tachycardia (CPVT) was described in the 1970s. Patients present unremarkable resting ECG and a peculiar pattern of ventricular arrhythmias (bidirectional or polymorphic ventricular tachycardia) reproducibly triggered by exercise or acute emotion. CPVT is characterized by a high incidence of cardiac events among untreated patients (79% in patients up to 40 years of age) and 30% incidence of sudden cardiac death. 53,54 Investigations directed to disclose the molecular basis of CPVT led to the identification of mutations of 2 genes, the ryanodine receptor RyR2 55 and the cardiac calsequestrin CASQ2, 56 which are associated with the autosomal dominant and recessive forms of CPVT, respectively (Table 4 and Figure 1). Both genes are involved in the control of calcium release from the sarcoplasmic reticulum (SR): RyR2 is the SR calcium-releasing channel, and CASQ2 is a calciumbuffering protein in the SR that may also exert a regulatory function of RyR2. CPVT mutations lead to a loss of calcium release inhibition from the SR during diastole. As a consequence, when SR calcium content augments adrenergic activation, it drives a pathological increase in Ca 2 release (leak) that leads to delayed afterdepolarization and triggered activity. 57 Approximately 60% of CPVT individuals carry an RyR2 mutation. Although no prognostic value is linked to specific RyR2 mutations, the value of genotyping resides in the importance of extending genetic screening to family members to identify and protect mutation carriers with antiadrenergic therapy because -blockers are effective. Pharmacological Therapy Based on Mechanisms When a CPVT diagnosis is established, -blockers should be administered. Although this approach affords protection in the majority of patients, 30% experience at least 1 arrhythmic event while on therapy. 53,58,59 In these cases, an ICD may be indicated. Watanabe et al 60 recently showed that flecainide was able to suppress arrhythmias and triggered activity in a CPVT mouse model. This effect was explained by the ability of flecainide to directly modulate the ryanodine receptor. We recently performed additional investigations on the antiarrhythmic effect of flecainide 61 in our RyR2-R4496C CPVT mouse model that support an alternative explanation. This study collected data suggesting that flecainide does not abolish delayed afterdepolarizations, ie, SR leak, but it prevents triggered activity because of its ability to block sodium current and to raise the threshold for action potential triggering by delayed afterdepolarizations (Figure 5). Despite these discordant results, data supporting the clinical value of flecainide are accumulating; therefore, the drug may be regarded as a reasonable adjunctive treatment of recurrences of arrhythmias while the patient is on -blockers. Concluding Remarks: Future Development Thanks to the work of several groups, the community has witnessed a remarkable growth of the awareness of inherited arrhythmogenic disease. The role of these conditions as key determinants of juvenile sudden death is now largely recognized. Currently, there is a large gap between the clinically useful information that we may derive from genetic testing of the more prevalent variants and the scant insight provided by the screening of rare genetic forms that account for 1% to 5% of all cases. Accordingly, the prediction of clinical outcome based on the identification of rare DNA variants is difficult and may even be unrealistic if gathering an adequate number of patients to allow meaningful conclusions is proved to be impossible. Grouping patients under functionally homogeneous variants (eg, all patients with mutations producing a loss of sodium current) may represent a way to overcome this limitation. This approach should be flanked by highthroughput genotyping technology, providing comprehensive coverage of analyzed genes and identifying modifier singlenucleotide polymorphisms affecting outcome. The goal for the future is to fulfill the transition from a population-based management to personalized therapeutic strategies. Acknowledgments We thankfully acknowledge Jessica Wilson for careful revising and editing of the manuscript. Sources of Funding Many of the data presented here have been produced thanks to the contribution of the following research grants: Telethon grants

7 Napolitano et al Genetics and Mechanisms of Ion Channelopathies 2033 GGP04066 and GGP06007; Italian University Research and Technology Ministry FIRB (Fondo Italiano Ricerca di Base) RBNE01XMP4 006 and RFMAU D; a Fondation Leducq Award to the Alliance for Calmodulin Kinase Signaling in Heart Disease (08CVD01); and a Fondazione Veronesi Award on inherited arrhythmogenic diseases. None. Disclosures References 1. Bowker TJ, Wood DA, Davies MJ, Shepard MN, Cary NRB, Hobson HL, Burton JDK, Chambers DR, Dawilng S, Riemerma RA, Pyke SDM, Thompson SD. A national survey of sudden unexpected cardiac or unexplained death in adults (SADS). Heart. 1996;75: Corrado D, Basso C, Thiene G. Sudden cardiac death in young people with apparently normal heart. Cardiovasc Res. 2001;50: Puranik R, Chow CK, Duflou JA, Kilborn MJ, McGuire MA. Sudden death in the young. Heart Rhythm. 2005;2: Survivors of out-of-hospital cardiac arrest with apparently normal heart: need for definition and standardized clinical evaluation: consensus statement of the Joint Steering Committees of the Unexplained Cardiac Arrest Registry of Europe and of the Idiopathic Ventricular Fibrillation Registry of the United States. Circulation. 1997;95: Priori SG, Borggrefe M, Camm AJ, Hauer RN, Klein H, Kuck KH, Schwartz PJ, Touboul P, Wellens HJ. Unexplained cardiac arrest: the need for a prospective registry. Eur Heart J. 1992;13: Curran ME, Splawski I, Timothy KW, Vincent GM, Green ED, Keating MT. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell. 1995;80: Wang Q, Shen J, Splawski I, Atkinson D, Li Z, Robinson JL, Moss AJ, Towbin JA, Keating MT. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell. 1995;80: Wang Q, Curran ME, Splawski I, Burn TC, Millholland JM, VanRaay TJ, Shen J, Timothy KW, Vincent GM, de Jager T, Schwartz PJ, Towbin JA, Moss AJ, Atkinson DL, Landes GM, Connors TD, Keating MT. Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat Genet. 1996;12: Priori SG, Napolitano C, Schwartz PJ. Low penetrance in the long-qt syndrome: clinical impact. Circulation. 1999;99: Priori SG, Napolitano C. Genetics of channelopathies and clinical implications. In: Fuster V, Walsh RA, Harrington RA, eds. Hurst s The Heart. 13th ed. New York, NY: McGraw Hill; 2011: Napolitano C, Priori SG, Schwartz PJ, Bloise R, Ronchetti E, Nastoli J, Bottelli G, Cerrone M, Leonardi S. Genetic testing in the long QT syndrome: development and validation of an efficient approach to genotyping in clinical practice. JAMA. 2005;294: Goldenberg I, Horr S, Moss AJ, Lopes CM, Barsheshet A, McNitt S, Zareba W, Andrews ML, Robinson JL, Locati EH, Ackerman MJ, Benhorin J, Kaufman ES, Napolitano C, Platonov PG, Priori SG, Qi M, Schwartz PJ, Shimizu W, Towbin JA, Vincent GM, Wilde AA, Zhang L. Risk for life-threatening cardiac events in patients with genotypeconfirmed long-qt syndrome and normal-range corrected QT intervals. J Am Coll Cardiol. 2011;57: Skinner JR, Crawford J, Smith W, Aitken A, Heaven D, Evans CA, Hayes I, Neas KR, Stables S, Koelmeyer T, Denmark L, Vuletic J, Maxwell F, White K, Yang T, Roden DM, Leren TP, Shelling A, Love DR. Prospective, population-based long QT molecular autopsy study of postmortem negative sudden death in 1 to 40 year olds. Heart Rhythm. 2011;8: Chugh SS, Senashova O, Watts A, Tran PT, Zhou Z, Gong Q, Titus JL, Hayflick SJ. Postmortem molecular screening in unexplained sudden death. J Am Coll Cardiol. 2004;43: Tester DJ, Spoon DB, Valdivia HH, Makielski JC, Ackerman MJ. Targeted mutational analysis of the RyR2-encoded cardiac ryanodine receptor in sudden unexplained death: a molecular autopsy of 49 medical examiner/coroner s cases. Mayo Clin Proc. 2004;79: Tester DJ, Ackerman MJ. Postmortem long QT syndrome genetic testing for sudden unexplained death in the young. J Am Coll Cardiol. 2007;49: Ackerman MJ, Siu BL, Sturner WQ, Tester DJ, Valdivia CR, Makielski JC, Towbin JA. Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome. JAMA. 2001;286: Otagiri T, Kijima K, Osawa M, Ishii K, Makita N, Matoba R, Umetsu K, Hayasaka K. Cardiac ion channel gene mutations in sudden infant death syndrome. Pediatr Res. 2008;64: Arnestad M, Crotti L, Rognum TO, Insolia R, Pedrazzini M, Ferrandi C, Vege A, Wang DW, Rhodes TE, George AL Jr, Schwartz PJ. Prevalence of long-qt syndrome gene variants in sudden infant death syndrome. Circulation. 2007;115: Tester DJ, Ackerman MJ. Sudden infant death syndrome: how significant are the cardiac channelopathies? Cardiovasc Res. 2005;67: Ackerman MJ, Priori SG, Willems S, Berul C, Brugada R, Calkins H, Camm AJ, Ellinor PT, Gollob M, Hamilton R, Hershberger RE, Judge DP, Le Marec H, McKenna WJ, Schulze-Bahr E, Semsarian C, Towbin JA, Watkins H, Wilde A, Wolpert C, Zipes DP. HRS/EHRA Expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies: this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Europace. 2011;13: McNair WP, Sinagra G, Taylor MR, Di Lenarda A, Ferguson DA, Salcedo EE, Slavov D, Zhu X, Caldwell JH, Mestroni L. SCN5A mutations associate with arrhythmic dilated cardiomyopathy and commonly localize to the voltage-sensing mechanism. J Am Coll Cardiol. 2011;57: Shimizu W, Noda T, Takaki H, Kurita T, Nagaya N, Saura D, Suyama K, Aihara N, Kamakura S, Sunagawa K, Echigo K, Nakamura K, Ohe T, Towbin JA, Napolitano C, Priori SG. Epinephrine unmasks latent mutation carriers with LQT1 form of congenital long-qt syndrome. JAm Coll Cardiol. 2003;41: Lane RD, Zareba W, Reis HT, Peterson DR, Moss AJ. Changes in ventricular repolarization duration during typical daily emotion in patients with long QT syndrome. Psychosom Med. 2010;73: Hekkala AM, Viitasalo M, Vaananen H, Swan H, Toivonen L. Abnormal repolarization dynamics revealed in exercise test in long QT syndrome mutation carriers with normal resting QT interval. Europace. 2010;12: Priori SG, Napolitano C, Schwartz PJ, Grillo M, Bloise R, Ronchetti E, Moncalvo C, Tulipani C, Veia A, Bottelli G, Nastoli J. Association of long QT syndrome loci and cardiac events among patients treated with beta-blockers. JAMA. 2004;292: Vincent GM, Schwartz PJ, Denjoy I, Swan H, Bithell C, Spazzolini C, Crotti L, Piippo K, Lupoglazoff JM, Villain E, Priori SG, Napolitano C, Zhang L. High efficacy of beta-blockers in long-qt syndrome type 1: contribution of noncompliance and QT-prolonging drugs to the occurrence of beta-blocker treatment failures. Circulation. 2009;119: Schwartz PJ, Priori SG, Cerrone M, Spazzolini C, Odero A, Napolitano C, Bloise R, De Ferrari GM, Klersy C, Moss AJ, Zareba W, Robinson JL, Hall WJ, Brink PA, Toivonen L, Epstein AE, Li C, Hu D. Left cardiac sympathetic denervation in the management of high-risk patients affected by the long-qt syndrome. Circulation. 2004;109: Priori SG, Schwartz PJ, Napolitano C, Bloise R, Ronchetti E, Grillo M, Vicentini A, Spazzolini C, Nastoli J, Bottelli G, Folli R, Cappelletti D. Risk stratification in the long-qt syndrome. N Engl J Med. 2003;348: Moss AJ, Shimizu W, Wilde AAM, Towbin JA, Zareba W, Robinson JL, Qi M, Vincent GM, Ackerman MJ, Kaufman ES, Hofman N, Seth R, Kamakura S, Miyamoto Y, Goldenberg I, Andrews ML, McNitt S. Clinical aspects of type-1 long-qt syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene. Circulation. 2007;115: Jons C, Moss AJ, Lopes CM, McNitt S, Zareba W, Goldenberg I, Qi M, Wilde AA, Shimizu W, Kanters JK, Towbin JA, Ackerman MJ, Robinson JL. Mutations in conserved amino acids in the KCNQ1 channel and risk of cardiac events in type-1 long-qt syndrome. J Cardiovasc Electrophysiol. 2009;20: Goldenberg I, Thottathil P, Lopes CM, Moss AJ, McNitt S, O-Uuchi J, Robinson JL, Zareba W, Ackerman MJ, Kaufman ES, Towbin JA, Vincent M, Barsheshet A. Trigger-specific ion-channel mechanisms, risk factors, and response to therapy in type 1 long QT syndrome. Heart Rhythm. 2012;9: Pfeufer A, Sanna S, Arking DE, Muller M, Gateva V, Fuchsberger C, Ehret GB, Orru M, Pattaro C, Kottgen A, Perz S, Usala G, Barbalic M, Li M, Putz B, Scuteri A, Prineas RJ, Sinner MF, Gieger C, Najjar SS, Kao WH, Muhleisen TW, Dei M, Happle C, Mohlenkamp S, Crisponi L, Erbel R, Jockel KH, Naitza S, Steinbeck G, Marroni F, Hicks AA, Lakatta E, Muller-Myhsok B, Pramstaller PP, Wichmann HE, Schlessinger D, Boer-

8 2034 Circulation April 24, 2012 winkle E, Meitinger T, Uda M, Coresh J, Kaab S, Abecasis GR, Chakravarti A. Common variants at ten loci modulate the QT interval duration in the QTSCD Study. Nat Genet. 2009;41: Tomas M, Napolitano C, De Giuli L, Bloise R, Subirana I, Malovini A, Bellazzi R, Arking DE, Marban E, Chakravarti A, Spoon DB, Priori SG. Polymorphisms in the NOS1AP gene modulate QT interval duration and risk of arrhythmias in the long QT syndrome. J Am Coll Cardiol. 2010; 55: Priori SG, Napolitano C, Cantu F, Brown AM, Schwartz PJ. Differential response to Na channel blockade, beta-adrenergic stimulation, and rapid pacing in a cellular model mimicking the SCN5A and HERG defects present in the long-qt syndrome. Circ Res. 1996;78: Ruan Y, Liu N, Bloise R, Napolitano C, Priori SG. Gating properties of SCN5A mutations and the response to mexiletine in long-qt syndrome type 3 patients. Circulation. 2007;116: Ruan Y, Denegri M, Liu N, Bachetti T, Seregni M, Morotti S, Severi S, Napolitano C, Priori SG. Trafficking defects and gating abnormalities of a novel SCN5A mutation question gene-specific therapy in long QT syndrome type 3. Circ Res. 2010;106: Nishizaki M, Sakurada H, Mizusawa Y, Niki S, Hayashi T, Tanaka Y, Maeda S, Fujii H, Ashikaga T, Yamawake N, Isobe M, Hiraoka M. Influence of meals on variations of ST segment elevation in patients with Brugada syndrome. J Cardiovasc Electrophysiol. 2008;19: Antzelevitch C, Brugada P, Borggrefe M, Brugada J, Brugada R, Corrado D, Gussak I, LeMarec H, Nademanee K, Perez Riera AR, Shimizu W, Schulze-Bahr E, Tan H, Wilde A. Brugada syndrome: report of the Second Consensus Conference: endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Circulation. 2005;111: Watanabe H, Darbar D, Kaiser DW, Jiramongkolchai K, Chopra S, Donahue BS, Kannankeril PJ, Roden DM. Mutations in sodium channel beta1 and beta2 subunits associated with atrial fibrillation. Circ Arrhythm Electrophysiol. 2009;2: London B, Michalec M, Mehdi H, Zhu X, Kerchner L, Sanyal S, Viswanathan PC, Pfahnl AE, Shang LL, Madhusudanan M, Baty CJ, Lagana S, Aleong R, Gutmann R, Ackerman MJ, McNamara DM, Weiss R, Dudley SC Jr. Mutation in glycerol-3-phosphate dehydrogenase 1 like gene (GPD1-L) decreases cardiac Na current and causes inherited arrhythmias. Circulation. 2007;116: Napolitano C, Antzelevitch C. Phenotypical manifestations of mutations in the genes encoding subunits of the cardiac voltage-dependent L-type calcium channel. Circ Res. 2011;108: Priori SG, Napolitano C, Gasparini M, Pappone C, Bella PD, Giordano U, Bloise R, Giustetto C, De Nardis R, Grillo M, Ronchetti E, Faggiano G, Nastoli J. Natural history of Brugada syndrome: insights for risk stratification and management. Circulation. 2002;105: Probst V, Veltmann C, Eckardt L, Meregalli PG, Gaita F, Tan HL, Babuty D, Sacher F, Giustetto C, Schulze-Bahr E, Borggrefe M, Haissaguerre M, Mabo P, Le Marec H, Wolpert C, Wilde AA. Long-term prognosis of patients diagnosed with Brugada syndrome: results from the FINGER Brugada Syndrome Registry. Circulation. 2010;121: Priori S, Gasparini M, Napolitano C, Della Bella P, Ghidini Ottonelli A, Sassone B, Giordano U, Pappone C, Mascioli G, Rossetti G, De Nardis R, Colombo M. Risk stratification in Brugada Syndrome: results of the PRELUDE (PRogrammed ELectrical stimulation predictive value) Registry. J Am Coll Cardiol. 2012;59: Morita H, Kusano KF, Miura D, Nagase S, Nakamura K, Morita ST, Ohe T, Zipes DP, Wu J. Fragmented QRS as a marker of conduction abnormality and a predictor of prognosis of Brugada syndrome. Circulation. 2008;118: Probst V, Allouis M, Sacher F, Pattier S, Babuty D, Mabo P, Mansourati J, Victor J, Nguyen JM, Schott JJ, Boisseau P, Escande D, Le Marec H. Progressive cardiac conduction defect is the prevailing phenotype in carriers of a Brugada syndrome SCN5A mutation. J Cardiovasc Electrophysiol. 2006;17: Meregalli PG, Tan HL, Probst V, Koopmann TT, Tanck MW, Bhuiyan ZA, Sacher F, Kyndt F, Schott JJ, Albuisson J, Mabo P, Bezzina CR, Le Marec H, Wilde AA. Type of SCN5A mutation determines clinical severity and degree of conduction slowing in loss-of-function sodium channelopathies. Heart Rhythm. 2009;6: Shimizu W, Aiba T, Antzelevitch C. Specific therapy based on the genotype and cellular mechanism in inherited cardiac arrhythmias: long QT syndrome and Brugada syndrome. Curr Pharm Des. 2005;11: Ruan Y, Liu N, Priori SG. Sodium channel mutations and arrhythmias. Nat Rev Cardiol. 2009;6: Gollob MH, Redpath CJ, Roberts JD. The short QT syndrome: proposed diagnostic criteria. J Am Coll Cardiol. 2011;57: Giustetto C, Schimpf R, Mazzanti A, Scrocco C, Maury P, Anttonen O, Probst V, Blanc JJ, Sbragia P, Dalmasso P, Borggrefe M, Gaita F. Long-term follow-up of patients with short QT syndrome. J Am Coll Cardiol. 2011;58: Priori SG, Napolitano C, Memmi M, Colombi B, Drago F, Gasparini M, DeSimone L, Coltorti F, Bloise R, Keegan R, Cruz Filho FE, Vignati G, Benatar A, DeLogu A. Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia. Circulation. 2002;106: Cerrone M, Napolitano C, Priori SG. Catecholaminergic polymorphic ventricular tachycardia: a paradigm to understand mechanisms of arrhythmias associated to impaired Ca(2 ) regulation. Heart Rhythm. 2009;6: Priori SG, Napolitano C, Tiso N, Memmi M, Vignati G, Bloise R, Sorrentino V, Danieli GA. Mutations in the cardiac ryanodine receptor gene (hryr2) underlie catecholaminergic polymorphic ventricular tachycardia. Circulation. 2001;103: Lahat H, Pras E, Olender T, Avidan N, Ben Asher E, Man O, Levy- Nissenbaum E, Khoury A, Lorber A, Goldman B, Lancet D, Eldar M. A missense mutation in a highly conserved region of CASQ2 is associated with autosomal recessive catecholamine-induced polymorphic ventricular tachycardia in Bedouin families from Israel. Am J Hum Genet. 2001;69: Priori SG, Chen SR. Inherited dysfunction of sarcoplasmic reticulum Ca 2 handling and arrhythmogenesis. Circ Res. 2011;108: Postma AV, Denjoy I, Kamblock J, Alders M, Lupoglazoff JM, Vaksmann G, Dubosq-Bidot L, Sebillon P, Mannens MM, Guicheney P, Wilde AA. Catecholaminergic polymorphic ventricular tachycardia: RYR2 mutations, bradycardia, and follow up of the patients. J Med Genet. 2005;42: Sy RW, Gollob MH, Klein GJ, Yee R, Skanes AC, Gula LJ, Leong-Sit P, Gow RM, Green MS, Birnie DH, Krahn AD. Arrhythmia characterization and long-term outcomes in catecholaminergic polymorphic ventricular tachycardia. Heart Rhythm. 2011;8: Watanabe H, Chopra N, Laver D, Hwang HS, Davies SS, Roach DE, Duff HJ, Roden DM, Wilde AA, Knollmann BC. Flecainide prevents catecholaminergic polymorphic ventricular tachycardia in mice and humans. Nat Med. 2009;15: Liu N, Denegri M, Ruan Y, Avelino-Cruz JE, Perissi A, Negri S, Napolitano C, Coetzee WA, Boyden PA, Priori SG. Short communication: flecainide exerts an antiarrhythmic effect in a mouse model of catecholaminergic polymorphic ventricular tachycardia by increasing the threshold for triggered activity. Circ Res. 2011;109: KEY WORDS: arrhythmias, cardiac genetics, Brugada syndrome heart ventricles long QT syndrome mutation