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Background: Mutations in desmoplakin ( DSP ), the primary force transducer between cardiac desmosomes and intermediate filaments, cause an arrhythmogenic form of cardiomyopathy that has been variably associated with arrhythmogenic right ventricular cardiomyopathy. Clinical correlates of DSP cardiomyopathy have been limited to small case series. Methods: Clinical and genetic data were collected on 107 patients with pathogenic DSP mutations and 81 patients with pathogenic plakophilin 2 ( PKP2 ) mutations as a comparison cohort. A composite outcome of severe ventricular arrhythmia was assessed. Results: DSP and PKP2 cohorts included similar proportions of probands (41% versus 42%) and patients with truncating mutations (98% versus 100%). Left ventricular (LV) predominant cardiomyopathy was exclusively present among patients with DSP (55% versus 0% for PKP2 , P DSP versus 40% for PKP2 ( P DSP cardiomyopathy. LV late gadolinium enhancement was present in a primarily subepicardial distribution in 40% of patients with DSP (23/57 with magnetic resonance images). LV late gadolinium enhancement occurred with normal LV systolic function in 35% (8/23) of patients with DSP . Episodes of acute myocardial injury (chest pain with troponin elevation and normal coronary angiography) occurred in 15% of patients with DSP and were strongly associated with LV late gadolinium enhancement (90%), even in cases of acute myocardial injury with normal ventricular function (4/5, 80% with late gadolinium enhancement). In 4 DSP cases with 18F-fluorodeoxyglucose positron emission tomography scans, acute LV myocardial injury was associated with myocardial inflammation misdiagnosed initially as cardiac sarcoidosis or myocarditis. Left ventricle ejection fraction DSP cases ( P PKP2 cases ( P DSP cases ( P =0.8). Frequent premature ventricular contractions were common among patients with severe arrhythmias for both DSP (80%) and PKP2 (91%) groups ( P =non-significant). Conclusions: DSP cardiomyopathy is a distinct form of arrhythmogenic cardiomyopathy characterized by episodic myocardial injury, left ventricular fibrosis that precedes systolic dysfunction, and a high incidence of ventricular arrhythmias. A genotype-specific approach for diagnosis and risk stratification should be used.

Background— The role of programmed ventricular stimulation in identifying patients with Brugada syndrome at the highest risk for sudden death is uncertain. Methods and Results— We performed a systematic review and pooled analysis of prospective, observational studies of patients with Brugada syndrome without a history of sudden cardiac arrest who underwent programmed ventricular stimulation. We estimated incidence rates and relative hazards of cardiac arrest or implantable cardioverter-defibrillator shock. We analyzed individual-level data from 8 studies comprising 1312 patients who experienced 65 cardiac events (median follow-up, 38.3 months). A total of 527 patients were induced into arrhythmias with up to triple extrastimuli. Induction was associated with cardiac events during follow-up (hazard ratio, 2.66; 95% confidence interval [CI], 1.44–4.92, P Conclusions— In patients with Brugada syndrome, arrhythmias induced with programmed ventricular stimulation are associated with future ventricular arrhythmia risk. Induction with fewer extrastimuli is associated with higher risk. However, clinical risk factors are important determinants of arrhythmia risk, and lack of induction does not necessarily portend low ventricular arrhythmia risk, particularly in patients with high-risk clinical features.

Background: Short QT Syndrome (SQTS) is one of the rarest and most lethal inherited arrhythmogenic syndromes. Preliminary data have shown that hydroquinidine (HQ) is effective in prolonging the duration of QT interval and in preventing the induction of ventricular arrhythmias during programmed electrical stimulation in SQTS patients. No data exist regarding the efficacy of HQ in reducing cardiac events in SQTS patients. Objective: To determine whether HQ reduces the occurrence of Life-threatening Arrhythmic Events (LAE), defined as aborted cardiac arrest and sudden cardiac death, in SQTS patients. Methods: Cohort study on consecutive SQTS patients referred to our center and treated with HQ. The endpoint was to evaluate the antiarrhythmic efficacy of HQ, by comparing the percentage of patients with LAE, the number of LAE per patient and the annual rate of LAE before and after the beginning of therapy with HQ (mean duration of therapy 6±1 years). Results: The study population was comprised of 17 SQTS patients with the following characteristics: 13 (76%) males, age at beginning of therapy with HQ 29±3 years, QTc interval before treatment 331±3 ms. Therapy with HQ was ceased in 2 cases (12%) after 1 week due to gastrointestinal intolerance, while in the remaining 15 patients HQ was administered continuously for 6±1 years, at an average dose of 528±42 mg per day (7±0.6 mg/kg/day). HQ significantly prolonged the QTc interval in all patients, by a mean of 60±6 ms (p Conclusions: We showed for the first time that HQ, besides normalizing the duration of the QT interval, is associated with a major reduction of life-threatening arrhythmic events in SQTS patients, thus representing an efficacious therapeutic approach in this group of individuals. Early discontinuation due to gastrointestinal intolerance occurred in 12% of patients.

Background— β-Blocker efficacy in long-QT syndrome type 1 is good but variably reported, and the causes of cardiac events despite β-blocker therapy have not been ascertained. Methods and Results— This was a retrospective study of the details surrounding cardiac events in 216 genotyped long-QT syndrome type 1 patients treated with β-blocker and followed up for a median time of 10 years. Before β-blocker, cardiac events occurred in 157 patients (73%) at a median age of 9 years, with cardiac arrest (CA) in 26 (12%). QT-prolonging drugs were used by 17 patients; 9 of 17 (53%) had CA compared with 17 of 199 nonusers (8.5%; odds ratio, 12.0; 95% confidence interval, 4.1 to 35.3; P P P =0.001). None of the 26 patients with CA before β-blocker had CA/sudden death on β-blockers. Conclusions— β-Blockers are extremely effective in long-QT syndrome type 1 and should be administered at diagnosis and ideally before the preteen years. β-Blocker noncompliance and use of QT-prolonging drug are responsible for almost all life-threatening “β-blocker failures.” β-Blockers are appropriate therapy for asymptomatic patients and those who have never had a CA or β-blocker therapy. Routine implantation of cardiac defibrillators in such patients does not appear justified.

Background— Brugada syndrome (BrS) primarily associates with the loss of sodium channel function. Previous studies showed features consistent with sodium current ( I Na ) deficit in patients carrying desmosomal mutations, diagnosed with arrhythmogenic cardiomyopathy (or arrhythmogenic right ventricular cardiomyopathy). Experimental models showed correlation between the loss of expression of desmosomal protein plakophilin-2 (PKP2) and reduced I Na . We hypothesized that PKP2 variants that reduce I Na could yield a BrS phenotype, even without overt structural features characteristic of arrhythmogenic right ventricular cardiomyopathy. Methods and Results— We searched for PKP2 variants in the genomic DNA of 200 patients with a BrS diagnosis, no signs of arrhythmogenic cardiomyopathy, and no mutations in BrS-related genes SCN5A, CACNa1c, GPD1L , and MOG1. We identified 5 cases of single amino acid substitutions. Mutations were tested in HL-1–derived cells endogenously expressing Na V 1.5 but made deficient in PKP2 (PKP2-KD). Loss of PKP2 caused decreased I Na and Na V 1.5 at the site of cell contact. These deficits were restored by the transfection of wild-type PKP2, but not of BrS-related PKP2 mutants. Human induced pluripotent stem cell cardiomyocytes from a patient with a PKP2 deficit showed drastically reduced I Na . The deficit was restored by transfection of wild type, but not BrS-related PKP2. Super-resolution microscopy in murine PKP2-deficient cardiomyocytes related I Na deficiency to the reduced number of channels at the intercalated disc and increased separation of microtubules from the cell end. Conclusions— This is the first systematic retrospective analysis of a patient group to define the coexistence of sodium channelopathy and genetic PKP2 variations. PKP2 mutations may be a molecular substrate leading to the diagnosis of BrS.

Objectives: To discover the role of altered gene expression regulation in Brugada Syndrome (BrS) and to find biomarkers for BrS diagnosis. Methods: Twenty-five control patients (Control), 25 BrS patients without SCN5A mutation (SCN5A(-)) and 20 BrS patients with SCN5A mutation (SCN5A(+)) were included in this study. Specified gene expression of white blood cells (WBC) were measured by RT-qPCR using TaqMan® Gene Expression assay. Results: MEF2C and MESP1 are the two major cardiac specific transcription factors expressed in WBC. The mRNA expression levels of SCN5A, MEF2C and HuR, one of mRNA stabilizers, were decreased in the SCN5A (+) group (P=0.047, 0.02, 0.000 vs. control group, respectively). The mRNA expression of MESP1 in WBCs was significantly lower in both SCN5A(-) (P=0.012 vs. control) and SCN5A(+) (P=0.000 vs. control) groups. There was no difference between the two BrS groups in MESP1 expression (P=0.215). The area under the Receiver Operating Characteristics (ROC) analysis curve for prediction of BrS using MESP1 levels was 0.775 (95% CI 0.668, 0.882, asymptotic Sig.=0.000). At the optimal cutoff, the corresponding maximum sensitivity and specificity were 0.62 (95% CI: 0.47, 0.76) and 0.88 (0.69, 0.97), respectively. The diagnostic odds ratio (DOR) of MESP1 for BrS diagnosis was 11.96 (95% CI: 5.79, 24.73). The assessment of the mRNA levels in blood SCN5A, MEF2C and HuR were useful for predicting BrS patients with an SCN5A mutation. The area under the ROC analysis curve for prediction of BrS with an SCN5A mutation using SCN5A, MEF2C and HuR mRNA levels in WBCs was 0.847 (95% CI 0.752, 0.942, asymptotic Sig.=0.000), 0.685 (95% CI 0.542, 0.828, asymptotic Sig.=0.016) and 0.777 (95% CI 0.652, 0.902, asymptotic Sig.=0.000), respectively. At the optimal cutoff, the DOR of SCN5A, MEF2C and HuR for SCN5A(+) BrS diagnosis was 17.5 (95% CI: 8.06, 37.86), 4.9 (95% CI: 2.61, 9.17) and 23.5 (95% CI: 9.39, 58.80), respectively. Conclusions: Our results suggest that assessment of circulating MESP1 may be used as a biomarker for BrS diagnosis while decreased SCN5A, MEF2C and HuR mRNA in WBCs is associated with BrS patients with an SCN5A mutation. Our results also suggest that decreased expression of SCN5A, MEF2C, MESP1, and HuR may be pathophysiologically related to BrS.

Myocardial infarction is a major cause of death and disability worldwide. Coronary atherosclerosis is a chronic disease with stable and unstable periods. During unstable periods with activated inflammation in the vascular wall, patients may develop a myocardial infarction. Myocardial infarction may be a minor event in a lifelong chronic disease, it may even go undetected, but it may also be a major catastrophic event leading to sudden death or severe hemodynamic deterioration. A myocardial infarction may be the first manifestation of coronary artery disease, or it may occur, repeatedly, in patients with established disease. Information on myocardial infarction attack rates can provide useful data regarding the burden of coronary artery disease within and across populations, especially if standardized data are collected in a manner that demonstrates the distinction between incident and recurrent events. From the epidemiological point of view, the incidence of myocardial infarction in a population can be used as a proxy for the prevalence of coronary artery disease in that population. Furthermore, the term myocardial infarction has major psychological and legal implications for the individual and society. It is an indicator of one of the leading health problems in the world, and it is an outcome measure in clinical trials and observational studies. With these perspectives, myocardial infarction may be defined from a number of different clinical, electrocardiographic, biochemical, imaging, and pathological characteristics. In the past, a general consensus existed for the clinical syndrome designated as myocardial infarction. In studies of disease prevalence, the World Health Organization (WHO) defined myocardial infarction from symptoms, ECG abnormalities, and enzymes. However, the development of more sensitive and specific serological biomarkers and precise imaging techniques allows detection of ever smaller amounts of myocardial necrosis. Accordingly, current clinical practice, health care delivery systems, as well as epidemiology and clinical trials all require a …

Background— Mexiletine (Mex) has been proposed as a gene-specific therapy for patients with long-QT syndrome type 3 (LQT3) caused by mutations in the cardiac sodium channel gene ( SCN5A ). The degree of QT shortening and the protection from arrhythmias vary among patients harboring different mutations. We tested whether the clinical response to Mex in LQT3 could be predicted by the biophysical properties of the different mutations. Methods and Results— We identified 4 SCN5A mutations in 5 symptomatic LQT3 patients with different responses to Mex (6 to 8 mg · kg −1 · d −1 ). We classified the mutations as sensitive to Mex (P1332L, R1626P; ≥10% of QTc shortening and QTc + current from HEK 293 cells transfected with wild-type (WT) or mutant Nav1.5. All mutations showed impaired inactivation of Na + current, but the mutations identified in patient responders to Mex (P1332L, R1626P) showed a hyperpolarizing shift of V 1/2 of steady-state inactivation. Furthermore, Mex produced use-dependent block with the order R1626P=P1332L>S941N=WT>M1652R, suggesting that Mex-sensitive mutants present prolonged recovery from Mex block. Conclusions— We propose that voltage dependence of channel availability and shifts of V 1/2 of steady-state inactivation correlate with the clinical response observed in LQT3 patients. This supports the view that the response to Mex is mutation specific and that in vitro testing may help to predict the response to therapy in LQT3.

Background —The ECG pattern of right bundle branch block and ST-segment elevation in leads V 1 to V 3 (Brugada syndrome) is associated with high risk of sudden death in patients with a normal heart. Current management and prognosis are based on a single study suggesting a high mortality risk within 3 years for symptomatic and asymptomatic patients alike. As a consequence, aggressive management (implantable cardioverter defibrillator) is recommended for both groups. Methods and Results —Sixty patients (45 males aged 40±15 years) with the typical ECG pattern were clinically evaluated. Events at follow-up were analyzed for patients with at least one episode of aborted sudden death or syncope of unknown origin before recognition of the syndrome (30 symptomatic patients) and for patients without previous history of events (30 asymptomatic patients). Prevalence of mutations of the cardiac sodium channel was 15%, demonstrating genetic heterogeneity. During a mean follow-up of 33±38 months, ventricular fibrillation occurred in 5 (16%) of 30 symptomatic patients and in none of the 30 asymptomatic patients. Programmed electrical stimulation was of limited value in identifying patients at risk (positive predictive value 50%, negative predictive value 46%). Pharmacological challenge with sodium channel blockers was unable to unmask most silent gene carriers (positive predictive value 35%). Conclusions —At variance with current views, asymptomatic patients are at lower risk for sudden death. Programmed electrical stimulation identifies only a fraction of individuals at risk, and sodium channel blockade fails to unmask most silent gene carriers. This novel evidence mandates a reappraisal of therapeutic management.

ACC/AHA/ESC guidelines for the management of patients with supraventricular arrhythmias--executive summary : a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Supraventricular Arrhythmias).

Background — The hereditary long-QT syndrome is characterized by prolonged ventricular repolarization and a variable clinical course with arrhythmia-related syncope and sudden death. Mutations involving the human ether-a-go-go–related gene (HERG) channel are responsible for the LQT2 form of long-QT syndrome, and in cellular expression studies these mutations are associated with reduction in the rapid component of the delayed rectifier repolarizing current (I Kr ). We investigated the clinical features and prognostic implications of mutations involving pore and nonpore regions of the HERG channel in the LQT2 form of this disorder. Methods and Results — A total of 44 different HERG mutations were identified in 201 subjects, with 14 mutations located in the pore region (amino acid residues 550 through 650). Thirty-five subjects had mutations in the pore region and 166 in nonpore regions. Follow-up extended through age 40 years. Subjects with pore mutations had more severe clinical manifestations of the genetic disorder and experienced a higher frequency (74% versus 35%; P P Conclusion — Patients with mutations in the pore region of the HERG gene are at markedly increased risk for arrhythmia-related cardiac events compared with patients with nonpore mutations.

Background Whenever a proband is identified with long-QT syndrome (LQTS), his or her parents and siblings should be evaluated regarding the possibility of carrying the disorder. In the majority of cases, one of the proband’s parents and one or more siblings are affected. The aim of this study was (1) to determine whether the clinical severity of LQTS in the proband is useful in identifying first-degree family members at high risk for cardiac events, and (2) to evaluate the clinical course of affected parents and siblings of LQTS probands. Methods and Results The clinical and ECG characteristics of 211 LQTS probands and 791 first-degree relatives (422 parents and 369 siblings) were studied to determine if the clinical profile of the proband is useful in determining the clinical severity of LQTS in affected parents and siblings. Affected female parents of an LQTS proband had a greater cumulative risk for a first cardiac event than affected male parents. The probability of a parent or sibling having a first cardiac event was not significantly influenced by the severity of the proband’s clinical symptoms. Female sex and QT c duration were risk factors for cardiac events among affected parents, and QT c was the only risk factor for cardiac events in affected siblings. Conclusions The severity profile of LQTS in a proband was not found to be useful in identifying the clinical severity of LQTS in affected first-degree relatives of the proband.

Background —Long-QT Syndrome (LQTS) is a cardiovascular disorder characterized by prolongation of the QT interval on ECG and presence of syncope, seizures, and sudden death. Five genes have been implicated in Romano-Ward syndrome, the autosomal dominant form of LQTS: KVLQT1 , HERG , SCN5A , KCNE1 , and KCNE2 . Mutations in KVLQT1 and KCNE1 also cause the Jervell and Lange-Nielsen syndrome, a form of LQTS associated with deafness, a phenotypic abnormality inherited in an autosomal recessive fashion. Methods and Results —We used mutational analyses to screen a pool of 262 unrelated individuals with LQTS for mutations in the 5 defined genes. We identified 134 mutations in addition to the 43 that we previously reported. Eighty of the mutations were novel. The total number of mutations in this population is now 177 (68% of individuals). Conclusions — KVLQT1 (42%) and HERG (45%) accounted for 87% of identified mutations, and SCN5A (8%), KCNE1 (3%), and KCNE2 (2%) accounted for the other 13%. Missense mutations were most common (72%), followed by frameshift mutations (10%), in-frame deletions, and nonsense and splice-site mutations (5% to 7% each). Most mutations resided in intracellular (52%) and transmembrane (30%) domains; 12% were found in pore and 6% in extracellular segments. In most cases (78%), a mutation was found in a single family or an individual.

Background —Unexplained female predominance is observed in long-QT syndrome (LQTS), a congenital autosomal disorder with prolonged repolarization and syncope or sudden death due to ventricular tachyarrhythmias. Our objectives were to evaluate age- and sex-related differences in events among LQTS patients referred to the LQTS International Registry. Methods and Results —Age- and sex-related occurrence of events was analyzed in 479 probands (70% females) and 1041 affected family members (QT c >440 ms, 58% females). LQTS-gene mutations were identified in 162 patients: 69 LQT1 carriers ( KVLQT1 on 11p15.5), 62 LQT2 carriers ( HERG on 7q35-36), and 31 LQT3 carriers ( SCN5A on 3p21-24). Females predominated among 366 probands (71% females) and 230 symptomatic family members (62% females). Male probands were younger than females at first event (8±7 versus 14±10 years, P P c duration, the hazard ratio for female probands of experiencing events by age 15 years was 0.48 ( P P =0.09) by age 15 to 40 years. In female family members, the hazard ratio was 0.58 ( P P P =0.001). No age-sex difference in event rate was detected in LQT2 and LQT3 carriers. Conclusions —Among LQTS patients, the risk of cardiac events was higher in males until puberty and higher in females during adulthood. The same pattern was evident among LQT1 gene carriers. Unknown sex factors modulate QT duration and arrhythmic events, with preliminary evidence of gene-specific differences in age-sex modulation.

Background —Long-QT syndrome (LQTS) is an inherited cardiac arrhythmia that causes sudden death in young, otherwise healthy people. Four genes for LQTS have been mapped to chromosome 11p15.5 ( LQT1 ), 7q35–36 ( LQT2 ), 3p21–24 ( LQT3 ), and 4q25–27 ( LQT4 ). Genes responsible for LQT1 , LQT2 , and LQT3 have been identified as cardiac potassium channel genes ( KVLQT1 , HERG ) and the cardiac sodium channel gene ( SCN5A ). Methods and Results —After studying 115 families with LQTS, we used single-strand conformation polymorphism (SSCP) and DNA sequence analysis to identify mutations in the cardiac potassium channel gene, KVLQT1 . Affected members of seven LQTS families were found to have new, previously unidentified mutations, including two identical missense mutations, four identical splicing mutations, and one 3-bp deletion. An identical splicing mutation was identified in affected members of four unrelated families (one Italian, one Irish, and two American), leading to an alternatively spliced form of KVLQT1 . The 3-bp deletion arose de novo and occurs at an exon-intron boundary. This results in a single base deletion in the KVLQT1 cDNA sequence and alters splicing, leading to the truncation of KVLQT1 protein. Conclusions —We have identified LQTS-causing mutations of KVLQT1 in seven families. Five KVLQT1 mutations cause the truncation of KVLQT1 protein. These data further confirm that KVLQT1 mutations cause LQTS. The location and character of these mutations expand the types of mutation, confirm a mutational hot spot, and suggest that they act through a loss-of-function mechanism or a dominant-negative mechanism.

Background — Treatment of patients with Brugada syndrome is complicated by the incomplete information on the natural history of the disease related to the small number of cases reported. Furthermore, the value of programmed electrical stimulation (PES) for risk stratification is highly debated. The objective of this study was to search for novel parameters to identify patients at risk of sudden death. Methods and Results — Clinical data were collected for 200 patients (152 men, 48 women; age, 41±18 years) and stored in a dedicated database. Genetic analysis was performed, and mutations on the SCN5A gene were identified in 28 of 130 probands and in 56 of 121 family members. The life-table method of Kaplan-Meier used to define the cardiac arrest-free interval in patients undergoing PES failed to demonstrate an association between PES inducibility and spontaneous occurrence of ventricular fibrillation. Multivariate Cox regression analysis showed that after adjusting for sex, family history of sudden death, and SCN5A mutations, the combined presence of a spontaneous ST-segment elevation in leads V 1 through V 3 and the history of syncope identifies subjects at risk of cardiac arrest (HR, 6.4; 95% CI, 1.9 to 21; P Conclusions — The information on the natural history of patients obtained in this study allowed elaboration of a risk-stratification scheme to quantify the risk for sudden cardiac death and to target the use of the implantable cardioverter-defibrillator.

Background— Catecholaminergic polymorphic ventricular tachycardia is characterized by stress-triggered syncope and sudden death. Patients with catecholaminergic polymorphic ventricular tachycardia manifest sinoatrial node (SAN) dysfunction, the mechanisms of which remain unexplored. Methods and Results— We investigated SAN [Ca 2+ ] i handling in mice carrying the catecholaminergic polymorphic ventricular tachycardia–linked mutation of ryanodine receptor (RyR2 R4496C ) and their wild-type (WT) littermates. In vivo telemetric recordings showed impaired SAN automaticity in RyR2 R4496C mice after isoproterenol injection, analogous to what was observed in catecholaminergic polymorphic ventricular tachycardia patients after exercise. Pacemaker activity was explored by measuring spontaneous [Ca 2+ ] i transients in SAN cells within the intact SAN by confocal microscopy. RyR2 R4496C SAN presented significantly slower pacemaker activity and impaired chronotropic response under β-adrenergic stimulation, accompanied by the appearance of pauses (in spontaneous [Ca 2+ ] i transients and action potentials) in 75% of the cases. Ca 2+ spark frequency was increased by 2-fold in RyR2 R4496C SAN. Whole-cell patch-clamp experiments performed on isolated RyR2 R4496C SAN cells showed that L-type Ca 2+ current ( I Ca,L ) density was reduced by ≈50%, an effect blunted by internal Ca 2+ buffering. Isoproterenol dramatically increased the frequency of Ca 2+ sparks and waves by ≈5 and ≈10-fold, respectively. Interestingly, the sarcoplasmic reticulum Ca 2+ content was significantly reduced in RyR2 R4496C SAN cells in the presence of isoproterenol, which may contribute to stopping the “Ca 2+ clock” rhythm generation, originating SAN pauses. Conclusion— The increased activity of RyR2 R4496C in SAN leads to an unanticipated decrease in SAN automaticity by a Ca 2+ -dependent decrease of I Ca,L and sarcoplasmic reticulum Ca 2+ depletion during diastole, identifying subcellular pathophysiological alterations contributing to the SAN dysfunction in catecholaminergic polymorphic ventricular tachycardia patients.

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 disorders5 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 penetrance9 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).13–20 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 …

showed that the morphology of the ST-T–wave complexpresents a remarkably distinctive shape in each of the geneticvariants of LQTS. This study generated the view that LQTSis not 1 disease but rather represents a group of pathologiescharacterized by prolongation of cardiac repolarization thatare caused by different genes and therefore should be re-garded as distinct entities. The publication of this seminalarticle stimulated the search for genotype-phenotype correla-tions that dominated the field for the subsequent 15 years.Investigators around the world started performing genetictesting in LQTS families and describing the distinguishingclinical manifestations of patients with mutations in each ofthe 3 key genes. Among the pivotal observations that haveshaped the field is the report by Schwartz et al

For new or updated text, view the 2011 Focused Update and the 2011 Focused Update on Dabigatran. Text supporting unchanged recommendations has not been updated. It is important that the medical profession play a significant role in critically evaluating the use of diagnostic procedures and therapies as they are introduced and tested in the detection, management, or prevention of disease states. Rigorous and expert analysis of the available data documenting absolute and relative benefits and risks of those procedures and therapies can produce helpful guidelines that improve the effectiveness of care, optimize patient outcomes, and favorably affect the overall cost of care by focusing resources on the most effective strategies. The American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) have jointly engaged in the production of such guidelines in the area of cardiovascular disease since 1980. The ACC/AHA Task Force on Practice Guidelines, whose charge is to develop, update, or revise practice guidelines for important cardiovascular diseases and procedures, directs this effort. The Task Force is pleased to have this guideline developed in conjunction with the European Society of Cardiology (ESC). Writing committees are charged with the task of performing an assessment of the evidence and acting as an independent group of authors to develop or update written recommendations for clinical practice. Experts in the subject under consideration have been selected from all 3 organizations to examine subject-specific data and write guidelines. The process includes additional representatives from other medical practitioner and specialty groups when appropriate. Writing committees are specifically charged to perform a formal literature review, weigh the strength of evidence for or against a particular treatment or procedure, and include estimates of expected health outcomes where data exist. Patient-specific modifiers, comorbidities, and issues of patient preference that might influence the choice of particular …

Although findings from several reports suggest that nonreentrant or focal mechanisms contribute to the genesis of arrhythmias during early ischemia, the contribution of triggered activity arising from early or delayed afterdepolarizations has not been resolved. We have previously demonstrated that beta- but not alpha-adrenergic stimulation induces afterdepolarizations and triggered activity in isolated normoxic myocytes. In the present study, the influence of the extent of cellular derangements as well as increases in [K+]o on alpha- and beta-adrenergic-mediated afterdepolarizations and triggered activity was evaluated. Adult canine myocytes were exposed to one of the following experimental conditions with simultaneous intracellular transmembrane action potential recordings: 1) low PO2 (less than 10 mm Hg, obtained using a specially designed hypoxic chamber) and low (6.8) pH; 2) low PO2, low pH, and high extracellular potassium ([K+]o) (10 mM); or 3) severe metabolic inhibition with cyanide (10(-6) M). Cells from each group were superfused with either the alpha-agonist phenylephrine (10(-5) or 10(-7) M, with 10(-5) M nadolol) or the beta-agonist isoproterenol (10(-6) M). Moderate changes in the action potentials were observed under conditions 1 and 2 (moderate hypoxia), whereas marked but reversible changes were observed with cyanide (severe metabolic inhibition). During moderate hypoxia in normal [K+]o, delayed afterdepolarizations or triggered activity were elicited by both alpha- (12 of 13 cells) and beta-adrenergic (five of five cells) stimulation. Increasing [K+]o during moderate hypoxia completely abolished the afterdepolarizations induced by alpha-adrenergic stimulation and prevented the occurrence of triggered activity. In contrast, the influence of beta-adrenergic stimulation was only attenuated by an increase in [K+]o. Exposure to cyanide completely prevented the induction of afterdepolarizations and triggered activity by both alpha- and beta-adrenergic stimulation. Our findings indicate that moderate hypoxia in normal [K+]o is associated with the development of adrenergic-mediated afterdepolarizations and triggered activity. In contrast, accumulation of [K+]o or severe impairment of cellular metabolism is accompanied by inhibition of adrenergic-mediated afterdepolarizations and triggered activity.

Background —The congenital long-QT syndrome (LQTS) is a genetically heterogeneous disease characterized by prolonged ventricular repolarization and life-threatening arrhythmias. Mutations of the KVLQT1 gene, a cardiac potassium channel, generate two allelic diseases: the Romano-Ward syndrome, inherited as a dominant trait, and the Jervell and Lange-Nielsen syndrome, inherited as an autosomal recessive trait. Methods and Results —A consanguineous family with the clinical phenotype of LQTS was screened for mutations in the KVLQT1 gene. Complementary RNAs for injection into Xenopus oocytes were prepared, and currents were recorded with the double microelectrode technique. A homozygous missense mutation, leading to an alanine-to-threonine substitution at the beginning of the pore domain of the KVLQT1 channel, was found in the proband, a 9-year-old boy with normal hearing, a prolonged QT interval, and syncopal episodes during physical exercise. The parents of the proband were heterozygous for the mutation and had a normal QT interval. The functional evaluation of the mutant channel activity showed reduction in total current, a hyperpolarizing shift in activation, and a faster activation rate consistent with a mild mutation likely to require homozygosity to manifest the phenotype. Conclusions —These findings provide the first evidence for a recessive form of the Romano-Ward long-QT syndrome and indicate that homozygous mutations on KVLQT1 do not invariably produce the Jervell and Lange-Nielsen syndrome. The implications of this observation prompt a reconsideration of the penetrance of different mutations responsible for LQTS and suggest that mild mutations in LQTS genes may be present among the general population and may predispose to drug-induced ventricular arrhythmias.

Short QT syndrome (SQTS) is a rare genetic disorder characterized by abnormally short QT interval and high risk of sudden cardiac death (SCD). This study addresses the issue of natural history, genetics and electrocardiographic features in the largest prospective SQTS cohort (47 individuals in 24 families). Diagnosis was made in the presence of QTc interval ≤ 350 ms w./out history of cardiac arrest (CA) or SCD without structural abnormalities. Median age at diagnosis was 27 years (range 4–56); mean QTc was 323±17 ms, 22/36 (61%) pts had abnormal T wave (n=17) and/or J point elevation (n=8) and/or QRS slurring (n=3); at a mean observation time of 30±14 years, 22 (47%) pts had cardiac events: 11 SCD, 4 resuscitated CA and 7 syncopal episodes. Median age at SCD or CA was 19 (range 0 – 48) years (4 death/CA occurred in the first year of life). The Kaplan Meyer curve shows survival-free interval before drugs. Triggers for the 15 death/CA were exercise (44%) and rest (56%). Eight pts were treated with quinidine (250 mg bid) that prolonged QTc: from 320±18 ms to 380±18 ms (pKCNH2, KCNQ1 and KCNJ2 genes was positive in 3/24 probands and 3 family members. Interestingly, genotyped pts (n=6) presented significantly shorter QTc than non-genotyped pts (303±13 ms vs. 328±14 ms, p

Background— Previous studies that assessed the risk of life-threatening cardiac events in patients with congenital long-QT syndrome (LQTS) have focused mainly on the first 4 decades of life, whereas the clinical course of this inherited cardiac disorder in the older population has not been studied. Methods and Results— The risk of aborted cardiac arrest or death from age 41 though 75 years was assessed in 2759 subjects from the International LQTS Registry, categorized into electrocardiographically affected (corrected QT interval [QTc] ≥470 ms), borderline (QTc 440 to 469 ms), and unaffected (QTc P P =0.31) in the age range of 61 to 75 years. The clinical course of study subjects displayed gender differences: Affected LQTS women experienced a significantly higher cumulative event rate (26%) than borderline (16%) and unaffected (12%) women ( P =0.001), whereas event rates were similar among the 3 respective subgroups of men (29%, 26%, and 27%; P =0.16). Recent syncope (P P =0.02). Conclusions— LQTS subjects maintain a high risk for life-threatening cardiac events after age 40 years. The phenotypic expression of affected subjects is influenced by age-specific factors related to gender, clinical history, and the LQTS genotype.

Background : Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease characterized by adrenergically mediated polymorphic or bidirectional ventricular tachycardia (BVT). Andersen-Tawil syndrome (ATS1), which are mainly caused by KCNJ2 mutations, phenocopies CPVT and may manifest the typical adrenergically mediated BVT. The purpose of this study was assess whether patients (pts) lacking periodic paralysis typical of ATS1 and diagnosed as CPVT because of BVT carry KCNJ2 mutations. Methods and Results : Mutational analysis of KCNJ2 was performed in 23 RyR2 and CASQ2 genotype-negative CPVT pts with normal QT interval. Two novel missense mutations (S220I and T305I) were identified. Mutations were absent in >400 reference alleles. Both of the pts present exercise or isoproterenol induced BVT, baseline ECG with prominent U wave and mild facial abnormalities. In vitro characterization showed that no current is detectable when S220I and T305I mutants clones are expressed; on the contrary co-expression of WT and mutant KCNJ2 to mimic heterozygosis present in patients, caused significant dominant negative effect (see figure ). Confocal laser microscopy revealed normal sarcolemmal localization of the mutant channels and of the heterozygous channels. Conclusions : KCNJ2 mutation with loss of function are present in a minority of pts with clinical diagnosis of CPVT. Given the limited number of CPVT pts with KCNJ2 mutations it is impossible to determine whether their prognosis is identical to that of RyR2 and CASQ2 related CPVT. Screening of KCNJ2 should be considered in CPVT pts without mutations in RyR2 and CASQ2 genes.

The conclusive diagnosis of Brugada Syndrome (BrS) is established in patients (pts) with spontaneous type 1 ECG or in carriers of a loss of function SCN5A mutation. We carried out a systematic analysis of ECG recordings in BrS pts to test the hypothesis that the presence of intraventricular (Intra-Ven) and atrioventricular (A-Ven) conduction delay is the distinguishing common feature of pts with SCN5A mutations (Mut+) and in pts with a spontaneous type 1 ECG pattern (spont-ECG). We assessed the following 5 ECG parameters: late potentials (quantified as RMS at 40 Hz), aVR sign (relative size of the R and q waves in aVR), QRS complex fragmentation (defined as an additional R′ or notching of the of S wave), PQ and QRS duration. We studied 200 consecutive BrS pts to define whether the prevalence of ECG markers correlate with 1) the presence of a SCN5A mutation (Mut+) or 2) the presence of a spontaneous type 1 pattern ECG (spont-ECG). Results are summarized in the table . Interestingly, Mut+ not only presented prolonged PQ (p Brugada syndrome is a disease characterized by impairment of A-Ven and Intra-Ven conduction, the presence of a mutation in the SCN5A gene and, the presence of a spontaneous type 1 ECG identify patients with accentuated conduction defects. These findings suggest that the presence of interventricular conduction delay is a landmark of BrS and should be considered as diagnostic markers in BrS.

Cardiac Calsequestrin (CASQ2) is a high affinity low capacity calcium binding protein essential in the regulation of intracellular Ca storage and release. Mutations in CASQ2 have been linked to the recessive form of catecholaminergic polymorphic ventricular tachycardia (CPVTr). To elucidate the mechanisms of arrhythmogensis in CPVTr, we generated a knock-in mouse model carrier of the R33Q mutation identified in one of our patients (pts) with a severe CPVT phenotype. Continuous ECG recording (DSI implantable monitors) showed that homozygous (CASQ2 R33Q/R33Q ) mice develop bidirectional and polymorphic VT upon exposure to adrenergic triggers (noise, physical contact). CASQ2 R33Q/R33Q mice have no sign of structural cardiac abnormality (normal heart/body weight ratio, histology no fibrosis nor myofibrillar disarray). Calcium-binding affinity of CASQ2 R33Q/R33Q is identical to that of wild type (WT) CASQ2, its localization evaluated with confocal microscopy is superimposable to that of WT. Western blot analysis shows that CASQ2 R33Q/R33Q content in myocytes is reduced by 40% but Real Time PCR showed that levels of mRNA are not reduced suggesting an abnormal protein turn-over. Evaluation of electrophysiological properties of isolated CASQ2 R33Q/R33Q myocytes revealed that pacing (1–5 Hz) induces delayed afterdepolarizations (DADs; 18/32 cells 56%) and triggered activity (TA; 9/31 29%) addition of adrenalin (200 nM) enhances DADs and TA (DADs 15/16 cells 93%; TA 8/17 cells 47%) and also elicits (25% of myocytes) early after depolarizations (EADs) and EADs-mediated TA. Our data demonstrate that in analogy with our knock-in model of the dominant form of CPVT due to mutations in the cardiac ryanodine receptor (RyR2) the CASQ2 R33Q/R33Q mice 1) do not present signs of cardiomyopathy, 2) develop DADs and TA in vitro and bidirectional and polymorphic VT in vivo. At variance with RyR2 mice, CASQ2 R33Q/R33Q mice 1) present a more malignant phenotype, lower threshold for DADs, TA and VT; 2) EADs concur to arrhythmogenesis 3) overcoming with a knock-in the limitations of previous in vitro and in vivo models overexpressing mutant CASQ2 on the background of the WT protein we demonstrated that a reduction in CASQ2 is implicated in the arrhythmogenesis of recessive CPVT.

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an arrhythmo-genic cardiac disease predisposing affected individuals to sudden cardiac death (SCD). Methods and Results: Here we provide data on the largest CPVT population thus far described. The study population consisted of 177 patients (64% female) of 93 families. All 93 probands (pbs) were screened for RYR2 mutations: 54 (58%) pbs carried a heterozygous RYR2 mutation, 1 pb a compound heterozygous RYR2 mutation and 3 pbs a homozygous (1), compound heterozygous (1) or heterozygous (1) CASQ2 mutation. One KCNJ2 mutation (T305I) was detected in a total of 15 pbs. In family members, another 40 RYR2 mutation carriers were identified. Only 29 of 95 gene carriers were phenotypically silent, therefore the penetrance of a RYR2 mutation was 69%. Of note, female sex was predominant among CPVT probands without a RYR2 mutation. Before the initiation of any treatment related to CPVT, 77 of 93 (83%) pbs experienced a cardiac e vent. Mean age of first event was 12±9 years. Neither sex nor the presence/absence of a RYR2 mutation was associated with a higher risk of developing events or with a younger age at onset of symptoms. Before therapy, 70% and 40% of 177 patients remained free of cardiac arrest and SCD before therapy by age 20 and 40 years, respectively. A history of juvenile SCD ( Conclusions: In this largest CPVT population reported so far, the presence/absence of a RYR2 mutation wasn’t associated with different clinical characteristics or response to therapy as compared to non-mutation carriers. CPVT remains a highly malignant disease with only a moderate response to β-blockers.