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ABSTRACT: Inferolateral early repolarization (ER) patterns on standard electrocardiogram (ECG) are associated with increased risk for cardiac and arrhythmic death in general adult population cohorts. We sought to determine the prevalence of inferolateral ER on surface ECG in multiracial pre- and postadolescent populations and to analyze its association with age, race, gender, and ST-segment patterns. A retrospective review was conducted of all ECGs recorded from preadolescent (aged 8-12 years, n = 719) and postadolescent (aged 21-25 years, n = 755) patients seen at a large academic medical center between January 1, 2009, and December 31, 2010. The overall prevalence of inferolateral ER was similar in the preadolescent and postadolescent populations (17% vs 16%, NS). The prevalence of ER increased after puberty in male patients (16% to 25%, p <0.001) and decreased in female patients (18% to 9%, p <0.001). Prevalence of ascending early repolarization (benign variant) also increased in males after puberty (15% to 23%, p <0.004) and decreased in females (11% to 4%, p <0.001). There were no differences in the prevalence of the risk-associated horizontal/descending pattern (3% in both groups). Subgroup analysis was performed on ECGs from the cohort of outpatients without cardiac disease, and the statistical trends remained the same. In conclusion, the overall prevalence of inferolateral ER was higher in pre- and postadolescent populations than in adult populations. However, the prevalence of the risk-associated horizontal/descending ST-segment pattern was only 3%, comparable to prevalence rates in the adult population. The variations in prevalence by gender and age suggest a possible influence of reproductive hormones.
The American journal of cardiology 05/2013; · 3.58 Impact Factor
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ABSTRACT: BACKGROUND: The slowly-activating delayed rectifier current I(Ks) contributes to repolarization of the cardiac action potential, and is composed of a pore-forming α-subunit, KCNQ1, and a modulatory β-subunit, KCNE1. Mutations in either subunit can cause long QT syndrome, a potentially fatal arrhythmic disorder. How KCNE1 controls the kinetics of I(Ks)remains unresolved. METHODS AND RESULTS: We identified 2 adjacent mutations, S338F and F339S,in the KCNQ1 S6 domainin unrelated probands. Thenovel KCNQ1S338F mutation segregated with prolonged QT interval and torsade de pointes; the second variant, F339S, was associated with fetal bradycardia and prolonged QT interval, but no other clinical events.S338F channelsexpressed in Xenopus oocytes hadslightly increased peak conductance relative to wild type, with a more positive activation voltage. F339S channels conducted minimal current. Unexpectedly, S338F currents were abolished by co-expression with intactWT KCNE1 orits C-terminus (aa63-129), despite normal membrane trafficking and surface co-localization of KCNQ1 S338F and wt KCNE1. Structural modeling indicatedthat the S338F mutation specifically alters the interaction between the S6 domain of one KCNQ1 subunit and the S4-S5 linker of another, inhibiting voltage-induced movement synergistically with KCNE1 binding. CONCLUSION: A novel KNCQ1 mutation specifically impaired channel function in the presence of KCNE1. Our structural model shows that this mutation effectively immobilizes voltage gating by an inhibitory interaction that is additive with that of KCNE1. Our findings illuminate a previously unreported mechanism for LQTS, and validate recent theoretical models of the closed state of the KCNQ1:KCNE1 complex.
Heart rhythm: the official journal of the Heart Rhythm Society 01/2013; · 4.56 Impact Factor
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ABSTRACT: The variations in the electrocardiographic patterns of J-point elevations, and the complex of J-points and J-waves in early repolarization (ER), in conjunction with disparities in associated sudden cardiac death (SCD) risk, have lead to a recognition of the need to carefully classify the spectrum of these observations. Many questions about the pathogenesis of J-wave patterns, and the associated magnitudes of risk, remain unanswered, especially in regard to the risk implications in certain high-prevalence subpopulations such as athletes, children, and adolescents. Interest in these electrocardiography (ECG) patterns has grown dramatically in recent years, in large part because of the frequency with which these patterns are observed on routine ECGs. In this review, we discuss the current knowledge on the prevalence of different J-point/J-wave patterns and estimates of the magnitude of mortality and SCD risk associated with J-point elevations and J-waves, in what has become known as ER patterns.
European Heart Journal 05/2012; · 10.48 Impact Factor
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Circulation 02/2012; 125(8):1043-52. · 14.74 Impact Factor
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Stefan Kääb,
Dana C Crawford,
Moritz F Sinner,
Elijah R Behr,
Prince J Kannankeril,
Arthur A M Wilde,
Connie R Bezzina,
Eric Schulze-Bahr,
Pascale Guicheney,
Nanette H Bishopric, [......],
Thomas Meitinger,
Annette Peters,
H-Erich Wichmann,
Christiana Ingram,
Yuki Bradford,
Shannon Carter,
Kris Norris,
Marylyn D Ritchie,
Alfred L George,
Dan M Roden
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ABSTRACT: Drug-induced long-QT syndrome (diLQTS) is an adverse drug effect that has an important impact on drug use, development, and regulation. We tested the hypothesis that common variants in key genes controlling cardiac electric properties modify the risk of diLQTS.
In a case-control setting, we included 176 patients of European descent from North America and Europe with diLQTS, defined as documented torsades de pointes during treatment with a QT-prolonging drug. Control samples were obtained from 207 patients of European ancestry who displayed <50 ms QT lengthening during initiation of therapy with a QT-prolonging drug and 837 control subjects from the population-based KORA study. Subjects were successfully genotyped at 1424 single-nucleotide polymorphisms (SNPs) in 18 candidate genes including 1386 SNPs tagging common haplotype blocks and 38 nonsynonymous ion channel gene SNPs. For validation, we used a set of cases (n=57) and population-based control subjects of European descent. The SNP KCNE1 D85N (rs1805128), known to modulate an important potassium current in the heart, predicted diLQTS with an odds ratio of 9.0 (95% confidence interval, 3.5-22.9). The variant allele was present in 8.6% of cases, 2.9% of drug-exposed control subjects, and 1.8% of population control subjects. In the validation cohort, the variant allele was present in 3.5% of cases and in 1.4% of control subjects.
This high-density candidate SNP approach identified a key potassium channel susceptibility allele that may be associated with the rare adverse drug reaction torsades de pointes.
Circulation Cardiovascular Genetics 11/2011; 5(1):91-9. · 6.11 Impact Factor
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Heart rhythm: the official journal of the Heart Rhythm Society 08/2011; 8(12):1972-4. · 4.56 Impact Factor
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ABSTRACT: Abstract The annual incidence of sudden cardiac death (SCD) is estimated at 1 per 1,000 for adults over the age of 35 years, and 1 per 100,000 for adolescents and young adults. Although the overall incidence of unexpected SCD among previously healthy persons is small, the emotional impact of these events is devastating.The 12-lead electrocardiogram (ECG) has been used as a risk assessment tool from healthy occupational applicants and athletes to patients with cardiovascular disorders. The ECG is also routinely recorded in the majority of patients hospitalized for non-cardiovascular causes. Thus, it is a widely used tool intended for identification of unsuspected heart disease generally, as well as for diagnosing specific disorders predisposing to fatal arrhythmias in subjects who have not experienced such events but who are at increased risk. Recognition of specific ECG features is of importance for prevention of SCD in asymptomatic persons. The purpose of this review is to catalog the disorders associated with SCD that may be reflected in 12-lead ECGs seen in office or hospital practices and to discuss their prevalence and the magnitude of risks. The focus is on ECG findings suggesting increased SCD risk among the asymptomatic subjects without previously diagnosed cardiac disease.
Annals of medicine 07/2011; · 3.52 Impact Factor
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ABSTRACT: Previous data have shown that various nonischemic cardiac diseases account for about 20% of sudden cardiac deaths (SCDs) and that dilated and hypertrophic cardiomyopathy (CM) are major causes of nonischemic SCD.
The purpose of this study was to define the prevalence and causes of SCD due to nonischemic CM in the current era given the substantial change in the diagnosis and treatment of cardiac diseases and in lifestyle patterns.
A total of 2661 consecutive victims of SCD from among a population of approximately 470,000 inhabitants in the Province of Oulu, Northern Finland, were included in the study. The causes of deaths were determined from the uniformly required autopsies of SCD victims in Finland, plus available medical records and standardized questionnaires.
Nonischemic cause of SCD was found in 579 victims (21.8% of all the SCDs). Mean age (± SD) was 55 (±12) years; 78% were males. After subgrouping the nonischemic SCDs into various categories, SCDs associated most closely with obesity (23.7%), followed by alcoholic CM (19.0%), hypertensive CM (15.5%), and fibrotic CM (13.6%). Fibrotic CM was the most common association with SCD in subjects younger than 40 years (28.3%), whereas alcoholic CM was the most common cause of death in subjects between 40 and 59 years of age (25.8%).
CM related to obesity, fibrotic CM, and alcoholic CM are commonly associated with nonischemic SCD in the current era. The association of SCD with fibrotic CM is notably frequent among victims younger than 40 years.
Heart rhythm: the official journal of the Heart Rhythm Society 07/2011; 8(10):1570-5. · 4.56 Impact Factor
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Jani T Tikkanen,
M Juhani Junttila,
Olli Anttonen,
Aapo L Aro,
Samuli Luttinen,
Tuomas Kerola,
Solomon J Sager,
Harri A Rissanen, Robert J Myerburg,
Antti Reunanen,
Heikki V Huikuri
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ABSTRACT: Early repolarization (ER) in inferior/lateral leads of standard ECGs increases the risk of arrhythmic death. We tested the hypothesis that variations in the ST-segment characteristics after the ER waveforms may have prognostic importance.
ST segments after ER were classified as horizontal/descending or rapidly ascending/upsloping on the basis of observations from 2 independent samples of young healthy athletes from Finland (n=62) and the United States (n=503), where ascending type was the dominant and common form of ER. Early repolarization was present in 27/62 (44%) of the Finnish athletes and 151/503 (30%) of the US athletes, and all but 1 of the Finnish (96%) and 91/107 (85%) of US athletes had an ascending/upsloping ST variant after ER. Subsequently, ECGs from a general population of 10 864 middle-aged subjects were analyzed to assess the prognostic modulation of ER-associated risk by ST-segment variations. Subjects with ER ≥0.1 mV and horizontal/descending ST variant (n=412) had an increased hazard ratio of arrhythmic death (relative risk 1.43; 95% confidence interval 1.05 to 1.94). When modeled for higher amplitude ER (>0.2 mV) in inferior leads and horizontal/descending ST-segment variant, the hazard ratio of arrhythmic death increased to 3.14 (95% confidence interval 1.56 to 6.30). However, in subjects with ascending ST variant, the relative risk for arrhythmic death was not increased (0.89; 95% confidence interval 0.52 to 1.55).
ST-segment morphology variants associated with ER separates subjects with and without an increased risk of arrhythmic death in middle-aged subjects. Rapidly ascending ST segments after the J-point, the dominant ST pattern in healthy athletes, seems to be a benign variant of ER.
Circulation 06/2011; 123(23):2666-73. · 14.74 Impact Factor
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ABSTRACT: Early repolarization (ER) has been considered a common benign ECG pattern among young athletes. In contrast, an inferolateral early repolarization pattern has been associated with an increased risk for sudden cardiac death (SCD). The aim of the study was to assess the prevalence of inferolateral ER among young collegiate athletes and to describe the characteristics associated to the pattern.
We analyzed ECGs from 503 athletes (51% males; age range, 17-24). Information on gender, body weight, race, sport, and family history of SCD was collected. ER was defined as a slow deflection of the down slope of the R wave (≥0.1 mV) or positive wave at J point (≥0.1 mV) in two consecutive inferior or in lateral leads. Additionally, we included voltage measurements according to the Sokolow-Lyon criteria and RR interval measurement.
The prevalence of ER was 30% (inferior, 20%; lateral, 21%; both, 11%). Male gender (59% vs. 48%, p = 0.019), left ventricular hypertrophy (LVH) voltage (39% vs. 12%, p < 0.001) was significantly associated with the ER pattern. In addition, there was a trend towards longer RR interval in the inferior ER group (p = 0.06) and there were slightly more African-Americans with ER compared to non-African-American (34% vs. 28%, p = 0.22). Among females (p = 0.039) and African-Americans (p = NS), the association of LVH to ER was not as strong.
ER is a common finding among young athletes. The ECG marker of LVH is the dominant shared characteristic among the athletes with ER, along with male gender and a trend to greater prevalence among African-American athletes.
Journal of Interventional Cardiac Electrophysiology 12/2010; 31(1):33-8. · 1.17 Impact Factor
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M Juhani Junttila,
Petra Barthel, Robert J Myerburg,
Timo H Mäkikallio,
Axel Bauer,
Kurt Ulm,
Antti Kiviniemi,
Mikko Tulppo,
Juha S Perkiömäki,
Georg Schmidt,
Heikki V Huikuri
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ABSTRACT: Type 2 diabetes mellitus is a well-established risk factor for atherosclerosis, but its contribution to sudden cardiac death (SCD) risk after myocardial infarction (MI) is not well defined.
The purpose of this study was to compare the incidence and time-dependent risk of SCD in diabetic patients versus nondiabetic patients during 5-year follow-up after acute MI.
A total of 3,276 patients were enrolled at the time of acute MI between 1996 and 2005. Mean age at entry was 60 ± 11 years, and the cohort was followed until 2009. At entry into the study, diabetes was present in 629 (19.2%) patients. The primary endpoint was SCD, and the secondary endpoints were non-SCD and all-cause mortality.
Among diabetic patients, the incidence of SCD was higher (5.9%) than in nondiabetic patients (1.7%), with a hazard ratio (HR) of 3.8 (95% confidence interval [CI] 2.4-5.8; P <.001) and adjusted HR of 2.3 (95% CI 1.4-3.8; P <.01). In diabetic patients with left ventricular ejection fraction >35%, the incidence of SCD was nearly identical to that of nondiabetic patients with ventricular ejection fraction ≤35% (4.1% vs 4.9%; P = .48). An excess in the incidence of non-SCD began to appear among diabetic patients within the first 6 months of follow-up (P <.001) but not in the incidence of SCD (P = .09). The excess in SCD among diabetic patients began to appear more than 6 months after the index event.
Patients with type 2 diabetes are at higher risk for SCD after MI than are nondiabetic patients. The incidence of SCD in post-MI type 2 diabetic patients with left ventricular ejection fraction >35% is equal to that of nondiabetic patients with left ventricular ejection fraction <35%.
Heart rhythm: the official journal of the Heart Rhythm Society 10/2010; 7(10):1396-403. · 4.56 Impact Factor
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Connie R Bezzina,
Raha Pazoki,
Abdennasser Bardai,
Roos F Marsman,
Jonas S S G de Jong,
Marieke T Blom,
Brendon P Scicluna,
J Wouter Jukema,
Navin R Bindraban,
Peter Lichtner, [......],
Dan M Roden,
Thomas Meitinger,
Sumeet S Chugh, Robert J Myerburg,
Xavier Jouven,
Stefan Kääb,
Lukas R C Dekker,
Hanno L Tan,
Michael W T Tanck,
Arthur A M Wilde
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ABSTRACT: Sudden cardiac death from ventricular fibrillation during acute myocardial infarction is a leading cause of total and cardiovascular mortality. To our knowledge, we here report the first genome-wide association study for this trait, conducted in a set of 972 individuals with a first acute myocardial infarction, 515 of whom had ventricular fibrillation and 457 of whom did not, from the Arrhythmia Genetics in The Netherlands (AGNES) study. The most significant association to ventricular fibrillation was found at 21q21 (rs2824292, odds ratio = 1.78, 95% CI 1.47-2.13, P = 3.3 x 10(-10)). The association of rs2824292 with ventricular fibrillation was replicated in an independent case-control set consisting of 146 out-of-hospital cardiac arrest individuals with myocardial infarction complicated by ventricular fibrillation and 391 individuals who survived a myocardial infarction (controls) (odds ratio = 1.49, 95% CI 1.14-1.95, P = 0.004). The closest gene to this SNP is CXADR, which encodes a viral receptor previously implicated in myocarditis and dilated cardiomyopathy and which has recently been identified as a modulator of cardiac conduction. This locus has not previously been implicated in arrhythmia susceptibility.
Nature Genetics 08/2010; 42(8):688-91. · 35.53 Impact Factor
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Journal of the American College of Cardiology 07/2010; 56(3):215-7. · 14.16 Impact Factor
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ABSTRACT: Implantable cardioverter-defibrillators (ICDs) are generally reliable medical devices that have the potential to add quality years of life for appropriate candidates. Indications for ICDs have emerged from a series of randomized clinical trials, observational data from cohorts of high-risk patients with less common diseases, and expert opinion based on limited data in uncommon disorders. The randomized trials are limited by inadequate stratification designs that resulted from insufficient funding availability. The result was outcomes that led to uneven applications, based in part on post-implant experience of device utilization. In this document, we explore the basis for the features of the evidence available to support ICD use, the role of clinical judgment in circumstances in which data are limited or lacking, and the need for additional research to improve the specificity of indications. Directions for new research initiatives are considered. In addition, a general overview of a clinical research paradigm is presented, in which the research and health care delivery arms of the health care enterprise combine in research design and funding, as the latter bears the impact of the outcomes of the former. Impact estimates during the design of trials, considering reasonable contingencies for outcomes, are suggested as a means of justifying the size, scope, and appropriate costs of studies. If we who are involved in clinical research and health care delivery do not resolve this problem, for both ICDs and other new therapies that appear in the future, society will do it for us.
Journal of the American College of Cardiology 09/2009; 54(9):747-63. · 14.16 Impact Factor
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Robert J Myerburg
Heart rhythm: the official journal of the Heart Rhythm Society 08/2009; 6(11):1613-5. · 4.56 Impact Factor
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Robert J Myerburg
New England Journal of Medicine 12/2008; 359(21):2245-53. · 53.30 Impact Factor
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ABSTRACT: The association between early repolarization patterns on electrocardiograms and risk of idiopathic ventricular fibrillation reported by Haïssaguerre et al. raises questions about the generally held concept that early repolarization is a benign electrocardiographic pattern. Although the association reported is strong enough to suggest validity, the data do not permit distinction between the following two possibilities: that early repolarization is a single pathophysiological entity with variable expression, or that early repolarization is a nonspecific electrocardiographic pattern that might be associated with specific high-risk or low-risk entities. Until prospective population data are available, physicians should continue to view this common electrocardiographic variant as generally benign. Careful attention should, however, be paid to patients with early repolarization and J-point elevations of more than 2 mm, especially those with otherwise unexplained arrhythmias or a family history of unexplained sudden death.
Nature Clinical Practice Cardiovascular Medicine 11/2008; 5(12):760-1. · 7.04 Impact Factor
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Circulation 12/2007; 116(22):2616-26; discussion 2626. · 14.74 Impact Factor
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11/2007: pages 95 - 108; , ISBN: 9780470988725
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Circulation 03/2007; 115(7):e200; author reply e204. · 14.74 Impact Factor
