Results on the association between P-wave duration and the risk of atrial fibrillation (AF) are conflicting.
The purpose of this study was to obtain a detailed description of the relationship between ...P-wave duration and the risk of AF.
Using computerized analysis of electrocardiograms from a large primary care population, we evaluated the association between P-wave duration and the risk of AF. Secondary end-points were death from cardiovascular causes and putative ischemic stroke. Data on drug use, comorbidity, and outcomes were collected from administrative registries.
A total of 285,933 individuals were included. During median follow-up period of 6.7 years, 9550 developed AF, 9371 died of a cardiovascular cause, and 8980 had a stroke. Compared with the reference group (100-105 ms), individuals with very short (≤89 ms; hazard ratio HR 1.60, 95% confidence interval CI 1.41-1.81), intermediate (112-119 ms; HR 1.22, 95% CI 1.13-1.31), long (120-129 ms; HR 1.50, 95% CI 1.39-1.62), and very long P-wave duration (≥130 ms; HR 2.06, 95% CI 1.89-2.23) had an increased risk of incident AF. With respect to death from cardiovascular causes, we found an increased risk for very short (≤89 ms; HR 1.20, 95% CI 1.06-1.34), long (120-129 ms; HR 1.11, 95% CI 1.04-1.19), and very long P-wave duration (≥130 ms; HR 1.30, 95% CI 1.21-1.40) compared with the reference group (106-111 ms). Similar but weaker associations were found between P-wave duration and the risk of putative ischemic stroke.
In a large primary care population we found both short and long P-wave duration to be robustly associated with an increased risk of AF.
A family history of atrial fibrillation constitutes a substantial risk of developing the disease, however, the pathogenesis of this complex disease is poorly understood. We perform whole-exome ...sequencing on 24 families with at least three family members diagnosed with atrial fibrillation (AF) and find that titin-truncating variants (TTNtv) are significantly enriched in these patients (P = 1.76 × 10
). This finding is replicated in an independent cohort of early-onset lone AF patients (n = 399; odds ratio = 36.8; P = 4.13 × 10
). A CRISPR/Cas9 modified zebrafish carrying a truncating variant of titin is used to investigate TTNtv effect in atrial development. We observe compromised assembly of the sarcomere in both atria and ventricle, longer PR interval, and heterozygous adult zebrafish have a higher degree of fibrosis in the atria, indicating that TTNtv are important risk factors for AF. This aligns with the early onset of the disease and adds an important dimension to the understanding of the molecular predisposition for AF.
Preparticipation screening programs have been suggested to reduce the numbers of sports-related sudden cardiac deaths (SrSCD).
The purpose of this study was to identify and characterize all SrSCD ...aged 12-49 years and to address the difference in incidence rates between competitive and noncompetitive athletes.
All deaths among persons aged 12-49 years from 2007-2009 were included. Death certificates were reviewed. History of previous admissions to hospital was assessed, and discharge summaries and autopsy reports were read. Sudden cardiac deaths (SCDs) and SrSCD cases were identified.
In the 3-year period, there were 881 SCDs, of which we identified 44 SrSCD. In noncompetitive athletes aged 12-35 years, the incidence rate of SrSCD was 0.43 (95% confidence interval CI 0.16-0.94) per 100,000 athlete person-years vs 2.95 (95% CI 1.95-4.30) in noncompetitive athletes aged 36-49 years. In competitive athletes, the incidence rate of SrSCD was 0.47 (95% CI 0.10-1.14) and 6.64 (95% CI 2.86-13.1) per 100,000 athlete person-years in those aged 12-35 years and 36-49 years, respectively. The incidence rate of SCD in the general population was 10.7 (95% CI 10.0-11.5) per 100.000 person-years.
The incidence rates of SrSCD in noncompetitive and competitive athletes are not different. The study showed an increase in the incidence rate of SrSCD in persons aged 36-49 years in both noncompetitive and competitive athletes compared to those aged 12-35 years. Importantly, SCD in the general population is much more prevalent than is SrSCD in all age groups.
Atrial fibrillation (AF) is the most common cardiac arrhythmia affecting 1-2% of the general population. A number of studies have demonstrated that AF, and in particular lone AF, has a substantial ...genetic component. Monogenic mutations in lone and familial AF, although rare, have been recognized for many years. Presently, mutations in 25 genes have been associated with AF. However, the complexity of monogenic AF is illustrated by the recent finding that both gain- and loss-of-function mutations in the same gene can cause AF. Genome-wide association studies (GWAS) have indicated that common single-nucleotide polymorphisms (SNPs) have a role in the development of AF. Following the first GWAS discovering the association between PITX2 and AF, several new GWAS reports have identified SNPs associated with susceptibility of AF. To date, nine SNPs have been associated with AF. The exact biological pathways involving these SNPs and the development of AF are now starting to be elucidated. Since the first GWAS, the number of papers concerning the genetic basis of AF has increased drastically and the majority of these papers are for the first time included in a review. In this review, we discuss the genetic basis of AF and the role of both common and rare genetic variants in the susceptibility of developing AF. Furthermore, all rare variants reported to be associated with AF were systematically searched for in the Exome Sequencing Project Exome Variant Server.
Prolongation of the PR interval has been associated with an increased risk of incident atrial fibrillation (AF).
To determine if there was a nonlinear relation between PR interval duration and the ...risk of AF.
We included 288,181 individuals, corresponding to one third of the population in the greater region of Copenhagen. These individuals had a digital electrocardiogram (ECG) recorded in a general practitioner's core facility from 2001 to 2010. Data on drug use, comorbidity, and outcomes were collected from Danish registries.
During a median follow-up period of 5.7 years, 11,087 developed AF. Having a PR interval ≥95th percentile (≥196 ms for women, ≥204 ms for men) was associated with an increased risk of AF as evidenced by a multivariable-adjusted hazard ratio (HR) of 1.18 (95% confidence interval CI 1.06-1.30, P = .001) for women and 1.30 (1.17-1.44, P < .001) for men compared with the respective reference groups (PR interval between 40th and 60th percentile). Having a short PR interval <5th percentile (≤121 ms for women, ≤129 ms for men) was also associated with an increased risk of AF for women (HR 1.32, 95% CI 1.12-1.56, P = .001), but this was not significant for men (HR 1.09, 95% CI 0.92-1.29, P = .33).
In this large ECG study, we found an increased risk of AF for longer PR intervals for both women and men. With respect to short PR intervals, we also observed an increased risk of AF for women.
Atrial fibrillation (AF) has traditionally been considered an electrical heart disease. However, genetic studies have revealed that the structural architecture of the heart also play a significant ...role. We evaluated the functional and structural consequences of harboring a titin-truncating variant (TTNtv) in AF patients, using cardiac magnetic resonance (CMR). Seventeen early-onset AF cases carrying a TTNtv, were matched 1:1 with non-AF controls and a replication cohort of early-onset AF cases without TTNtv, and underwent CMR. Cardiac volumes and left atrial late gadolinium enhancement (LA LGE), as a fibrosis proxy, were measured by a blinded operator. Results: AF cases with TTNtv had significantly reduced left ventricular ejection fraction (LVEF) compared with controls (57 ± 4 vs 64 ± 5%, P < 0.001). We obtained similar findings in early-onset AF patients without TTNtv compared with controls (61 ± 4 vs 64 ± 5%, P = 0.02). We furthermore found a statistically significant increase in LA LGE when comparing early-onset AF TTNtv cases with controls. Using state-of-the-art CMR, we found that early-onset AF patients, irrespective of TTNtv carrier status, had reduced LVEF, indicating that early-onset AF might not be as benign as previously thought.
Cardiomyopathies are a heterogeneous group of diseases with various etiologies. We focused on three genetically determined cardiomyopathies: hypertrophic (HCM), dilated (DCM), and arrhythmogenic ...right ventricular cardiomyopathy (ARVC). Eighty-four genes have so far been associated with these cardiomyopathies, but the disease-causing effect of reported variants is often dubious. In order to identify possible false-positive variants, we investigated the prevalence of previously reported cardiomyopathy-associated variants in recently published exome data. We searched for reported missense and nonsense variants in the NHLBI-Go Exome Sequencing Project (ESP) containing exome data from 6500 individuals. In ESP, we identified 94 variants out of 687 (14%) variants previously associated with HCM, 58 out of 337 (17%) variants associated with DCM, and 38 variants out of 209 (18%) associated with ARVC. These findings correspond to a genotype prevalence of 1:4 for HCM, 1:6 for DCM, and 1:5 for ARVC. PolyPhen-2 predictions were conducted on all previously published cardiomyopathy-associated missense variants. We found significant overrepresentation of variants predicted as being benign among those present in ESP compared with the ones not present. In order to validate our findings, seven variants associated with cardiomyopathy were genotyped in a control population and this revealed frequencies comparable with the ones found in ESP. In conclusion, we identified genotype prevalences up to more than one thousand times higher than expected from the phenotype prevalences in the general population (HCM 1:500, DCM 1:2500, and ARVC 1:5000) and our data suggest that a high number of these variants are not monogenic causes of cardiomyopathy.
Studies on incidences of sports-related sudden cardiac death (SrSCD) are few and data are needed for the discussion of preparticipation screening for cardiac disease.
We sought to chart the incidence ...and etiology of SrSCD in the young in Denmark (population 5.4 million) and to compare this to the incidence of sudden cardiac death (SCD) in the background population.
All 5,662 death certificates for decedents in the period 2000 to 2006 in the age group 12 to 35 years in Denmark were read independently by 2 physicians to identify cases of SCD. Information from autopsy reports, selected hospital records, and multiple registries was used to identify cases of SCD and SrSCD. SrSCD was defined as SCD occurring during or within 1 hour after exercise in a competitive athlete. The size of the athlete population was estimated from national survey data.
Fifteen (range 0 to 5 per year) cases of SrSCD were found, 8 of which had antecedent symptoms. The incidence rate was 1.21 (95% confidence interval CI: 0.68 to 2.00) per 100,000 athlete person-years. The most common autopsy findings were arrhythmogenic right ventricular cardiomyopathy (n = 4), sudden unexplained death (n = 4), and coronary artery disease (n = 2). The incidence of SCD in the general population age 12 to 35 was 3.76 (95% CI: 3.42 to 4.14) per 100,000 person-years.
In Denmark, SrSCD is a rare occurrence and the incidence rate is lower than that of SCD in the general population. This may imply a low value of preparticipation screening of athletes in Denmark.
Atrial fibrillation (AF) is the most common cardiac arrhythmia, and early-onset lone AF has been linked to mutations in genes encoding ion channels. Mutations in the pore forming subunit KV4.3 ...leading to an increase in the transient outward potassium current (Ito) have previously been associated with the Brugada Syndrome. Here we aim to determine if mutations in KV4.3 or in the auxiliary subunit K(+) Channel-Interacting Protein (KChIP) 2 are associated with early-onset lone AF.
Two hundred and nine unrelated early-onset lone AF patients (<40 years) were recruited. The entire coding sequence of KCND3 and KCNIP2 was bidirectionally sequenced. One novel non-synonymous mutation A545P was found in KCND3 and was neither present in the control group (n = 432 alleles) nor in any publicly available database. The proband had onset of persistent AF at the age of 22, and no mutations in genes previously associated with AF were found. Electrophysiological analysis of KV4.3-A545P expressed in CHO-K1 cells, revealed that peak-current density was increased and the onset of inactivation was slower compared with WT, resulting in a significant gain-of-function both in the absence and the presence of KChIP2.
Gain-of-function mutations in KV4.3 have previously been described in Brugada Syndrome, however, this is the first report of a KV4.3 gain-of-function mutation in early-onset lone AF. This association of KV4.3 gain-of-function and early-onset lone AF further supports the hypothesis that increased potassium current enhances AF susceptibility.
Knowledge of the burden and causes of sudden cardiac death (SCD) is sparse in persons aged<50 years; better understanding is needed to lower the risk of SCD. The aim of this study was to report SCD ...incidence rates and autopsy findings in persons aged 1 to 49 years.
All deaths in persons aged 1 to 49 years were included in 2007 to 2009. Death certificates were reviewed by 2 physicians. History of previous admissions to hospital was assessed, and discharge summaries were read. Sudden unexpected death cases were identified and autopsy reports were collected. In the 3-year study period, there were 7849 deaths of which we identified 893 (11%) SCD cases. The annual incidence rate per 100 000 persons increased from 2.3 (95% confidence interval, 2.0-2.7) to 21.7 (95% confidence interval, 20.2-23.4) in persons aged 1 to 35 and 36 to 49 years, respectively. Coronary artery disease was the most common cause of death and was found in 158 (36%) autopsied cases, followed by 135 (31%) cases of sudden unexplained death.
In a nationwide cohort of persons aged<50 years, the annual incidence rate of SCD was ≈10× higher in persons aged 36 to 49 years than in persons aged 1 to 35 years. Notably, coronary artery disease was the most common cause of SCD, followed by unexplained deaths. These findings may help in developing strategies to prevent SCD in the future.
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