Oxidized Ca(2+)/calmodulin-dependent protein kinase II triggers atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is a growing public health problem without adequate therapies. Angiotensin II and reactive oxygen species are validated risk factors for AF in patients, but the molecular pathways connecting reactive oxygen species and AF are unknown. The Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) has recently emerged as a reactive oxygen species-activated proarrhythmic signal, so we hypothesized that oxidized CaMKIIδ could contribute to AF. METHODS AND RESULTS: We found that oxidized CaMKII was increased in atria from AF patients compared with patients in sinus rhythm and from mice infused with angiotensin II compared with mice infused with saline. Angiotensin II-treated mice had increased susceptibility to AF compared with saline-treated wild-type mice, establishing angiotensin II as a risk factor for AF in mice. Knock-in mice lacking critical oxidation sites in CaMKIIδ (MM-VV) and mice with myocardium-restricted transgenic overexpression of methionine sulfoxide reductase A, an enzyme that reduces oxidized CaMKII, were resistant to AF induction after angiotensin II infusion. CONCLUSIONS: Our studies suggest that CaMKII is a molecular signal that couples increased reactive oxygen species with AF and that therapeutic strategies to decrease oxidized CaMKII may prevent or reduce AF.

Atrial fibrillation is associated with reduced brain volume and cognitive function independent of cerebral infarcts.

BACKGROUND AND PURPOSE: Atrial fibrillation (AF) has been associated with cognitive decline independent of stroke, suggesting additional effects of AF on the brain. We aimed to assess the association between AF and brain function and structure in a general elderly population. METHODS: This is a cross-sectional analysis of 4251 nondemented participants (mean age, 76 ± 5 years) in the population-based Age, Gene/Environment Susceptibility-Reykjavik Study. Medical record data were collected for the presence, subtype, and time from first diagnosis of AF; 330 participants had AF. Brain volume measurements, adjusted for intracranial volume, and presence of cerebral infarcts were determined with magnetic resonance imaging. Memory, speed of processing, and executive function composites were calculated from a cognitive test battery. In a multivariable linear regression model, adjustments were made for demographic factors, cardiovascular risk factors, and cerebral infarcts. RESULTS: Participants with AF had lower total brain volume compared with those without AF (P<0.001). The association was stronger with persistent/permanent than paroxysmal AF and with increased time from the first diagnosis of the disease. Of the brain tissue volumes, AF was associated with lower volume of gray and white matter hyperintensities (P<0.001 and P = 0.008, respectively), but not of white matter hyperintensities (P = 0.49). Participants with AF scored lower on tests of memory. CONCLUSIONS: AF is associated with smaller brain volume, and the association is stronger with increasing burden of the arrhythmia. These findings suggest that AF has a cumulative negative effect on the brain independent of cerebral infarcts.

Trends in the incidence and prevalence of atrial fibrillation in Iceland and future projections.

AIMS: Data are scarce on the epidemiology of atrial fibrillation (AF) in Europe. The aim of this study was to examine recent trends in the incidence and prevalence of AF and project the prevalence to the year 2050. METHODS AND RESULTS: From 1991 to 2008 a total of 4905 residents of Reykjavik, Iceland were diagnosed with AF at the city's main health care centre. The age-standardized incidence of AF increased in women (0.9% per year, 95% CI 0.1-1.8) but not in men (0.1% per year, 95% CI -0.6 to 0.9). The age-standardized prevalence increased per year by 1.8% (95% CI 1.3-2.3) in men and 2.3% (95% CI 1.7-2.9) in women from 1998 to 2008. The number of adults with AF in Iceland is projected to increase from 4495 (prevalence 2.0%) in 2008 to 11 088 (prevalence 3.5%) in 2050, if the incidence of AF and mortality remain constant beyond 2008. However, if the incidence continues to increase as it has and mortality decreases according to projections for the general population, the projected number will rise to 13 583 (prevalence 4.3%). CONCLUSION: In this study in a northern European population, the incidence of AF increased in women but not men from 1991 to 2008. The prevalence of AF is currently high and the number of patients with AF is expected to triple in the next four decades. AF is already a serious public health problem and the burden of this disease could reach epidemic proportions in the coming years.

A rare variant in MYH6 is associated with high risk of sick sinus syndrome.

Through complementary application of SNP genotyping, whole-genome sequencing and imputation in 38,384 Icelanders, we have discovered a previously unidentified sick sinus syndrome susceptibility gene, MYH6, encoding the alpha heavy chain subunit of cardiac myosin. A missense variant in this gene, c.2161C>T, results in the conceptual amino acid substitution p.Arg721Trp, has an allelic frequency of 0.38% in Icelanders and associates with sick sinus syndrome with an odds ratio = 12.53 and P = 1.5 × 10⁻²9. We show that the lifetime risk of being diagnosed with sick sinus syndrome is around 6% for non-carriers of c.2161C>T but is approximately 50% for carriers of the c.2161C>T variant.

Several common variants modulate heart rate, PR interval and QRS duration.

Electrocardiographic measures are indicative of the function of the cardiac conduction system. To search for sequence variants that modulate heart rate, PR interval and QRS duration in individuals of European descent, we performed a genome-wide association study in approximately 10,000 individuals and followed up the top signals in an additional approximately 10,000 individuals. We identified several genome-wide significant associations (with P < 1.6 x 10(-7)). We identified one locus for heart rate (MYH6), four for PR interval (TBX5, SCN10A, CAV1 and ARHGAP24) and four for QRS duration (TBX5, SCN10A, 6p21 and 10q21). We tested for association between these loci and subjects with selected arrhythmias in Icelandic and Norwegian case-control sample sets. We observed correlations between TBX5 and CAV1 and atrial fibrillation (P = 4.0 x 10(-5) and P = 0.00032, respectively), between TBX5 and advanced atrioventricular block (P = 0.0067), and between SCN10A and pacemaker implantation (P = 0.0029). We also replicated previously described associations with the QT interval.