Transgenic Insights Linking Pitx2 and Atrial Arrhythmias

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in humans and is characterized by chaotic electrical activity of the atria. It affects one in ten individuals over the age of 80 years, causes significant morbidity and is an independent predictor of mortality. Recent studies have provided evidence of a genetic contribution to AF. Mutations in potassium-channel genes have been associated with familial AF but account for only a small fraction of all cases of AF. We have performed a genome-wide association scan, followed by replication studies in three populations of European descent and a Chinese population from Hong Kong and find a strong association between two sequence variants on chromosome 4q25 and AF. Here we show that about 35% of individuals of European descent have at least one of the variants and that the risk of AF increases by 1.72 and 1.39 per copy. The association with the stronger variant is replicated in the Chinese population, where it is carried by 75% of individuals and the risk of AF is increased by 1.42 per copy. A stronger association was observed in individuals with typical atrial flutter. Both variants are adjacent to PITX2, which is known to have a critical function in left-right asymmetry of the heart.

Atrial fibrillation (AF) is the most common of the serious cardiac rhythm disturbances and is responsible for substantial morbidity and mortality in the general population. Its prevalence doubles with each advancing decade of age, from 0.5% at age 50-59 years to almost 9% at age 80-89 years. It is also becoming more prevalent, increasing in men aged 65-84 years from 3.2% in 1968-1970 to 9.1% in 1987-1989. This statistically significant increase in men was not explained by an increase in age, valve disease, or myocardial infarctions in the cohort. The incidence of new onset of AF also doubled with each decade of age, independent of the increasing prevalence of known predisposing conditions. Based on 38-year follow-up data from the Framingham Study, men had a 1.5-fold greater risk of developing AF than women after adjustment for age and predisposing conditions. Of the cardiovascular risk factors, only hypertension and diabetes were significant independent predictors of AF, adjusting for age and other predisposing conditions. Cigarette smoking was a significant risk factor in women adjusting only for age (OR = 1.4), but was just short of significance on adjustment for other risk factors. Neither obesity nor alcohol intake was associated with AF incidence in either sex. For men and women, respectively, diabetes conferred a 1.4- and 1.6-fold risk, and hypertension a 1.5- and 1.4-fold risk, after adjusting for other associated conditions. Because of its high prevalence in the population, hypertension was responsible for more AF in the population (14%) than any other risk factor. Intrinsic overt cardiac conditions imposed a substantially higher risk. Adjusting for other relevant conditions, heart failure was associated with a 4.5- and 5.9-fold risk, and valvular heart disease a 1.8- and 3.4-fold risk for AF in men and women, respectively. Myocardial infarction significantly increased the risk factor-adjusted likelihood of AF by 40% in men only. Echocardiographic predictors of nonrheumatic AF include left atrial enlargement (39%/ increase in risk per 5-mm increment), left ventricular fractional shortening (34% per 5% decrement), and left ventricular wall thickness (28% per 4-mm increment). These echocardiographic features offer prognostic information for AF beyond the traditional clinical risk factors. Electrocardiographic left ventricular hypertrophy increased risk of AF 3-4-fold after adjusting only for age, but this risk ratio is decreased to 1.4 after adjustment for the other associated conditions. The chief hazard of AF is stroke, the risk of which is increased 4-5-fold. Because of its high prevalence in advanced age, AF assumes great importance as a risk factor for stroke and by the ninth decade becomes a dominant factor. The attributable risk for stroke associated with AF increases steeply from 1.5% at age 50-59 years to 23.5% at age 80-89 years. AF is associated with a doubling of mortality in both sexes, which is decreased to 1.5-1.9-fold after adjusting for associated cardiovascular conditions. Decreased survival associated with AF occurs across a wide range of ages.

Atrial fibrillation (AF) is a common cardiac arrhythmia whose molecular etiology is poorly understood. We studied a family with hereditary persistent AF and identified the causative mutation (S140G) in the KCNQ1 (KvLQT1) gene on chromosome 11p15.5. The KCNQ1 gene encodes the pore-forming alpha subunit of the cardiac I(Ks) channel (KCNQ1/KCNE1), the KCNQ1/KCNE2 and the KCNQ1/KCNE3 potassium channels. Functional analysis of the S140G mutant revealed a gain-of-function effect on the KCNQ1/KCNE1 and the KCNQ1/KCNE2 currents, which contrasts with the dominant negative or loss-of-function effects of the KCNQ1 mutations previously identified in patients with long QT syndrome. Thus, the S140G mutation is likely to initiate and maintain AF by reducing action potential duration and effective refractory period in atrial myocytes.