Mutation location and IKs regulation in the arrhythmic risk of long QT syndrome type 1: the importance of the KCNQ1 S6 region.

AIMS: Mutation type, location, dominant-negative IKs reduction, and possibly loss of cyclic adenosine monophosphate (cAMP)-dependent IKs stimulation via protein kinase A (PKA) influence the clinical severity of long QT syndrome type 1 (LQT1). Given the malignancy of KCNQ1-p.A341V, we assessed whether mutations neighbouring p.A341V in the S6 channel segment could also increase arrhythmic risk. METHODS AND RESULTS: Clinical and genetic data were obtained from 1316 LQT1 patients [450 families, 166 unique KCNQ1 mutations, including 277 p.A341V-positive subjects, 139 patients with p.A341-neighbouring mutations (91 missense, 48 non-missense), and 900 other LQT1 subjects]. A first cardiac event represented the primary endpoint. S6 segment missense variant characteristics, particularly cAMP stimulation responses, were analysed by cellular electrophysiology. p.A341-neighbouring mutation carriers had a QTc shorter than p.A341V carriers (477 ± 33 vs. 490 ± 44 ms) but longer than the remaining LQT1 patient population (467 ± 41 ms) (P < 0.05 for both). Similarly, the frequency of symptomatic subjects in the p.A341-neighbouring subgroup was intermediate between the other two groups (43% vs. 73% vs. 20%; P < 0.001). These differences in clinical severity can be explained, for p.A341V vs. p.A341-neighbouring mutations, by the p.A341V-specific impairment of IKs regulation. The differences between the p.A341-neighbouring subgroup and the rest of LQT1 mutations may be explained by the functional importance of the S6 segment for channel activation. CONCLUSION: KCNQ1 S6 segment mutations surrounding p.A341 increase arrhythmic risk. p.A341V-specific loss of PKA-dependent IKs enhancement correlates with its phenotypic severity. Cellular studies providing further insights into IKs-channel regulation and knowledge of structure-function relationships could improve risk stratification. These findings impact on clinical management.

Prevalence, correlates, and mortality impacts of ventricular arrhythmia among older men and women: a population-based cohort study in Moscow.

BACKGROUND: In Russia, cardiovascular disease (CVD) mortality is high and the mortality gap between men and women is large. Conventional risk factors cannot explain these phenomena. Ventricular arrhythmia (VA) is an important contributor to the death toll in community-based populations. The study examines the prevalence and the mortality impacts of VA in men and women and the role of VA in the male mortality excess at older ages. METHODS: This is a secondary analysis of data from the Stress, Aging, and Health in Russia (SAHR) study that was fielded in 2007-9 in Moscow (1800 individuals, mean age 68.8 years), with mean mortality follow-up of 7.4 years (416 deaths, 248 CVD deaths). Indicators reflecting the frequency and the complexity of VA were derived from 24-h ambulatory ECG recordings. Other covariates were: socio-demographic characteristics, conventional risk factors, markers of inflammation, reported myocardial infarction, and stroke. The impacts of VA and other variables on CVD and all-cause mortality among men and women were estimated with the proportional hazard models. We assessed the contributions of VAs to the male-female mortality gap using hazard models that do and do not include groups of the predictors. Logistic models were used to assess the associations between VA and other biomarkers. RESULTS: VAs were about twice as prevalent among men as among women. In both sexes, they were significantly associated with CVD and all-cause mortality independently of conventional risk factors. The highest hazard ratios (HRs) for CVD death were found for the runs of ventricular premature complexes (VPCs) HR = 2.45, 95% CI 1.63-3.68 for men and 2.75, 95% CI 1.18-6.40 for women. The mortality impacts of the polymorphic VPCs were significant among men only (HR = 1.50, 95% CI 1.08-2.07). VA indicators can potentially explain 12.3% and 9.1% of the male-female gaps in mortality from CVD and all causes, respectively. VAs were associated with ECG-registered ischemic problems and reported MI, particularly among men. CONCLUSIONS: VA indicators predicted mortality in older Muscovites independently of other risk factors, and have the potential to explain a non-trivial share of the excess male mortality. The latter may be related to more severe coronary problems in men compared to women.

Atrial fibrillation among Russian men and women aged 55 years and older: prevalence, mortality, and associations with biomarkers in a population-based study.

OBJECTIVE: To examine the prevalence of atrial fibrillation (AF), its impacts on cardiovascular disease (CVD) and all-cause mortality, and the associations between AF and inflammatory and serum biomarkers in a population-based sample of Muscovites. METHODS: The study is a secondary analysis of data from the Stress, Aging and Health in Russia (SAHR) survey that includes information on 1800 individuals with an average age of 68.5 years at baseline, and on their subsequent mortality during 7.4 years on average. AF is detected by 12-lead electrocardiogram (ECG) and 24-hour Holter monitoring. The statistical analysis includes proportional hazard and logistic regression models. RESULTS: Of the 1732 participants with relevant Holter data, AF was detected in 100 (74 by ECG and Holter, 26 by Holter only). The prevalence of AF was 5.8% for men and 7.4% for women. The fully adjusted model showed strongly elevated hazard of CVD and all-cause mortality in men and women with long non-self-limiting AF (LAF). LAF was found to be negatively associated with elevated total and low-density lipoprotein cholesterol and to be positively associated with elevated markers of inflammation in women. CONCLUSIONS: The study assessed for the first time the prevalence and the risks of death related to AF among older Russians. LAF was shown to be a strong and independent predictor of CVD and all-cause mortality. AF is unlikely to contribute to the large excess male mortality in Russia. The finding that one-quarter of AF cases were detected only by Holter monitoring demonstrates the usefulness of diagnostics with prolonged ECG registration.

Recalibration of the SCORE risk chart for the Russian population.

Persisting high levels of cardiovascular mortality in Russia present a specific case among developed countries. Application of cardiovascular risk prediction models holds great potential for primary prevention in this country. Using a unique set of cohort follow-up data from Moscow and Saint Petersburg, this study aims to test and recalibrate the Systematic Coronary Risk Evaluation (SCORE) methods for predicting CVD mortality risks in the general population. The study is based on pooled epidemiological cohort data covering the period 1975-2001. The algorithms from the SCORE project were used for the calibration of the SCORE equation for the Moscow and St. Petersburg populations (SCORE-MoSP). Age-specific 10-year cumulative cardiovascular mortality rates were estimated according to the original SCORE-High and SCORE-Low equations and compared to the estimates based on the recalibrated SCORE-MoSP model and observed CVD mortality rates. Ten-year risk prediction charts for CVD mortality were derived and compared using conventional SCORE-High and recalibrated SCORE-MoSP methods. The original SCORE-High model tends to substantially under-estimate 10-year cardiovascular mortality risk for females. The SCORE-MoSP model provided better results which were closer to the observed rates. For males, both the SCORE-High and SCORE-MoSP provided similar estimates which tend to under-estimate CVD mortality risk at younger ages. These differences are also reflected in the risk prediction charts. Using non-calibrated scoring models for Russia may lead to substantial under-estimation of cardiovascular mortality risk in some groups of individuals. Although the SCORE-MoSP provide better results for females, more complex scoring methods involving a wider range of risk factors are needed.

Sodium-channel blockers might contribute to the prevention of ventricular tachycardia in patients with long QT syndrome type 2: a description of 4 cases.

Four patients with long QT type 2, aged 11 to 18 years from unrelated families, with recurrent syncope and polymorhic ventricular tachycardia were studied. Long QT syndrome was diagnosed in these children at ages 4 to 7 years. Syncope, QT prolongation on electrocardiogram (corrected QT interval ≥ 490 milliseconds), notched T-wave morphology, bradycardia, and polymorphic ventricular arrhythmia were found in all of the patients. The KCNH2-L586M; KCNH2-G604S, KCNH2-L1045F; and a combined mutation KCNH2 T613M + SCN5A R190G were genotyped. Syncope, implantable cardioverter-defibrillator shocks, and tachycardia persisted in these patients, although they were receiving a full dose of ß-blocker therapy. Adding a sodium-channel blocker (IC class) led to a reduction in the polymorphic ventricular arrhythmia. No syncope episodes were registered during the patients' 8 to 60 months of follow-up on the combined antiarrhythmic therapy. Further studies are needed to better define the possible role of sodium-channel blockers in patients with long QT type 2.

Prevalence, components, and correlates of metabolic syndrome (MetS) among elderly Muscovites.

The goal of this study is to estimate the prevalence of MetS, together with its components and correlates, among elderly Russians. Our population-based sample included randomly selected residents of Moscow aged 55 and older: 955 women with an average age of 67.6, and 833 men with an average age of 68.9. MetS was defined according to National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATPIII). The prevalence of MetS was found to be 41.7% in women and 26.8% in men. It tended to decrease with age in men, but not in women. MetS was inversely related to education in women, but not in men. The most prevalent individual components of MetS were as follows: hypertension (64.4%), abdominal obesity (55%), and decreased high density lipoprotein cholesterol (HDL C) (46%) for women; and hypertension (71%) and fasting hyperglycemia (35.2%) for men. An elevated level of triglycerides (TG) was the rarest MetS component, affecting 23.5% of women and 22.1% of men. The higher female prevalence of MetS was attributable to abdominal obesity. MetS was found to be associated with markers of insulin resistance (IR), low-grade inflammation, and insufficient fibrinolysis. Although the metabolic burden is an important contributor to high levels of ill-health and cardiovascular mortality among elderly Russians (especially women), it does not explain why cardiovascular mortality is much higher in Russia than in other industrialized countries.