Maria Shkolnikova

Biological mechanisms of disease and death in Moscow: rationale and design of the survey on Stress Aging and Health in Russia (SAHR)

BackgroundPrior research has revealed large differences in health and mortality across countries, socioeconomic groups, and individuals. Russia experiences one of the worlds highest levels of all-cause and cardiovascular mortality, great mortality differences within the population, and a heavy burden of ill health. Psychological stress has been suggested as a likely explanation of health loss and premature death in Russia and Eastern Europe. However, physiological mechanisms connecting stress with health in Russia remain unclear since existing epidemiological data are scarce and limited to conventional risk factors.Method and DesignThe survey on Stress Aging and Health in Russia (SAHR) is addressing this knowledge gap by collecting an unusually rich database that includes a wide range of reported information, physical and cognitive health outcomes, and biomarkers in a sample of Muscovite men and women aged 55 and older. The total planned sample size is 2,000 individuals. The sample was randomly selected from epidemiological cohorts formed in Moscow between the mid-1970s and the 1990s and from medical population registers. The baseline data collection was carried out from December 2006 to June 2009. Interviews and medical tests were administered at hospital or at home according to standardized protocol. Questionnaire information includes health, socio-demographic characteristics, economic well-being, cognitive functioning, and batteries on stress and depression. Biomarkers include anthropometry, grip strength, resting ECG, conventional cardiovascular factors of risk such as lipid profile and blood pressure, and other biochemical parameters such as those related to inflammation, glucose and insulin resistance, coagulation, fibrinolysis, and stress hormones. In addition to these measurements, SAHR includes dynamic biomarkers provided by 24-hour ECG (Holter) monitoring. This method continuously registers the beat-to-beat heart rate in naturalistic conditions without restrictions on normal daily activities. It provides information about heart functioning, including heart rate variability and ischemic and arrhythmic events.Re-examination of the study subjects will be conducted in 2009–2011 and will focus on health, functional status, economic conditions, behaviors, and attitudes towards aging. The subjects are also followed up for mortality and non-fatal health events.DiscussionThe SAHR will produce a valuable set of established and novel biomarkers combined with self-reported data for the international research community and will provide important insights into factors and biological mechanisms of mortality and health losses in Russia.

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.

Perceived stress and biological risk: is the link stronger in Russians than in Taiwanese and Americans?

Abstract Allostatic load theory implies a relationship between exposure to psychological stress and multi-system physiological dysregulation. We used data from population-based samples of men and women in Russia (Moscow; n = 1800; age, mean 68.6 years), Taiwan (n = 1036; 65.6 years) and the United States (US; n = 1054; 58.0 years) -- which are likely to vary widely with respect to levels of stress exposure and biological markers -- to determine the magnitude of the association between perceived stress and physiological dysregulation. The measure of overall dysregulation was based on 15 markers including standard cardiovascular/metabolic risk factors as well as markers of inflammation and neuroendocrine activity. Subjective psychological stress was measured by the perceived stress scale. Only the Moscow sample demonstrated a positive association with overall dysregulation in both sexes. In the US, we found an association among women but not men. Among the Taiwanese, who report the lowest perceived stress, there was no association in women but an unexpected inverse relationship in men. The effects also varied across system-level subscores: the association with perceived stress was most consistent for standard cardiovascular/metabolic factors. Perceived stress was associated with inflammation and neuroendocrine activity in some samples. Although the evidence that perceived stress is the primary source of physiological dysregulation is generally modest, it was stronger in Russia where the level of perceived stress was particularly high. For Russia only, we had information about heart function based on a 24 h ambulatory electrocardiogram; perceived stress was consistently associated with heart rate dysregulation in Russian men and women.

Latent time-varying factors in longitudinal analysis: a linear mixed hidden Markov model for heart rates.

Longitudinal data are often segmented by unobserved time-varying factors, which introduce latent heterogeneity at the observation level, in addition to heterogeneity across subjects. We account for this latent structure by a linear mixed hidden Markov model. It integrates subject-specific random effects and Markovian sequences of time-varying effects in the linear predictor. We propose an expectationŰ-maximization algorithm for maximum likelihood estimation, based on data augmentation. It reduces to the iterative maximization of the expected value of a complete likelihood function, derived from an augmented dataset with case weights, alternated with weights updating. In a case study of the Survey on Stress Aging and Health in Russia, the model is exploited to estimate the influence of the observed covariates under unobserved time-varying factors, which affect the cardiovascular activity of each subject during the observation period.

TO WHAT EXTENT DO BIOMARKERS ACCOUNT FOR THE LARGE SOCIAL DISPARITIES IN HEALTH IN MOSCOW

The Russian population continues to face political and economic challenges, has experienced poor general health and high mortality for decades, and has exhibited widening health disparities. The physiological factors underlying links between health and socioeconomic position in the Russian population are therefore an important topic to investigate. We used data from a population-based survey of Moscow residents aged 55 and older (n = 1495), fielded between December 2006 and June 2009, to address two questions. First, are social disparities evident across different clusters of biomarkers? Second, does biological risk mediate the link between socioeconomic status and health? Health outcomes included subscales for general health, physical function, and bodily pain. Socioeconomic status was represented by education and an index of material resources. Biological risk was measured by 20 biomarkers including cardiovascular, inflammatory, and neuroendocrine markers as well as heart rate parameters from 24-h ECG monitoring. For both sexes, the age-adjusted educational disparity in standard cardiovascular risk factors was substantial (men: standardized β = -0.16, 95% CI = -0.23 to -0.09; women: β = -0.25, CI = -0.32 to -0.18). Education differences in inflammation were also evident in both men (β = -0.17, CI = -0.25 to -0.09) and women (β = -0.09, CI = -0.17 to -0.01). Heart rate parameters differed by education only in men (β = -0.10, CI = -0.18 to -0.02). The associations between material resources and biological risk scores were generally weaker than those for education. Social disparities in neuroendocrine markers were negligible for men and women. In terms of mediating effects, biological risk accounted for more of the education gap in general health and physical function (19-36%) than in bodily pain (12-18%). Inclusion of inflammatory markers and heart rate parameters-which were important predictors of health outcomes-may explain how we accounted for more of the social disparities than previous studies.

Sex Differences in Biological Markers of Health in the Study of Stress, Aging and Health in Russia.

Background The apparent contradiction that women live longer but have worse health than men, the so called male-female health-survival paradox, is very pronounced in Russia. The present study investigates whether men in Moscow are healthier than women at the level of biomarkers, and whether the associations between biomarkers and subjective health have sex-specific patterns. Materials Previously collected data in the study of Stress, Aging, and Health in Russia (SAHR, n = 1800) were used to examine sex differences in biomarkers and their associations with physical functioning and self-rated health. Results The present study found mixed directions and magnitudes for sex differences in biomarkers. Women were significantly disadvantaged with regard to obesity and waist circumference, whereas men had a tendency toward higher prevalence of electrocardiographic abnormalities. No sex differences were indicated in the prevalence of immunological biomarkers, and mixed patterns were found for lipid profiles. Many biomarkers were associated with physical functioning and general health. Obesity and waist circumference were related to lower physical functioning among females only, while major Q-wave abnormalities with high probabilities of myocardial infarction and atrial fibrillation or atrial flutter were associated with physical functioning and self-rated health among males only. Conclusion No clear patterns of sex differences in prevalence of high-risk levels of biomarkers suggest that the male-female health-survival paradox is weaker at the level of health biomarkers. We found some evidence that certain biomarkers reflecting pathophysiological changes in the organism that do not possess acute health risks, but over many years may lead to physical disability, are associated with physical functioning and self-rated health in women, whereas others reflecting more serious life-threatening pathophysiological changes are associated with physical functioning and self-rated health in men.

Handgrip strength and its prognostic value for mortality in Moscow, Denmark, and England

Background This study compares handgrip strength and its association with mortality across studies conducted in Moscow, Denmark, and England. Materials The data collected by the Study of Stress, Aging, and Health in Russia, the Study of Middle-Aged Danish Twins and the Longitudinal Study of Aging Danish Twins, and the English Longitudinal Study of Ageing was utilized. Results Among the male participants, the age-standardized grip strength was 2 kg and 1 kg lower in Russia than in Denmark and in England, respectively. The age-standardized grip strength among the female participants was 1.9 kg and 1.6 kg lower in Russia than in Denmark and in England, respectively. In Moscow, a one-kilogram increase in grip strength was associated with a 4% (hazard ratio [HR] = 0.96, 95% confidence interval [CI]: 0.94, 0.99) reduction in mortality among men and a 10% (HR = 0.90, 95%CI: 0.86, 0.94) among women. Meanwhile, a one-kilogram increase in grip strength was associated with a 6% (HR = 0.94, 95%CI: 0.93, 0.95) and an 8% (HR = 0.92, 95%CI: 0.90, 0.94) decrease in mortality among Danish men and women, respectively, and with a 2% (HR = 0.98, 95%CI: 0.97, 0.99) and a 3% (HR = 0.97, 95%CI: 0.95, 0.98) reduction in mortality among the English men and women, respectively. Conclusion The study suggests that, although absolute grip strength values appear to vary across the Muscovite, Danish, and English samples, the degree to which grip strength is predictive of mortality is comparable across national populations with diverse socioeconomic and health profiles and life expectancy levels.

Clinical Management of Catecholaminergic Polymorphic Ventricular TachycardiaCLINICAL PERSPECTIVE

Background— Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic disorder causing life-threatening arrhythmias whenever sympathetic activity increases. &bgr;-&Bgr;lockers are the mainstay of therapy; when they fail, implantable cardioverter-defibrillators (ICDs) are used but often cause multiple shocks. Preliminary results with flecainide appear encouraging. We proposed left cardiac sympathetic denervation (LCSD) as useful additional therapy, but evidence remains anecdotal. Methods and Results— We report 63 patients with CPVT who underwent LCSD as secondary (n=54) or primary (n=9) prevention. The median post-LCSD follow-up was 37 months. The 9 asymptomatic patients remained free of major cardiac events. Of the 54 patients with prior major cardiac events either on (n=38) or off (n=16) optimal medical therapy, 13 (24%) had at least 1 recurrence: 0 patients had an aborted cardiac arrest, 2 patients had syncope only, 10 patients had ≥1 appropriate ICD discharges, and 1 patient died suddenly. The 1- and 2-year cumulative event-free survival rates were 87% and 81%. The percentage of patients with major cardiac events despite optimal medical therapy (n=38) was reduced from 100% to 32% (P<0.001) after LCSD, and among 29 patients with a presurgical ICD, the rate of shocks dropped by 93% from 3.6 to 0.6 shocks per person per year (P<0.001). Patients with an incomplete LCSD (n=7) were more likely to experience major cardiac events after LCSD (71% versus 17%; P<0.01) than those with a complete LCSD. Conclusions— LCSD is an effective antifibrillatory intervention for patients with CPVT. Whenever syncope occurs despite optimal medical therapy, LCSD could be considered the next step rather than an ICD and could complement ICDs in patients with recurrent shocks.Background— Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic disorder causing life-threatening arrhythmias whenever sympathetic activity increases. β-Βlockers are the mainstay of therapy; when they fail, implantable cardioverter-defibrillators (ICDs) are used but often cause multiple shocks. Preliminary results with flecainide appear encouraging. We proposed left cardiac sympathetic denervation (LCSD) as useful additional therapy, but evidence remains anecdotal. Methods and Results— We report 63 patients with CPVT who underwent LCSD as secondary (n=54) or primary (n=9) prevention. The median post-LCSD follow-up was 37 months. The 9 asymptomatic patients remained free of major cardiac events. Of the 54 patients with prior major cardiac events either on (n=38) or off (n=16) optimal medical therapy, 13 (24%) had at least 1 recurrence: 0 patients had an aborted cardiac arrest, 2 patients had syncope only, 10 patients had ≥1 appropriate ICD discharges, and 1 patient died suddenly. The 1- and 2-year cumulative event-free survival rates were 87% and 81%. The percentage of patients with major cardiac events despite optimal medical therapy (n=38) was reduced from 100% to 32% ( P <0.001) after LCSD, and among 29 patients with a presurgical ICD, the rate of shocks dropped by 93% from 3.6 to 0.6 shocks per person per year ( P <0.001). Patients with an incomplete LCSD (n=7) were more likely to experience major cardiac events after LCSD (71% versus 17%; P <0.01) than those with a complete LCSD. Conclusions— LCSD is an effective antifibrillatory intervention for patients with CPVT. Whenever syncope occurs despite optimal medical therapy, LCSD could be considered the next step rather than an ICD and could complement ICDs in patients with recurrent shocks. # CLINICAL PERSPECTIVE {#article-title-34}