Expert opinion on design and endpoints for studies on catheter ablation of atrial fibrillation.

INTRODUCTION: Catheter ablation of atrial fibrillation (AF) is frequently studied in randomized trials, observational and registry studies. The aim of this expert opinion is to provide guidance for clinicians and industry regarding the development of future clinical studies on catheter ablation of AF, implement lessons learned from previous studies, and promote a higher degree of consistency across studies. BACKGROUND: Studies on catheter ablation of AF may benefit from well-described definitions of endpoints and consistent methodology and documentation of outcomes related to efficacy, safety and cost-effectiveness. The availably of new, innovative technologies warrants further consideration about their application and impact on study design and the choice of endpoints. Moreover, recent insights gained from AF ablation studies suggest a reconsideration of some methodological aspects. METHODS: A panel of clinical experts on catheter ablation of AF and designing and conducting clinical studies developed an expert opinion on the design and endpoints for studies on catheter ablation of AF. Discussions within the expert panel with the aim to reach consensus on predefined topics were based on outcomes reported in the literature and experiences from recent clinical trials. RESULTS: A comprehensive set of recommendations is presented. Key elements include the documentation of clinical AF, medication during the study, repeated ablations and their effect on endpoint assessments, postablation blanking and the choice of rhythm-related and other endpoints. CONCLUSION: This expert opinion provides guidance and promotes consistency regarding design of AF catheter ablation studies and identified aspects requiring further research to optimize study design and methodology. CONDENSED ABSTRACT: Recent insights from studies on catheter ablation of atrial fibrillation (AF) and the availability of new innovative technologies warrant reconsideration of methodological aspects related to study design and the choice and assessment of endpoints. This expert opinion, developed by clinical experts on catheter ablation of AF provides a comprehensive set of recommendations related to these methodological aspects. The aim of this expert opinion is to provide guidance for clinicians and industry regarding the development of clinical studies, implement lessons learned from previous studies, and promote a higher degree of consistency across studies.

Effects of smoking and smoking cessation on human serum metabolite profile: results from the KORA cohort study.

BACKGROUND: Metabolomics helps to identify links between environmental exposures and intermediate biomarkers of disturbed pathways. We previously reported variations in phosphatidylcholines in male smokers compared with non-smokers in a cross-sectional pilot study with a small sample size, but knowledge of the reversibility of smoking effects on metabolite profiles is limited. Here, we extend our metabolomics study with a large prospective study including female smokers and quitters. METHODS: Using targeted metabolomics approach, we quantified 140 metabolite concentrations for 1,241 fasting serum samples in the population-based Cooperative Health Research in the Region of Augsburg (KORA) human cohort at two time points: baseline survey conducted between 1999 and 2001 and follow-up after seven years. Metabolite profiles were compared among groups of current smokers, former smokers and never smokers, and were further assessed for their reversibility after smoking cessation. Changes in metabolite concentrations from baseline to the follow-up were investigated in a longitudinal analysis comparing current smokers, never smokers and smoking quitters, who were current smokers at baseline but former smokers by the time of follow-up. In addition, we constructed protein-metabolite networks with smoking-related genes and metabolites. RESULTS: We identified 21 smoking-related metabolites in the baseline investigation (18 in men and six in women, with three overlaps) enriched in amino acid and lipid pathways, which were significantly different between current smokers and never smokers. Moreover, 19 out of the 21 metabolites were found to be reversible in former smokers. In the follow-up study, 13 reversible metabolites in men were measured, of which 10 were confirmed to be reversible in male quitters. Protein-metabolite networks are proposed to explain the consistent reversibility of smoking effects on metabolites. CONCLUSIONS: We showed that smoking-related changes in human serum metabolites are reversible after smoking cessation, consistent with the known cardiovascular risk reduction. The metabolites identified may serve as potential biomarkers to evaluate the status of smoking cessation and characterize smoking-related diseases.

Prospective association between self-reported life satisfaction and mortality: results from the MONICA/KORA Augsburg S3 survey cohort study.

BACKGROUND: To identify factors which determine high life satisfaction (LS) and to analyse the prognostic influence of LS on mortality. METHODS: Data collection was conducted on 2,675 participants, age 25-74 years, as part of the MONICA Augsburg Project 1994-95. Multivariate logistic regression analyses were used to determine factors associated with high LS (measured with one item, 6-level Likert scale, where "high" = very satisfied/most of the time very satisfied with ones personal life). After 12 years mean follow-up, a total of 245 deaths occurred. We calculated age- and sex-adjusted incident mortality rates per 10,000. Hazard ratios (HRs) were estimated from Cox proportional hazards models. RESULTS: Independent determinants of LS were income, health-perception, and social support, as well as somatisation, anger or depressive symptoms (all p < 0.05). Participants with higher LS (n = 721, 27%) benefited the most with respect to absolute mortality risk reduction (higher LS = 67; mid = 98; low = 140 per 10,000). The sex-stratified analyses indicated an independent association of higher LS and survival for men (HR 0.55; 95% CI 0.37 - 0.81) but not for women. CONCLUSIONS: Baseline assessment demonstrated that psychological, social and life-style factors, but not somatic co-morbidities, were relevant determinants of LS. Moreover, the analysis showed that men with higher LS have a substantial long-term survival benefit. The observed association between LS and mortality may be attributed to common underlying causes such as social network integration and/or self-rated health.

Mental health in the aged: prevalence, covariates and related neuroendocrine, cardiovascular and inflammatory factors of successful aging.

BACKGROUND: Although aging is accompanied by diminished functioning, many elderly individuals preserve a sense of well-being. While the concept of "successful aging" has been popular for many decades, little is known about its psycho-physiologic and endocrine underpinnings. KORA-Age is a population-based, longitudinal study designed to determine the prevalence of successfully aged men and women between 65 and 94 years old in the MONICA/KORA Augsburg cohort of randomly selected inhabitants. Specifically, we aim to identify predictors of successful aging and to elucidate bio-psychosocial mechanisms that maintain mental health and successful adaptation despite adverse experiences of life and aging. METHODS/DESIGN: Components of successful aging were assessed in a telephone survey of 4,127 participants (2008-2009) enrolled in the MONICA/KORA cohort, on average, 13 years earlier. Psychosocial, somatic and behavioural predictors are used to determine factors that contribute to successful aging. An age-stratified random sub-sample (n = 1,079) participated in a personal interview where further psychological mechanisms that may underlie successful adaptation (resilience, social support, attachment) were examined. The interactions among neuroendocrine systems in the aging process are investigated by studying the cortisol/dehydroepiandrosterone-sulfate ratio, the level of insulin-like growth factor I, and oxytocin. DISCUSSION: Longitudinal determinants of successful aging can be assessed based on a follow-up of an average of 13 years. A comprehensive analysis of biological as well as physio-psychological information provides a unique opportunity to investigate relevant outcomes such as resilience and frailty in the elderly population.

Socioeconomic position, resilience, and health behaviour among elderly people.

OBJECTIVES: Healthy psychological functioning, the ability to respond rapidly to environmental changes, has been associated with better health outcomes. Less work has examined the association with health behaviour. This study explores whether resilience (a specific expression of healthy psychological functioning) is positively associated with health behaviour in an elderly population aged ≥65 years and whether this association differs in different socioeconomic groups. METHODS: Resilience was measured in 3,942 elderly participating in a population-based cohort study (KORA-Age study) in Germany through a short version of the Resilience Scale developed by Wagnild and Young. Regression analyses were performed by socioeconomic position (low/high educational level or income) for two outcome variables, i.e. high consumption of fruit and vegetables and high/moderate physical activity. RESULTS: Resilient people were more likely to consume ≥5 servings of fruit and vegetables a day and to perform high/moderate physical activity as compared to non-resilient people (ORs ranging from 1.5 to 2.2), irrespective of socioeconomic position. CONCLUSIONS: Resilience could provide an important starting point for health promotion strategies, addressing resources rather than deficits and risk factors.

Systemic inflammation (Interleukin 6) predicts all-cause mortality in men: results from a 9-year follow-up of the MEMO Study.

This study aimed to investigate the association of biomarkers among circulating pro-inflammatory cytokines with all-cause mortality in elderly community dwellings of the MEMO study, Germany. All-cause mortality (cancer, cardiovascular diseases (CVD), and other causes of death) was assessed in a general population sample (N = 385) of the elderly (age 65-83 years) 9 years after baseline assessment in 1998. As markers of inflammation, a variety of cytokines (IL-1beta, IL-4sR, IL-6, IL-8, IL-10, IL-12, TNF-alpha) were assessed in serum. Cox proportional Hazard model was used to estimate the association of cytokines with all-cause mortality over 9 years. In total, 110 deaths had occurred during follow-up (cancer N = 36; CVD N = 56; other = 18). Deaths were more frequent in male (N = 76, 37.4%) as compared to females (N = 40, 21.9%; p = 0.001). Among individual cytokines, IL-1 beta, IL-6, IL-8, IL-10, and TNF-alpha were associated with all-cause mortality, of which IL-6, IL-8, and IL-10 remained significant after adjusting for confounders. When the upper tertiles of these cytokines were compared to the lower tertiles, only IL-6 was consistently related to all-cause mortality independently of the level of adjustment and showing a dose-response relationship between IL-6 tertiles and risk of death. This effect originated in the male population. The study shows that IL-6 is a powerful predictor of all-cause mortality in male elderly community dwellings. Higher levels of IL-6 may reflect a chronic low-level systemic inflammation prospectively increasing the risk of death in the elderly.

Metabolic profiling reveals distinct variations linked to nicotine consumption in humans--first results from the KORA study.

Exposure to nicotine during smoking causes a multitude of metabolic changes that are poorly understood. We quantified and analyzed 198 metabolites in 283 serum samples from the human cohort KORA (Cooperative Health Research in the Region of Augsburg). Multivariate analysis of metabolic profiles revealed that the group of smokers could be clearly differentiated from the groups of former smokers and non-smokers. Moreover, 23 lipid metabolites were identified as nicotine-dependent biomarkers. The levels of these biomarkers are all up-regulated in smokers compared to those in former and non-smokers, except for three acyl-alkyl-phosphatidylcholines (e.g. plasmalogens). Consistently significant results were further found for the ratios of plasmalogens to diacyl-phosphatidylcolines, which are reduced in smokers and regulated by the enzyme alkylglycerone phosphate synthase (alkyl-DHAP) in both ether lipid and glycerophospholipid pathways. Notably, our metabolite profiles are consistent with the strong down-regulation of the gene for alkyl-DHAP (AGPS) in smokers that has been found in a study analyzing gene expression in human lung tissues. Our data suggest that smoking is associated with plasmalogen-deficiency disorders, caused by reduced or lack of activity of the peroxisomal enzyme alkyl-DHAP. Our findings provide new insight into the pathophysiology of smoking addiction. Activation of the enzyme alkyl-DHAP by small molecules may provide novel routes for therapy.