Oxidized LDL, Gamma-Glutamyltransferase and Adverse Outcomes in Older Adults.
ABSTRACT: OBJECTIVES:Gamma-glutamyltransferase (GGT) is a biomarker of liver disease and oxidative stress which was associated with all-cause and cardiovascular (CV) mortality in the general population and in patients with high risk conditions. This study aims at assessing whether oxLDL modifies the relationship between GGT, all-cause, and CV mortality in elderly individuals from the general population. DESIGN:Observational longitudinal study. SETTING:Population-based cohort of older individuals (>65 years) free of liver disease. PARTICIPANTS:One thousand and thirty-eight individuals from the Invecchiare in Chianti (InCHIANTI) study. MEASUREMENTS:Serum GGT level, oxidized low-density lipoprotein (oxLDL), CV comorbidities, all-cause and CV mortality. RESULTS:The median age of the study population (n = 1,038) was 74 years (inter-quartile range: 69-79), 152 individuals (15%) had past CV events. During a median follow-up of 9 years, 401 individuals died, 168 of them (42%) for CV causes. In adjusted analyses, GGT predicted all-cause mortality (HR for 20 U/L increase in serum GGT: 1.11, 95% CI: 1.02-1.21, P = .02) and CV mortality (HR: 1.17, 95% CI: 1.03-1.33; P = .02). Furthermore, in an analysis for interaction circulating oxLDL amplified the effect of GGT on all-cause mortality (P = .003). CONCLUSION:Circulating oxLDL amplifies the effect of GGT on mortality in the elderly. The mechanism for this association remains unknown and requires further research, including studying the potential role of GGT in oxidative stress. These results are consistent with the hypothesis of a causal role of GGT in the CV morbidity and mortality in older individuals and indicate that oxLDL plays a crucial role in the interpretation of the link between GGT and the risk of adverse clinical events in this population.
Project description:Although it has been suggested that the ?-glutamyltransferase (GGT) level is an indicator of cardiometabolic disorders, there is no previous study to evaluate the implication of GGT variability on the development of myocardial infarction (MI), stroke, all-cause mortality, and cardiovascular disease (CVD)-related mortality. GGT variability was measured as the coefficient variance (GGT-CV), standard deviation (GGT-SD), and variability independent of the mean (GGT-VIM). Using the population-based Korean National Health Insurance Service-Health Screening Cohort, we followed 158,736 Korean adults over a median duration of 8.4 years. In multivariable Cox proportional hazard analysis, the risk of mortality, MI, and stroke showed a stepwise increase according to the quartiles of GGT-CV, GGT-SD or GGT-VIM. In the highest quartile of GGT-CV compared to the lowest quartile after adjusting for confounding variables including mean GGT, the hazard ratios (HRs) for incident MI, stroke, mortality, and CVD-related mortality were 1.19 (95% confidence interval (CI), 1.06-1.34; <i>p</i> < 0.001), 1.20 (95% CI, 1.10-1.32; <i>p</i> < 0.001), 1.41 (95% CI, 1.33-1.51; <i>p</i> < 0.001), and 1.52 (95% CI, 1.30-1.78; <i>p</i> < 0.001), respectively, which were similar or even higher compared with those associated with total cholesterol variability. This is the first study to demonstrate that high GGT variability is associated with increased risk of MI, stroke, all-cause mortality, and CVD-related mortality in the general population.
Project description:<h4>Background</h4>Serum gamma-glutamyltransferase (GGT) elevation likely contributes to cardiovascular (CV) mortality, however it has remained unknown whether a dose-response relationship exists between serum GGT and CV mortality.<h4>Methods</h4>We searched the PubMed, EMBASE, and Cochrane library databases for prospective cohort studies published up to October 2, 2016. Summary hazard ratios (HRs) with their corresponding 95% confidence intervals (CIs) were calculated using a fixed effects model.<h4>Findings</h4>Nine prospective studies, including 527,589 participants and more than 7,011 cases, were included in this meta-analysis. For the moderate, high, and highest levels of GGT, the pooled HRs of CV mortality were 1.11 (95% CI = 1.04-1.19), 1.29 (95% CI = 1.21-1.38) and 1.59 (95% CI = 1.47-1.72), respectively (all p < 0.05 as compared to the lowest levels of GGT). Additionally, the HR per incremental increase of GGT by 10 U/L was 1.10 (95% CI = 1.08-1.11). Evidence of a positive relationship with nonlinear trend for GGT elevation with CV mortality in females was found (P = 0.04 for nonlinearity). However, a linear model was better fit to illustrate the GGT-CV mortality among males (P = 0.304 for nonlinearity).<h4>Conclusions</h4>These findings indicate that serum GGT activity within the reference interval is positively associated with increased risk of CV mortality in a dose-response manner.
Project description:BACKGROUND:The frailty index (FI) is a sensitive instrument to measure the degree of frailty in older adults, and is increasingly used in cohort studies on aging. AIMS:To operationalize an FI among older adults in the "Invecchiare in Chianti" (InCHIANTI) study, and to validate its predictive capacity for mortality. METHODS:Longitudinal data were used from 1129 InCHIANTI participants aged???65 years. A 42-item FI was operationalized following a standard procedure using baseline data (1998/2000). Associations of the FI with 3- and 6-year all-cause and cardiovascular disease (CVD) mortality were studied using Cox regression. Predictive accuracy was estimated by the area under the ROC curve (AUC), for a continuous FI score and for different cut-points. RESULTS:The median FI was 0.13 (IQR 0.08-0.21). Scores were higher in women, and at advanced age. The FI was associated with 3- and 6-year all-cause and CVD mortality (HR range per 0.01 FI increase?=?1.03-1.07, all p?<?0.001). The continuous FI score predicted the mortality outcomes with moderate-to-good accuracy (AUC range 0.72-0.83). When applying FI cut-offs between 0.15 and 0.35, the accuracy of this FI for predicting mortality was moderate (AUC range 0.61-0.76). Overall, the predictive accuracy of the FI was higher in women than in men. CONCLUSIONS:The FI operationalized in the InCHIANTI study is a good instrument to grade the risk of all-cause mortality and CVD mortality. More measurement properties, such as the responsiveness of this FI when used as outcome measure, should be investigated in future research.
Project description:Objective: The aim of this study was to investigate whether an index of overall cardiovascular health (CVH) is associated with disability in older individuals. Method: Data on 925 participants of the InCHIANTI study (Invecchiare in Chianti, aging in the Chianti area, ?65 years, 55% women) with median follow-up of 9 years were used. CVH score was assessed by smoking status, physical activity, body mass index, diet quality, blood pressure, plasma cholesterol, and fasting blood glucose. Disability was examined using instrumental activities of daily living (IADL disabilities >0 vs. 0) and activities of daily living (ADL disabilities >0 vs. 0). Generalized estimating equations and Cox models assessed relationships between baseline CVH with disability and worsening over 9 years. Results: A 1-point increase in the CVH score was associated with 23% and 17% of lower odds of ADL (p < .001) and IADL (p < .001) disability and was protective of worsening of disability over 9 years. Cox models demonstrated that a 1-point increase in CVH score was associated with lower hazards of both ADL (hazard ratio [HR] = 0.86, p = .005) and IADL (HR = 0.91, p = .007) disability. Discussion: Among older individuals, better CVH was associated with lower risk of disability and worsening over 9 years.
Project description:<h4>Background</h4>The hormone klotho is encoded by aging-suppressor gene klotho and has multiple roles, including regulating mineral (calcium and phosphate) homeostasis. Vitamin D also regulates mineral homeostasis and upregulates klotho expression. Klotho positively relates to longevity, upper-extremity strength, and reduced disability in older adults; however, it is unknown whether circulating klotho relates to lower-extremity physical performance or whether the relation of vitamin D with physical performance is mediated by klotho.<h4>Methods</h4>Klotho and 25-hydroxyvitamin D [25(OH)D] were measured in 860 participants aged ? 55 years in Invecchiare in Chianti, "Aging in Chianti" (InCHIANTI), a prospective cohort study comprising Italian adults. Lower-extremity physical performance was measured using the Short Physical Performance Battery, a summary score of balance, chair stand ability, and walking speed. Weighted estimating equations related plasma klotho and serum 25(OH)D concentrations measured at one visit to Short Physical Performance Battery measured longitudinally at multiple visits.<h4>Results</h4>Each additional natural log of klotho (pg/mL) was associated with 0.47 higher average Short Physical Performance Battery scores (95% confidence interval: 0.08 to 0.86, p value = .02) after adjustment for covariates, including 25(OH)D. Each natural log of 25(OH)D (ng/mL) was associated with 0.61 higher average Short Physical Performance Battery scores (95% confidence interval: 0.35 to 0.88, p value < .001) after adjustment for covariates, a result that changed little after adjustment for klotho.<h4>Conclusions</h4>Plasma klotho and 25(OH)D both positively related to lower-extremity physical performance. However, the findings did not support the hypothesis that klotho mediates the relation of 25(OH)D with physical performance.
Project description:<h4>Aims</h4>Although absolute (AID) and functional iron deficiency (FID) are known risk factors for patients with cardiovascular (CV) disease, their relevance for the general population is unknown. The aim was to assess the association between AID/FID with incident CV disease and mortality in the general population.<h4>Methods and results</h4>In 12 164 individuals from three European population-based cohorts, AID was defined as ferritin < 100 μg/L or as ferritin < 30 μg/L (severe AID), and FID was defined as ferritin < 100 μg/L or ferritin 100-299 μg/L and transferrin saturation < 20%. The association between iron deficiency and incident coronary heart disease (CHD), CV mortality, and all-cause mortality was evaluated by Cox regression models. Population attributable fraction (PAF) was estimated. Median age was 59 (45-68) years; 45.2% were male. AID, severe AID, and FID were prevalent in 60.0%, 16.4%, and 64.3% of individuals. AID was associated with CHD [hazard ratio (HR) 1.20, 95% confidence interval (CI) 1.04-1.39, P = 0.01], but not with mortality. Severe AID was associated with all-cause mortality (HR 1.28, 95% CI 1.12-1.46, P < 0.01), but not with CV mortality/CHD. FID was associated with CHD (HR 1.24, 95% CI 1.07-1.43, P < 0.01), CV mortality (HR 1.26, 95% CI 1.03-1.54, P = 0.03), and all-cause mortality (HR 1.12, 95% CI 1.01-1.24, P = 0.03). Overall, 5.4% of all deaths, 11.7% of all CV deaths, and 10.7% of CHD were attributable to FID.<h4>Conclusions</h4>In the general population, FID was highly prevalent, was associated with incident CHD, CV death, and all-cause death, and had the highest PAF for these events, whereas AID was only associated with CHD and severe AID only with all-cause mortality. This indicates that FID is a relevant risk factor for CV diseases in the general population.
Project description:We examined whether long-term gamma-glutamyl transferase (GGT) variability can predict cardiovascular disease (CVD) and mortality in individuals with diabetes. We included 698,937 Koreans diabetes patients older than 40 years without histories of CVD, chronic liver disease, or heavy alcoholics who received health exams supported by the Korean government more than once in 2009-2012 (baseline). We used Cox proportional analyses to estimate the risk of stroke, myocardial infarction (MI), and all-cause mortality until December 31, 2016, according to the quartiles of the average successive variability (ASV) of GGT measured during the five years before the baseline. A total 26,119, 15,103, and 39,982 cases of stroke, MI, and death, respectively, were found. GGT ASV quartile 4 had a significantly higher risk of stroke and all-cause mortality than quartile 1, with adjustment for risk factors, such as baseline glucose and GGT level, and comorbidities. Hazard ratios (95% confidence intervals) for GGT ASV quartile 4 were 1.06 (1.03-1.10) and 1.23 (1.20-1.27) for stroke and mortality, respectively. This significant association was shown consistently across the baseline GGT quartiles. GGT variability was related to the risk of stroke and all-cause mortality. The effect was most pronounced in all-cause mortality, irrespective of baseline GGT level.
Project description:Although liver enzymes, such as ?-glutamyltransferase (GGT), alanine aminotransferase (ALT), and aspartate aminotransferase (AST), have recently been suggested as risk factors for cardiovascular diseases (CVD), impact on mortality after myocardial infarction (MI) or ischemic stroke (IS) was not previously examined. Using a population-based, nationwide cohort database, we explored the implication of GGT and aminotransferases on the development of CVD and all-cause mortality during a median 9.1 years of follow-up. Among 16,624,006 Korean adults, both GGT and aminotransferases exhibited a positive relationship with MI, IS, and mortality in a multivariate adjusted model. ALT and AST showed U-shaped associations with mortality, whereas GGT showed a positive linear relationship with mortality. The risk of 1-year mortality after MI or IS was significantly higher in the highest quartile of GGT compared to the lowest quartile (HR, 1.46; 95% CI, 1.40-1.52). The implication of GGT on MI, IS, and mortality persisted regardless of traditional cardiovascular risk parameters. This study demonstrated the unique pattern of association of ALT, AST, and GGT with the development of CVD and all-cause mortality in the Korean population. In particular, GGT showed the most robust linear relationship with mortality before and after cardiovascular events independent of risk factors.
Project description:<h4>Background</h4>L-Arginine and its dimethylated derivatives asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) have been associated with cardiovascular (CV) and all-cause mortality in populations at risk. The present study aimed to investigate the prognostic value of L-arginine and its derivatives in the general population.<h4>Methods and results</h4>We evaluated 3,952 individuals (1,936 men and 2,016 women) aged 20-81 (median (IQR) 51 (37; 64) years) from the population-based Study of Health in Pomerania (SHIP). Associations of continuous [per standard deviation (SD) increase] and categorized (age- and sex-specific tertiles) serum L-arginine, ADMA, and SDMA concentrations with all-cause and cause-specific mortality were analysed. During a median (IQR) follow-up period of 10.1 (9.3; 10.8) years (38,476 person-years), 426 deaths (10.8%) were observed, including 139 CV deaths (3.5%), and 150 cancer deaths (3.8%). After multivariable adjustment, we revealed a positive association of SDMA with all-cause [hazard ratio (HR) per SD increase: 1.16, 95% confidence interval (CI): 1.07-1.25] and CV mortality [HR: 1.19, 95% CI: 1.05-1.35]. In contrast, we did not observe any association of SDMA with cancer mortality. Neither L-arginine nor ADMA were associated with all-cause or CV mortality.<h4>Conclusion</h4>SDMA, but not ADMA, is an independent predictor of all-cause and CV mortality in a large population-based cohort of European ancestry.
Project description:<h4>Background</h4>Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic disease and independently affects the development of cardiovascular (CV) disease. We investigated whether hepatic steatosis and/or fibrosis are associated with the development of incident heart failure (iHF), hospitalized HF (hHF), mortality, and CV death in both the general population and HF patients.<h4>Methods</h4>We analyzed 778,739 individuals without HF and 7445 patients with pre-existing HF aged 40 to 80 years who underwent a national health check-up from January 2009 to December 2012. The presence of hepatic steatosis and advanced hepatic fibrosis was determined using cutoff values for fatty liver index (FLI) and BARD score. We evaluated the association of FLI or BARD score with the development of iHF, hHF, mortality and CV death using multivariable-adjusted Cox regression models.<h4>Results</h4>A total of 28,524 (3.7%) individuals in the general population and 1422 (19.1%) pre-existing HF patients developed iHF and hHF respectively. In the multivariable-adjusted model, participants with an FLI ≥ 60 were at increased risk for iHF (hazard ratio [HR], 95% confidence interval [CI], 1.30, 1.24-1.36), hHF (HR 1.54, 95% CI 1.44-1.66), all-cause mortality (HR 1.62, 95% CI 1.54-1.70), and CV mortality (HR 1.41 95% CI 1.22-1.63) in the general population and hHF (HR 1.26, 95% CI 1.21-1.54) and all-cause mortality (HR 1.54 95% CI 1.24-1.92) in the HF patient group compared with an FLI < 20. Among participants with NAFLD, advanced liver fibrosis was associated with increased risk for iHF, hHF, and all-cause mortality in the general population and all-cause mortality and CV mortality in the HF patient group (all p < 0.05).<h4>Conclusion</h4>Hepatic steatosis and/or advanced fibrosis as assessed by FLI and BARD score was significantly associated with the risk of HF and mortality.