High triglyceride-glucose index in young adulthood is associated with incident cardiovascular disease and mortality in later life: insight from the CARDIA study.

BACKGROUND: This study aimed to investigate the associations between the triglyceride-glucose (TyG) index in young adulthood with incident cardiovascular disease (CVD) and mortality. METHODS: We included 4,754 participants from the Coronary Artery Risk Development in Young Adults study at baseline. The TyG index was calculated as ln (fasting TG [mg/dl] × fasting glucose [mg/dl]/2), and the TyG index trajectories were identified by using the latent class growth mixture model. We evaluated the association between the baseline and trajectories of the TyG index with incident CVD events and all-cause mortality using Cox proportional hazards regression analysis. The added value of the TyG index included in pooled cohort equations for CVD prediction was also analyzed. RESULTS: Among 4754 participants (mean age 24.72 years, 45.8% male, 51.2% black), there were 158 incident CVD events and 246 all-cause mortality during a median 25 years follow-up. After adjusting for multiple confounding variables, each one-unit increase in the TyG index was associated with a 96% higher CVD risk (hazard ratio [HR] 1.96, 95% confidence interval [CI] 1.44-2.66) and a 85% higher all-cause mortality risk (HR 1.85, 95% CI 1.45-2.36). Three distinct trajectories of the TyG index along the follow-up duration were identified: low (44.0%), moderate (45.5%), and high (10.5%). Compared with those participants in the low TyG index trajectory group, those in the high TyG index trajectory group had a greater risk of CVD events (HR 2.35, 95% CI 1.34-4.12) and all-cause mortality (HR 3.04, 95% CI 1.83-5.07). The addition of baseline TyG index to pooled cohort equations for CVD improved the C-statistics (P < 0.001), integrated discrimination improvement value (P < 0.001), and category-free net reclassification improvement value (P = 0.003). CONCLUSIONS: Higher baseline TyG index levels and higher long-term trajectory of TyG index during young adulthood were significantly associated with an increased risk of incident CVD events and all-cause mortality in later life.

The gut microbe-derived metabolite trimethylamine-N-oxide induces aortic valve fibrosis via PERK/ATF-4 and IRE-1α/XBP-1s signaling in vitro and in vivo.

BACKGROUND AND AIMS: The gut microbe-derived metabolite trimethylamine-N-oxide (TMAO) has been implicated in the development of cardiovascular fibrosis. Endoplasmic reticulum (ER) stress occurs after the dysfunction of ER and its structure. The three signals PERK/ATF-4, IRE-1α/XBP-1s and ATF6 are activated upon ER stress. Recent reports have suggested that the activation of PERK/ATF-4 and IRE-1α/XBP-1s signaling contributes to cardiovascular fibrosis. However, whether TMAO mediates aortic valve fibrosis by activating PERK/ATF-4 and IRE-1α/XBP-1s signaling remains unclear. METHODS: Human aortic valve interstitial cells (AVICs) were isolated from aortic valve leaflets. PERK IRE-1α, ATF-4, XBP-1s and CHOP expression, and production of collagen Ⅰ and TGF-ß1 were analyzed following treatment with TMAO. The role of PERK/ATF-4 and IRE-1α/XBP-1s signaling pathways in TMAO-induced fibrotic formation was determined using inhibitors and small interfering RNA. RESULTS: Diseased valves produced greater levels of ATF-4, XBP-1, collagen Ⅰ and TGF-ß1. Interestingly, diseased cells exhibited augmented PERK/ATF-4 and IRE-1α/XBP-1s activation after TMAO stimulation. Inhibition and silencing of PERK/ATF-4 and IRE-1α/XBP-1s each resulted in enhanced suppression of TMAO-induced fibrogenic activity in diseased cells. Mice treated with dietary choline supplementation had substantially increased TMAO levels and aortic valve fibrosis, which were reduced by 3,3-dimethyl-1-butanol (DMB, an inhibitor of trimethylamine formation) treatment. Moreover, a high-choline and high-fat diet remodeled the gut microbiota in mice. CONCLUSIONS: TMAO promoted aortic valve fibrosis through activation of PERK/ATF-4 and IRE-1α/XBP-1s signaling pathways in vitro and in vivo. Modulation of diet, gut microbiota, TMAO, PERK/ATF-4 and IRE1-α/XBP-1s may be a promising approach to prevent aortic valve fibrosis.

Serum Klotho Modifies the Associations of 25-Hydroxy Vitamin D With All-Cause and Cardiovascular Mortality.

BACKGROUND: The association between 25-hydroxyvitamin D and mortality remains controversial. Klotho, a biomarker of vitamin D activation and metabolism, may play a key role in this association. However, it is unclear whether the association between vitamin D deficiency and mortality risk is modified by klotho levels. Therefore, this study investigated the joint association of serum 25-hydroxyvitamin D [25(OH)D] and klotho with mortality risk in American community-dwelling adults. METHODS: A total of 9870 adults from the National Health and Nutrition Examination Survey (2007-2016) were included in our study. Mortality data were ascertained by linking participants to National Death Index records. Cox proportional hazards models were used to assess the association among serum 25(OH)D, serum klotho, and all-cause and cardiovascular disease (CVD) mortality. RESULTS: We found a significant interaction between klotho and serum 25(OH)D in all-cause mortality (P = .028). With klotho > 848.4 pg/mL (risk threshold on mortality), no significant all-cause and CVD mortality risk was observed at any level of serum 25(OH)D. However, with klotho < 848.4 pg/mL, a significant all-cause and CVD mortality risk was observed with serum 25(OH)D < 50 nmol/L [hazards ratio (HR), 1.36; 95% confidence interval (CI), 1.10-1.69; HR, 1.78; 95% CI, 1.16-3.45) and serum 25(OH)D of continuous variable (HR, 0.98; 95% CI, .97-.99; HR, 0.98; 95% CI, .98-.99). In addition, vitamin D metabolism disruption accessed by the combination of decreasing serum 25(OH)D (<50 nmol/L) and klotho (<848.4 pg/mL) was associated with significant all-cause mortality (HR, 1.48; 95% CI, 1.11-1.96) and CVD mortality (HR, 2.36; 95% CI, 1.48-3.75). CONCLUSIONS: Vitamin D-associated mortality risk is observed only with concurrently decreasing klotho, indicating that vitamin D metabolism dysfunction increases the risk of mortality. Klotho levels could help predict long-term mortality outcomes and thus may be useful concurrently for guiding vitamin D supplementation therapy decision-making in populations with vitamin D deficiency.

Predictive performance of established cardiovascular risk scores in the prediabetic population: external validation using the UK Biobank data set.

AIMS: Prediabetes is a highly heterogenous metabolic state with increased risk of cardiovascular disease (CVD). Current guidelines raised the necessity of CVD risk scoring for prediabetes without clear recommendations. Thus, this study aimed to systematically assess the performance of 11 models, including five general population-based and six diabetes-specific CVD risk scores, in prediabetes. METHODS AND RESULTS: A cohort of individuals aged 40-69 years with prediabetes (HbA1c ≥ 5.7 and <6.5%) and without baseline CVD or known diabetes was identified from the UK Biobank, which was used to validate 11 prediction models for estimating 10- or 5-year risk of CVD. Model discrimination and calibration were evaluated by Harrell's C-statistic and calibration plots, respectively. We further performed decision curve analyses to assess the clinical usefulness.Overall, 56 831 prediabetic individuals were included, of which 4303 incident CVD events occurred within a median follow-up of 8.9 years. All the 11 risk scores assessed had modest C-statistics for discrimination ranging from 0.647 to 0.680 in prediabetes. Scores developed in the general population did not outperform those diabetes-specific models (C-statistics, 0.647-0.675 vs. 0.647-0.680), while the PREDICT-1° Diabetes equation developed for Type 2 diabetes performed best [0.680 (95% confidence interval, 0.672-0.689)]. The calibration plots suggested overall poor calibration except that the PREDICT-1° Diabetes equation calibrated well after recalibration. The decision curves generally indicated moderate clinical usefulness of each model, especially worse within high threshold probabilities. CONCLUSION: Neither risk stratification schemes for the general population nor those specific for Type 2 diabetes performed well in the prediabetic population. The PREDICT-1° Diabetes equation could be a substitute in the absence of better alternatives, rather than the general population-based scores. More precise and targeted risk assessment tools for this population remain to be established.

GP73 enhances the ox-LDL-induced inflammatory response in THP-1 derived macrophages via affecting NLRP3 inflammasome signaling.

BACKGROUND: Atherosclerosis is a chronic inflammatory disease with its molecular basis incompletely understood. Here, we determined whether the Golgi phosphoprotein 73 (GP73), a novel protein highly related to inflammation and disrupted lipid metabolism, was involved in the development of atherosclerosis. METHODS: Public microarray databases of human vascular samples were analyzed for expression patterns. Apolipoprotein-E-gene-deficient (ApoE-/-) mice (8-week-old) were randomly assigned to either a chow diet group or a high-fat diet group. The levels of serum GP73, lipid profiles and key inflammatory cytokines were determined by ELISA. The aortic root plaque was isolated and used for by Oil Red O staining. PMA-differentiated THP-1 macrophages were transfected with GP73 small interfering RNA (siRNA) or infected with adenovirus expressing GP73, and then stimulated with oxidized low density lipoprotein (ox-LDL). The expressions of pro-inflammatory cytokines and signal pathway key targets were determined by ELISA kit and Western blot respectively. In addition, ichloro-dihydro-fluorescein diacetate (DCFH-DA) was used to measure the intracellular ROS levels. RESULTS: The expressions of GP73 and NLRP3 were substantially upregulated in human atherosclerotic lesions. There were significant linear correlations between GP73 and inflammatory cytokines expressions. High-fat diet-induced atherosclerosis and increased levels of plasma inflammatory mediators (IL-1ß, IL-18, and TNF-α) were observed in ApoE-/- mice. Besides, the expressions of GP73 in the aorta and serum were significantly upregulated and positively correlated with the NLRP3 expression. In the THP-1 derived macrophages, ox-LDL treatment upregulated the expressions of GP73 and NLRP3 proteins and activated the inflammatory responses in a concentration-dependent and time-dependent manner. Silencing of GP73 attenuated the inflammatory response and rescued the decreased migration induced by ox-LDL, inhibiting the NLRP3 inflammasome signaling and the ROS and p-NF-κB activation. CONCLUSIONS: We demonstrated that GP73 promoted the ox-LDL-induced inflammation in macrophages by affecting the NF-κB/NLRP3 inflammasome signaling, and may play a role in atherosclerosis.

Body weight time in target range and cardiovascular outcomes in adults with overweight/obesity and type 2 diabetes.

AIMS: Prescription of weight loss to individuals is often characterized by weight fluctuations. However, current body weight management metrics may have difficulty characterizing the changes in body weight over time. We aim to characterize the long-term changes using body weight time in target range (TTR) and test its independent association with cardiovascular outcomes. METHODS AND RESULTS: We included 4468 adults from the Look AHEAD (Action for Health in Diabetes) trial. Body weight TTR was defined as the percentage of time during which body weight was within the Look AHEAD weight loss goal range. The associations of body weight TTR with cardiovascular outcomes were analysed using multivariable Cox modelling and restricted cubic spline function. Among the participants (mean age 58.9 years, 58.5% women, 66.5% White), there were 721 incident primary outcomes [cumulative incidence: 17.5%, 95% confidence interval (CI): 16.3-18.8%] during a median of 9.5 years of follow-up. Each 1 SD increase in body weight TTR was significantly associated with a decreased risk of the primary outcome (hazard ratio: 0.84, 95% CI: 0.75-0.94) after adjusting for mean and variability of body weight and traditional cardiovascular risk factors. Further analyses using restricted cubic spline indicated the inverse association between body weight TTR and the primary outcome in a dose-dependent manner. Similar associations remained significant among the participants with lower baseline or mean body weight. CONCLUSION: In adults with overweight/obesity and type 2 diabetes, higher body weight TTR was independently associated with lower risks of cardiovascular adverse events in a dose-response manner.

We used time in target range (TTR) to characterize the long-term changes in body weight among 4468 adults with overweight/obesity and type 2 diabetes and assessed the associations of body weight TTR with cardiovascular outcomes.Participants with TTR of >50­100% achieved and maintained the target of body weight loss during the 10 years of follow-up.Higher body weight TTR was independently associated with lower risks of cardiovascular adverse events in a dose­response manner.

Triglyceride-glucose index in the development of heart failure and left ventricular dysfunction: analysis of the ARIC study.

AIMS: We aimed to investigate whether the triglyceride-glucose (TyG) index, an easy-calculated and reliable surrogate of insulin resistance, was associated with the development of heart failure (HF) and left ventricular (LV) dysfunction. METHODS AND RESULTS: A total of 12 374 participants (mean age: 54.1 ± 5.7 years, male: 44.7%) free of history of HF and coronary heart disease at baseline from the Atherosclerosis Risk in Communities study were included. The TyG index was calculated as ln[fasting triglyceride (mg/dL) × fasting glucose (mg/dL)/2]. The long-term TyG index was calculated as the updated cumulative average TyG index using all available TyG index from baseline to the events of HF or the end of follow-up. We evaluated the associations of both the baseline and the long-term TyG index with incident HF using Cox regression analysis. We also analysed the effect of the TyG index on LV structure and function among 4889 participants with echocardiographic data using multivariable linear regression analysis. There were 1958 incident HF cases over a median follow-up of 22.5 years. After adjusting for potential confounders, 1-SD (0.60) increase in the baseline TyG index was associated with a 15% higher risk of HF development [hazard ratio (HR): 1.15, 95% confidence interval (CI): 1.10-1.21]. Compared with participants in the lowest quartile of the baseline TyG index, those in the highest quartile had a greater risk of incident HF [HR (95% CI): 1.25 (1.08-1.45)]. In terms of LV structure and function, a greater baseline TyG index was associated with adverse LV remodelling and LV dysfunction. Similar results were found for the long-term TyG index. CONCLUSION: In a community-based cohort, we found that a greater TyG index was significantly associated with a higher risk of incident HF and impaired LV structure and function.