Association between pulse pressure and carotid plaques in old adults with uncontrolled hypertension: results from a community-based screening in Hangzhou, China.

BACKGROUND: There is a broad pulse pressure (PP) and a high prevalence of carotid plaques in old adults. Previous studies have indicated that PP is strongly associated with carotid plaque formation. This study aimed to explore this association in old adults with uncontrolled hypertension. METHODS: 1371 hypertensive patients aged ≥ 60 years with uncontrolled hypertension were enrolled in a community-based screening in Hangzhou, China. Carotid plaques were assessed using ultrasonography. Logistic regression models were used to estimate the association between PP and carotid plaques by odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Carotid plaques were detected in 639 (46.6%) of subjects. Multiple plaques were found in 408 (63.8%) and soft plaques in 218 (34.1%). Elevated PP was associated with a high prevalence of carotid plaques. After adjusting for traditional risk factors, compared to patients within the lowest tertile of PP, those within the highest tertiles had an increased risk of carotid plaques (OR 2.061, CI 1.547-2.745). For each 1-SD increase, the risk increased by 40.1% (OR 1.401, CI 1.237-1.587). There was a nonlinear association between PP and carotid plaques (P nonlinearity = 0.039). The risk increased rapidly after the predicted PP level reached around 60 mmHg. The associations were stronger among participants with multiple and soft plaques. CONCLUSIONS: Our findings suggested that PP was independently associated with carotid plaques in old adults with uncontrolled hypertension who have an increased risk of atherosclerosis.

Remnant cholesterol and the risk of carotid plaque in hypertension: results from a community-based screening among old adults in Hangzhou, China.

Elevated remnant cholesterol (RC) is considered a risk factor for atherosclerotic cardiovascular disease, but the evidence on this association applies to the Chinese population with hypertension is limited. We aimed to explore the association between RC levels and carotid plaque in old adults with hypertension. 8523 hypertensive patients aged ≥ 60 years with serum lipids and carotid ultrasonography data were included in this community-based screening. Fasting RC was calculated as total cholesterol minus high-density lipoprotein cholesterol minus low-density lipoprotein cholesterol (LDLC). The associations of RC levels with carotid plaque risk were evaluated using Logistic regression and restricted cubic spline models. Carotid plaque was screened in 4821 (56.56%) subjects. After multivariable-adjusted, RC was significantly related to carotid plaque [Odd ratio (OR)] = 1.043 per 0.1 mmol/L increase, 95% confidence interval (CI): 1.030-1.056). The highest versus the lowest quartile of RC was 1.928 (1.673-2.223) for carotid plaque. A nonlinear association was found between serum RC levels and the risk of carotid plaque (P for nonlinearity < 0.001). Moreover, an RC > 0.78 mmol/L differentiated patients at a higher risk of carotid plaque compared to those at lower concentrations, regardless of whether LDLC was on target at 2.59 mmol/L. In old adults with hypertension, elevated RC was positively associated with carotid plaque, independent of LDLC and other conventional risk factors.

Associations of metabolic heterogeneity of obesity with frailty progression: Results from two prospective cohorts.

BACKGROUND: Previous studies indicated that obesity would accelerate frailty progression. However, obesity is heterogeneous by different metabolic status. The associations of metabolic heterogeneity of obesity with frailty progression remain unclear. METHODS: A total of 6730 participants from the China Health and Retirement Longitudinal Study (CHARLS) and 4713 from the English Longitudinal Study of Ageing (ELSA) were included at baseline. Metabolic heterogeneity of obesity was evaluated based on four obesity and metabolic phenotypes as metabolically healthy normal weight (MHNW), metabolically unhealthy normal weight (MUNW), metabolically healthy overweight/obesity (MHOO), and metabolically unhealthy overweight/obesity (MUOO). Frailty status was assessed by the frailty index (FI) ranging from 0 to 100 and frailty was defined as FI ≥ 25. Linear mixed-effect models were used to analyse the associations of metabolic heterogeneity of obesity with frailty progression. RESULTS: In the CHARLS, MUOO and MUNW presented the accelerated FI progression with additional annual increases of 0.284 (95% CI: 0.155 to 0.413, P < 0.001) and 0.169 (95% CI: 0.035 to 0.303, P = 0.013) as compared with MHNW. MHOO presented no accelerated FI progression (ß: -0.011, 95% CI: -0.196 to 0.173, P = 0.904) as compared with MHNW. In the ELSA, the accelerated FI progression was marginally significant for MUOO (ß: 0.103, 95% CI: -0.005 to 0.210, P = 0.061) and MUNW (ß: 0.157, 95% CI: -0.011 to 0.324, P = 0.066), but not for MHOO (ß: -0.047, 95% CI: -0.157 to 0.062, P = 0.396) in comparison with MHNW. The associations of MUOO and MUNW with the accelerated FI progression were stronger after excluding the baseline frail participants in both cohorts. The metabolic status changed over time. When compared with stable MHNW, participants who changed from MHNW to MUNW presented the accelerated FI progression with additional annual increases of 0.356 (95% CI: 0.113 to 0.599, P = 0.004) and 0.255 (95% CI: 0.033 to 0.477, P = 0.024) in the CHARLS and ELSA, respectively. The accelerated FI progression was also found in MHOO participants who transitioned to MUOO (CHARLS, ß: 0.358, 95% CI: 0.053 to 0.663, P = 0.022; ELSA, ß: 0.210, 95% CI: 0.049 to 0.370, P = 0.011). CONCLUSIONS: Metabolically unhealthy overweight/obesity and normal weight, but not metabolically healthy overweight/obesity, accelerated frailty progression as compared with metabolically healthy normal weight. Regardless of obesity status, transitions from healthy metabolic status to unhealthy metabolic status accelerated frailty progression as compared with stable metabolically healthy normal weight. Our findings highlight the important role of metabolic status in frailty progression and recommend the stratified management of obesity based on metabolic status.

Gamma-glutamyl-leucine levels are causally associated with elevated cardio-metabolic risks.

Objective: Gamma-glutamyl dipeptides are bioactive peptides involved in inflammation, oxidative stress, and glucose regulation. Gamma-glutamyl-leucine (Gamma-Glu-Leu) has been extensively reported to be associated with the risk of cardio-metabolic diseases, such as obesity, metabolic syndrome, and type 2 diabetes. However, the causality remains to be uncovered. The aim of this study was to explore the causal-effect relationships between Gamma-Glu-Leu and metabolic risk. Materials and methods: In this study, 1,289 subjects were included from a cross-sectional survey on metabolic syndrome (MetS) in eastern China. Serum Gamma-Glu-Leu levels were measured by untargeted metabolomics. Using linear regressions, a two-stage genome-wide association study (GWAS) for Gamma-Glu-Leu was conducted to seek its instrumental single nucleotide polymorphisms (SNPs). One-sample Mendelian randomization (MR) analyses were performed to evaluate the causality between Gamma-Glu-Leu and the metabolic risk. Results: Four SNPs are associated with serum Gamma-Glu-Leu levels, including rs12476238, rs56146133, rs2479714, and rs12229654. Out of them, rs12476238 exhibits the strongest association (Beta = -0.38, S.E. = 0.07 in discovery stage, Beta = -0.29, S.E. = 0.14 in validation stage, combined P-value = 1.04 × 10-8). Each of the four SNPs has a nominal association with at least one metabolic risk factor. Both rs12229654 and rs56146133 are associated with body mass index, waist circumference (WC), the ratio of WC to hip circumference, blood pressure, and triglyceride (5 × 10-5 < P < 0.05). rs56146133 also has nominal associations with fasting insulin, glucose, and insulin resistance index (5 × 10-5 < P < 0.05). Using the four SNPs serving as the instrumental SNPs of Gamma-Glu-Leu, the MR analyses revealed that higher Gamma-Glu-Leu levels are causally associated with elevated risks of multiple cardio-metabolic factors except for high-density lipoprotein cholesterol and low-density lipoprotein cholesterol (P > 0.05). Conclusion: Four SNPs (rs12476238, rs56146133, rs2479714, and rs12229654) may regulate the levels of serum Gamma-Glu-Leu. Higher Gamma-Glu-Leu levels are causally linked to cardio-metabolic risks. Future prospective studies on Gamma-Glu-Leu are required to explain its role in metabolic disorders.

Frailty is associated with the progression of prediabetes to diabetes and elevated risks of cardiovascular disease and all-cause mortality in individuals with prediabetes and diabetes: Evidence from two prospective cohorts.

AIMS: To investigate the impacts of frailty on the progression of prediabetes to diabetes, cardiovascular disease (CVD) and all-cause mortality in individuals with prediabetes and diabetes. METHODS: 7,933 subjects with prediabetes and diabetes were included from the China Health and Retirement Longitudinal Study (CHARLS) and English Longitudinal Study of Ageing (ELSA). Frailty status was assessed by frailty index and classified as robust, pre-frail, and frail. Logistic regression was used to calculate risks of progression to diabetes. Cox regression was used to calculate risks of CVD and all-cause mortality. RESULTS: In prediabetes, frail subjects had significantly increased risks of progression to diabetes (CHARLS, OR = 1.55, 95 %CI: 1.09-2.20; ELSA, OR = 1.86, 95 %CI: 1.02-3.37) compared with robust subjects. Frail subjects with prediabetes also presented significantly increased risks of CVD (CHARLS: HR = 1.90, 95 %CI: 1.45-2.48; ELSA: HR = 1.94, 95 %CI: 1.31-2.88) and all-cause mortality (CHARLS: HR = 2.45, 95 %CI: 1.79-3.36; ELSA: HR = 2.13, 95 %CI: 1.46-3.10) than robust subjects with prediabetes. In diabetes, frailty still increased risks of CVD (CHARLS, HR = 2.72, 95 %CI: 1.97-3.77; ELSA, HR = 2.41, 95 %CI: 1.43-4.06) and all-cause mortality (CHARLS, HR = 2.28, 95 %CI: 1.56-3.33; ELSA, HR = 2.28, 95 %CI: 1.47-3.53). CONCLUSIONS: Frailty is associated with the progression of prediabetes to diabetes and elevated risks of CVD and all-cause mortality in individuals with prediabetes and diabetes.

Dynamic Status of SII and SIRI Alters the Risk of Cardiovascular Diseases: Evidence from Kailuan Cohort Study.

Background: Two novel systemic inflammation indices, SII and SIRI, are associated with increased risk of cardiovascular diseases (CVD). However, SII and SIRI are prone to change over time and the association between changeable status and long-term outcome risk remains to be uncovered. This study aims to examine the association between the dynamic status of SII and SIRI and risk of CVD. Methods: This prospective study included a total of 45,809 subjects without MI, stroke and cancer prior to or in 2010 (baseline of this study). The dynamic status of SII and SIRI during 2006, 2008, and 2010 was assessed by dynamic trajectories (primary exposure), annual increase, and average value. The outcome was CVD incidence during 8.6 years' follow-up. Multiple Cox regression models were used to calculate the adjusted hazard ratios (HRs) and confidence intervals (95% CIs). Results: Four dynamic trajectories of SII and SIRI were identified as follows: low stable pattern, moderate stable pattern, increase pattern, and decrease pattern. For SII, compared with "low stable pattern", after controlling confounders and level of SII in 2006, adjusted HRs were 1.24 (95% CI = 1.02-1.51) for "increase pattern" and 1.11 (95% CI = 1.00-1.23) for "moderate-stable pattern" while the association was not significant for "decrease pattern". Additionally, the highest group of annual SII increase and average SII had respective HR of 1.20 (95% CI = 1.05-1.37) and 1.32 (95% CI = 1.13-1.55). The results were consistent for SIRI. "Increase pattern" and "moderate stable pattern" increased the risk of CVD by 38% (HR = 1.38, 95% CI = 1.17-1.63) and 12% (HR = 1.12, 95% CI = 1.01-1.25), while no significant association was found for "decrease pattern". The highest group of annual SIRI increase and average SIRI had respective HR of 1.25 (95% CI = 1.09-1.44) and 1.39 (95% CI = 1.19-1.63). Conclusion: Dynamic status of SII and SIRI was significantly associated with risk of CVD, which highlighted that we should focus on the dynamic change of SII and SIRI.

C-reactive protein and white blood cell are associated with frailty progression: a longitudinal study.

BACKGROUND: Systemic inflammation has been linked to diseases and frailty. However, little is known about the effect of systemic inflammation on frailty progression with a longitudinal study design. OBJECTIVES: This study aimed to investigate the associations of two inflammation indicators, C-reactive protein (CRP) and white blood cell (WBC), with frailty progression. METHODS: This study utilized data from the China Health and Retirement Longitudinal Study 2011-2018 (wave 1-wave 4). Frailty index (FI) was calculated using 40 items from wave 1 to wave 4 (range: 0 to 1). Two systemic inflammation biomarkers, CRP and WBC, were measured at baseline (wave 1) and logs transformed as continuous variables or grouped using quartiles. Linear mixed-effect models were used to analyze the associations of these two biomarkers with the progression of frailty with adjustment for potential confounding factors. RESULTS: The study enrolled 9111 middle-aged and older participants (52.7% females, mean age 58.8 ± 9.3 years). The median follow-up time was 7.0 years. In a fully adjusted model with further adjustment for baseline FI, higher CRP (ß for the interaction with time = 0.239, 95% CI: 0.139 to 0.338) and WBC (ß for the interaction with time = 0.425, 95% CI: 0.024 to 0.825) significantly accelerated the rate of increase in the FI during the follow-up period. The associations were more pronounced in younger people (< 60 years) than older people (≥60 years). CONCLUSIONS: Higher CRP and WBC accelerated the progression of frailty, particularly in younger groups (< 60 years). The findings suggest the importance of systemic inflammation for the early identification of people at high risk of rapid progression of frailty.

Association between MRI-based visceral adipose tissues and metabolic abnormality in a Chinese population: a cross-sectional study.

BACKGROUND: Previous studies have indicated that the deposition of abdominal adipose tissue was associated with the abnormalities of cardiometabolic components. The aim of this study was to examine the relationship of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and metabolic status and the different effects between males and females. METHODS: The 1388 eligible subjects were recruited in a baseline survey of metabolic syndrome in China, from two communities in Hangzhou and Chengdu. Areas of abdominal VAT and SAT were measured by magnetic resonance imaging (MRI). Serum total triglycerides (TG), high-density lipoprotein cholesterol (HDL-C) were measured by an automated biochemical analyzer. Metabolic abnormality (MA) was defined more than one abnormal metabolic components, which was based on the definition of metabolic syndrome (IDF 2005). Multiple logistic regression was used to calculate the odds ratios (ORs) and 95% confidence intervals (95%CI). Predictive value was assessed by area under the curve (AUC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI), respectively. RESULTS: Their mean age was 53.8 years (SD: 7.1 years), the mean body mass index (BMI) was 23.7 kg/m2, and 44.8% of the subjects were male. Both male and female with MA had higher VAT levels compared to subjects with normal metabolism (MN), and male had higher SAT levels than female (P < 0.05). Higher VAT was significantly associated with MA with ORs in the fourth quartile (Q4) of 6.537 (95% CI = 3.394-12.591) for male and 3.364 (95% CI = 1.898-5.962) for female (P for trend < 0.05). In female, VAT could increase the risk of metabolic abnormalities, but SAT could increase the risk of MA in the second and fourth quartiles (Q2 and Q4) only at BMI > 24 kg/m2. In male, VAT improved the predictive value of MA compared to BMI and waist circumference (WC), the AUC was 0.727 (95% CI = 0.687-0.767), the NRI was 0.139 (95% CI = 0.070-0.208) and 0.106 (95% CI = 0.038-0.173), and the IDI was 0.074 (95% CI = 0.053-0.095) and 0.046 (95% CI = 0.026-0.066). Similar results were found in female. CONCLUSIONS: In male, VAT and SAT could increase the risk of metabolic abnormalities both at BMI < 24 kg/m2 and at BMI ≥ 24 kg/m2. In female, VAT could increase the risk of metabolic abnormalities but SAT could increase the risk of MA in the second and fourth quartiles (Q2 and Q4) only at BMI > 24 kg/m2. Deposition of abdominal adipose tissue was associated with metabolic abnormalities. VAT improved the predictive power of MA.

Different Risks of Mortality and Longitudinal Transition Trajectories in New Potential Subtypes of the Preserved Ratio Impaired Spirometry: Evidence From the English Longitudinal Study of Aging.

Background: Preserved ratio impaired spirometry (PRISm), characterized by the decreased forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) with a preserved FEV1/FVC ratio, is highly prevalent and heterogeneous. We aimed to identify the subtypes of PRISm and examine their differences in clinical characteristics, long-term mortality risks, and longitudinal transition trajectories. Methods: A total of 6,616 eligible subjects were included from the English longitudinal study of aging. Two subtypes of the PRISm were identified as mild PRISm (either of FEV1 and FVC <80% predicted value, FEV1/FVC ≥0.7) and severe PRISm (both FEV1 and FVC <80% predicted values, FEV1/FVC ≥0.7). Normal spirometry was defined as both FEV1 and FVC ≥80% predicted values and FEV1/FVC ≥0.7. Hazard ratios (HRs) and 95% CIs were calculated by the multiple Cox regression models. Longitudinal transition trajectories were described with repeated spirometry data. Results: At baseline, severe PRISm had increased respiratory symptoms, including higher percentages of phlegm, wheezing, dyspnea, chronic bronchitis, and emphysema than mild PRISm. After an average of 7.7 years of follow-up, severe PRISm significantly increased the risks of all-cause mortality (HR=1.91, 95%CI = 1.58-2.31), respiratory mortality (HR = 6.02, 95%CI = 2.83-12.84), and CVD mortality (HR = 2.11, 95%CI = 1.42-3.13) compared with the normal spirometry, but no significantly increased risks were found for mild PRISm. In the two longitudinal transitions, mild PRISm tended to transition toward normal spirometry (40.2 and 54.7%), but severe PRISm tended to maintain the status (42.4 and 30.4%) or transition toward Global Initiative for Chronic Obstructive Lung Disease (GOLD)2-4 (28.3 and 33.9%). Conclusion: Two subtypes of PRISm were identified. Severe PRISm had increased respiratory symptoms, higher mortality risks, and a higher probability of progressing to GOLD2-4 than mild PRISm. These findings provided new evidence for the stratified management of PRISm.

Multi-stage metabolomics and genetic analyses identified metabolite biomarkers of metabolic syndrome and their genetic determinants.

BACKGROUND: Metabolic syndrome (MetS) is a cluster of multiple cardiometabolic risk factors that increase the risk of type 2 diabetes and cardiovascular diseases. Identifying novel biomarkers of MetS and their genetic associations could provide insights into the mechanisms of cardiometabolic diseases. METHODS: Potential MetS-associated metabolites were screened and internally validated by untargeted metabolomics analyses among 693 patients with MetS and 705 controls. External validation was conducted using two well-established targeted metabolomic methods among 149 patients with MetS and 253 controls. The genetic associations of metabolites were determined by linear regression using our previous genome-wide SNP data. Causal relationships were assessed using a one-sample Mendelian Randomization (MR) approach. FINDINGS: Nine metabolites were ultimately found to be associated with MetS or its components. Five metabolites, including LysoPC(14:0), LysoPC(15:0), propionyl carnitine, phenylalanine, and docosapentaenoic acid (DPA) were selected to construct a metabolite risk score (MRS), which was found to have a dose-response relationship with MetS and metabolic abnormalities. Moreover, MRS displayed a good ability to differentiate MetS and metabolic abnormalities. Three SNPs (rs11635491, rs7067822, and rs1952458) were associated with LysoPC(15:0). Two SNPs, rs1952458 and rs11635491 were found to be marginally correlated with several MetS components. MR analyses showed that a higher LysoPC(15:0) level was causally associated with the risk of overweight/obesity, dyslipidaemia, high uric acid, high insulin and high HOMA-IR. INTERPRETATION: We identified five metabolite biomarkers of MetS and three SNPs associated with LysoPC(15:0). MR analyses revealed that abnormal LysoPC metabolism may be causally linked the metabolic risk. FUNDING: This work was supported by grants from the National Key Research and Development Program of China (2017YFC0907004).

The Associations of Two Novel Inflammation Indexes, SII and SIRI with the Risks for Cardiovascular Diseases and All-Cause Mortality: A Ten-Year Follow-Up Study in 85,154 Individuals.

BACKGROUND: SII and SIRI are two novel systemic inflammation indexes that were suggested in predicting poor outcomes in cancers. However, no studies have examined their effect on cardiovascular diseases (CVDs) and all-cause mortality. Thus, this study aims to investigate associations between SII, SIRI, and the risks for CVDs and all-cause mortality. METHODS: A total of 85,154 participants from the Kailuan cohort were included and followed up for incidents of CVDs (including MI, stroke) and all-cause death for 10 years. Multiple Cox regression was used to calculate the adjusted hazard ratios (HRs). RESULTS: During the follow-up period, 4262 stroke events, 1233 MI events, and 7225 all-cause deaths were identified, respectively. Compared with the lowest quantile (Q1) of SII or SIRI, after adjusted for most cardiovascular risk factors, both indexes showed positive associations with the risk for stroke (adjusted HRs in Q4 were 1.264 (95% CI: 1.157,1.382) for SII, 1.194 (95% CI: 1.087,1.313) for SIRI), and all-cause death (adjusted HRs in Q4 were 1.246 (95% CI: 1.165,1.331) for SII, 1.393 (95% CI: 1.296,1.498) for SIRI). Additionally, higher SII and SIRI are also associated with increased risk of hemorrhagic stroke and ischemic stroke. Higher SIRI but not SII exhibited a higher MI risk, the adjusted HR in Q4 was 1.204 (1.013,1.431). The significant association remained after additional adjustment for CRP. Subgroup analysis and sensitivity analysis displayed consistent results except for SIRI with MI, where the association did not arrive at significance in subjects aged ≥60. CONCLUSION: Elevated SII and SIRI increased the risk of stroke, two stroke subtypes, and all-cause death. Higher SIRI, but not SII associated with increased MI incidence, and the association of SIRI was only significant in subjects aged <60.