Frailty is a common geriatric syndrome associated with many adverse health outcomes. Identifying the risk factors of frailty is crucial and the insulin resistance (IR) is considered as a potential target. The estimated glucose disposal rate (eGDR) is a simple and reliable surrogate marker of IR. Associations of eGDR with frailty have not been explored. This study aimed to investigate the associations of eGDR with frailty progression. We used data from two prospective cohorts of the China Health and Retirement Longitudinal Study (CHARLS) and Health and Retirement Study (HRS). The eGDR was calculated as follows: eGDR (mg/kg/min) = 21.158 − (0.09×waist circumference) − (3.407×hypertension) − (0.551×glycosylated hemoglobin A1c) [waist circumference (cm), hypertension (yes = 1/no = 0), and glycosylated hemoglobin A1c (%)]. Participants were divided into three categories by tertiles of eGDR. Frailty index (FI) was calculated every two years and used to assess the degree of frailty which ranged from 0 to 100. Frailty progression was assessed by repeated measurements of FI during follow-up. Linear mixed-effect models were used to analyze the associations of eGDR with frailty progression. 8872 participants from CHARLS (mean age: 58.9 years, female: 53.3%) and 5864 participants from HRS (mean age: 67.0 years, female: 59.0%) were included. The median follow-up periods were 7.0 years in the CHARLS and 12.8 years in the HRS, respectively. Compared to participants with lower tertile (T1) of eGDR, those with upper tertile (T3) of eGDR showed decelerated FI progression (CHARLS, β: -0.294, 95%CI -0.390 to -0.198, P < 0.001; HRS, β: -0.378, 95%CI -0.474 to -0.281, P < 0.001). Continuous eGDR was also associated with FI progression for significant deceleration in FI progression with per 1 SD increase in eGDR (CHARLS, β: -0.142, 95%CI -0.181 to -0.103, P < 0.001; HRS, β: -0.170, 95%CI -0.209 to -0.130, P < 0.001). These associations were still observed after excluding baseline frail participants. Furthermore, the associations of eGDR with FI progression were consistent among participants with and without diabetes. Regardless of diabetes or not, a higher level of eGDR was associated with the decelerated frailty progression. Our findings highlight the role of eGDR in frailty progression and recommend taking effective interventions to improve eGDR for preventing frailty progression. The estimated glucose disposal rate and frailty progression. CHARLS, China Health and Retirement Longitudinal Study; HRS, Health and Retirement Study; eGDR, the estimated glucose disposal rate; FI, frailty index.

Background: Epigallocatechin gallate (EGCG) is the most abundant catechin in green tea and has proven benefits on endothelial cells in diabetes. However, it remains unclear whether EGCG could improve function of late endothelial progenitor cells (L-EPCs) in diabetes. Methods: Thirty-six rabbits were randomized into six groups. Thirty diabetic rabbits were induced by a single dose of alloxan (100 mg/kg injection intraperitoneally). All of them were given intragastrically EGCG (50 mg/kg/day) or saline for 7 days after carotid injury. In autotransfusion experiment, L-EPCs were cultured with pre-treated EGCG (40 μM for 72 h) and then were injected into the site of injured vascular. Proliferation and migration of EGCG pre-treated L-EPCs in high glucose condition were assessed by EDU incorporation assay and modified Boyden chamber assay, respectively. The mRNA and protein expression of Akt-eNOS pathway were detected by real-time PCR and western blot. Results: Reendothelialization rate in injured carotid artery of diabetic rabbits was augmented in the EGCG group (50 mg/kg/d for 7 days) compared with the non-EGCG group (74.2 ± 4.6% vs. 25.6 ± 5.9%, P < 0.001). EGCG pre-treated L-EPCs autologous transfusion also accelerated the diabetic rabbits’ carotid reendothelialization compared with the diabetic sham-operated group (65.6 ± 8.5% vs. 32.9 ± 5.0%, P = 0.011). In vitro studies showed, 40 μM EGCG treatment for 72 h recovered L-EPCs’ proliferation and migration, as well as restored the phosphorylation level of Akt and eNOS blocked by high glucose condition. Conclusion: EGCG accelerated reendothelialization in diabetic rabbits after carotid injury in part by reactivating the Akt/eNOS pathway, which might contribute to recovering proliferation and migration of L-EPCs impaired by high glucose.

Atherosclerotic plaques pose a substantial risk for life-threatening cardiovascular complications due to their propensity to trigger acute clinical events. Foam cell formation, resulting from dysregulated lipid homeostasis, serves as a pivotal pathological hallmark in the progression of atherosclerosis. In this study, we presented a precision therapeutic strategy targeting foam cells of multiple origins. The carrier-free nanomedicine Dlut based on luteolin was constructed, featuring CD44 active targeting and stimulus-driven traceless release. Dlut demonstrated active foam cell targeting capability and complete disintegration triggered by oxidative stress and acidic microenvironment, enabling a traceless release of luteolin. Transcriptomic profiling revealed that Dlut inhibited foam cell formation by accelerating lipid efflux. In vivo studies further demonstrated that Dlut significantly reduced plaque burden and improved plaque stability, highlighting a translational potential of atherosclerosis.

Vascular graft fibrosis can cause a decrease in cellular infiltration and capillary ingrowth in vascular walls. It can also lead to vascular stiffening. As such, there are still no vascular grafts that can be used in blood vessels where their diameters are less than 6 mm in patients. Although various approaches have been evaluated to mitigate implant-associated fibrosis, effective treatments remain quite limited. In this study, we demonstrated that Apolipoprotein E (APOE) significantly increased during vascular regeneration after graft implantation in vivo. APOE knockout (KO) increased compliance of the regenerated aortas, reduced extracellular matrix (ECM) deposition, and increased capillary ingrowth in adventitia of the regenerated aortas. Using single cell RNA sequencing (scRNA-seq), a subset of profibrotic macrophages was found to be involved in graft fibrosis. APOE KO reduced the formation of profibrotic macrophages during vascular regeneration. The interaction between APOE and low-density lipoprotein receptor related protein 1 (LRP1) partially mediated the profibrotic macrophage formation. The profibrotic macrophages promoted graft fibrosis mainly through secretion of insulin-like growth factor-1 (IGF-1) that could support fibroblast proliferation. Finally, we showed that APOE knockdown in vivo using adeno-associated virus (AAV) improved the compliance of the regenerated aortas, reduced extracellular matrix (ECM) deposition and increased capillary ingrowth in the adventitial areas of the regenerated aortas by reducing the formation of profibrotic macrophages and their secreted IGF-1. Collectively, these data indicate that APOE can promote profibrotic macrophage formation partially through LRP1, and the profibrotic macrophages mediate graft fibrosis by increasing fibroblast proliferation via IGF-1. Inhibition of APOE generation in regenerated aortas can alleviate graft fibrosis that occurs during vascular regeneration.

Background: Frailty is common among patients with coronary heart disease (CHD). This study aimed to examine both baseline frailty and its longitudinal changes in relation to the risk of major adverse cardiovascular events (MACEs) in patients with CHD. Methods: Data were sourced from the ARIC (Atherosclerosis Risk in Communities) study. Frailty status was assessed using a modified Fried frailty phenotype at 2 consecutive surveys. The outcome was MACEs, defined as a composite of recurrent CHD, incident heart failure, stroke, or cardiovascular death. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs. Results: In baseline frailty analyses, 1793 patients with CHD were included. Compared with robust patients, prefrail and frail patients had a higher risk of MACEs (HR, 1.24 [95% CI, 1.08–1.42] for prefrail; and HR, 1.75 [95% CI, 1.43–2.15] for frail). In frailty transition analyses, 862 patients with CHD were included. Patients who progressed from robust to prefrail/frail status had a higher MACE risk (HR, 1.43 [95% CI, 1.07–1.91]) compared with those who remained robust. Similarly, progression from prefrail to frail status was associated with an increased risk of MACEs (HR, 2.30 [95% CI, 1.62–3.27]) compared with stable prefrailty. Conversely, recovery from prefrail to robust status was related to a decreased MACE risk (HR, 0.62 [95% CI, 0.40–0.96]). Conclusions: Both baseline frailty and its temporal changes were associated with the risk of MACEs among patients with CHD, highlighting the clinical value of monitoring and intervening for frailty in CHD management.

Background. Previous observational studies have found that negative moods are associated with cardiovascular diseases (CVDs). However, their causal association remains unclear. We aim to evaluate the causal associations of genetically determined negative moods with CVDs including coronary artery disease (CAD), myocardial infarction (MI), stroke, and subtypes of stroke using Mendelian randomization study. Methods. Summary statistics for negative moods were extracted from the UK Biobank and a large genome-wide association study including 366,726 subjects. Six negative moods, tiredness, depressed mood, tenseness, unenthusiasm, anxiety, and anger, were included. Genetic associations with CVDs were extracted from the CardiogramplusC4D consortium and MEGASTROKE consortium: CAD (n = 184,305), MI (n = 171,875), stroke (n = 446,696), and subtypes of stroke. Causal effects were inferred between related traits by univariable, reverse and multivariable Mendelian randomization (MR) method. Results. Univariable MR analyses found that tiredness was genetically correlated with CAD (OR 1.91; 95% CI 1.23–2.97; P = 0.004) and MI (OR 2.12; 95% CI 1.29–3.47; P = 0.003). Besides, we found that the genetic liability to depressed mood was associated with higher risks of CAD (OR 2.97; 95%CI: 1.25–7.09; P = 0.014) and MI (OR 2.81; 95%CI: 1.06–7.42; P = 0.037). No causal relationship between negative moods and stroke was found. Bidirectional MR analysis failed to find any significant causal effect of CVDs on the risk of negative moods. Multivariable MR analyses revealed compelling evidence of tiredness on the risk of CAD and MI. However, after adjusting for other cardiovascular risk traits, the causal relationship between depressed mood and CVDs disappeared. Conclusions. This MR study found that genetic predisposition to tiredness may have a causal effect on the risk of CAD and MI. Early diagnosis and prevention of tiredness may be helpful in the management of CAD and MI.