Cumulative blood pressure predicts risk of stroke in individuals with type 2 diabetes.

AIMS: To determine whether cumulative blood pressure (BP) could predict stroke in individuals with type 2 diabetes (T2D). METHODS: BP levels at baseline and the initial three visits were obtained from individuals participating in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial who had not experienced a stroke. Cumulative elevations in BP were assessed by adding the weighted mean BP values at various time intervals. The association of cumulative BP with stroke was evaluated by a multivariate-adjusted Cox proportional hazard model analysis. RESULTS: Overall, 8282 participants were included (62.10% males and 37.90% females; mean age, 62.73 years). With a median follow-up period of 6.36 years, 324 (3.91%) and 305 (3.68%) patients had any and nonfatal stroke events, respectively. Only baseline systolic BP (SBP) independently predicted any stroke after adjustment for potential confounders, whereas cumulative SBP and pulse pressure independently predicted elevated stroke events. A strong dose-response relationship between cumulative BP and stroke was identified, and conventional risk factors combined with cumulative SBP improved prediction efficiency. CONCLUSION: Cumulative SBP independently predicts stroke in individuals with T2D and provides an incremental predictive value for stroke compared with baseline BP assessments. TRIAL REGISTRATION: URL: http://www. CLINICALTRIALS: gov. Unique identifier: NCT00000620).

Dapagliflozin impedes endothelial cell senescence by activating the SIRT1 signaling pathway in type 2 diabetes.

Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) clinically reduce atherosclerosis and lower blood pressure. However, their impact on endothelial dysfunction in type 2 diabetes (T2D) remains unclear. In this study, we investigated the protective effect and underlying mechanism of the SGLT2 inhibitor dapagliflozin in diabetes. Methods: Vascular reactivity was measured to assess the vasoprotective effect of dapagliflozin in a mouse model of high glucose (HG)-induced T2D. Pulse wave velocity was measured to quantify arterial stiffness. Protein expression was assessed by western blotting and immunofluorescence, oxidative stress was evaluated using dihydroethidium, nitric oxide was evaluated using the Griess reaction, and cellular senescence was assessed based on senescence-associated beta-galactosidase (SA-ß-gal) activity and the expression of senescence markers. Furthermore, the endothelial nitric oxide synthase (eNOS) acetylation status was determined and eNOS interactions with SIRT1 were evaluated by coimmunoprecipitation assays. Results: Dapagliflozin protected against impaired endothelium-dependent vasorelaxation and improved arterial stiffness in the mouse model of T2D; mouse aortas had significantly reduced levels of senescence activity and senescence-associated inflammatory factors. HG-induced increases in senescence activity, protein marker levels, and oxidative stress in vitro were all ameliorated by dapagliflozin. The decreases in eNOS phosphorylation and nitric oxide (NO) production in senescent endothelial cells were restored by dapagliflozin. SIRT1 expression was reduced in HG-induced senescent endothelial cells, and dapagliflozin restored SIRT1 expression. SIRT1 inhibition diminished the antisenescence effects of dapagliflozin. Coimmunoprecipitation showed that SIRT1 was physically associated with eNOS, suggesting that the effects of dapagliflozin are dependent on SIRT1 activation. Conclusion: These findings indicate that dapagliflozin protects against endothelial cell senescence by regulating SIRT1 signaling in diabetic mice.

Role of cGAS-STING signaling pathway in cardiometabolic diseases. / cGAS-STINGé€šè·¯åœ¨ä»£è°¢æ€§å¿ƒè¡€ç®¡ç–¾ç— ä¸­çš„ä½œç”¨.

Cardiometabolic disease is a common clinical syndrome with exact causal relationship between the aberrant of glucose/lipid metabolism and cardiovascular disfunction, but its pathogenesis is unclear. Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon gene (STING) signaling pathway regulates the activation of innate immunity by sensing intracellular double stranded DNA. Metabolic risk factors drive the activation of cGAS-STING pathway through mitochondrial DNA, nuclear DNA and endoplasmic reticulum stress. In addition, the activation of the cGAS-STING pathway triggers chronic sterile inflammation, excessive activation of autophagy, senescence and apoptosis in related cells of cardiovascular system. These changes induced by cGAS-STING pathway might be implicated in the onset and deterioration of cardiometabolic disease. Therefore, the targeting intervention of cGAS-STING signaling pathway may emerge as a novel treatment for cardiometabolic disease.

Dapagliflozin prevents oxidative stress-induced endothelial dysfunction via sirtuin 1 activation.

Recent studies have demonstrated that dapagliflozin, a sodium-glucose cotransporter type 2 (SGLT2) inhibitor, prevents endothelial dysfunction; however, direct effects of dapagliflozin on the endothelium under oxidative stress and the underlying mechanism of action are not completely understood. This study aimed to define the role and related mechanisms of dapagliflozin in hydrogen peroxide (H2O2)-induced endothelial dysfunction. The endothelium-dependent vasorelaxation effect of dapagliflozin was assessed in an organ bath study. Endothelial dysfunction was assessed using protein expression level and phosphorylation of endothelial nitric oxide synthase (eNOS), nitric oxide (NO), reactive oxygen species (ROS), senescence-associated beta-galactosidase (SA-ß-gal) activity, and senescence marker proteins (p21, p53). Co-immunoprecipitation and protein acetylation were performed to detect protein interactions. Dapagliflozin exerted a direct vasorelaxant effect in the aortic rings of C57BL/6 J mice. Furthermore, there was a significant improvement in endothelium-dependent vasorelaxation in dapagliflozin-treated diabetic mice compared to vehicle controls. Moreover, intracellular ROS levels and ONOO- levels, increased by H2O2, were reduced by dapagliflozin. Importantly, dapagliflozin inhibited H2O2-induced senescence in the human umbilical vein endothelial cells (HUVECs), as indicated by reduced SA-ß-gal, p21, and p53. Mechanistically, dapagliflozin reversed the H2O2-mediated inhibition of eNOS serine phosphorylation and sirtuin 1 (SIRT1) expression in endothelial cells. In particular, SIRT1-mediated eNOS deacetylation is reportedly involved in dapagliflozin-enhanced eNOS activity. These findings indicate that dapagliflozin ameliorates endothelial dysfunction by restoring eNOS activity, restoring NO bioavailability, and reducing ROS generation via SIRT1 activation in oxidative stress-stimulated endothelial cells.

Outcomes of ABO-incompatible liver transplantation in end-stage liver disease patients co-infected with hepatitis B and human immunodeficiency virus.

BACKGROUND: Human immunodeficiency virus (HIV)-positive patients coinfected with hepatitis B virus (HBV) are eligible for liver transplantation (LT) in Africa and Southeast Asia, particularly China. However, the outcome of HIV-HBV coinfected patients referred for ABO-incompatible LT (ABOi-LT) is unknown. AIM: To clarify the outcome of ABOi-LT for HIV-HBV coinfected patients with end-stage liver disease (ESLD). METHODS: We report on two Chinese HIV-HBV coinfected patients with ESLD who underwent A to O brain-dead donor LT and reviewed the literature on HIV-HBV coinfected patients treated with ABO-compatible LT. The pretransplantation HIV viral load was undetectable, with no active opportunistic infections. Induction therapy consisted of two sessions of plasmapheresis and a single dose of rituximab in two split doses, followed by an intraoperative regimen of intravenous immunoglobulin, methylprednisolone, and basiliximab. Post-transplant maintenance immunosuppressive agents consisted of tacrolimus and mycophenolate mofetil, and prednisone. RESULTS: At the intermediate-term follow-up, patients showed undetectable HIV viral load, CD4(+) T cell counts greater than 150 cells/µL, no HBV recurrence, and stable liver function. A liver allograft biopsy showed no evidence of acute cellular rejection. Both patients survived at 36-42 mo of follow-up. CONCLUSION: This is the first report of ABOi-LT in HIV-HBV recipients with good intermediate-term outcomes, suggesting that ABOi-LT may be feasible and safe for HIV-HBV coinfected patients with ESLD.

Metformin suppresses vascular smooth muscle cell senescence by promoting autophagic flux.

INTRODUCTION: Vascular smooth muscle cell (VSMC) senescence in the vasculature results in vascular aging as well as age-related diseases, while metformin improves the inflamm-aging profile by enhancing autophagy. However, metformin's impact on VSMC senescence is largely undefined. OBJECTIVES: To test the hypothesis that metformin exerts an anti-senescence role by restoring autophagic activity in VSMCs and vascular tissues. METHODS: Animal models established by angiotensin II (Ang II) induction and physiological aging and senescent primary VSMCs from the aortas of elderly patients were treated with metformin. Cellular and vascular senescence were assessed by measuring the amounts of senescence-associated ß-galactosidase and senescence markers, including p21 and p53. Autophagy levels were assessed by autophagy-related protein expression, transmission electron microscope, and autolysosome staining. In order to explore the underlying mechanism of the anti-senescence effects of metformin, 4D label-free quantitative proteomics and bioinformatic analyses were conducted, with subsequent experiments validating these findings. RESULTS: Ang II-dependent senescence was suppressed by metformin in VSMCs and vascular tissues. Metformin also significantly improved arterial stiffness and alleviated structural changes in aged arteries, reduced senescence-associated secretory phenotype (SASP), and improved proliferation and migration of senescent VSMCs. Mechanistically, the proteomic analysis indicated that autophagy might contribute to metformin's anti-senescence effects. Reduced autophagic flux was observed in Ang II-induced cellular and vascular senescence; this reduction was reversed by metformin. Specifically, metformin enhanced the autophagic flux at the autophagosome-lysosome fusion level, whereas blockade of autophagosome-lysosome fusion inhibited the anti-senescence effects of metformin. CONCLUSIONS: Metformin prevents VSMC and vascular senescence by promoting autolysosome formation.

Reconstructing the portal vein through a posterior pancreatic tunnel: New choice for portal vein thrombosis during liver transplantation.

BACKGROUND: Thrombectomy and anatomical anastomosis (TAA) has long been considered the optimal approach to portal vein thrombosis (PVT) in liver transplantation (LT). However, TAA and the current approach for non-physiological portal reconstructions are associated with a higher rate of complications and mortality in some cases. AIM: To describe a new choice for reconstructing the portal vein through a posterior pancreatic tunnel (RPVPPT) to address cases of unresectable PVT. METHODS: Between August 2019 and August 2021, 245 adult LTs were performed. Forty-five (18.4%) patients were confirmed to have PVT before surgery, among which seven underwent PV reconstruction via the RPVPPT approach. We retrospectively analyzed the surgical procedure and postoperative complications of these seven recipients that underwent PV reconstruction due to PVT. RESULTS: During the procedure, PVT was found in all the seven cases with significant adhesion to the vascular wall and could not be dissected. The portal vein proximal to the superior mesenteric vein was damaged in one case when attempting thrombolectomy, resulting in massive bleeding. LT was successfully performed in all patients with a mean duration of 585 min (range 491-756 min) and mean intraoperative blood loss of 800 mL (range 500-3000 mL). Postoperative complications consisted of chylous leakage (n = 3), insufficient portal venous flow to the graft (n = 1), intra-abdominal hemorrhage (n = 1), pulmonary infection (n = 1), and perioperative death (n = 1). The remaining six patients survived at 12-17 mo follow-up. CONCLUSION: The RPVPPT technique might be a safe and effective surgical procedure during LT for complex PVT. However, follow-up studies with large samples are still warranted due to the relatively small number of cases.

Topological approach of liver segmentation based on 3D visualization technology in surgical planning for split liver transplantation.

BACKGROUND: Split liver transplantation (SLT) is a complex procedure. The left-lateral and right tri-segment splits are the most common surgical approaches and are based on the Couinaud liver segmentation theory. Notably, the liver surface following right tri-segment splits may exhibit different degrees of ischemic changes related to the destruction of the local portal vein blood flow topology. There is currently no consensus on preoperative evaluation and predictive strategy for hepatic segmental necrosis after SLT. AIM: To investigate the application of the topological approach in liver segmentation based on 3D visualization technology in the surgical planning of SLT. METHODS: Clinical data of 10 recipients and 5 donors who underwent SLT at Shenzhen Third People's Hospital from January 2020 to January 2021 were retrospectively analyzed. Before surgery, all the donors were subjected to 3D modeling and evaluation. Based on the 3D-reconstructed models, the liver splitting procedure was simulated using the liver segmentation system described by Couinaud and a blood flow topology liver segmentation (BFTLS) method. In addition, the volume of the liver was also quantified. Statistical indexes mainly included the hepatic vasculature and expected volume of split grafts evaluated by 3D models, the actual liver volume, and the ischemia state of the hepatic segments during the actual surgery. RESULTS: Among the 5 cases of split liver surgery, the liver was split into a left-lateral segment and right tri-segment in 4 cases, while 1 case was split using the left and right half liver splitting. All operations were successfully implemented according to the preoperative plan. According to Couinaud liver segmentation system and BFTLS methods, the volume of the left lateral segment was 359.00 ± 101.57 mL and 367.75 ± 99.73 mL, respectively, while that measured during the actual surgery was 397.50 ± 37.97 mL. The volume of segment IV (the portion of ischemic liver lobes) allocated to the right tri-segment was 136.31 ± 86.10 mL, as determined using the topological approach to liver segmentation. However, during the actual surgical intervention, ischemia of the right tri-segment section was observed in 4 cases, including 1 case of necrosis and bile leakage, with an ischemic liver volume of 238.7 mL. CONCLUSION: 3D visualization technology can guide the preoperative planning of SLT and improve accuracy during the intervention. The simulated operation based on 3D visualization of blood flow topology may be useful to predict the degree of ischemia in the liver segment and provide a reference for determining whether the ischemic liver tissue should be removed during the surgery.

Association of the cumulative triglyceride-glucose index with major adverse cardiovascular events in patients with type 2 diabetes.

BACKGROUND: The triglyceride-glucose (TyG) index is a reliable surrogate marker of insulin resistance and is associated with major adverse cardiovascular events (MACEs) in patients with type 2 diabetes mellitus (T2DM). However, the long-term effect of the TyG index on the incidence of MACEs remains unclear. We aimed to investigate the association between the cumulative TyG index and the risk of MACEs in patients with T2DM. METHODS: This post-hoc analysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial assessed patients' (T2DM > 3 months) cumulative TyG index and MACE data from the study database. Five fasting blood glucose and triglyceride measurements, at baseline and the first four visits, were taken from 5695 participants who had not experienced MACEs. Cumulative exposure to the TyG index was calculated as the weighted sum of the mean TyG index value for each time interval (value × time). Multivariable-adjusted Cox proportional hazard models and restricted cubic spline analysis were used to determine the association between the cumulative TyG index and MACEs. The incremental predictive value of the cumulative TyG index was further assessed. RESULTS: Over a median follow-up of 5.09 years, 673 (11.82%) MACEs occurred, including 256 (4.50%) cardiovascular disease (CVD) deaths, 288 (5.06%) non-fatal myocardial infarctions (MIs), and 197 (3.46%) strokes. The risk of developing MACEs increased with the cumulative TyG index quartile. After adjusting for multiple potential confounders, the hazard ratios for the very high cumulative TyG index group versus the low group were 1.59 (95% confidence interval [CI], 1.17-2.16), 1.97 (95% CI 1.19-3.26), and 1.66 (95% CI 1.02-2.70) for overall MACEs, CVD death, and non-fatal MI, respectively. Restricted cubic spline analysis also showed a cumulative increase in the risk of MACEs with an increase in the magnitude of the cumulative TyG index. The addition of the cumulative TyG index to a conventional risk model for MACEs improved the C-statistics, net reclassification improvement value, and integrated discrimination improvement value. CONCLUSIONS: In patients with T2DM, the cumulative TyG index independently predicts the incidence of MACEs, and monitoring the long-term TyG index may assist with optimized-for-risk stratification and outcome prediction for MACEs. Trial registration URL: http://www. CLINICALTRIALS: gov . Unique identifier: NCT00000620.

Remnant Cholesterol and Its Visit-to-Visit Variability Predict Cardiovascular Outcomes in Patients With Type 2 Diabetes: Findings From the ACCORD Cohort.

OBJECTIVE: Remnant cholesterol (remnant-C) predicts atherosclerotic cardiovascular disease, regardless of LDL-cholesterol (LDL-C) levels. This study assessed the associations between remnant-C and cardiovascular outcomes in type 2 diabetes. RESEARCH DESIGN AND METHODS: This post hoc analysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial used patient (type 2 diabetes >3 months) remnant-C and major adverse cardiovascular event (MACE) data from the study database. The associations between remnant-C and MACEs were evaluated using Cox proportional hazards regression analyses. We examined the relative MACE risk in remnant-C versus LDL-C discordant/concordant groups using clinically relevant LDL-C targets by discordance analyses. RESULTS: The baseline analysis included 10,196 participants, with further visit-to-visit variability analysis including 9,650 participants. During follow-up (median, 8.8 years), 1,815 patients (17.8%) developed MACEs. After adjusting for traditional cardiovascular risk factors, each 1-SD increase in remnant-C was associated with a 7% higher MACE risk (hazard ratio [HR] 1.07, 95% CI 1.02-1.12, P = 0.004). In the fully adjusted model, the visit-to-visit remnant-C variability calculated using logSD (HR 1.41, 95% CI 1.18-1.69, P < 0.001) and logARV (HR 1.45, 95% CI 1.22-1.73, P < 0.001) was associated with MACEs. Residual lipid risk (remnant-C ≥31 mg/dL) recognized individuals at a higher MACE risk, regardless of LDL-C concentrations. Within each LDL-C subgroup (>100 or ≤100 mg/dL), high baseline remnant-C was associated with a higher MACE risk (HR 1.37, 95% CI 1.09-1.73, P = 0.007; HR 1.22, 95% CI 1.04-1.41, P = 0.015, respectively). CONCLUSIONS: Remnant-C levels were associated with MACEs in patients with type 2 diabetes independent of LDL-C, and visit-to-visit remnant-C variability helped identify those with higher cardiovascular risk.

Clinical characteristics of severe aortic stenosis patients combined with diabetes mellitus after transcatheter aortic valve replacement and short-term outcome. / ç»å¯¼ç®¡ä¸»åŠ¨è„‰ç“£ç½®æ¢æœ¯åŽé‡åº¦ä¸»åŠ¨è„‰ç“£ç‹­çª„æ‚£è€ åˆå¹¶ç³–å°¿ç— çš„ä¸´åºŠç‰¹å¾åŠå ¶çŸ­æœŸé¢„åŽ.

OBJECTIVES: Type 2 diabetes (T2DM) is a common comorbidity in patients with degenerative aortic stenosis (AS).As a key item of the American Society of Thoracic Surgeons (STS) score, it has a vital impact on the clinical prognosis of traditional thoracic surgery. T2DM has an adverse effect on the morbidity and mortality of cardiovascular diseases. At the same time, studies have shown that T2DM are associated with myocardial hypertrophy and remodeling, decreased left ventricular function, and worsening heart failure symptoms in the AS patients. Transcatheter aortic valve replacement (TAVR) as an interventional method to replace the aortic valve has better safety for middle and high risk patients in surgery, but the impact of T2DM on the clinical outcome of TAVR in AS patients is not clear.By analyzing the clinical and image characteristics of patients with AS and T2DM who received TAVR treatment, so as to explore the effect of T2DM on the perioperative complications and prognosis of TAVR. METHODS: A total of 100 consecutive patients with severe AS, who underwent TAVR treatment and were followed up for more than 1 month, were selectedin the Second Xiangya Hospital of Central South University from January 2016 to December 2020.Among them, 5 patients who were treated with TAVR due to simple severe aortic regurgitation were not included, therefore a total of 95 patients with severe aortic stenosis were enrolled in this study.The age of the patients was (72.7±4.8) years old, and there were 58 males (61.1%), and the patients with moderate or above aortic regurgitation had 30 cases (31.6%). The patients were divided into a diabetic group and a non-diabetic group according to whether they were combined with T2DM.There was no statistical difference in age, gender, body mass index (BMI), STS score, and New York Heart Association (NYHA) cardiac function classification between the 2 groups (all P>0.05). The primary end point was defined as a composite event consisting of all-cause death and stroke one month after surgery, and the secondary end point was defined as TAVR-related complications immediately after surgery and one month after surgery.The preoperative clinical data, cardiac ultrasound data, CT data, postoperative medication and the incidence of each endpoint event were compared between the 2 groups.The predictive model of adverse events was constructed by single factor and multivariate logistic regression. RESULTS: Compared with the non-diabetic group, the diabetic group had high blood pressure and chronic renal insufficiency.There was no significant difference in preoperative ultrasound echocardiography between the 2 groups. Preoperative CT evaluation found that the anatomical structure of the aortic root in the diabetic group was smaller than that in the non-diabetic group, and there was no significant difference in the incidence of bicuspid aortic valve between the 2 groups (all P<0.05). In terms of postoperative medication, the use of statins in the diabetes group was significantly higher than that in the non-diabetic group. In the diabetes group, 6 patients (37.5%) received insulin therapy, and 9 patients (56.3%) received oral medication alone.Univariate logistic regression analysis showed that the all-cause death and stroke compound events was increased in the diabetes group in 30 days after TAVR (OR=6.86; 95% CI: 2.14 to 21.79; P<0.01). Heart disease (OR=2.80; 95% CI: 0.99 to 7.88; P<0.05) and chronic renal insufficiency (OR=3.75; 95% CI: 1.24 to 11.34; P<0.05) were also risk factors for all-cause death and stroke compound events.In a multivariate analysis, after adjusting for age, gender, BMI, comorbidities, N-terminal pro-B type natriuretic peptide (NT-proBNP), total calcification score, ejection fraction, and degree of aortic regurgitation, T2DM was still a risk factor for all-cause death and stroke compound events in 30 days after TAVR (OR=12.68; 95% CI: 1.76 to 91.41; P<0.05). CONCLUSIONS: T2DM is a risk factor for short-term poor prognosis in patients with symptomatic severe AS after TAVR treatment. T2DM should play an important role in the future construction of the TAVR surgical risk assessment system, but the conclusions still need to be further verified by long-term follow-up of large-scale clinical studies.

Abdominal Obesity Is Associated with an Increased Risk of All-Cause Mortality in Males but Not in Females with HFpEF.

Background: Association between abdominal obesity and development of heart failure (HF) with preserved ejection fraction (HFpEF) between the sexes is not completely understood. Objectives: This study evaluated the association between abdominal obesity and the risk of all-cause mortality in patients with HFpEF while performing a gender outcome comparison. Methods: A post hoc analysis was undertaken from the American cohort of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT). The primary outcome (all-cause mortality) and the secondary outcomes (cardiovascular mortality, hospitalization for HF, stroke, and MI) were evaluated via Cox proportional hazards models to compare the hazard ratios (HRs) between sexes in HFpEF patients. Abdominal obesity was defined as a waist circumference of ≥102 cm in men and ≥88 cm in women. Results: A total of 3320 HFpEF patients (1620 men [48.80%] and 1700 women [51.20%]) were included in the analysis. The mean follow-up period was 3.4 ± 1.7 years, with 503 patients dying during that time. After multivariable adjustment, abdominal obesity was significantly associated with an increased risk of all-cause mortality in males (adjusted HR: 1.32; 95% confidence interval [CI]: 1.02 to 1.71; p = 0.038). Abdominal obesity was associated with hospitalization for HF in both male (adjusted HR: 1.39; 95% CI: 1.01 to 1.93; p = 0.045) and female patients (adjusted HR: 1.15; 95% CI: 1.18 to 3.28; p = 0.010). Conclusions: Abdominal obesity is associated with increased risks of all-cause mortality in the male but not the female HFpEF population and is associated with increased risks of hospitalization for HF in both sexes.

Impact of Baseline and Trajectory of Triglyceride-Glucose Index on Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus.

Background and Aims: This study aimed to evaluate the association of the triglyceride-glucose (TyG) index with the cardiovascular incidence in patients with type 2 diabetes mellitus (T2DM). Methods and Results: Secondary analysis in patients with long-lasting T2DM from the Action to Control Cardiovascular Risk in Diabetes study was performed. The primary outcome was the first occurrence of major adverse cardiovascular events (MACEs). The association between the baseline and trajectories of the TyG index and MACEs was evaluated by Cox proportional hazards regression analysis. During a median follow-up period of 8.8 years, 1,815 (17.8%) patients developed MACEs. After traditional cardiovascular risk factor adjustments, each 1-standard deviation increase in the TyG index was associated with a 19.00% higher MACE risk, similar to that in the TyG index quartile characterization. Four distinct trajectories of TyG indexes were identified: low (16.17%), moderate (40.01%), high (34.60%), and very high (9.30%). In multivariate analysis, high and very high TyG index trajectories showed a greater risk of future MACE incidence than the low TyG index trajectory. A similar association was observed between the TyG index and the occurrence of coronary heart disease. Conclusions: The baseline and trajectories of the TyG index were significantly associated with the occurrence of MACEs in patients with T2DM. Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT00000620.

Emerging Roles of Sodium Glucose Cotransporter 2 (SGLT-2) Inhibitors in Diabetic Cardiovascular Diseases: Focusing on Immunity, Inflammation and Metabolism.

Diabetes mellitus (DM) is one of the most fast evolving global issues characterized by hyperglycemia. Patients with diabetes are considered to face with higher risks of adverse cardiovascular events. Those are the main cause of mortality and disability in diabetes patients. There are novel antidiabetic agents that selectively suppress sodium-glucose cotransporter-2 (SGLT-2). They work by reducing proximal tubule glucose reabsorption. Although increasing evidence has shown that SGLT-2 inhibitors can contribute to a series of cardiovascular benefits in diabetic patients, including a reduced incidence of major adverse cardiovascular events and protection of extracardiac organs, the potential mechanisms of SGLT2 inhibitors' cardiovascular protective effects are still not fully elucidated. Given the important role of inflammation and metabolism in diabetic cardiovascular diseases, this review is intended to rationally compile the multifactorial mechanisms of SGLT-2 inhibitors from the point of immunity, inflammation and metabolism, depicting the fundamental cellular and molecular processing of SGLT-2 inhibitors exerting regulating immunity, inflammation and metabolism. Finally, future directions and perspectives to prevent or delay cardiovascular complications in DM by SGLT-2 inhibitors are presented.

Significantly Increased Risk of All-Cause Mortality Among Type 2 Diabetes Patients Living Alone.

BACKGROUND: There is a lack of studies evaluating the association between living status and subsequent outcomes in patients with type 2 diabetes (T2DM). OBJECTIVES: This study aimed to assess the association between living alone and the risk of all-cause mortality in T2DM patients. METHODS: We performed a secondary analysis in patients with long-lasting T2DM from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study. The primary outcome was all-cause mortality. Multivariable Cox proportional hazard models was used to analyze and compare the hazard ratios (HRs) in patients living alone and with one or more adults. RESULTS: This study included 10,249 patients with T2DM. Of these, 2,078 (20.28%) were living alone and 8,171 (79.72%) lived with one or more adults. Over a median total follow-up of 8.8 years, 1,958 patients developed the primary endpoint. The all-cause mortality rates in patients living alone or living with one or more adults were 23.24 and 18.05%, respectively. Cox proportional hazard analysis showed that T2DM patients living alone had significantly higher rate of all-cause mortality than those living with others (HR, 1.34; 95% confidence interval [CI], 1.20-1.48; p < 0.001). After multivariable adjustment, living alone was an independent risk factor for all-cause mortality in patients with T2DM (adjusted HR, 1.27; 95% CI, 1.14-1.41; p < 0.001). Furthermore, the risks of both congestive heart failure (CHF) and fatal coronary heart disease (CHD) among 4,050 propensity score-matched patients were higher for patients living alone (respectively HR, 1.37; 95% CI, 1.08-1.74; p = 0.010; and HR, 1.16; 95% CI, 1.00-1.34; p = 0.047). CONCLUSIONS: The risk of all-cause mortality was significantly higher in T2DM patients living alone than in those living with one or more adults.

Gut bacterial metabolite Urolithin A inhibits myocardial fibrosis through activation of Nrf2 pathway in vitro and in vivo.

BACKGROUND: Myocardial fibrosis after myocardial infarction (MI) is one of the leading causes of cardiovascular diseases. Cardiac fibroblasts (CFs) are activated and promoted by MI to undergo myofibroblast transformation (CMT). Urolithin A (UA) is an active and effective gut metabolite derived from polyphenolics of berries and pomegranate fruits, which has been reported to have anti-inflammatory and anti-oxidant functions. However, whether UA affects the CMT process during myocardial fibrosis remains unclear. METHODS: TGF-ß1-treated primary rat cardiac fibroblasts were used for in vitro study. Cell proliferation ability was evaluated by MTT assay. Cell migration and invasion abilities were tested by wound healing and Transwell assays. The expression of CMT process-related markers were measured by qRT-PCR and western blot. The rat MI model was established by left anterior descending coronary artery (LAD) ligation and evaluated by H&E and Masson staining. RESULTS: Our data demonstrated that UA treatment could inhibit the CMT process in TGF-ß1-induced CFs, including cell proliferation, migration and invasion abilities. Knocking down of Nrf2, which was activated by UA treatment, could mitigate the effects of UA treatment on CMT process. Moreover, in vivo administration of UA in rat MI model successfully up-regulated Nrf2 expression and improved the myocardial damage and fibrosis. CONCLUSIONS: The study discovered the function and mechanism of UA on myocardial fibrosis and demonstrated the protective effects of UA administration through activation of Nrf2 pathway.

Efficacy and safety of sirolimus early conversion protocol in liver transplant patients with hepatocellular carcinoma: A single-arm, multicenter, prospective study.

Mammalian target of rapamycin (mTOR) inhibitor as an attractive drug target with promising antitumor effects has been widely investigated. High quality clinical trial has been conducted in liver transplant (LT) recipients in Western countries. However, the pertinent studies in Eastern world are paucity. Therefore, we designed a clinical trial to test whether sirolimus can improve recurrence-free survival (RFS) in hepatocellular carcinoma (HCC) patients beyond the Milan criteria after LT. This is an open-labeled, single-arm, prospective, multicenter, and real-world study aiming to evaluate the clinical outcomes of early switch to sirolimus-based regimens in HCC patients after LT. Patients with a histologically proven HCC and beyond the Milan criteria will be enrolled. The initial immunosuppressant regimens are center-specific for the first 4-6 weeks. The following regimens integrated sirolimus into the regimens as a combination therapy with reduced calcineurin inhibitors based on the condition of patients and centers. The study is planned for 4 years in total with a 2-year enrollment period and a 2-year follow-up. We predict that sirolimus conversion regimen will provide survival benefits for patients particular in the key indicator RFS as well as better quality of life. If the trial is conducted successfully, we will have a continued monitoring over a longer follow-up time to estimate indicator of overall survival. We hope that the outcome will provide better evidence for clinical decision-making and revising treatment guidelines based on Chinese population data. Trial register: Trial registered at http://www.chictr.org.cn: ChiCTR2100042869.

PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Triggers Vascular Smooth Muscle Cell Senescence and Apoptosis: Implication of Its Direct Role in Degenerative Vascular Disease.

OBJECTIVE: PCSK9 (proprotein convertase subtilisin/kexin type 9) plays a critical role in cholesterol metabolism via the PCSK9-LDLR (low-density lipoprotein receptor) axis in the liver; however, evidence indicates that PCSK9 directly contributes to the pathogenesis of various diseases through mechanisms independent of its LDL-cholesterol regulation. The objective of this study was to determine how PCSK9 directly acts on vascular smooth muscle cells (SMCs), contributing to degenerative vascular disease. Approach and Results: We first examined the effects of PCSK9 on cultured human aortic SMCs. Overexpression of PCSK9 downregulated the expression of ApoER2 (apolipoprotein E receptor 2), a known target of PCSK9. Treatment with soluble recombinant human ApoER2 or the DNA synthesis inhibitor, hydroxyurea, inhibited PCSK9-induced polyploidization and other cellular responses of human SMCs. Treatment with antibodies against ApoER2 resulted in similar effects to those observed with PCSK9 overexpression. Inducible, SMC-specific knockout of Pcsk9 accelerated neointima formation in mouse carotid arteries and reduced age-related arterial stiffness. PCSK9 was expressed in SMCs of human atherosclerotic lesions and abundant in the "shoulder" regions of vulnerable atherosclerotic plaques. PCSK9 was also expressed in SMCs of abdominal aortic aneurysm, which was inversely related to the expression of smooth muscle α-actin. CONCLUSIONS: Our findings demonstrate that PCSK9 inhibits proliferation and induces polyploidization, senescence, and apoptosis, which may be relevant to various degenerative vascular diseases.

Association Between Metabolic Syndrome and an Increased Risk of Hospitalization for Heart Failure in Population of HFpEF.

Background: The association between metabolic syndrome and the development of heart failure (HF) with preserved ejection fraction (HFpEF) has not been completely clarified. Aim: To evaluate the association between metabolic syndrome and the risk of HF hospitalization for patients with HFpEF. Methods: Patient data were obtained from the American cohort of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial database. Data for the primary outcome (hospitalization for HF) and secondary outcomes (all-cause mortality, cardiovascular mortality, and all-cause hospitalization) were collected, and hazard ratios (HRs) for the patients with and without metabolic syndrome were analyzed by applying a multivariable Cox proportional hazard model. Results: Among the 1,548 total participants, 1,197 had metabolic syndrome. The patients with metabolic syndrome exhibited worse heart function and a lower quality of life than those without metabolic syndrome. During the 3.3 years of follow-up, 351 patients were hospitalized for HF. After a multivariable adjustment, the risk of hospitalization for HF and all-cause hospitalization (adjusted HR = 1.42, 95% CI: 1.01-2.00; p = 0.042 and adjusted HR = 1.27; 95% CI: 1.04-1.54; p = 0.017, respectively) were independently associated with HFpEF for the patients with metabolic syndrome. In addition, the risks of HF hospitalization and all-cause hospitalization among 267 propensity score-matched patients were higher for patients with metabolic syndrome (HR = 1.53, 95% CI = 1.05-2.23, and p = 0.025 and HR = 1.34, 95% CI = 1.08-1.67, and p = 0.009, respectively). Conclusion: The risks of HF hospitalization and all-cause hospitalization were higher for patients with HFpEF having metabolic syndrome than for those without metabolic syndrome.

Atherogenic index of plasma is associated with major adverse cardiovascular events in patients with type 2 diabetes mellitus.

BACKGROUND: Previous studies reported the prognostic value of the atherogenic index of plasma (AIP) in the course of atherosclerosis and other cardiovascular diseases (CVDs). Still, the predictive utility of the AIP is unknown among patients with type 2 diabetes mellitus (T2DM). METHODS: This was a secondary analysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, which randomized 10,251 patients with long-lasting T2DM. ROC curve analysis was used to determine an optimal threshold for AIP, and the study population was divided into high and low AIP groups. Univariable and multivariable Cox proportional hazards regression analyses were used to determine the association between AIP and primary (major adverse cardiovascular events [MACEs], including nonfatal myocardial infarction, nonfatal stroke, and/or death from cardiovascular causes) and secondary outcomes (all-cause mortality). Stratified analyses were performed to control for the confounding factors. RESULTS: AIP was an independent risk factor for the prognosis of T2DM (HR = 1.309; 95% CI 1.084-1.581; P = 0.005). The threshold for AIP was determined to be 0.34 in the study population. After adjustments for confounding factors, multivariable analysis showed that AIP was associated with the risk of MACEs (Model 1: HR = 1.333, 95% CI 1.205-1.474, P < 0.001; Model 2: HR = 1.171, 95% CI 1.030-1.333, P = 0.016; Model 3: HR = 1.194, 95% CI 1.049-1.360, P = 0.007), all-cause mortality (Model 1: HR = 1.184, 95% CI 1.077-1.303, P < 0.001), cardiovascular death (Model 1: HR = 1.422, 95% CI 1.201-1.683, P < 0.001; Model 3: HR = 1.264, 95% CI 1.015-1.573, P = 0.036), and nonfatal myocardial infarction (Model 1: HR = 1.447, 95% CI 1.255-1.669, P < 0.001; Model 2: HR = 1.252, 95% CI 1.045-1.499, P = 0.015; Model 3: HR = 1.284, 95% CI 1.071-1.539, P = 0.007). Subgroup stratified analyses showed that AIP might interact with sex, a classical risk factor of cardiovascular events. CONCLUSIONS: This study showed that AIP might be a strong biomarker that could be used to predict the risk of cardiovascular events in patients with T2DM. TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov . Unique identifier: NCT00000620.