Cardiovascular Diabetology最新文献

Background and aims: Previous study found that estimated glucose disposal rate (eGDR) was significantly associated with cardiovascular disease (CVD). However, little is known about the change in eGDR over time and its association with the development of CVD. The aim of this study was to investigate the association of change in eGDR with CVD risk.

Methods: This study used data of two prospective cohorts: UK Biobank and China Health and Retirement Longitudinal Study (CHARLS) with two measurements of eGDR. Changes in the eGDR were classified using K‑means clustering analysis, and the cumulative eGDR was also calculated. Cox proportional hazard models were used to calculate the hazard ratio (HR) and 95% confidence interval (95% CI) after adjusting for potential confounders.

Results: A total of 11,682 individuals from the UK Biobank, and 4,974 individuals from the CHARLS were included. The median follow-up periods were 9.7 years in the UK Biobank and 3.0 years in the CHARLS. Compared with persistently high level of eGDR (class 1), individuals with low level increasing (class 3) and persistently low level of eGDR (class 4) showed elevated risks of incident CVD in both UK Biobank (HR = 2.79, 95% 2.15-3.62 for class 3; HR = 3.19, 95% 2.50-4.08 for class 4) and CHARLS (HR = 1.66, 95% 1.29-2.13 for class 3; HR = 1.69, 95% 1.34-2.14 for class 4). In addition, lower level of cumulative eGDR were associated with elevated risks of incident CVD. The dose-response curve between cumulative eGDR and CVD risk showed a negative linear relationship.

Conclusion: Different changes in eGDR level are associated with different risks of incident CVD. Dynamic monitoring of eGDR level is of significant importance for the CVD prevention and treatment.

Determining whether someone has cardiometabolic disease (CMD), especially in the early stages, can be complicated. Risk stratification ordinarily depends on an extended process relying on medical history that typically considers blood pressure, cholesterol, smoking and diabetes status. Physicians have long relied on these key patient characteristics to assess CMD risk. However, these widely used clinical assessments are often identified later in life and by definition, in those individuals with progressed disease. This is partly because the onset of CMD naturally occurs in adulthood, however, the underlying processes can occur much earlier in life, even in the absence of obvious symptoms. For one thing, the pathways towards pathology may exist for years before symptom onset. Thus, among other things, there are opportunities to provide doctors with better insights into future disease prediction especially in younger adults with diabetes. The rapid rise in CMD together with the increased rates of obesity and diabetes in this population only emphasises the importance of predictive molecular biomarkers. One notable aspect is that traditional risk scores, such as those based on cholesterol measurements, are frequently found to be within normal ranges in younger populations. At the same time, given the significant overlap in risk factors for cardiovascular disease (CVD) and diabetes, the unmet clinical need is for early biomarkers of CMD that may help improve risk assessment in younger adults. This editorial highlights advances in the use of polygenic risk scores and emerging utility of genetic biomarkers to define intermediate CMD phenotypes discussing new classification criteria involving DNA methylation of genes to improve risk assessment. CMD is the number one cause of mortality and accounts for 31% of all global deaths. CMD is also multifactorial, comprising cardiovascular disease (CVD) and diabetes that have significant overlap in risk factors and disease biology. Diabetes is arguably the strongest risk factor for CVD development. Accounting for almost 90% of diabetes cases worldwide, type 2 diabetes (T2D) affects about 527 million people. The global economic burden is estimated at 1.3 trillion USD annually and is close to 1.8% of global GDP [1]. Despite the progress in preventive and therapeutic measures of CVD, the increasing CMD rates only underscore the important need of molecular biomarkers for early detection [2]. Determining whether someone has CMD usually involves an extended diagnostic process that has become essential for risk stratification and disease prevention [3]. While the onset of CMD typically occurs in adulthood, disease development commences much earlier, and this has scientists questioning whether molecular biomarkers could improve current prognostic risk scores. Predicting which people with T2D are most likely to develop CVD remains a significant challenge despite the recent advances in genetic mapping.

Background: Although the exact role of mitophagy in the pathogenesis of diabetic cardiomyopathy (DCM) caused by type 2 diabetes mellitus (T2DM) remains controversial, recent studies revealed inhibition of mitophagy exacerbates cardiac injury in DCM. The zinc transporter ZIP7 has been reported to be upregulated by high glucose in cardiomyocytes and ZIP7 upregulation leads to inhibition of mitophagy in mouse hearts in the setting of ischemia/reperfusion. Nevertheless, little is known about the role of ZIP7 and its relationship with mitophagy in DCM caused by T2DM.

Methods: T2DM was induced with high-fat diet (HFD) and streptozotocin. The cardiac-specific ZIP7 conditional knockout (ZIP7 cKO) mice were generated by adopting CRISPR/Cas9 system. Cardiac function was evaluated with echocardiography. Mitophagy was assessed by detecting mito-LC3II, mitoKeima, and mitoQC. Reactive oxygen species (ROS) were detected with DHE and mitoB.

Results: ZIP7 was upregulated by T2DM in mouse hearts and ZIP7 cKO reduced mitochondrial ROS generation in mouse hearts with T2DM. Mitophagy was suppressed by T2DM in mouse hearts, which was prevented by ZIP7 cKO. T2DM inhibited PINK1 and Parkin accumulation in cardiac mitochondria, an effect that was prevented by ZIP7 cKO, pointing to that ZIP7 upregulation mediates T2DM-induced suppression of mitophagy by inhibiting the PINK1/Parkin pathway. T2DM induced mitochondrial hyperpolarization and decrease of mitochondrial Zn²⁺ and this was blocked by ZIP7 cKO, indicating that upregulation of ZIP7 leads to mitochondrial hyperpolarization by reducing Zn²⁺ within mitochondria. Finally, ZIP7 cKO prevented cardiac dysfunction and fibrosis caused by T2DM.

Conclusions: ZIP7 upregulation mediates the inhibition of mitophagy by T2DM in mouse hearts by suppressing the PINK1/Parkin pathway. Reduction of mitochondrial Zn²⁺ due to upregulation of ZIP7 accounts for the inhibition of the PINK1/Parkin pathway. Prevention of ZIP7 upregulation is essential for the treatment of T2DM-induced cardiomyopathy.

Background: Obesity is a complex, diverse and multifactorial disease that has become a major public health concern in the last decades. The current classification systems relies on anthropometric measurements, such as BMI, that are unable to capture the physiopathological diversity of this disease. The aim of this study was to redefine the classification of obesity based on the different H-NMR metabolomics profiles found in individuals with obesity to better assess the risk of future development of cardiometabolic disease.

Materials and methods: Serum samples of a subset of the Di@bet.es cohort consisting of 1387 individuals with obesity were analyzed by H-NMR. A K-means algorithm was deployed to define different H-NMR metabolomics-based clusters. Then, the association of these clusters with future development of cardiometabolic disease was evaluated using different univariate and multivariate statistical approaches. Moreover, machine learning-based models were built to predict the development of future cardiometabolic disease using BMI and waist-to-hip circumference ratio measures in combination with H-NMR metabolomics.

Results: Three clusters with no differences in BMI nor in waist-to-hip circumference ratio but with very different metabolomics profiles were obtained. The first cluster showed a metabolically healthy profile, whereas atherogenic dyslipidemia and hypercholesterolemia were predominant in the second and third clusters, respectively. Individuals within the cluster of atherogenic dyslipidemia were found to be at a higher risk of developing type 2 DM in a 8 years follow-up. On the other hand, individuals within the cluster of hypercholesterolemia showed a higher risk of suffering a cardiovascular event in the follow-up. The individuals with a metabolically healthy profile displayed a lower association with future cardiometabolic disease, even though some association with future development of type 2 DM was still observed. In addition, H-NMR metabolomics improved the prediction of future cardiometabolic disease in comparison with models relying on just anthropometric measures.

Conclusions: This study demonstrated the benefits of using precision techniques like H-NMR to better assess the risk of obesity-derived cardiometabolic disease.

Backgrounds: High-intensity statin is recommended for patients undergoing percutaneous coronary intervention (PCI), and ezetimibe is recommended to be added in patients not achieving low-density lipoprotein cholesterol (LDL-C) targets. Moderate-intensity statin plus ezetimibe can reduce LDL-C levels similar to high-intensity statin. The aim of this study is to examine the long-term efficacy and safety of moderate-intensity statin plus ezetimibe as the first-line strategy compared to high-intensity statin in patients undergoing PCI.

Method: Data was obtained from the Health Insurance Review and Assessment Service database of South Korea. Patients who underwent PCI from 2012 to 2017 were included. The primary efficacy endpoint was major adverse cardiac cerebrovascular events (MACCEs), a composite of all-cause death, revascularization, or ischemic stroke. The safety endpoint was new-onset diabetes mellitus (DM).

Results: A total of 45,501 patients received high-intensity statin (n = 38,340) or moderate-intensity statin plus ezetimibe (n = 7,161). Among propensity-score-matched 7,161 pairs, MACCEs occurred in 1,460 patients with high-intensity statin and 1,406 patients with moderate-intensity statin plus ezetimibe (33.8% vs. 31.9%, hazard ratio 0.96, 95% confidence interval 0.89-1.03, P = 0.27) at a median follow-up of 2.7 years. DM was newly diagnosed in 398 patients with high-intensity statin and 342 patients with moderate-intensity statin plus ezetimibe (12.5% vs. 10.7%; hazard ratio 0.84, 95% confidence interval 0.73-0.97, P = 0.02).

Conclusion: In patients undergoing PCI, moderate-intensity statin plus ezetimibe demonstrated a similar risk of MACCEs but a lower risk of new-onset DM than high-intensity statin. Early combination treatment of moderate-intensity statin and ezetimibe may be a useful and safe lipid-lowering strategy after PCI.

Background: Diabetes is associated with a prothrombotic state that contributes to cardiovascular (CV) events in type 2 diabetes (T2DM). Activated factor VII (FVIIa)- antithrombin (AT) complexes are indicative of tissue factor (TF) exposure and have been associated with thromboembolic risk in coronary artery disease. To our knowledge there have been no reports on FVIIa-AT complexes in T2DM, therefore we assessed factors that determine FVIIa-AT complexes in this disease and the impact of higher complexes on a prothrombotic state.

Methods: In 108 T2DM patients (mean age 63.8 years, 52.8% men, median HbA1c of 6.9 [interquartile range 6.1-8.2] %) and 83 age- and sex-matched non-diabetic subjects, we measured FVIIa-AT complexes. Metabolic control of T2DM involved fasting glucose, glycated hemoglobin (HbA1c), albumin/creatinine ratio (ACR), and lipid levels. To characterize a prothrombotic state, we determined thrombin generation parameters, fibrinolysis markers, and plasma fibrin clot properties.

Results: FVII-AT complexes in T2DM patients were similar to controls (73.6 [59.4-91.7] vs. 79.6 [59.2-97.1]pM, respectively, p = 0.30). The T2DM patients with FVIIa-AT in the top vs. the bottom quartile had a larger prevalence of active smoking and insulin use, along with higher fasting glucose (+ 36.4%), HbA1c (+ 27.4%), ACR (+ 72.8%), total cholesterol (+ 34.5%), and LDL-cholesterol (+ 80%). FVIIa-AT complexes showed no associations with in vitro thrombin generation potential, plasma fibrin clot properties, or fibrinolysis variables. On multivariable analysis HbA1c, ACR, and total cholesterol remained independently associated with FVIIa-AT complexes in T2DM.

Conclusions: This is the first study to show that in T2DM higher FVIIa-AT complexes are associated with markers of dyslipidemia and glycemia control, indicating that TF-induced coagulation activation could be suppressed by achieving treatment targets.

Aims: Aging is influenced by genetic determinants and comorbidities, among which diabetes increases the risk for heart failure with preserved ejection fraction. There is no therapy to prevent heart dysfunction in aging and diabetic individuals. In previous studies, a single administration of the longevity-associated variant (LAV) of the human BPIFB4 gene halted heart decline in older and type 2 diabetic mice. Here, we asked whether orally administered LAV-BPIFB4 protein replicates these benefits.

Materials and methods: In two controlled, randomized studies, 18-month-old male C57BL/6 J mice and 9-week-old C57BLKS/J-Leprdb/Leprdb/Dock7 + [db/db] mice of both sexes underwent baseline echocardiography. They then received a recombinant purified LAV-BPIFB4 protein (3 µg/animal, every three days) or vehicle by gavage. After 30 days, the animals underwent echocardiography, and the hearts were collected post-termination for histology.

Results: All the animals completed the study except one female diabetic mouse, which was culled prematurely because tooth malocclusion caused eating problems. There was no effect of the LAV-BPIFB4 protein on body weight in the two studies or glycosuria in the diabetic study. In aging mice, LAV-BPIFB4 increased myocardial Bpifb4 expression, improving heart contractility and capillarity while reducing perivascular fibrosis and senesce. In male diabetic mice, LAV-BPIFB4 therapy improved systolic function, microvascular density, and senescence, whereas the benefit was limited to systolic function in females.

Conclusions: This study shows the feasibility and efficacy of a variant protein associated with human longevity in contrasting pivotal risk factors for heart failure in animal models. The diabetic study revealed that sex influences the treatment efficacy.

Background: There has been a concerning rise in the incidence of major adverse cardiovascular and cerebrovascular events (MACCE) following noncardiac surgeries (NCS), significantly impacting surgical outcomes and patient prognosis. Glucose metabolism abnormalities induced by stress response under acute medical conditions may be a risk factor for postoperative MACCE. This study aims to explore the association between stress hyperglycemia ratio (SHR) and postoperative MACCE in patients undergoing general anesthesia for NCS.

Methods: There were 12,899 patients in this perioperative cohort study. The primary outcome was MACCE within 30 days postoperatively, defined as angina, acute myocardial infarction, cardiac arrest, arrhythmia, heart failure, stroke, or in-hospital all-cause mortality. Kaplan-Meier curves visualized the cumulative incidence of MACCE. Cox proportional hazard models were utilized to assess the association between the risk of MACCE and different SHR groups. Restricted cubic spline analyses were conducted to explore potential nonlinear relationships. Additionally, exploratory subgroup analyses and sensitivity analyses were performed.

Results: A total of 592 (4.59%) participants experienced MACCE within 30 days after surgery, and 1,045 (8.10%) within 90 days. After adjusting for confounding factors, compared to the SHR T2 group, the risk of MACCE within 30 days after surgery increased by 1.34 times (95% CI 1.08-1.66) in the T3 group and by 1.35 times (95% CI 1.08-1.68) in the T1 group respectively. In the non-diabetes group, the risk of MACCE within 30 days after surgery increased by 1.60 times (95% CI 1.21-2.12) in the T3 group and by 1.61 times (95% CI 1.21-2.14) in the T1 group respectively, while no statistically significant increase in risk was observed in the diabetes group. Similar results were observed within 90 days after surgery in the non-diabetes group. Additionally, a statistically significant U-shaped nonlinear relationship was observed in the non-diabetes group (30 days: P for nonlinear = 0.010; 90 days: P for nonlinear = 0.008).

Conclusion: In this large perioperative cohort study, we observed that both higher and lower SHR were associated with an increased risk of MACCE within 30 and 90 days after NCS, especially in patients without diabetes. These findings suggest that SHR potentially plays a key role in stratifying cardiovascular and cerebrovascular risk after NCS.

Background: Dysglycemia and insulin resistance increase type 2 diabetes (T2D) and cardiovascular disease (CVD) risk, yet associations with specific glucose-insulin homeostatic biomarkers have been inconsistent. Vitamin D and marine omega-3 fatty acids (n-3 FA) may improve insulin resistance. We sought to examine the association between baseline levels of insulin, C-peptide, HbA1c, and a novel insulin resistance score (IRS) with incident cardiometabolic diseases, and whether randomized vitamin D or n-3 FA modify these associations.

Methods: VITamin D and OmegA-3 TriaL (NCT01169259) was a randomized clinical trial testing vitamin D and n-3 FA for the prevention of CVD and cancer over a median of 5.3 years. Incident cases of T2D and CVD (including cardiovascular death, myocardial infarction, stroke, and coronary revascularization) were matched 1:1 on age, sex, and fasting status to controls. Conditional logistic regressions adjusted for demographic, clinical, and adiposity-related factors were used to assess the adjusted odds ratio (aOR) per-standard deviation (SD) and 95%CI of baseline insulin, C-peptide, HbA1c, and IRS (Insulin×0.0295 + C-peptide×0.00372) with risk of T2D, CVD, and coronary heart disease (CHD).

Results: We identified 218 T2D case-control pairs and 715 CVD case-control pairs including 423 with incident CHD. Each of the four biomarkers at baseline was separately associated with incident T2D, aOR (95%CI) per SD increment: insulin 1.46 (1.03, 2.06), C-peptide 2.04 (1.35, 3.09), IRS 1.72 (1.28, 2.31) and HbA1c 7.00 (3.76, 13.02), though only HbA1c remained statistically significant with mutual adjustments. For cardiovascular diseases, we only observed significant associations of HbA1c with CVD (1.19 [1.02, 1.39]), and IRS with CHD (1.25 [1.04, 1.50]), which persisted after mutual adjustment. Randomization to vitamin D and/or n-3 FA did not modify the association of these biomarkers with the endpoints.

Conclusions: Each of insulin, C-peptide, IRS, and HbA1c were associated with incident T2D with the strongest association noted for HbA1c. While HbA1c was significantly associated with CVD risk, a novel IRS appears to be associated with CHD risk. Neither vitamin D nor n-3 FA modified the associations between these biomarkers and cardiometabolic outcomes.