Association of Blood Copper With the Subclinical Carotid Atherosclerosis: An Observational Study.

BACKGROUND: Copper exposure is reported to be associated with increased risk of stroke. However, the association of copper exposure with subclinical carotid atherosclerosis remains unclear. METHODS AND RESULTS: This observational study included consecutive participants from Xinqiao Hospital between May 2020 and August 2021. Blood metals were measured using inductively coupled plasma mass spectrometry and carotid atherosclerosis was assessed using ultrasound. Modified Poisson regression was performed to evaluate the associations of copper and other metals with subclinical carotid plaque presence. Blood metals were analyzed as categorical according to the quartiles. Multivariable models were adjusted for age, sex, body mass index, education, smoking, drinking, hypertension, diabetes, dyslipidemia, estimated glomerular filtration rate, and coronary artery disease history. Bayesian Kernel Machine Regression was conducted to evaluate the overall association of metal mixture with subclinical carotid plaque presence. One thousand five hundred eighty-five participants were finally enrolled in our study, and carotid plaque was found in 1091 subjects. After adjusting for potential confounders, metal-progressively-adjusted models showed that blood copper was positively associated with subclinical carotid plaque (relative risk according to comparing quartile 4 to quartile 1 was 1.124 [1.021-1.238], relative risk according to per interquartile increment was 1.039 [1.008-1.071]). Blood cadmium and lead were also significantly associated with subclinical carotid plaque. Bayesian Kernel Machine Regression analyses suggested a synergistic effect of copper-cadmium-lead mixture on subclinical carotid plaque presence. CONCLUSIONS: Our findings identify copper as a novel risk factor of subclinical carotid atherosclerosis and show the potential synergistic proatherogenic effect of copper, cadmium, and lead mixture.

Association of multiple blood metals and systemic atherosclerosis: A cross-sectional study in the CAD population.

BACKGROUND: Coronary atherosclerotic disease (CAD) is often accompanied by peripheral atherosclerosis, resulting in a higher risk of ischemia and cardiovascular death. Exposure to metals is associated with atherosclerotic plaques at specific sites. However, less is known about the effects of mixed metals on systemic atherosclerotic burden in CAD patients. OBJECTIVES: To investigate the association of metal mixtures with systemic atherosclerotic burden in a CAD population. METHODS: A cross-sectional study including 1562 CAD patients from Southwest China was conducted. The levels of 10 blood metals were measured via inductively coupled plasma spectrometry. More than one vessel with a stenosis ≥50% vessel diameter was defined as CAD. Carotid and lower limb atherosclerosis was assessed by using ultrasound, and coronary atherosclerosis was quantified via arterial angiography. Systemic atherosclerosis was scored according to the presence or absence of lesions at the three sites and the total number of lesions. To investigate the combined impacts and interaction effects of metals, Bayesian kernel machine regression was used. Weighted quantile regression was used to identify the contributions of the metals. RESULTS: Significant overall associations of mixed metals with systemic atherosclerotic burden were found. These positive overall associations were mainly driven by Cd, Cu and Pb in systemic atherosclerosis. The main contributing factors were As and Cu for coronary atherosclerosis as well as Cd, Cu and Pb for carotid and lower limb atherosclerosis. Cd and Pb or Cr can interact, and Pb interacts with age, sex and alcohol. CONCLUSIONS: In CAD patients, exposure to combinations of metals was highly positively associated with systemic atherosclerotic burden. These significant trends were more pronounced in the peripheral arteries and carotid arteries. Controlling environmental metal exposure can contribute to reducing systemic atherosclerosis in CAD patients.

Iodixanol-associated acute kidney injury and prognosis in patients undergoing elective percutaneous coronary intervention: a prospective, multi-center study.

OBJECTIVE: To evaluate iodixanol-associated acute kidney injury (AKI) and prognosis in patients undergoing elective percutaneous coronary intervention (PCI). METHODS: Patients undergoing elective PCI and iodixanol administration were prospectively enrolled in 8 centers between May 2020 and November 2021. The primary endpoint was AKI, defined as an increase in SCr of ≥ 0.3 mg/dL (26.4 µmol/L) or relative elevation ≥ 50% from baseline in the 48-72 h after PCI. Prognosis evaluations included the major adverse renal and cardiovascular events (MARCE): all-cause mortality, new-onset renal replacement therapy (NRRT), non-fatal myocardial infarction, and non-fatal stroke. AKI predictors were identified using multivariable logistic regression and associations between AKI and outcomes were examined using Cox regression. RESULTS: A total of 3630 patients were included in the final analysis and 2.9% of patients (107/3,630) suffered AKI. Among them, 95.3% (102/107) of AKI were stage 1, and 4.6% (5/107) of stage 2. The multivariable analysis indicated that age over 75-year-old, diabetes, NT-pro-BNP > 300 pg/mL, hemoglobin < 110 g/L, eGFR < 60 mL/min/1.73m2, and diuretics were independently associated with AKI (p < 0.05). After a median follow-up of 13 months, MARCE occurred in 3.6% (131/3630) of the study population, and their incidence was higher in AKI (9.4%, 10/107) vs. non-AKI patients (3.4%, 121/3,523). However, after multivariable adjustment, there was no statistically significant association between AKI and MARCE (p = 0.382). CONCLUSIONS: In patients undergoing elective PCI, cases of iodixanol-associated AKI were mostly mild and, after multivariable adjustment, held no statistically significant association with MARCE on mid-term follow-up. CLINICAL RELEVANCE STATEMENT: The incidence of iodixanol-associated AKI was low and mainly limited to mild renal impairment in patients undergoing elective PCI. Physicians should provide adequate contrast for coronary artery evaluation and, at the same time, minimize the contrast volume. KEY POINTS: • The incidence of iodixanol-associated acute kidney injury was low and mostly limited to mild renal impairment. • Iodixanol administration had no statistically significant impact on the major adverse renal and cardiovascular events in patients undergoing elective percutaneous coronary intervention.

Low serum Klotho reflects senile inflammation in middle-aged and elderly patients with coronary atherosclerosis.

BACKGROUND: Anti-aging protein Klotho has been reported to be associated with atherosclerosis, which was considered as a chronic inflammatory disease. However, the relationship between Klotho and senile inflammation remained unclear. The present study aims to ascertain the correlation of Klotho with inflammation in middle-aged and elderly coronary atherosclerotic disease (CAD). METHODS: A total of 302 patients with CAD were included in this study. Coronary atherosclerosis was confirmed and quantified for all patients by coronary angiography. Serum Klotho was detected by enzyme linked immunosorbent assay. Serum concentrations of IL-6 and IL-8 were quantified by chemiluminescence assay. T-lymphocyte subsets were measured using flow cytometry. RESULTS: Multivariate linear regression analysis showed that serum Klotho was an independent predictor for circulating monocytes (standard ß = -0.321, P < 0.001) and CD4+/CD8+ ratio (standard ß = -0.522, P < 0.001). After adjustment, serum Klotho was still independently associated with IL-6 (standard ß = -0.395, P < 0.001) and IL-8 (standard ß = -0.296, P < 0.001). Moreover, circulating monocytes, CD4+ and CD8+ lymphocytes were correlated with increased serum concentrations of IL-6 and IL-8, independent of CRP (P < 0.05). In receiver operating characteristic curve analysis, CD4+/CD8+ ratio (AUC = 0.863, P < 0.001), IL-6 (AUC = 0.893, P < 0.001) and IL-8 (AUC = 0.884, P < 0.001) presented the excellent predictive performance for significant CAD. CONCLUSIONS: Decreased concentrations in serum Klotho reflect senile inflammation, which is related to the severity of CAD in middle-aged and elderly patients.

Klotho ameliorates angiotension-II-induced endothelial senescence via restoration of autophagy by inhibiting Wnt3a/GSK-3ß/mTOR signaling: A potential mechanism involved in prognostic performance of Klotho in coronary atherosclerotic disease.

OBJECTIVE: We aimed to evaluate the prognostic performance of circulating Klotho in coronary atherosclerotic disease (CAD), and to further explore the effect of Klotho on stress-mediated endothelial senescence and underlying mechanism. METHODS: A cohort of 295 patients had a 12-month follow-up for major adverse cardiovascular events (MACE). Serum Klotho was detected by enzyme linked immunosorbent assay. Cell viability, SA-ß-Gal staining, the expression of P53 and P16 were analyzed for endothelial senescence. Oxidative stress was evaluated by measurement of reactive oxygen species, superoxide dismutase and malondialdehyde. LC3, P62, Wnt3a, GSK-3ß and mTOR were analyzed by western blotting. Autophagosome formation was detected by adenovirus transfection. RESULTS: In epidemiological analysis, low Klotho (≤295.9 pg/ml) was significantly associated with MACE risk (HR=2.266, 95 %CI 1.229-4.176). In experimental analysis, Klotho alleviated endothelial senescence and oxidative stress caused by Ang-II exposure; Klotho restored impaired autophagic flux to ameliorate Ang-II induced endothelial senescence; Ang-II activated Wnt3a/GSK-3ß/mTOR signaling to inhibit autophagy, whereas Klotho restored autophagy through blockade of Wnt3a/GSK-3ß/mTOR signaling; Klotho ameliorated endothelial senescence by suppressing Wnt3a/GSK-3ß/mTOR pathway under Ang-II exposure. CONCLUSIONS: Prognostic significance of Klotho in CAD is potentially ascribed to its anti-endothelial senescence effect via autophagic flux restoration by inhibiting Wnt3a/ GSK-3ß/mTOR signaling.

Independent association of blood cadmium with subclinical lower extremity atherosclerosis: An observational study based on dose-response analysis.

BACKGROUND: Atherosclerosis is an increasingly public health issue globally. Previous studies have showed a causal link between heavy metal exposure and atherosclerosis. However, the association of cadmium concentration with subclinical lower extremity atherosclerosis (SLEA) remains unclear. AIMS: To investigate the association of blood cadmium with SLEA and its extent, and further analyze the potential dose-response relationship. METHODS: Blood cadmium concentration was measured using inductively coupled plasma mass spectrometry. SLEA and its extent were assessed by ultrasound diagnosis system. Multivariate models were applied to evaluate the association of blood cadmium with SLEA and its extent. Restricted cubic splines were performed to explore the potential dose-response relationship. RESULTS: This observational study consisted of 1664 participants from cardiovascular outpatient, with an average age of 62.4 years and 1218 (73.2%) men. When blood cadmium was included as a categorical variable in multivariate models, logistic regression analysis showed that high quartile in blood cadmium was an independent risk factor of SLEA (OR = 2.704, 95%CI 1.866-3.919). After log-transformed for SLEA extent parameters, linear regression analysis indicated that high quartile in blood cadmium was significantly associated with higher Crouse score (GMR = 1.21, 95%CI 1.15-1.28), plaque maximum thickness (GMR = 1.13, 95%CI 1.09-1.18) and diseased vessel count (GMR = 1.14, 95%CI 1.10-1.19), respectively. When blood cadmium was used as a continuous variable in restricted cubic splines, the dose-response relationship presented a positive progression in SLEA (P = 0.302), plaque maximum thickness (P = 0.145) and diseased vessel count (P = 0.055) apparently that did not deviate from linearity. CONCLUSIONS: Blood cadmium exhibited an independent association with SLEA, and this dose-response relationship was progressive without significant departure from linearity.

Klotho Ameliorates Vascular Calcification via Promoting Autophagy.

Vascular calcification (VC) is regarded as a common feature of vascular aging. Klotho deficiency reportedly contributes to VC, which can be ameliorated by restoration of Klotho expression. However, the specific mechanisms involved remain unclear. Here, we investigated the role of autophagy in the process of Klotho-inhibiting VC. The clinical study results indicated that, based on Agatston score, serum Klotho level was negatively associated with aortic calcification. Then, Klotho-deficient mice exhibited aortic VC, which could be alleviated with the supplementation of Klotho protein. Moreover, autophagy increased in the aorta of Klotho-deficient mice and protected against VC. Finally, we found that Klotho ameliorated calcification by promoting autophagy both in the aorta of Klotho-deficient mice and in mouse vascular smooth muscle cells (MOVAS) under calcifying conditions. These findings indicate that Klotho deficiency induces increased autophagy to protect against VC and that Klotho expression further enhances autophagy to ameliorate calcification. This study is beneficial to exploring the underlying mechanisms of Klotho regulating VC, which has important guiding significance for future clinical studies in the treatment of VC.

Ceria nanoparticles prophylactic used for renal ischemia-reperfusion injury treatment by attenuating oxidative stress and inflammatory response.

Renal ischemia-reperfusion (IR) injury (RIRI) is the leading cause of acute kidney injury (AKI), a common disease with high morbidity and mortality. However, due to the lack of effective diagnostic and therapeutic tools, patients have to resort to conservative treatment. To address this issue, we have developed a novel prophylactic strategy that involves the pre-treatment use of ceria nanoparticles (CNPs) before surgery. Based on our careful study of the three different sizes of CNPs that we synthesized, 46 nm (NP46), 81 nm (NP81), and 118 nm (NP118), we have found that NP118 can be used as effective prophylactic agents against RIRI and subsequent renal fibrosis. In our experiments, the CNPs exhibited excellent antioxidant and anti-inflammatory activities in vitro and effectively protected the kidney against RIRI and renal fibrosis in vivo, as proved by the decreases in renal lesions, serum creatinine, blood urea nitrogen, apoptotic cell, KIM-1 expression, and fibrotic area in CNPs treated samples relative to RIRI group. Mechanistically, not only did the CNPs reduce oxidative stress by regulating the Nrf2 pathway, but they also attenuated RIRI induced inflammatory response by decreasing macrophage infiltration and polarization to M1 phenotype, and reducing pro-inflammatory cytokine and chemokine production. In vitro results further confirmed that CNPs pre-treatment not only dramatically decreased intracellular ROS production in renal tubular epithelial cells and vascular endothelial cells, but also effectively attenuated lipopolysaccharide-induced inflammation in RAW264.7 cells. In addition, we found that one fourth of the NP118 persisted for more than 21 days in IR kidneys, and that out of the three sizes of CNPs, NP118 achieved the best results in all our experiments. Our study provides new insights into the usage and majorization of CNPs as a potential therapy to treat or prevent RIRI and renal fibrosis.

Effect of Paclitaxel-Coated Balloon Angioplasty on Side Branch Lesion and Cardiovascular Outcomes in Patients with De Novo True Coronary Bifurcation Lesions Undergoing Percutaneous Coronary Intervention.

PURPOSE: To compare the effects of paclitaxal-coated balloon (PCB) versus conventional balloon (CB) on side branch (SB) lesion and cardiovascular outcomes in patients with de novo true bifurcation lesions. METHODS: In total, 219 patients with de novo true bifurcation lesions were enrolled and divided into PCB group (102 cases) and CB group (117 cases) according to angioplasty strategy in SB. Drug-eluting stent (DES) was implanted in main vessel (MV) for each subject. All subjects underwent a 12-month follow-up for late lumen loss (LLL), restenosis, and major adverse cardiovascular events (MACE) after percutaneous coronary intervention (PCI). MACEs included cardiac death, nonfatal myocardial infarction, and unstable angina requiring admission. RESULTS: There were no differences in diameter, minimum lumen diameter (MLD), and stenosis for bifurcation lesions between the two groups before and immediately after PCI (P > 0.05). After 12-month follow-up, no differences occurred in MV-MLD and MV-LLL between the two groups (P > 0.05); SB-MLD in PCB group was higher than that in CB group (1.97 ± 0.36 mm vs. 1.80 ± 0.43 mm, P = 0.007); SB-LLL in PCB group was lower than that in CB group (0.11 ± 0.18 mm vs. 0.19 ± 0.25 mm, P = 0.024). Multivariate COX analyses indicated that PCB group had lower MACE risk than CB group (HR = 0.480, 95%CI 0.244-0.941, P = 0.033). CONCLUSION: PCB could decrease SB-LLL and MACE risk in patients with de novo true coronary bifurcation lesion 12 months after single-DES intervention.

The Triglyceride-Glucose Index Predicts Coronary Artery Disease Severity and Cardiovascular Outcomes in Patients with Non-ST-Segment Elevation Acute Coronary Syndrome.

Non-ST-segment elevation acute coronary syndrome (NSTE-ACS) is the leading cause of morbidity and mortality from cardiovascular disease worldwide. Several recent studies have shown the relationship between the triglyceride-glucose (TyG) index and vascular disease; however, the role of the TyG index in NSTE-ACS has not been extensively assessed. Thus, we aimed to investigate the association of the TyG index with cardiovascular risk factors and outcomes in NSTE-ACS. Overall, 438 patients with NSTE-ACS were enrolled to examine the association of the TyG index with the SYNTAX score and major adverse cardiovascular events (MACEs). The TyG index was calculated as ln (fasting triglyceride (mg/dL) × fasting glucose (mg/dL)/2). The severity of coronary lesions was quantified by the SYNTAX score. MACEs included cardiac death, nonfatal myocardial infarction, target vessel revascularization, congestive heart failure, and nonfatal stroke. All the patients underwent a 12-month follow-up for MACEs after admission. Multivariate regression analysis identified metabolic risk factors as independent parameters correlated with the TyG index. The prevalence of glucose metabolism disorder, metabolic syndrome, and MACEs increased with increasing TyG index. The TyG index showed a strong diagnostic performance for cardiovascular risk factors and was independently associated with the SYNTAX score (OR 6.055, 95% CI 2.915-12.579, P < 0.001). The risk of MACEs (12.8% and 22.8% for the low TyG index and high TyG index groups, respectively; adjusted HR = 1.791, 95% CI 1.045-3.068, P = 0.034) significantly increased in the high TyG index group as compared with the low TyG index group. The multivariate Cox regression analysis further revealed that the TyG index was an independent predictor of MACEs (HR 1.878, 95% CI 1.130-3.121, P = 0.015). In conclusion, the TyG index might be an independent predictor of coronary artery disease severity and cardiovascular outcomes in NSTE-ACS.

Effects of Ticagrelor versus Clopidogrel in Patients with Coronary Bifurcation Lesions Undergoing Percutaneous Coronary Intervention.

BACKGROUND: Percutaneous treatment of coronary bifurcation lesions can potentially lead to higher risk of ischemic events than the nonbifurcation ones, thus calling for further optimization of dual antiplatelet therapy (DAPT). This study aimed to compare the clinical outcomes from ticagrelor and clopidogrel in bifurcation lesions patients undergoing percutaneous coronary intervention (PCI). METHODS: We performed a retrospective cohort study in patients with coronary bifurcation lesions. A total of 553 patients discharged on ticagrelor or clopidogrel combined with aspirin were recruited for 1-year follow-up. The incidences of primary endpoint (major adverse cardiovascular event [MACE]: a composite of cardiac death, myocardial infarction [MI] or stroke), secondary endpoints (the individual component of the primary endpoint or definite/probable stent thrombosis), and major bleeding (Bleeding Academic Research Consortium [BARC]≥3 bleeding events) were evaluated. To minimize the selection bias, a propensity score-matched population analysis was also conducted. RESULTS: The risks of both primary endpoint (8.15% and 12.01% for the ticagrelor and clopidogrel groups, respectively; adjusted hazards ratio [HR]: 0.488, 95% confidence interval [CI]: 0.277-0.861, P=0.013) and MI (4.44% and 8.48% for the ticagrelor and clopidogrel groups, respectively; adjusted HR: 0.341, 95% CI: 0.162-0.719, P=0.005) were significantly reduced in the ticagrelor group as compared with those of the clopidogrel counterpart, whereas the risk of major bleeding was comparable (2.96% and 2.47% for the ticagrelor and clopidogrel groups, respectively; adjusted HR: 0.972, 95% CI: 0.321-2.941, P=0.960). Propensity score-matched analysis confirmed such findings. CONCLUSIONS: For patients with bifurcation lesions after PCI, ticagrelor treatment shows lower MACE and MI rates than the clopidogrel one, along with comparable major bleeding.