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.

Effects of a High Dose of the Contrast Medium Iodixanol on Renal Function in Patients Following Percutaneous Coronary Intervention.

Iodixanol is associated with lower rates of contrast-induced acute kidney injury (CI-AKI). However, the effects of high volumes of iodixanol on renal function after percutaneous coronary intervention (PCI) have not been fully elucidated. This study evaluates the effects of high-dose (>300 mL) iodixanol on renal function within 72 hours of PCI. We retrospectively reviewed 676 consecutive patients who received high-dose (>300 mL) iodixanol during PCI between October 2015 and December 2017 in 4 centers. Logistic regression analysis was used to identify significant independent predictors for CI-AKI. The incidence of CI-AKI was 3.5% (23/651). In patients administered 300 to 500 mL and >500 mL iodixanol, the incidence of CI-AKI was 3.9% and 1.7%, respectively. In patients with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, the incidence of CI-AKI was 2.6%. In high-risk and very high-risk patients, stratified by the Mehran risk score, the incidence of CI-AKI was 3.3% and 4.3%, respectively. In patients received high-dose iodixanol (>300 mL), logistic regression analysis demonstrated that female sex, chronic kidney disease, and eGFR were independent risk factors for CI-AKI, but contrast volume was not. The administration of high (300-500 mL) and very high (>500 mL) dose of iodixanol is associated with low rates of CI-AKI.

A novel MYBPC3 c.2737+1 (IVS26) G>T mutation responsible for high-risk hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy is an autosomal dominant hereditary disease characterised by left ventricular asymmetry hypertrophy. However, our knowledge of the genetic background in hypertrophic cardiomyopathy cases is limited. Here, we aimed to evaluate pathogenic gene mutations in a family with high-risk hypertrophic cardiomyopathy and analyse the genotype/phenotype relationships in this family. METHODS: The proband, her parents, and her niece underwent whole-exome sequencing, and the genotypes of family members were identified using Sanger sequencing. mRNA expression was detected using reverse transcription sequencing. Structural impairments were predicted by homologous modelling. A family survey was conducted for patients with positive results to obtain information on general clinical symptoms, electrocardiography, ambulatory electrocardiography, echocardiography, and 3.0T cardiac magnetic resonance findings. Regular follow-up was performed for up to 6 months. RESULTS: Five family members, including the proband, carried a cleavage site mutation in the MYBPC3 gene (c.2737+1 (IVS26) G>T), causing exon 26 of the MYBPC3 gene transcript to be skipped and leading to truncation of cardiac myosin-binding protein C. Family survey showed that the earliest onset age was 13 years old, and three people had died suddenly at less than 40 years old. Three pathogenic gene carriers were diagnosed with hypertrophic cardiomyopathy, and all showed severe ventricular septal hypertrophy. CONCLUSION: The c.2737+1 (IVS26) G>T mutation in the MYBPC3 gene led to exon 26 skipping, thereby affecting the structure and function of cardiac myosin-binding protein C and leading to severe ventricular hypertrophy and sudden death.

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.