Abstract Doxorubicin is known to have cumulative dose-dependent cardiotoxicity, and a tumor suppressor protein p53 has been implicated in the pathogenesis of doxorubicin cardiotoxicity. However, how ...p53 is induced by doxorubicin and mediates the cardiotoxic effects of doxorubicin remains elusive. In cultured cardiac myocytes, doxorubicin induced oxidative stress, DNA damage, ATM activation, and p53 induction. A free radical scavenger NAC attenuated all of these events, whereas an ATM kinase inhibitor wortmannin attenuated doxorubicin-induced ATM activation and p53 induction but not oxidative stress. Doxorubicin treatment in vivo also induced oxidative stress, DNA damage, ATM activation, and p53 accumulation. These observations suggest that p53 induction by doxorubicin is mediated by oxidative DNA damage-ATM pathway. Doxorubicin-induced contractile dysfunction and myocyte apoptosis in vivo were attenuated in heterozygous p53 deficient mice and cardiac-restricted Bcl-2 transgenic mice, suggesting that myocyte apoptosis plays a central role downstream of p53 in doxorubicin cardiotoxicity. We also tested whether pitavastatin exerts protective effects on doxorubicin cardiotoxicity. Pitavastatin attenuated doxorubicin-induced oxidative stress, DNA damage, ATM activation, p53 accumulation, and apoptosis in vitro. Pitavastatin also attenuated myocyte apoptosis and contractile dysfunction in vivo. The beneficial effects of pitavastatin were reversed by intermediate products of the mevalonate pathway that are required for the activation of Rac1, and Rac1 inhibitor exhibited cardioprotective effects comparable to those of pitavastatin. These data collectively suggest that doxorubicin-induced cardiotoxicity is mediated by oxidative DNA damage-ATM-p53-apoptosis pathway, and is attenuated by pitavastatin through its antioxidant effect involving Rac1 inhibition.
Eicosapentaenoic acid (EPA)-derived resolvin E1 (RvE1) and E2 (RvE2) have antidepressant effects. Here, we investigated the antidepressant effects of resolvin E3 (RvE3) in a mouse model of ...lipopolysaccharide (LPS)-induced depression. We observed that LPS (0.8 mg/kg, i.p.) significantly increased immobility time on the tail suspension test, and this depression-like behavior was dose-dependently attenuated by intracerebroventricular infusion of RvE3 (10 or 100 ng). No effects of LPS or intracerebroventricular infusion of RvE3 on locomotor activity were observed. These results indicate that RvE3, as well as RvE1 and RvE2, have antidepressant effects.
Although the recently marketed stent retriever thrombectomy devices have demonstrated a high recanalization rate and favorable clinical outcomes, there is a concern about the risks of intimal ...injuries when pulling out the stent in the unfolded position. In this study, the Solitaire Flow Restoration System and the Trevo retriever were used in a histopathological comparison of vascular injuries caused by stent retriever thrombectomy devices.
Rabbit carotid arteries were used in the experiments with stent retriever thrombectomy devices. Carotid artery samples were harvested either 1 or 2 weeks postoperatively for histological examination.
Histological changes caused by the use of stent retriever thrombectomy devices were observed from the intimal to medial layers. With the Solitaire FR 4 mm, intimal and medial thickening was observed 1 week postoperatively, and progression of intimal thickening was observed 2 weeks postoperatively. The extent of intimal thickening tended to be greater with the Solitaire FR 6 mm than with the Solitaire FR 4 mm, but this difference was not significant. Compared with the Solitaire FR 4 mm, the Trevo had a significantly smaller area of intimal thickening.
Although there are some differences among devices, results from this study indicate that stent retriever thrombectomy devices induce vascular damage that extends to the medial layer.
We present the quasar luminosity function at z ∼ 5 derived from the optical wide-field survey data obtained as a part of the Subaru strategic program (SSP) with the Hyper Suprime-Cam (HSC). From a ...∼81.8 deg2 area in the Wide layer of the HSC-SSP survey, we selected 224 candidates of low-luminosity quasars at z ∼ 5 by adopting the Lyman-break method down to i = 24.1 mag. Based on our candidates and spectroscopically confirmed quasars from the Sloan Digital Sky Survey (SDSS), we derived the quasar luminosity function at z ∼ 5, covering a wide luminosity range of −28.76 < M1450 < −22.32 mag. We found that the quasar luminosity function is fitted by a double power-law model with a break magnitude of mag. The inferred number density of low-luminosity quasars is lower, and the derived faint-end slope, , is flatter than those of previous studies at z ∼ 5. A compilation of the quasar luminosity function at 4 ≤ z ≤ 6 from the HSC-SSP suggests that there is little redshift evolution in the break magnitude and in the faint-end slope within this redshift range, although previous studies suggest that the faint-end slope becomes steeper at higher redshifts. The number density of low-luminosity quasars decreases more rapidly from z ∼ 5 to z ∼ 6 than from z ∼ 4 to z ∼ 5.
We present the physical properties of AKARI sources without optical counterparts in optical images from the Hyper Suprime-Cam (HSC) on the Subaru telescope. Using the AKARI infrared (IR) source ...catalog and HSC optical catalog, we select 583 objects that do not have HSC counterparts in the AKARI North Ecliptic Pole wide survey field (∼5 deg2). Because the HSC limiting magnitude is deep (gAB ∼ 28.6), these are good candidates for extremely red star-forming galaxies (SFGs) and/or active galactic nuclei (AGNs), possibly at high redshifts. We compile multiwavelength data out to 500 m and use them for fitting the spectral energy distribution with CIGALE to investigate the physical properties of AKARI galaxies without optical counterparts. We also compare their physical quantities with AKARI mid-IR selected galaxies with HSC counterparts. The estimated redshifts of AKARI objects without HSC counterparts range up to z ∼ 4, significantly higher than for AKARI objects with HSC counterparts. We find that (i) 3.6 - 4.5 m color, (ii) AGN luminosity, (iii) stellar mass, (iv) star formation rate, and (v) V-band dust attenuation in the interstellar medium of AKARI objects without HSC counterparts are systematically larger than those of AKARI objects with counterparts. These results suggest that our sample includes luminous, heavily dust-obscured SFGs/AGNs at z ∼ 1-4 that are missed by previous optical surveys, providing very interesting targets for the coming era of the James Webb Space Telescope.
Experimental data suggest that cryoenergy is associated with less endothelial damage and thrombus formation than radiofrequency energy. This study aimed to compare the impact of pulmonary vein ...isolation (PVI) on the endothelial damage, myocardial damage, inflammatory response, and prothrombotic state between the two latest technologies, second-generation cryoballoon (CB2) and contact force-sensing radiofrequency catheter (CFRF) ablation. Eighty-six paroxysmal atrial fibrillation (AF) patients (55 men; 65 ± 12 years) underwent PVI with either the CB2 (
n
= 64) or CFRF (
n
= 22). Markers of the endothelial damage (
l
-arginine/asymmetric dimethylarginine ADMA), myocardial injury (creatine kinase-MB CK-MB, troponin-T, and troponin-I), inflammatory response (high-sensitive C-reactive protein), and prothrombotic state (D-dimer, soluble fibrin monomer complex, and thrombin–antithrombin complex) were determined before and up to 24-h post-procedure. The total application time was shorter (1,460 ± 287 vs. 2,395 ± 571 sec,
p
< 0.01) and total procedure time tended to be shorter (199 ± 37 vs. 218 ± 38 min,
p
= 0.06) with CB2 than CFRF ablation. The amount of myocardial injury was greater (CK-MB: 45 ± 17 vs. 11 ± 3 IU/l,
p
< 0.01) with CB2 than CFRF ablation. The
l
-arginine/ADMA ratio was lower (160 ± 51 vs. 194 ± 38,
p
= 0.028) after CB2 than CFRF ablation. Inflammatory and all prothrombotic markers were significantly elevated post-ablation; however, the magnitude was similar between the two groups. During a mean follow-up of 20 ± 6 months, the single-procedure AF freedom was similar between the CB2 and CFRF groups (60/64 vs. 20/22,
p
= 0.82). CB2-PVI produces significantly lesser endothelial damage with greater myocardial injury than CFRF-PVI; however, similar anticoagulant regimens are required during the peri-procedural periods in both technologies.
Aim: The aim of this study was to examine the effects of evolocumab on favorable limb events in patients with chronic limb-threatening ischemia (CLTI). Methods: A single-center, prospective ...observational study was performed on 30 patients with CLTI. The subjects were divided into 2 groups based on evolocumab administration: evolocumab-treated (E) group ( n=14) and evolocumab non-treated (non-E) group (n=16). The primary outcome was 12-month freedom from major amputation. The secondary outcomes were 12-month amputation-free survival (AFS), overall survival (OS), and wound-free limb salvage. The mean follow-up period was 18±11 months. Results: No significant difference was detected between the two groups for the 12-month freedom from major amputation (log-rank p=0.15), while the 12-month AFS rate was significantly higher in the E group than that in the non-E group (log-rank p=0.02). The 12-month OS rate in the E group was shown a tendency for improvement, as compared with that in the non-E group (log-rank p=0.056). Evolocumab administration was not associated with a significant change in freedom from major amputation (HR, 0.23, 95% CI, 0.03-2.07, p=0.19). However, evolocumab administration was related to a tendency for improvement of AFS and OS (HR, 0.13, 95% CI, 0.02-1.06, p=0.056; HR, 0.16, 95% CI, 0.02-1.37, p=0.09, respectively). Moreover, The E group had a higher proportion of wound-free limb salvage at 12 months (92% vs. 42%, p=0.03). Conclusion: Evolocumab administration was associated with a better AFS outcome in patients with CLTI. Long-term administration of evolocumab over 12 months contributed to improving proportion of wound-free limb salvage.
A 73-year-old woman with atrial fibrillation treated with rivaroxaban was hospitalized for nephrotic syndrome. After discontinuation of rivaroxaban to lower the risk of hemorrhagic events, a renal ...biopsy was performed. Rivaroxaban was scheduled to resume a week after the biopsy to prevent renal hemorrhaging. However, she developed acute brachial arterial embolic occlusion and mural thrombosis in the abdominal aorta before resuming rivaroxaban. If immune-mediated renal diseases are suspected in anticoagulated patients at a risk of thrombotic events, physicians should consider initiating glucocorticoid therapy without a renal biopsy in order to avoid hemorrhagic and thrombotic events.
Objectve To assess the impact of glycemic variability on blood pressure in hospitalized patients with cardiac disease. Methods In 40 patients with cardiovascular disease, the glucose levels were ...monitored by flash continuous glucose monitoring (FGM; Free-Style Libre™ or Free-Style Libre Pro; Abbott, Witney, UK) and self-monitoring blood glucose (SMBG) for 14 days. Blood pressure measurements were performed twice daily (morning and evening) at the same time as the glucose level measurement using SMBG. Results The detection rate of hypoglycemia using the FGM method was significantly higher than that with the 5-point SMBG method (77.5% vs. 5.0%, p<0.001). Changes in the systolic blood pressure from evening to the next morning morning - evening (ME) difference were significantly correlated with night glucose variability (r=0.63, P<0.001). A multiple regression analysis showed that night glucose variability using FGM was more closely correlated with the ME difference r=0.62 (95% confidence interval, 0.019-0.051); p<0.001 than with the age, body mass index, or smoking history. Night glucose variability was also more closely associated with the ME difference in patients with unstable angina pectoris (UAP) than in those with acute myocardial infarction (AMI) or heart failure (HF) (r=0.83, p=0.058). Conclusion Night glucose variability is associated with the ME blood pressure difference, and FGM is more accurate than the 5-point SMBG approach for detecting such variability.
Although many animal studies indicate insulin has cardioprotective effects, clinical studies suggest a link between insulin resistance (hyperinsulinemia) and heart failure (HF). Here we have ...demonstrated that excessive cardiac insulin signaling exacerbates systolic dysfunction induced by pressure overload in rodents. Chronic pressure overload induced hepatic insulin resistance and plasma insulin level elevation. In contrast, cardiac insulin signaling was upregulated by chronic pressure overload because of mechanical stretch-induced activation of cardiomyocyte insulin receptors and upregulation of insulin receptor and Irs1 expression. Chronic pressure overload increased the mismatch between cardiomyocyte size and vascularity, thereby inducing myocardial hypoxia and cardiomyocyte death. Inhibition of hyperinsulinemia substantially improved pressure overload-induced cardiac dysfunction, improving myocardial hypoxia and decreasing cardiomyocyte death. Likewise, the cardiomyocyte-specific reduction of insulin receptor expression prevented cardiac ischemia and hypertrophy and attenuated systolic dysfunction due to pressure overload. Conversely, treatment of type 1 diabetic mice with insulin improved hyperglycemia during pressure overload, but increased myocardial ischemia and cardiomyocyte death, thereby inducing HF. Promoting angiogenesis restored the cardiac dysfunction induced by insulin treatment. We therefore suggest that the use of insulin to control hyperglycemia could be harmful in the setting of pressure overload and that modulation of insulin signaling is crucial for the treatment of HF.
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