Search

Background Ventricular‐arterial coupling predicts outcomes in patients with heart failure. The arterial elastance to end‐systolic elastance ratio (Ea/Ees) is a noninvasively assessed index that reflects ventricular‐arterial coupling. We aimed to determine the prognostic value of ventricular‐arterial coupling assessed through Ea/Ees after transcatheter aortic valve replacement to predict clinical events. Methods and Results We retrieved data on 1378 patients (70% women) who underwent transcatheter aortic valve replacement between October 2013 and May 2017 from the OCEAN‐TAVI (Optimized transCathEter vAlvular iNtervention) Japanese multicenter registry. We determined the association between Ea/Ees and the composite end point of hospitalization for heart failure and cardiovascular death by classifying the patients into quartiles based on Ea/Ees values (group 1: 0.666) during the midterm follow‐up after transcatheter aortic valve replacement. During a median follow‐up period of 736 days (interquartile range, 414–956), there were 247 (17.9%) all‐cause deaths, 89 (6.5%) cardiovascular deaths, 130 (9.4%) hospitalizations for heart failure, and 199 (14.4%) composite events of hospitalization for heart failure and cardiovascular death. The incidence of the composite end point was significantly higher in group 2 (hazard ratio [HR], 1.76; 95% CI, 1.08–2.87 [ P =0.024]), group 3 (HR, 2.43; 95% CI, 1.53–3.86 [ P P P =0.015]). Conclusions These findings suggest that a higher Ea/Ees at discharge after transcatheter aortic valve replacement is associated with adverse clinical outcomes during midterm follow‐up. Registration URL: https://www.upload.umin.ac.jp/ . Unique identifier: UMIN000020423.

Serpentinites and serpentinized mantle peridotites with various tectonic origins occur in the Franciscan Complex of the Northern California Cordillera, USA. Boron isotopes of serpentinites differentiate with fluid-mediated processes, and have great potential for key geologic markers in convergent margins. To understand boron isotope behavior within the Franciscan subduction zone system, we apply a newly developed ablation volume correction (AVC) method for in-situ isotope/elemental analyses using a laser-ablation multiple collector inductively-coupled-plasma mass spectrometry (LA-MC-ICPMS) on seventeen different Franciscan serpentinites (sensu lato) collected from eight separate areas. Boron abundances and isotope compositions of the studied serpentinites show large variations B = 1.6–239 μg·g−1, δ11B = −12.0 to +24.4‰, which allow to discriminate the serpentinites into two groups: (1) a lighter δ11B of −12.0 to +8.8‰ with a lesser B ~2 GPa. Preferential partitioning of 11B into fluids released from the subducted slab at shallow leaves lighter δ11B in the slab resulting in lighter δ11B in the deep slab fluids. In contrast, the blueschist-absent serpentinites with heavier δ11B may have formed at a shallow environment where shallow slab or hydrothermal fluids with heavier 11B were present. Lesser versus greater amounts of B in the deep versus shallow serpentinites are also consistent with the dehydration profile of B from a slab. Our results show the versatility of boron isotopes and composition for identification of the origin of serpentinite in Pacific-type orogenic belts.

We previously reported the secretion of C-type natriuretic peptide (CNP) from vascular endothelial cells and proposed the existence of a vascular natriuretic peptide system composed of endothelial CNP and smooth muscle guanylyl cyclase-B (GC-B), the CNP receptor, and involved in the regulation of vascular tone, remodeling, and regeneration. In this study, we assessed the functional significance of this system in the regulation of blood pressure in vivo using vascular endothelial cell–specific CNP knockout and vascular smooth muscle cell–specific GC-B knockout mice. These mice showed neither the skeletal abnormality nor the early mortality observed in systemic CNP or GC-B knockout mice. Endothelial cell–specific CNP knockout mice exhibited significantly increased blood pressures and an enhanced acute hypertensive response to nitric oxide synthetase inhibition. Acetylcholine-induced, endothelium-dependent vasorelaxation was impaired in rings of mesenteric artery isolated from endothelial cell–specific CNP knockout mice. In addition, endothelin-1 gene expression was enhanced in pulmonary vascular endothelial cells from endothelial cell–specific CNP knockout mice, which also showed significantly higher plasma endothelin-1 concentrations and a greater reduction in blood pressure in response to an endothelin receptor antagonist than their control littermates. By contrast, vascular smooth muscle cell–specific GC-B knockout mice exhibited blood pressures similar to control mice, and acetylcholine-induced vasorelaxation was preserved in their isolated mesenteric arteries. Nonetheless, CNP-induced acute vasorelaxation was nearly completely abolished in mesenteric arteries from vascular smooth muscle cell–specific GC-B knockout mice. These results demonstrate that endothelium-derived CNP contributes to the chronic regulation of vascular tone and systemic blood pressure by maintaining endothelial function independently of vascular smooth muscle GC-B.

BACKGROUND Venous thromboembolism (VTE) has a long-term risk of recurrence, which can be prevented by anticoagulation therapy.Methods and Results:The COMMAND VTE Registry is a multicenter registry enrolling 3,027 consecutive patients with acute symptomatic VTE between January 2010 and August 2014. The entire cohort was divided into the transient risk (n=855, 28%), unprovoked (n=1,477, 49%), and cancer groups (n=695, 23%). The rate of anticoagulation discontinuation was highest in the cancer group (transient risk: 37.3% vs. unprovoked: 21.4% vs. cancer: 43.5% at 1 year, P

[Aims]The progression of pathological left ventricular remodelling leads to cardiac dysfunction and contributes to the occurrence of malignant arrhythmias and sudden cardiac death. The underlying molecular mechanisms remain unclear, however. Our aim was to examine the role of the renin–angiotensin system (RAS) in the mechanism underlying arrhythmogenic cardiac remodelling using a transgenic mouse expressing a cardiac-specific dominant-negative form of neuron-restrictive silencer factor (dnNRSF-Tg). This mouse model exhibits progressive cardiac dysfunction leading to lethal arrhythmias. [Methods and results]Subcutaneous administration of aliskiren, a direct renin inhibitor, significantly suppressed the progression of pathological cardiac remodelling and improved survival among dnNRSF-Tg mice while reducing arrhythmogenicity. Genetic deletion of the angiotensin type 1a receptor (AT1aR) similarly suppressed cardiac remodelling and sudden death. In optical mapping analyses, spontaneous ventricular tachycardia (VT) and fibrillation (VF) initiated by breakthrough-type excitations originating from focal activation sites and maintained by functional re-entry were observed in dnNRSF-Tg hearts. Under constant pacing, dnNRSF-Tg hearts exhibited markedly slowed conduction velocity, which likely contributes to the arrhythmogenic substrate. Aliskiren treatment increased conduction velocity and reduced the incidence of sustained VT. These effects were associated with suppression of cardiac fibrosis and restoration of connexin 43 expression in dnNRSF-Tg ventricles. [Conclusion]Renin inhibition or genetic deletion of AT1aR suppresses pathological cardiac remodelling that leads to the generation of substrates maintaining VT/VF and reduces the occurrence of sudden death in dnNRSF-Tg mice. These findings demonstrate the significant contribution of RAS activation to the progression of arrhythmogenic substrates.

Background The prognosis of asymptomatic deep vein thrombosis (DVT) is uncertain and there is no consensus on the necessity of detection and treatment.Methods and Results:We retrospectively evaluated 300 patients with asymptomatic lower extremity DVT screened from 4,514 consecutive patients on ultrasound at Kyoto University Hospital between January 2010 and September 2015. The subjects had concomitant active cancer in 40%, unprovoked DVT in 59%, and distal DVT in 70%. The cumulative 5-year incidences of symptomatic recurrent venous thromboembolism (VTE); major bleeding; and all-cause death were 14.5%, 16.6%, and 34.1%, respectively. Among 232 patients (77%) with prolonged anticoagulant therapy, anticoagulants were discontinued in 48.4% at 1 year. Anticoagulant therapy was associated with a significantly higher incidence of major bleeding compared with the non-anticoagulant group (20.5% vs. 1.5%, P=0.01) with no significant effect on the incidence of VTE. In patients with active cancer, the favorable effect of anticoagulants relative to no anticoagulants for VTE was significant (HR, 0.22; 95% CI: 0.05-0.95). Conclusions Prolonged anticoagulants therapy was implemented in the majority of patients with asymptomatic DVT, but was associated with a significantly higher risk for major bleeding. On subgroup analysis in patients with active cancer, however, there appeared to be a benefit of prolonged anticoagulant therapy in decreasing the rate of symptomatic recurrent VTE.

Background: It has been reported that biological inactive pro-brain natriuretic peptide(proBNP), precursor peptide of bioactive BNP, is increased in patients with heart failure, as well as mature BNP-32. However, underlying mechanisms of increased plasma proBNP levels in heart failure remain unclear. Methods: We used the conventional BNP assay system, which detects both proBNP and BNP-32, and our recently developed specific human proBNP assay system. We assessed cardiac production of proBNP and BNP(=proBNP+BNP-32) in patients with heart failure. To elucidate the molecular mechanisms underlying the processing and secretion of proBNP, we generated lentivirus vectors carrying several mutations in glycosylation sites of human proBNP. We evaluated the proBNP/BNP ratio, as an efficacy of processing of proBNP to BNP-32. Results: In coronary sinus, plasma proBNP/BNP ratios were significantly elevated in heart failure patients in accordance with the disease severity. In conditioned medium of cultured ventricular myocytes expressing wild type human proBNP, proBNP/BNP ratio was 37%, while in those of myocytes expressing glycosylation-resistant mutant of proBNP, proBNP/BNP ratio was only 3%, demonstrating the essential contribution of glycosylation to the secretion of proBNP. Among 7 glycosylation sites, we found that glycosylation of Thr48 and Thr71 in proBNP is critical for the secretion of proBNP from ventricular myocytes by attenuating proBNP processing. GalNAc-transferase(GALNT) is the largest glycosyltransferase enyme family, which controll O-glycosylasion. We identified GALNT 1 and 2 mediated the glycosylation-regulated increase in cardiac proBNP secretion by screening with siRNAs. Indeed, GALNT1 and 2-expression was increased in FCS-treated ventricular myocytes and failing hearts. We further found that GALNT1 and 2 expression is suppressed by miR-30 family, and that miR-30s expression is decreased in FCS-treated ventricular myocytes and failing hearts. Conclusions: We have elucidated novel molecular pathways that miR-30-GALNTs axis-mediated O -glycosylation in proBNP contributes to increased proportion of proBNP among secreted BNP in the pathological myocardium.

We investigated the molecular mechanism underlying the processing of pro-B-type natriuretic peptide (proBNP). Rat neonatal atrial and ventricular myocytes were cultured separately. We examined the molecular forms of secreted and intracellular BNP in atrial and ventricular myocytes; levels of corin and furin mRNA in atrial and ventricular myocytes; the effect their knockdown on proBNP processing; plasma molecular forms of BNP from rats and humans with and without heart failure; and the impact of the distance between the glycosylation and cleavage sites in wild-type and mutant human proBNP, expressed in rat myocytes transfected with lentiviral vectors. BNP was the major molecular form secreted by atrial and ventricular myocytes. Transfection of furin siRNA reduced proBNP processing in both atrial and ventricular myocytes; however, transfection of corin siRNA did not reduce it. BNP was the major molecular form in rat plasma, whereas proBNP was the major form in human plasma. The relative fraction of human BNP in rat myocytes expressing human proBNP was about 60%, but increasing the distance between the glycosylation and cleavage sites through mutation, increased the processed fraction correspondingly. These results suggest that proBNP is processed into BNP intracellularly by furin. The level of proBNP processing is lower in humans than rats, most likely due to the smaller distance between the O-glycosylation and cleavage sites in humans.