Masanori Yamamoto

The semiquantitative Clinical Frailty Scale (CFS) is a simple tool to assess patients' frailty and has been shown to correlate with mortality in elderly patients even when evaluated by nongeriatricians. The aim of the current study was to determine the prognostic value of CFS in patients who underwent transcatheter aortic valve replacement.We utilized the OCEAN (Optimized Catheter Valvular Intervention) Japanese multicenter registry to review data of 1215 patients who underwent transcatheter aortic valve replacement. Patients were categorized into 5 groups based on the CFS stages: CFS 1-3, CFS 4, CFS 5, CFS 6, and CFS ≥7. We subsequently evaluated the relationship between CFS grading and other indicators of frailty, including body mass index, serum albumin, gait speed, and mean hand grip. We also assessed differences in baseline characteristics, procedural outcomes, and early and midterm mortality among the 5 groups.Patient distribution into the 5 CFS groups was as follows: 38.0% (CFS 1-3), 32.9% (CFS4), 15.1% (CFS 5), 10.0% (CFS 6), and 4.0% (CFS ≥7). The CFS grade showed significant correlation with body mass index (Spearman's ρ=-0.077, P=0.007), albumin (ρ=-0.22, P<0.001), gait speed (ρ=-0.28, P<0.001), and grip strength (ρ=-0.26, P<0.001). Cumulative 1-year mortality increased with increasing CFS stage (7.2%, 8.6%. 15.7%, 16.9%, 44.1%, P<0.001). In a Cox regression multivariate analysis, the CFS (per 1 category increase) was an independent predictive factor of increased late cumulative mortality risk (hazard ratio, 1.28; 95% confidence interval, 1.10-1.49; P<0.001).In addition to reflecting the degree of frailty, the CFS was a useful marker for predicting late mortality in an elderly transcatheter aortic valve replacement cohort.

The role of direct oral anticoagulants as compared with vitamin K antagonists for atrial fibrillation after successful transcatheter aortic-valve replacement (TAVR) has not been well studied.We conducted a multicenter, prospective, randomized, open-label, adjudicator-masked trial comparing edoxaban with vitamin K antagonists in patients with prevalent or incident atrial fibrillation as the indication for oral anticoagulation after successful TAVR. The primary efficacy outcome was a composite of adverse events consisting of death from any cause, myocardial infarction, ischemic stroke, systemic thromboembolism, valve thrombosis, or major bleeding. The primary safety outcome was major bleeding. On the basis of a hierarchical testing plan, the primary efficacy and safety outcomes were tested sequentially for noninferiority, with noninferiority of edoxaban established if the upper boundary of the 95% confidence interval for the hazard ratio did not exceed 1.38. Superiority testing of edoxaban for efficacy would follow if noninferiority and superiority were established for major bleeding.A total of 1426 patients were enrolled (713 in each group). The mean age of the patients was 82.1 years, and 47.5% of the patients were women. Almost all the patients had atrial fibrillation before TAVR. The rate of the composite primary efficacy outcome was 17.3 per 100 person-years in the edoxaban group and 16.5 per 100 person-years in the vitamin K antagonist group (hazard ratio, 1.05; 95% confidence interval [CI], 0.85 to 1.31; P = 0.01 for noninferiority). Rates of major bleeding were 9.7 per 100 person-years and 7.0 per 100 person-years, respectively (hazard ratio, 1.40; 95% CI, 1.03 to 1.91; P = 0.93 for noninferiority); the difference between groups was mainly due to more gastrointestinal bleeding with edoxaban. Rates of death from any cause or stroke were 10.0 per 100 person-years in the edoxaban group and 11.7 per 100 person-years in the vitamin K antagonist group (hazard ratio, 0.85; 95% CI, 0.66 to 1.11).In patients with mainly prevalent atrial fibrillation who underwent successful TAVR, edoxaban was noninferior to vitamin K antagonists as determined by a hazard ratio margin of 38% for a composite primary outcome of adverse clinical events. The incidence of major bleeding was higher with edoxaban than with vitamin K antagonists. (Funded by Daiichi Sankyo; ENVISAGE-TAVI AF ClinicalTrials.gov number, NCT02943785.).

We present here the annotation of the complete genome of rice Oryza sativa L. ssp. japonica cultivar Nipponbare. All functional annotations for proteins and non-protein-coding RNA (npRNA) candidates were manually curated. Functions were identified or inferred in 19,969 (70%) of the proteins, and 131 possible npRNAs (including 58 antisense transcripts) were found. Almost 5000 annotated protein-coding genes were found to be disrupted in insertional mutant lines, which will accelerate future experimental validation of the annotations. The rice loci were determined by using cDNA sequences obtained from rice and other representative cereals. Our conservative estimate based on these loci and an extrapolation suggested that the gene number of rice is approximately 32,000, which is smaller than previous estimates. We conducted comparative analyses between rice and Arabidopsis thaliana and found that both genomes possessed several lineage-specific genes, which might account for the observed differences between these species, while they had similar sets of predicted functional domains among the protein sequences. A system to control translational efficiency seems to be conserved across large evolutionary distances. Moreover, the evolutionary process of protein-coding genes was examined. Our results suggest that natural selection may have played a role for duplicated genes in both species, so that duplication was suppressed or favored in a manner that depended on the function of a gene.

The Rice Annotation Project Database (RAP-DB) was created to provide the genome sequence assembly of the International Rice Genome Sequencing Project (IRGSP), manually curated annotation of the sequence, and other genomics information that could be useful for comprehensive understanding of the rice biology. Since the last publication of the RAP-DB, the IRGSP genome has been revised and reassembled. In addition, a large number of rice-expressed sequence tags have been released, and functional genomics resources have been produced worldwide. Thus, we have thoroughly updated our genome annotation by manual curation of all the functional descriptions of rice genes. The latest version of the RAP-DB contains a variety of annotation data as follows: clone positions, structures and functions of 31 439 genes validated by cDNAs, RNA genes detected by massively parallel signature sequencing (MPSS) technology and sequence similarity, flanking sequences of mutant lines, transposable elements, etc. Other annotation data such as Gnomon can be displayed along with those of RAP for comparison. We have also developed a new keyword search system to allow the user to access useful information. The RAP-DB is available at: http://rapdb.dna.affrc.go.jp/ and http://rapdb.lab.nig.ac.jp/.

We examined the neointimal characteristics of bare-metal stents (BMS) in extended late phase by the use of optical coherence tomography (OCT).The long-term neointimal features after BMS implantation have not yet been fully characterized.Intracoronary OCT observation of BMS segments was performed during the early phase (<6 months, n = 20) and late phase (>or=5 years, n = 21) after implantation. Internal tissue of the BMS was categorized into normal neointima, characterized by a signal-rich band without signal attenuation, or lipid-leaden intima, with marked signal attenuation and a diffuse border. In addition, the presence of disrupted intima and thrombus was evaluated. Neovascularization was defined as small vesicular or tubular structures, and the location of the microvessels was classified into peristent or intraintima.Normal neointima proliferated homogeneously, and lipid-laden intima was not observed in the early phase. In the late phase, lipid-laden intima, intimal disruption, and thrombus frequently were found in comparison with the early phase (67% vs. 0%, 38% vs. 0%, and 52% vs. 5%, respectively; p < 0.05). Persistent neovascularization demonstrated a similar incidence between the 2 phases. The appearance of intraintima neovascularization was more prevalent in the late phase than the early phase (62% vs. 0%, respectively; p < 0.01) and in segments with lipid-laden intima than in nonlipidic segments (79% vs. 29%, respectively; p = 0.026).This OCT study suggests that neointima within the BMS often transforms into lipid-laden tissue during an extended period of time and that expansion of neovascularization from peristent to intraintima contributes to atherosclerotic progression of neointima.

Confirming complete neointimal coverage after implantation of a drug-eluting stent is clinically important because incomplete stent coverage is responsible for late thrombosis and sudden cardiac death. Optical coherence tomography is a high-resolution (≈10 μm) imaging technique capable of detecting a thin layer of neointimal hyperplasia (NIH) inside a sirolimus-eluting stent (SES) and stent malapposition. This investigation evaluated stent exposure and malapposition 3 months after SES implantation using optical coherence tomography in a different clinical presentations, such as acute coronary syndrome (ACS) and non-ACS. Motorized optical coherence tomographic pullback (1 mm/s) was performed at 3-month follow-up to examine consecutive implanted 31 SESs in 21 lesions in 21 patients (9 with ACS and 12 with non-ACS). NIH thickness inside each strut and percent NIH area in each cross section were measured. In total, 4,516 struts in 567-mm single-stented segments were analyzed. Overall, NIH thickness and percent NIH area were 29 ± 41 μm and 10 ± 4%, respectively. Rates of exposed struts and exposed struts with malapposition were 15% and 6%, respectively. These were more frequent in patients with ACS than in those with non-ACS (18% vs 13%, p <0.0001; 8% vs 5%, p <0.005, respectively). In conclusion, neointimal coverage over a SES at 3-month follow-up is incomplete in ACS and non-ACS. Our study suggests that dual antiplatelet therapy might be continued >3 months after SES implantation. Confirming complete neointimal coverage after implantation of a drug-eluting stent is clinically important because incomplete stent coverage is responsible for late thrombosis and sudden cardiac death. Optical coherence tomography is a high-resolution (≈10 μm) imaging technique capable of detecting a thin layer of neointimal hyperplasia (NIH) inside a sirolimus-eluting stent (SES) and stent malapposition. This investigation evaluated stent exposure and malapposition 3 months after SES implantation using optical coherence tomography in a different clinical presentations, such as acute coronary syndrome (ACS) and non-ACS. Motorized optical coherence tomographic pullback (1 mm/s) was performed at 3-month follow-up to examine consecutive implanted 31 SESs in 21 lesions in 21 patients (9 with ACS and 12 with non-ACS). NIH thickness inside each strut and percent NIH area in each cross section were measured. In total, 4,516 struts in 567-mm single-stented segments were analyzed. Overall, NIH thickness and percent NIH area were 29 ± 41 μm and 10 ± 4%, respectively. Rates of exposed struts and exposed struts with malapposition were 15% and 6%, respectively. These were more frequent in patients with ACS than in those with non-ACS (18% vs 13%, p <0.0001; 8% vs 5%, p <0.005, respectively). In conclusion, neointimal coverage over a SES at 3-month follow-up is incomplete in ACS and non-ACS. Our study suggests that dual antiplatelet therapy might be continued >3 months after SES implantation.

Full-length cDNA (FLcDNA) libraries consisting of 172,000 clones were constructed from a two-row malting barley cultivar (Hordeum vulgare 'Haruna Nijo') under normal and stressed conditions. After sequencing the clones from both ends and clustering the sequences, a total of 24,783 complete sequences were produced. By removing duplicates between these and publicly available sequences, 22,651 representative sequences were obtained: 17,773 were novel barley FLcDNAs, and 1,699 were barley specific. Highly conserved genes were found in the barley FLcDNA sequences for 721 of 881 rice (Oryza sativa) trait genes with 50% or greater identity. These FLcDNA resources from our Haruna Nijo cDNA libraries and the full-length sequences of representative clones will improve our understanding of the biological functions of genes in barley, which is the cereal crop with the fourth highest production in the world, and will provide a powerful tool for annotating the barley genome sequences that will become available in the near future.

This study sought to assess the influence of chronic kidney disease (CKD) classification on clinical outcomes in patients undergoing transcatheter aortic valve implantation (TAVI).The prognostic value of impaired renal function according to CKD classification has not been thoroughly investigated in very elderly TAVI cohorts.Data from 642 consecutive patients who underwent TAVI were prospectively collected. Clinical outcomes were compared in enrolled patients, divided into CKD stage 1+2, CKD stage 3a, CKD stage 3b, and CKD stage 4 on the basis of estimated glomerular filtration rate ≥60, 45 to 59, 30 to 44, and 15 to 29 ml/min/1.73 m(2), respectively.Among the study patients (mean age: 83.5 ± 6.5 years, logistic European System for Cardiac Operative Risk Evaluation score 20.0% [range: 13.6% to 28.8%]), 34% were categorized as CKD stage 1+2 (n = 218), 28.3% as CKD stage 3a (n = 182), 28.2% as CKD stage 3b (n = 181), and 9.5% as CKD stage 4 (n = 61). Thirty-day and cumulative 1-year mortality rates increased significantly across the 4 groups (6.9% vs. 8.8% vs. 13.3% vs. 26.2%, p = 0.002, and 17.2% vs. 23.4% vs. 29.2% vs. 47.8%, p < 0.001, respectively). After adjustment for considerable influential confounders in a Cox multivariate regression model, CKD stage 4 was associated with increased risk for 30-day mortality (hazard ratio: 3.04; 95% confidence interval [CI]: 1.43 to 6.49; p = 0.004), and CKD stages 3b and 4 were related to increased cumulative 1-year mortality (hazard ratios: 1.71 and 2.91; 95% CI: 1.09 to 2.68 and 1.73 to 4.90; p = 0.020 and p < 0.001, respectively) compared with CKD stage 1+2 as the referent.Classification of CKD stages before TAVI allows risk stratification for early and midterm clinical outcomes. TAVI for patients with CKD stage 4 is still considered challenging because of high mortality rates after the procedure.

Background— Transcatheter aortic valve implantation (TAVI) performed under local anesthesia (LA) is becoming increasingly common. We aimed to compare the clinical outcomes in patients who underwent transfemoral-TAVI under general anesthesia (GA) and LA. Methods and Results— Data from 2326 patients in the French Aortic National CoreValve and Edwards 2 (FRANCE 2) registry who underwent transfemoral-TAVI were analyzed. During the study period, the percentage of LA procedures increased gradually from 14% in January 2010 to 59% in October 2011. The clinical outcomes for GA (n=1377) and LA (n=949) were compared. Numerous baseline characteristics differed between the 2 groups, and the use of transesophageal echocardiographic guidance was more common in GA than in LA (76.3% versus 16.9%; P &lt;0.001). Device success and cumulative 30-day survival rates were similar in the 2 groups (97.6% versus 97.0%; P =0.41 and 91.6% versus 91.3%; P =0.69, respectively), whereas the incidence of postprocedural aortic regurgitation≥mild was significantly lower in GA than in LA (15.0% versus 19.1%; P =0.015). The groups were also analyzed using a propensity-matching model, including transesophageal echocardiographic usage (GA [n=401] versus LA [n=401]). This model indicated that there were no significant differences between the 2 groups in the rates of 30-day survival (GA [91.4%] versus LA [89.3%]; P =0.27] and postprocedural aortic regurgitation≥mild (GA [12.7%] versus LA [16.2%]; P =0.19). Conclusions— The less invasive transfemoral-TAVI under LA is preferred in clinical settings and seems to be acceptable; however, the higher incidence of postprocedural aortic regurgitation is emphasized. Therapeutic efforts should be made to reduce such complications during transfemoral-TAVI under LA.

The present study sought to assess the effectiveness of local anesthesia with conscious sedation (LACS) during transcatheter aortic valve implantation (TAVI). On its introduction, TAVI was mostly performed with the patient under general anesthesia (GA); however, evidence supporting the use of less-invasive LACS has been increasing. The data from 174 consecutive patients who underwent TAVI by way of the femoral artery from December 2007 to December 2011 were analyzed. GA was mainly used in early phase of the study (n = 44); this was gradually shifted to LACS in the late phase (n = 130). The clinical outcomes were compared for those patients who received GA versus LACS. The incidence and causes of “LACS failure,” defined as conversion to GA from LACS during TAVI, were also assessed. The rates of procedural success and 30-day mortality were not different between the 2 groups (93.3% vs 95.3%, p = 0.60; 6.7% vs 7.8%, p = 0.55, respectively). Although the clinical backgrounds of the patients showed differences, these results were not significant after adjusting for other influential confounders. The intensive care unit stay and hospital stay were longer in the GA group than in the LACS group (3.9 ± 2.2 vs 3.3 ± 1.5 days, p = 0.044; and 12.2 ± 8.3 vs 8.1 ± 6.5 days, p = 0.001, respectively). LACS failure occurred in 6 patients (4.6%), and the causes were multifactorial, as follows: cardiac tamponade in 2, cardiac arrest in 2, myocardial infarction in 1, and stroke in 1. In conclusion, transfemoral TAVI with the patient under LACS could be successfully performed in most patients, with the advantage of early recovery, although the perioperative risks involved in the TAVI procedure should be considered. The present study sought to assess the effectiveness of local anesthesia with conscious sedation (LACS) during transcatheter aortic valve implantation (TAVI). On its introduction, TAVI was mostly performed with the patient under general anesthesia (GA); however, evidence supporting the use of less-invasive LACS has been increasing. The data from 174 consecutive patients who underwent TAVI by way of the femoral artery from December 2007 to December 2011 were analyzed. GA was mainly used in early phase of the study (n = 44); this was gradually shifted to LACS in the late phase (n = 130). The clinical outcomes were compared for those patients who received GA versus LACS. The incidence and causes of “LACS failure,” defined as conversion to GA from LACS during TAVI, were also assessed. The rates of procedural success and 30-day mortality were not different between the 2 groups (93.3% vs 95.3%, p = 0.60; 6.7% vs 7.8%, p = 0.55, respectively). Although the clinical backgrounds of the patients showed differences, these results were not significant after adjusting for other influential confounders. The intensive care unit stay and hospital stay were longer in the GA group than in the LACS group (3.9 ± 2.2 vs 3.3 ± 1.5 days, p = 0.044; and 12.2 ± 8.3 vs 8.1 ± 6.5 days, p = 0.001, respectively). LACS failure occurred in 6 patients (4.6%), and the causes were multifactorial, as follows: cardiac tamponade in 2, cardiac arrest in 2, myocardial infarction in 1, and stroke in 1. In conclusion, transfemoral TAVI with the patient under LACS could be successfully performed in most patients, with the advantage of early recovery, although the perioperative risks involved in the TAVI procedure should be considered.

This study sought to assess whether the volume of contrast media (CM) influences the occurrence of acute kidney injury (AKI) following transcatheter aortic valve implantation (TAVI).The volume of CM has been shown to be associated with increasing risk of AKI; however, in a high-risk elderly TAVI population, the predictive value and optimal threshold of CM dose on AKI remain uncertain.Data of 415 consecutive transfemoral TAVI patients (age 83.6 ± 6.8 years, logistic EuroSCORE 23.0 ± 12.2%) were analyzed. AKI was defined by Valve Academic Research Consortium criteria. Based on a previous formula, the ratio of CM to serum creatinine (SCr) and body weight (BW) (CM × SCr/BW) was calculated as defining the degree of CM use. The association between CM dose and incidence of AKI, as well as predictive factors and prognosis of AKI, were investigated.AKI occurred in 63 patients (15.2%). Cumulative 1-year mortality showed significant differences between the AKI and non-AKI groups (47.9% vs. 15.7%, p < 0.001). Mean CM × SCr/BW ratio was higher in the AKI group than in the non-AKI group (4.1 ± 2.9 vs. 2.9 ± 1.6, p < 0.001). By multivariate analysis, CM × SCr/BW per 1.0 increase, ejection fraction <40%, and transfusion were associated with the occurrence of AKI (odds ratio [OR]: 1.16; 95% confidence interval [CI]: 1.03 to 1.20; p = 0.017, OR: 3.01; 95% CI: 1.49 to 5.00; p = 0.001, OR: 2.73; 95% CI: 1.54 to 6.15; p = 0.001, respectively). A threshold value of CM × SCr/BW for predicting AKI was statistically identified as 2.7.Although mechanisms of AKI following TAVI are multifactorial, the present study identified a relationship between CM dose increment and high prevalence of AKI. Therapeutic efforts not to exceed the threshold value may reduce the risk of AKI.

The authors sought to investigate the prevalence, risk factors, and mid-term mortality in Asian patients with prosthesis-patient mismatch (PPM) after transcatheter aortic valve replacement (TAVR).Little information is available on PPM after TAVR in Asian patients.The authors included 1,558 patients enrolled in the OCEAN-TAVI (Optimized transCathEter vAlvular iNtervention) Japanese multicenter registry from October 2013 to July 2016 after excluding patients who died following TAVR before discharge. PPM was defined as moderate if ≧0.65 but ≦0.85 cm2/m2, or severe if <0.65 cm2/m2 at the indexed effective orifice area by post-procedural echocardiography.Of the 1,546 patients, moderate and severe PPM were observed in 138 (8.9%) and 11 (0.7%) patients, respectively. These 149 patients were included in the PPM group. The median age and body surface area were 85 years (interquartile range [IQR]: 81 to 88 years) and 1.41 m2 (IQR: 1.30 to 1.53 m2), respectively. In our multivariate analysis, younger age, larger body surface area, smaller aortic valve area, smaller annulus area, no balloon post-dilatation, and use of Edwards Sapien 3 (Edwards Lifesciences, Irvine, California) were identified as independent predictors of PPM. The estimated cumulative all-cause mortality at 1 year using the Kaplan-Meier method was similar between the PPM and non-PPM groups (10.2% vs. 8.3%; log-rank; p = 0.41).The low prevalence of PPM and mortality at 1 year in patients with PPM after TAVR in this Japanese cohort implies that PPM is not a risk factor for mid-term mortality in Asian patients who have undergone TAVR.

The occurrence and clinical impact of untreated subclinical leaflet thrombosis beyond 1 year after transcatheter aortic valve replacement still remain unclear.In a multicenter transcatheter aortic valve replacement registry, we analyzed data from 485 patients who underwent 4-dimensional multidetector computed tomography posttranscatheter aortic valve replacement performed to survey hypoattenuated leaflet thickening with reduced leaflet motion compatible with thrombus at a median of 3 days, 6 months, 1 year, 2 years, and 3 years. Incidence, predictors, and clinical outcomes of early (median 3 days) and late (>30 days) leaflet thrombosis were assessed. Additional anticoagulation was not administered because of subclinical findings at the time of computed tomography in all patients. Early leaflet thrombosis occurred in 45 (9.3%) of 485 patients. Mean pressure gradient at discharge was higher in patients with early leaflet thrombosis than in those without. Independent predictors of early leaflet thrombosis in balloon-expandable prostheses were low-flow, low-gradient aortic stenosis, severe prosthesis-patient mismatch, and 29-mm prostheses. No predictors could be identified for self-expanding prosthesis. Cumulative event rates of death, stroke, or rehospitalization for heart failure over 2 years were 10.7% and 16.9% in patients with and without early leaflet thrombosis, respectively ( P=0.63). Late leaflet thrombosis occurred late up to 3 years, and male sex and paravalvular leak less than mild were independent predictors.Untreated early leaflet thrombosis did not affect the cumulative event rates of death, stroke, and rehospitalization for heart failure. Late leaflet thrombosis was newly detected during 3-year follow-up. Visual Overview: A visual overview is available for this article.

The aim of this study was to determine the impact of pre-existing right bundle branch block (RBBB) on clinical outcomes after transcatheter aortic valve replacement (TAVR). The impact of pre-existing RBBB on clinical outcomes after TAVR is unknown. Between October 2013 and August 2015, 749 patients undergoing TAVR using the Edwards SAPIEN XT prosthesis were prospectively enrolled in the OCEAN-TAVI (Optimized Transcatheter Valvular Intervention) registry from 8 Japanese centers. Electrocardiograms were obtained at baseline. After the procedure, follow-up outpatient visits or telephone interviews were conducted at 30 days, 6 months, and yearly. A total of 102 patients (13.6%) had pre-existing RBBB. The incidence of new pacemaker implantation was significantly higher in the RBBB group (17.6% vs. 2.9%; p < 0.01). The Kaplan-Meier analysis revealed that cardiovascular survival probability was significantly lower in the RBBB group than the no-RBBB group (log-rank p < 0.01). Patients with RBBB and without pacemakers were at higher risk for cardiovascular mortality in the early phase after discharge, and patients with RBBB and pacemakers had higher cardiovascular mortality at mid-term follow-up (log-rank p = 0.01). A multivariate Cox regression model indicated that pre-existing RBBB (hazard ratio: 2.59; 95% confidence interval: 1.15 to 5.85; p < 0.01) was an independent predictor of cardiovascular mortality. Patients with RBBB demonstrated an increased risk for cardiovascular mortality after TAVR, and patients with RBBB and without pacemakers were at higher risk for cardiac death early after discharge. Patients with prior RBBB should be carefully monitored after undergoing TAVR.

The aim of this study was to evaluate postprocedural and midterm outcomes of transcatheter aortic valve implantation (TAVI) in patients with aortic stenosis and active cancer. From October 2013 to August 2015, a total of 749 patients undergoing TAVI using the Edwards Sapien XT prosthesis (Edwards Lifesciences, Irvine, California) were prospectively included in the OCEAN-TAVI registry from 8 Japanese centers. A total of 47 patients (44.7% men; median age 83 years) had active cancer. The transfemoral approach was implemented in 85.1% of patients in the cancer group and 78.1% in the noncancer group (p = 0.22). The occurrence of major vascular complication (4.3% vs 7.5%, p = 0.24), life-threatening bleeding (2.1% vs 7.1%, p = 0.15), and major bleeding (8.5% vs 13%, p = 0.38) was similar between the cancer and noncancer groups. No significant differences were observed regarding device success (100% vs 96.2%, p = 0.17) or 30-day survival (95.7% vs 97.3%, p = 0.38). No difference in midterm survival was found between the patients with cancer and without cancer (log-rank, p = 0.42), regardless of advanced or limited cancer (log-rank, p = 0.68). In a multivariable Cox proportional hazard regression analysis, cancer metastasis was one of the most significant predictors of late mortality (hazard ratio 4.73, 95% CI 1.12 to 20.0; p = 0.035). In conclusion, patients with cancer with severe aortic stenosis who underwent TAVI had similar acute outcomes and midterm survival rates compared with patients without cancer. Cancer metastasis was associated with increased mortality after TAVI.

The aim of this study was to compare long-term all-cause mortality between direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) in patients with atrial fibrillation (AF) after transcatheter aortic valve replacement (TAVR). The optimal anticoagulant agent for patients with AF after TAVR has not been clarified. OCEAN (Optimized Transcatheter Valvular Intervention) is a prospective, multicenter, observational cohort registry comprising 2,588 patients who underwent TAVR between October 2013 and May 2017. Of these, 403 patients (15.6%) with AF on anticoagulant therapy were identified, of whom 227 (56.3%) were prescribed DOACs and 176 (43.7%) were prescribed VKAs. Patients who successfully discharged after TAVR were stratified into DOAC and VKA groups on the basis of the prescription of anticoagulant agents, and the analyses started from discharge. In total, 33.3% of patients were men. The mean age was 84.4 ± 4.7 years, and the average CHA2DS2-VASc score was 5.1 ± 1.1. The median follow-up duration was 568 days. A multivariate Cox regression model and inverse probability of treatment weighting based on the propensity score demonstrated that the DOAC group was significantly associated with a lower incidence of all-cause mortality compared with the VKA group (10.3% vs. 23.3%; Cox-adjusted hazard ratio: 0.391; 95% confidence interval: 0.204 to 0.749; p = 0.005; and 10.2% vs. 20.6%; inverse probability of treatment weighting-adjusted hazard ratio: 0.531; 95% confidence interval: 0.294 to 0.961; p = 0.036, respectively). Compared with VKAs, DOACs might be associated with lower long-term all-cause mortality in patients with concomitant AF who are successfully discharged after TAVR. This finding warrants investigation in ongoing prospective randomized trials.

Several trials demonstrated that aspirin monotherapy compared with aspirin plus clopidogrel is associated with a lower incidence of bleeding without an increased risk of ischemic events in patients after transcatheter aortic valve replacement (TAVR); however, there remains a paucity of data to prove the necessity of even aspirin monotherapy.This study aimed to compare clinical outcomes and valve performance of the 3 different antithrombotic strategies post-TAVR from the OCEAN-TAVI (Optimized transCathEter vAlvular iNtervention) registry.Patients who received anticoagulation or had procedural complications were excluded. The remaining patients were classified into 3 groups according to the antithrombotic regimen at discharge: 1) nonantithrombotic therapy (None); 2) single-antiplatelet therapy (SAPT); and 3) dual-antiplatelet therapy (DAPT). The primary outcome was the incidence of net adverse clinical events (NACEs) (ie, cardiovascular death, stroke, myocardial infarction, and life-threatening or major bleeding).Overall, 3,575 TAVR patients were included (None, 293; SAPT, 1,354; DAPT, 1,928). The median follow-up period was 841 days (IQR: 597-1,340 days). The incidence of NACEs did not differ between the groups (None vs SAPT: adjusted HR [aHR]: 1.18; P = 0.45; None vs DAPT: aHR: 1.09; P = 0.67). There was a lower incidence of all bleeding in patients with no antithrombotics (None vs SAPT: aHR: 0.63; P = 0.12; None vs DAPT: aHR: 0.51; P = 0.04). The valve performance was similar among the groups. Leaflet thrombosis was detected in 8.5% of the nonantithrombotic group.Compared with SAPT/DAPT, the nonantithrombotic strategy was not associated with an increased risk of NACEs and potentially reduced the risk of bleeding events. The nonantithrombotic strategy may be an acceptable alternative to SAPT/DAPT in selected patients with TAVR.

Transcatheter aortic valve replacement (TAVR)-related coronary artery obstruction prediction remains unsatisfactory despite high mortality and novel preventive therapies.This study sought to develop a predictive model for TAVR-related coronary obstruction in native aortic stenosis.Preprocedure computed tomography and fluoroscopy images of patients in whom TAVR caused coronary artery obstruction were collected. Central laboratories made measurements, which were compared with unobstructed patients from a single-center database. A multivariate model was developed and validated against a 1:1 propensity-matched subselection of the unobstructed cohort.Sixty patients with angiographically confirmed coronary obstruction and 1,381 without obstruction were included. In-hospital death was higher in the obstruction cohort (26.7% vs 0.7%; P < 0.001). Annular area and perimeter, coronary height, sinus width, and sinotubular junction height and width were all significantly smaller in the obstructed cohort. Obstruction was most common on the left side (78.3%) and at the level of the coronary artery ostium (92.1%). Coronary artery height and sinus width, but not annulus area, were significant risk factors for obstruction by logistic regression but performed poorly in predicting obstruction. The new multivariate model (coronary obstruction IF cusp height > coronary height, AND virtual valve-to-coronary distance ≤4 mm OR culprit leaflet calcium volume >600 mm3) performed well, with an area under the curve of 0.93 (sensitivity = 0.93, specificity = 0.84) for the left coronary artery and 0.94 (sensitivity = 0.92, specificity = 0.96) for the right.A novel computed tomography-based multivariate prediction model that can be implemented routinely in real-world practice predicted coronary artery obstruction from TAVR in native aortic stenosis.

We assessed whether subclinical varicocele ligation improves fertility and/or semen parameters.A total of 85 patients with a subclinical varicocele diagnosed by scrotal thermography presented with infertility. Patients were randomly assigned to groups 1 (high ligation of the internal spermatic vein) and 2 (followed without any treatment). At least 3 semen samples were obtained at study entry and 1 year later in both groups.The pregnancy rate in group 1 was 6.7% compared to 10% in group 2, and the difference was not statistically significant. Group 1 had significantly higher levels of sperm density and total motile sperm count at 1 year. There were no significant differences between groups 1 and 2 regarding change in seminal volume, sperm motility and abnormal sperm morphology.Subclinical varicocelectomy has some effect on spermatogenesis but no beneficial effect on pregnancy rate.

Understanding the organization of eukaryotic centromeres has both fundamental and applied importance because of their roles in chromosome segregation, karyotypic stability, and artificial chromosome-based cloning and expression vectors. Using clone-by-clone sequencing methodology, we obtained the complete genomic sequence of the centromeric region of rice (Oryza sativa) chromosome 8. Analysis of 1.97 Mb of contiguous nucleotide sequence revealed three large clusters of CentO satellite repeats (68.5 kb of 155-bp repeats) and >220 transposable element (TE)-related sequences; together, these account for approximately 60% of this centromeric region. The 155-bp repeats were tandemly arrayed head to tail within the clusters, which had different orientations and were interrupted by TE-related sequences. The individual 155-bp CentO satellite repeats showed frequent transitions and transversions at eight nucleotide positions. The 40 TE elements with highly conserved sequences were mostly gypsy-type retrotransposons. Furthermore, 48 genes, showing high BLAST homology to known proteins or to rice full-length cDNAs, were predicted within the region; some were close to the CentO clusters. We then performed a genome-wide survey of the sequences and organization of CentO and RIRE7 families. Our study provides the complete sequence of a centromeric region from either plants or animals and likely will provide insight into the evolutionary and functional analysis of plant centromeres.

Atherosclerotic yellow plaques identified by coronary angioscopy are considered as vulnerable plaques. However, characteristics of yellow plaques are not well understood. Optical coherence tomography (OCT) provides accurate tissue characterization in vivo and has the capability to measure fibrous cap thickness covering a lipid plaque. Characteristics of yellow plaques identified by angioscopy were evaluated by OCT. We examined 205 plaques of 41 coronary arteries in 26 patients. In OCT analysis, plaques were classified as fibrous or lipid. Minimal lumen area of the plaque, arch of the lipid, and fibrous cap thickness on the lipid plaque were measured. Yellow grade of the plaque was defined as 0 (white), 1 (light yellow), 2 (medium yellow), or 3 (dark yellow) based on the angioscopy. A total of 149 plaques were diagnosed as lipid plaques. Neither the minimal lumen area nor the arch of the lipid was related to the yellow grade. There was an inverse relationship between color grade and the fibrous cap thickness (grade 0 [n = 45] 218 +/- 89 microm, grade 1 [n = 40] 101 +/- 8 microm, grade 2 [n = 46] 72 +/- 10 microm, and grade 3 [n = 18] 40 +/- 14 microm; p <0.05). Sensitivity and specificity of the angioscopy-identified yellow plaque for having a thin fibrous cap (thickness <or=110 microm) were 98% and 96%, respectively. In conclusion, angioscopy-identified yellow plaques frequently were lipid tissue with an overlying thin fibrous cap. Fibrous caps of the intense yellow plaques were very thin, and these plaques might be structurally vulnerable.

The differentiation programs of spermatogenesis and oogenesis are largely independent. In the early stages, however, the mechanisms partly overlap. Here we demonstrated that a germ-cell-specific basic helix-loop-helix (bHLH) transcription factor gene, Sohlh2, is required for early spermatogenesis and oogenesis. SOHLH2 was expressed in mouse spermatogonia from the undifferentiated stage through differentiation and in primordial-to-primary oocytes. Sohlh2-null mice, produced by gene targeting, showed both male and female sterility, owing to the disrupted differentiation of mature (KIT(+)) spermatogonia and oocytes. The Sohlh2-null mice also showed the downregulation of genes involved in spermatogenesis and oogenesis, including the Sohlh1 gene, which is essential for these processes. Furthermore, we showed that SOHLH2 and SOHLH1 could form heterodimers. These observations suggested that SOHLH2 might coordinate with SOHLH1 to control spermatogonial and oocyte genes, including Sohlh1, to promote the differentiation of KIT(+) germ cells in vivo. This study lays the foundation for further dissection of the bHLH network that regulates early spermatogenesis and oogenesis.

The aim of this study was to assess the influence of chronic kidney disease (CKD) classification on clinical outcomes in patients undergoing transcatheter aortic valve implantation (TAVI).Data of 2,929 consecutive patients undergoing TAVI in the FRANCE 2 registry were analysed. Patients were divided into five groups: CKD 1+2, 3a, 3b, 4, and 5. Both 30-day and one-year mortality rates were significantly increased and positively correlated with CKD severity in all groups. After adjusting for significant influential confounders in a Cox regression multivariate model, CKD 4 and 5 were associated with increased risk of both 30-day mortality and one-year mortality when compared with CKD 1+2 as the reference. This higher mortality was predominantly driven by renal failure and infection in patients with CKD 4 and 5, respectively. Procedural success rate in CKD 5 was significantly lower than that in other groups. All CKD patients trended towards a higher incidence of acute kidney injury (AKI), in parallel with the degree of CKD severity.Classification of CKD stages before TAVI allows risk stratification for 30-day and one-year clinical outcomes. CKD 3b, 4 and 5 correlate with poor outcome and are considered a significant risk for TAVI.

The Golgi stress response is a mechanism by which, under conditions of insufficient Golgi function (Golgi stress), the transcription of Golgi-related genes is upregulated through an enhancer, the Golgi apparatus stress response element (GASE), in order to maintain homeostasis in the Golgi. The molecular mechanisms associated with GASE remain to be clarified. Here, we identified TFE3 as a GASE-binding transcription factor. TFE3 was phosphorylated and retained in the cytoplasm in normal growth conditions, whereas it was dephosphorylated, translocated to the nucleus and activated Golgi-related genes through GASE under conditions of Golgi stress, e.g. in response to inhibition of oligosaccharide processing in the Golgi apparatus. From these observations, we concluded that the TFE3-GASE pathway is one of the regulatory pathways of the mammalian Golgi stress response, which regulates the expression of glycosylation-related proteins in response to insufficiency of glycosylation in the Golgi apparatus.

The "obesity paradox" that patients with high body mass index (BMI) have good prognoses remains controversial. This study aimed to assess the impact of BMI on clinical outcomes in patients who underwent transcatheter aortic valve implantation (TAVI). Data from the French national TAVI registry were collected for 3,072 patients who underwent TAVI from January 2010 to October 2011. The patients were categorized into 4 groups according to BMI (kg/m(2)): underweight (<18.5 kg/m(2)), normal weight (18.5 to 25 kg/m(2)), overweight (25 to 30 kg/m(2)), and obese (>30 kg/m(2)). Thereafter, clinical outcomes were compared among the 4 groups. The BMI distribution was 3.1% (n = 95), 44.1% (n = 1,355), 34.2% (n = 1,050), and 18.6% (n = 572). Although the 4 groups greatly differed in baseline clinical background, they had similar procedural success rates (95.8%, 97.1%, 97.3%, and 95.6%, p = 0.23). Major vascular complication was significantly associated with the underweight patients after adjusting for the other potential confounders (odds ratio 2.33, 95% confidence interval 1.17 to 4.46, p = 0.016). The cumulative postoperative survival rates were increasing across the 4 groups at 30 days (83.2%, 88.9%, 91.6%, and 93.0%, p = 0.003) and 1 year (67.9%, 73.6%, 77.4%, and 80.3%, p = 0.006). In a multivariate Cox regression analysis, the overweight and obese patients were independently associated with superior cumulative survival rate at 1 year (hazard ratios 0.74 and 0.71, 95% confidence intervals 0.57 to 0.97 and 0.59 to 0.87, p = 0.050 and 0.029, respectively). In conclusion, major morbidity and 1-year mortality were less in overweight and obese patients than those classified as normal weight even in a TAVI cohort.

In a fraction of patients aged ≥90 years, less-invasive transcatheter aortic valve implantation (TAVI) has been considered a therapeutic option for aortic stenosis under careful clinical screening. However, the safety and effectiveness using TAVI in such a population has not been fully elucidated. The aim of the present study was to investigate the feasibility of TAVI in nonagenarians. We prospectively enrolled 136 consecutive patients with severe aortic stenosis who were referred for TAVI. The procedural, early, and midterm clinical outcomes were compared between patients aged <90 years (n = 110, average age 82.3 ± 8.3 years) and ≥90 years (n = 26; average age 91.6 ± 1.9 years). A comparison of the baseline characteristics revealed that among patients aged ≥90 years, the prevalence of women (50% vs 81%, p <0.001) and the mean aortic valve gradient (45.5 ± 15.4 vs 56.3 ± 23.4 mm Hg, p = 0.005) were greater than those in patients aged <90 years. Major vascular complications occurred more frequently in patients ≥90 years (5% vs 19%, p = 0.022), although the rate of procedural success and 30-day and 6-month mortality were not different between the 2 age groups (96% vs 100%, p = 0.58; 6% vs 15%, p = 0.22; and 14% vs 27%, p = 0.14, respectively). The mortality rates were greater among patients aged ≥90 years. At 6 months, both groups of survivors were similar in symptom status, with a New York Heart Association classification less than class II (89% vs 84%, p = 0.68). The cumulative survival (median 13.4 ± 8.0 months of follow-up) was not significantly different between the 2 age groups (p = 0.22, log-rank test). In conclusion, even very elderly nonagenarians can experience acceptable clinical results and benefits after TAVI. In a fraction of patients aged ≥90 years, less-invasive transcatheter aortic valve implantation (TAVI) has been considered a therapeutic option for aortic stenosis under careful clinical screening. However, the safety and effectiveness using TAVI in such a population has not been fully elucidated. The aim of the present study was to investigate the feasibility of TAVI in nonagenarians. We prospectively enrolled 136 consecutive patients with severe aortic stenosis who were referred for TAVI. The procedural, early, and midterm clinical outcomes were compared between patients aged <90 years (n = 110, average age 82.3 ± 8.3 years) and ≥90 years (n = 26; average age 91.6 ± 1.9 years). A comparison of the baseline characteristics revealed that among patients aged ≥90 years, the prevalence of women (50% vs 81%, p <0.001) and the mean aortic valve gradient (45.5 ± 15.4 vs 56.3 ± 23.4 mm Hg, p = 0.005) were greater than those in patients aged <90 years. Major vascular complications occurred more frequently in patients ≥90 years (5% vs 19%, p = 0.022), although the rate of procedural success and 30-day and 6-month mortality were not different between the 2 age groups (96% vs 100%, p = 0.58; 6% vs 15%, p = 0.22; and 14% vs 27%, p = 0.14, respectively). The mortality rates were greater among patients aged ≥90 years. At 6 months, both groups of survivors were similar in symptom status, with a New York Heart Association classification less than class II (89% vs 84%, p = 0.68). The cumulative survival (median 13.4 ± 8.0 months of follow-up) was not significantly different between the 2 age groups (p = 0.22, log-rank test). In conclusion, even very elderly nonagenarians can experience acceptable clinical results and benefits after TAVI.

Background: Tolvaptan, an oral selective vasopressin 2 receptor antagonist that acts on the distal nephrons to cause a loss of electrolyte-free water, is rarely used during the acute phase of acute heart failure (AHF). Methods and Results: We investigated 183 AHF patients admitted to the intensive care unit and administered tolvaptan (7.5mg) with continuous intravenous furosemide, and then additionally at 12-h intervals until HF was compensated. When intravenous furosemide was changed to peroral use, the administration of tolvaptan was stopped. The patients were assigned to tolvaptan (n=52) or conventional treatment (n=131) groups. The amount of intravenous furosemide was significantly lower (35.4 [16.3–56.0] mg vs. 80.0 [30.4–220.0] mg), the urine volume was significantly higher on days 1 and 2 (3,691 [3,109–4,198] ml and 2,953 [2,128–3,592] ml vs. 2,270 [1,535–3,258] ml and 2,129 [1,407–2,906] ml) and the numbers of patients with worsening-AKI (step-up RIFLE Class to I or F) and Class F were significantly fewer (5.8% and 1.9% vs. 19.1% and 16.0%) in the tolvaptan group than in the conventional group, respectively. One of the specific medications indicated worsening-AKI and in-hospital mortality was tolvaptan (odds ratio [OR] 0.155, 95% confidence interval [CI] 0.037–0.657 and OR 0.191, 95% CI 0.037–0.985). The Kaplan-Meier curves showed that the death rate within 6 months was significantly lower in the tolvaptan group. The same result was found after propensity matching of the data. Conclusions: Early administration of tolvaptan could prevent exacerbation of AKI and improve the prognosis for AHF patients. (Circ J 2014; 78: 911–921)

This study aimed to assess the effectiveness of preparatory coronary protection (CP) in patients considered at high risk of acute coronary obstruction (ACO) after transcatheter aortic valve implantation (TAVI).The Optimized CathEter vAlvular iNtervention (OCEAN-TAVI) Japanese multicenter registry enrolled 666 consecutive patients. All patients were assessed by preprocedural multidetector computed tomography. CP using a guide wire with or without a balloon was prospectively performed according to the following criteria: 1) coronary height length from the annulus <10mm, 2) evidence of ACO during balloon aortic valvuloplasty with simultaneous aortic injection, and 3) shallow valsalva or bulky calcification on the leaflet. The incidence of ACO and other procedural outcomes were compared between the CP and non-CP groups.CP was performed in 14.1% of all patients (94/666). ACO had an incidence of 1.5% (10/666) and mainly occurred in women (70%) and the left coronary artery (70%). The ACO rate was significantly higher in the CP group than in the non-CP group (7.4% [7/94] vs. 0.5% [3/572]; p<0.001), although notably 30% of ACO were occurred in non-CP group. All 10 ACO cases were successfully treated by catheter intervention, although periprocedural myocardial injury occurred in 42.9% of patients with CP group and 33.3% of those without CP group. Mortality and other periprocedural complications did not significantly differ between the 2 groups.The preparatory CP strategy was feasible for the management of ACO during TAVI, but the complication of ACO was difficult to predict completely.

Objective The persistence of left ventricular (LV) hypertrophy is associated with poor clinical outcomes after transcatheter aortic valve implantation (TAVI) for aortic stenosis. However, the optimal medical therapy after TAVI remains unknown. We investigated the effect of renin−angiotensin system (RAS) blockade therapy on LV hypertrophy and mortality in patients undergoing TAVI. Methods Between October 2013 and April 2016, 1215 patients undergoing TAVI were prospectively enrolled in the Optimized CathEter vAlvular iNtervention (OCEAN)-TAVI registry. This cohort was stratified according to the postoperative usage of RAS blockade therapy with angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs). Patients with at least two prescriptions dispensed 180 days apart after TAVI and at least a 6-month follow-up constituted the RAS blockade group (n=371), while those not prescribed any ACE inhibitors or ARBs after TAVI were included in the no RAS blockade group (n=189). Results At 6 months postoperatively, the RAS blockade group had significantly greater LV mass index regression than the no RAS blockade group (−9±24% vs −2±25%, p=0.024). Kaplan-Meier analysis revealed a significantly lower cumulative 2-year mortality in the RAS blockade than that in the no RAS blockade group (7.5% vs 12.5%; log-rank test, p=0.031). After adjusting for confounding factors, RAS blockade therapy was associated with significantly lower all-cause mortality (HR, 0.45; 95% CI 0.22 to 0.91; p=0.025). Conclusions Postoperative RAS blockade therapy is associated with greater LV mass index regression and reduced all-cause mortality. These data need to be confirmed by a prospective randomised controlled outcome trial.

Aims Permanent pacemaker (PPM) implantation following high‐degree atrioventricular block is frequently required after transcatheter aortic valve implantation (TAVI) using CoreValve ® . Recent improvement of the delivery system (CoreValve Accutrak ® ) aimed to ease delivery and reduce the PPM rate. Our study evaluated the incidences of PPM implantation following use of CoreValve ® or CoreValve Accutrak ® and the clinical outcome of these patients. Methods and results A total of 883 patients (82 ± 7 years; 41.3% female) with severe symptomatic aortic stenosis and self‐expanding bioprosthesis implantation were included between January 2010 and October 2011 in 29 centers from the FRANCE 2 Registry. Follow‐up data were available in 833 patients. CoreValve ® and CoreValve Accutrak ® were used in 343 (41.2%) and 490 (58.8%) patients, respectively. During a mean follow‐up of 242 ± 179 days, all‐cause mortality was similar in patients with versus without PPM implantation (16.3 vs. 16.9%, P = 0.832).There was no significant difference in the PPM incidence in CoreValve ® and CoreValve Accutrak ® patients (30.4% vs. 27.5%, P = 0.846). Conclusion PPM implantation remained frequent after TAVI using CoreValve Accutrak ® . All‐cause mortality was similar in patients with or without PPM implantation. The new device failed to show a significant decrease in PPM implantation incidence after TAVI. © 2015 Wiley Periodicals, Inc.

Hypoalbuminemia, a frailty criterion, belongs to a group of co-morbidities not captured as a traditional risk factor. We assessed its prognostic value in patients who underwent transcatheter aortic valve implantation (TAVI). The study included 1,215 consecutive patients from the Optimized Catheter Valvular Intervention -TAVI Japanese multicenter registry. Hypoalbuminemia was defined as serum albumin level <3.5 g/dl. Baseline characteristics, procedural outcomes, and all-cause, cardiovascular and noncardiovascular mortality rates after TAVI were compared between patients with albumin level <3.5 g/dl (hypo[h]-ALB group, n = 284) and those with albumin level >3.5 g/dl (nonhypo[nh]-ALB group, n = 931). Several baseline characteristics differed significantly between both groups, including age (85.1 ± 5.1 vs 84.2 ± 4.9 years, p = 0.012), ejection fraction (58.5 ± 14.3% vs 62.9 ± 12.4%, p <0.001), baseline kidney function, or liver disease. The 30-day mortality rate in all patients showed significant differences between the 2 groups (3.9% vs 1.3%, p = 0.005). During a mean follow-up of 330 days, cumulative all-cause, cardiovascular, and noncardiovascular mortality rates were significantly higher in the hALB group than in the nhALB group (log-rank test, p <0.001, p = 0.0021, and p <0.001, respectively). The groups were also analyzed using a propensity matching model for adjusting the baseline differences. The analysis revealed that the poorer prognosis of the hALB group in terms of cumulative all-cause and noncardiovascular mortality was retained (p = 0.038, and p = 0.0068, respectively); however, differences in cardiovascular mortality rates in the 2 groups were attenuated (p = 0.93). In conclusion, hypoalbuminemia was associated with poor prognosis, highlighted by the increase in noncardiovascular mortality. Baseline albumin level could be a useful marker for risk stratification before TAVI.

To evaluate the clinical benefit of pre-procedural antiplatelet therapy in patients undergoing transfemoral (TF) transcatheter aortic valve implantation (TAVI).OCEAN (Optimized transCathEter vAlvular interveNtion)-TAVI is a prospective, multicentre, observational cohort registry, enrolling 749 patients who underwent TAVI from October 2013 to August 2015 in Japan. We identified 540 patients (median age 85 years, 68.1% female) undergoing TF-TAVI; of these, 80 had no pre-procedural antiplatelet therapy and 460 had antiplatelet therapy. The endpoints were any bleeding (life-threatening, major, and minor bleeding) and thrombotic events (stroke, myocardial infarction, and valve thrombosis) during hospitalisation.Patients with dual antiplatelet therapy (DAPT) had a significantly higher incidence of any bleeding than those with single antiplatelet therapy (SAPT) (36.5% vs 27.5%, p=0.049) and no antiplatelet therapy (36.5% vs 21.3%, p=0.010). Patients without pre-procedural antiplatelet therapy did not experience an increased risk of thrombotic events. In multivariable logistic regression analysis, DAPT before TF-TAVI significantly increased any bleeding compared with SAPT (OR 2.05, 95% CI 1.16 to 3.65) and no antiplatelet therapy (OR 2.30, 95% CI 1.08 to 4.90).The current study demonstrated that DAPT before TF-TAVI increased the risk of bleeding compared with single or no antiplatelet therapy. Lower intensity antiplatelet therapy was not associated with thrombotic events. In modern practice, it might be reasonable to perform TAVI using single or no pre-procedural antiplatelet therapy with an expectation of no increase of adverse events.UMIN-ID; 000020423; Results.

Gait speed reflects an important factor of frailty and is associated with an increased risk of late mortality in patients with cardiac disease. This study sought to assess the prognostic value of gait speed in elderly patients who underwent transcatheter aortic valve replacement.We investigated the 5-m or 15-feet gait speed (m/sec) in 1256 patients who underwent transcatheter aortic valve implantation using data from the OCEAN-TAVI Japanese multicenter registry (Optimized Catheter Valvular Intervention-Transcatheter Aortic Valve Implantation). Baseline characteristics, procedural outcomes, and all-cause mortality were compared among groups defined by differential gait speed classification: model 1, normal (>0.83 m/sec; n=563; 44.8%), slow (0.5-0.83 m/sec; n=429; 34.2%), slowest (<0.83 m/sec; n=205; 16.3%), unable to walk (n=48; 3.8%); and model 2, classification and regression tree survival model indicating the threshold of gait speed as 0.385 m/sec (>0.385 m/sec; n=1080 versus ≤0.385 m/sec; n=117). The cumulative 1-year mortality rate showed significant differences in the classical gait speed groups in model 1 (7.6%, 6.6%, 18.2%, and 40.7%, respectively; P<0.001) and survival classification and regression tree group in model 2 (7.7% versus 21.9%; P<0.001). The slowest walkers and those unable to walk demonstrated independent associations with increased midterm mortality after adjustment for several confounding factors (hazard ratio, 1.83, 4.28; 95% confidence interval, 1.03-3.26, 2.22-8.72; P=0.039, <0.001, respectively). Gait speed <0.385 m/sec determined by classification and regression tree also independently associated with worse prognosis (hazard ratio, 2.40; 95% confidence interval, 1.75-5.88; P=0.001).Gait speed using both traditional and specific classification is useful as a potential marker for predicting vulnerable patients associated with adverse clinical outcomes after transcatheter aortic valve replacement.

This study aimed to assess the potential relationship between subclinical leaflet thickening and stent frame geometry in patients who underwent aortic valve replacement with a self-expanding transcatheter heart valve (THV).Seventy-five patients with a self-expanding THV were studied with 4D-computed tomography and analysed for leaflet thickening. There was no difference in THV size, overall THV expansion, eccentricity or implantation depth between patients with and those without leaflet thickening. Moderate-to-severe regional THV underexpansion (≤90°) more frequently occurred at the non-coronary and right coronary cusps with a significantly higher incidence of leaflet thickening than in cases of full regional THV expansion (24% vs. 3%, p<0.01). Regional THV underexpansion at the inflow level more often translated into the same issue at the valvular level in THV with intra-annular as compared to supra-annular valve position (54% vs. 17%; p=0.04). In case of post-dilatation, regional THV underexpansion occurred less frequently as compared to THV that were not post-dilated (18% vs. 43%, p=0.028). A similar but non-significant trend was found for leaflet thickening.Regional THV stent frame underexpansion is associated with an increased risk of leaflet thickening. Post-dilatation of self-expanding THV as well as a supra-annular valve position seem to reduce the occurrence of this phenomenon.

Nutritional condition is one marker of patients' frailty. The Geriatric Nutritional Risk Index (GNRI) is a well-known marker of nutritional status. This study sought to assess the clinical outcomes of GNRI after transcatheter aortic valve replacement (TAVR).We evaluated the GNRI value of 1,613 patients who underwent TAVR using data from a Japanese multicenter registry. According to baseline GNRI, patients were classified into 3 groups: GNRI ≥92 (n = 1,085; 67.3%), GNRI 82-92 (n = 396; 24.6%), and GNRI ≤82 (n = 132; 8.2%). Baseline characteristics, procedural outcomes, and cumulative mortality rates were compared. In addition, GNRI correlations with other frailty components (gait speed, grip strength, and Clinical Frailty Scale) and Society of Thoracic Surgeons (STS) score were also evaluated.Significantly increased mortality rates were observed across the 3 groups at 30 days (0.9%, 2.3%, and 6.8%, respectively; P < .001) and 1 year (6.5%, 16.4%, and 36.4%, respectively; P < .001). Both GNRI 82-92 and GNRI ≤82 (as a reference for GNRI ≥92) were independently associated with increased midterm mortality in the Cox regression multivariate model (hazard ratio: 1.97, 3.60; 95% confidence interval: 1.37-2.84, 2.30-5.64; P < .001, P < .001, respectively). The GNRI value was significantly correlated with gait speed (Spearman ρ = -0.15, P < .001), grip strength (ρ = 0.25, P < .001), Clinical Frailty Scale (ρ = -0.24, P < .001), and STS score (ρ = -0.29, P < .001).GNRI is related to both frailty components and the STS score and is an important surrogate marker for predicting worse clinical outcomes after TAVR. Assessment of the GNRI may be considered when deciding on TAVR.

This study aimed to analyze the prognostic impact of low-flow (LF) severe aortic stenosis in small-body patients undergoing transcatheter aortic valve replacement (TAVR). Western literature demonstrates a poor prognosis with paradoxical LF and low-flow low-gradient (LF-LG) severe aortic stenosis (AS), as defined by stroke volume index (SVi) <35 ml/m2 and mean pressure gradient <40 mm Hg with preserved left ventricular ejection fraction (LVEF). However, this poor prognosis is contested in Japan owing to the smaller body size of Japanese patients relative to that of Western patients. Additionally, there are no reports of the prognostic implication of paradoxical LF or LF-LG severe AS in small-body patients undergoing TAVR. This was a retrospective analysis of 723 consecutive Japanese patients (median age 85 years; 32.6% male; median body surface area 1.4 m2) who underwent TAVR for severe AS at 9 sites in Japan. The primary and secondary endpoints were cumulative all-cause and cardiovascular mortality after TAVR, respectively. Ninety-seven (13.4%) patients had paradoxical LF severe AS whereas 38 (5.3%) had paradoxical LF-LG with severe AS. PLF was associated with a significant increase in all-cause (hazard ratio [HR]: 3.00; 95% confidence interval [CI]: 1.34 to 6.72; p < 0.001) and cardiovascular mortality (HR: 5.58; 95% CI: 1.19 to 26.2; p < 0.01), as compared with patients’ normal flow and preserved LVEF. PLF-LG was associated with a significant increase in all-cause mortality (HR: 3.76; 95% CI: 1.09 to 13.73; p < 0.01), as compared with normal flow high gradient with preserved LVEF. SVi was an independent predictor of cardiovascular mortality on multivariate analysis after adjustments for age, sex, clinically relevant variables, and other echocardiographic parameters (HR: 1.96; 95% CI: 1.19 to 3.23; p < 0.01). Among Japanese small-body patients with severe AS, both paradoxical LF and LF-LG severe AS were associated with poor outcomes following TAVR. SVi was an independent predictor of cardiovascular mortality after TAVR. (Optimised Transcatheter Valvular Intervention registry [OCEAN-TAVI]; UMIN000020423)

We aimed to assess real-world clinical outcomes of transcatheter aortic valve replacement (TAVR) in Japan. Data are limited concerning procedural safety and valve performance following TAVR in Japanese. A program by an on-site proctor and procedure screening system was applied during TAVR introduction. We consecutively enrolled 1613 patients who underwent TAVR using data from the Optimized CathEter vAlvular iNtervention (OCEAN) Japanese registry, which consists of 14 centers. Baseline characteristics and procedural outcomes including combined early 30-day non-safety, and mortality rates were assessed among 4 groups, divided into quartiles (Q1-Q4). Most patients were women (70.4%), elderly (84.4 ± 5.1 years), and had a median Society of Thoracic Surgeons score of 6.7(4.7–9.5). The overall 30-day mortality, combined early non-safety, and cumulative 1-year mortality rates were 1.7%, 15.1%, and 11.3%, respectively. Thirty-day mortality was not affected by center experience differences divided into quartiles (1.0%, 2.0%, 2.5%, 1.5%, p = 0.404), whereas 30-day early safety was significantly improved (19.1%, 17.9%, 14.6%, 8.9%, p < 0.001). Thirty-day mortality was 0% under transfemoral on-site proctor. Cox-regression multivariate analysis revealed that male sex, clinical frailty scale, New York Heart Association class, creatinine, albumin, hemoglobin, liver disease, and non-transfemoral approach were independent predictive factors of increased midterm mortality risk. Owning to the global supporting system in Japan, excellent early and midterm outcomes have been achieved to overcome the learning curve of the newly introduced TAVR procedure.

Eosinophilic esophagitis (EoE) has increased rapidly and has been well characterized. However, no nationwide survey has been conducted regarding non-esophageal eosinophilic gastrointestinal disorders (non-EoE EGIDs), and they remain poorly understood.To compare the clinical features and natural histories of non-EoE EGIDs and EoE by using the same questionnaire, for all ages.We conducted a nationwide hospital-based survey of patients who visited hospitals from January 2013 through December 2017. We randomly selected 10,000 hospitals that perform endoscopy. We analyzed the demographics, symptoms, gastrointestinal histology, treatments, and natural histories of EoE and non-EoE EGIDs.A total of 2906 hospitals responded to the questionnaire. We identified 1542 patients and obtained detailed data for 786 patients, consisting of 39% EoE and 61% non-EoE EGIDs. The clinical characteristics were analyzed for patients who met the "definite" criteria that excluded comorbidities. Non-EoE EGIDs showed no gender difference, whereas EoE was male-predominant. Tissue eosinophilia was often seen in the small intestine (62%) and stomach (49%). The frequency of hypoproteinemia was high (27%) in childhood. Children also had more serious symptoms and complications than adults: restriction of daily life activity (P = .009), failure to grow/weight loss (P = .008), and surgery (P = .01). For both diseases, the most common natural history was the continuous type: 66% (95% confidence interval [CI]: 58-74) in EoE and 64% (95% CI: 55-72) in non-EoE EGIDs.The percentage of persistent patients with non-EoE EGIDs was almost the same as those with EoE. Complications were more frequent in children than in adults.

There are limited data on the prognostic impact of periprocedural pulmonary hypertension (PH) after transcatheter aortic valve replacement (TAVR).The aim of this study was to investigate the prognostic impact of normalized, new-onset, and residual PH after TAVR.The OCEAN-TAVI (Optimized Transcatheter Valvular Intervention-Transcatheter Aortic Valve Implantation) registry is an ongoing, multicenter Japanese registry that includes 2,588 patients who underwent TAVR. Patients were classified into 4 groups according to periprocedural systolic pulmonary artery pressure by echocardiography: no PH before and after TAVR (no PH), PH before but not after TAVR (normalized PH), PH after but not before TAVR (new-onset PH), and PH before and after TAVR (residual PH). A systolic pulmonary artery pressure cutoff of >36 mm Hg was applied for PH. The primary endpoint was all-cause mortality at 2 years. Logistic regression analysis was used to identify clinical predictors of residual and new-onset PH.In total, 1,872 patients were divided into 4 groups: 1,027 (54.9%) in the no PH group, 257 (13.7%) in the normalized PH group, 280 (15.0%) in the new-onset PH group, and 308 (16.5%) in the residual PH group. There was a significant difference in all-cause mortality among the 4 groups at 2 years (11.0%, 12.8%, 18.6%, and 24.7%, respectively; P < 0.01). Among 565 patients who had preprocedural PH, 257 (45.5%) experienced normalization of PH, with mortality comparable with that in the no PH group. In multivariable logistic regression analysis, predictors of residual PH after TAVR were atrial fibrillation and baseline tricuspid regurgitation moderate or greater, whereas prosthesis-patient mismatch was a predictor of new-onset PH.Risk stratification on the basis of post-TAVR PH status can identify patients at increased mortality after TAVR. Prosthesis-patient mismatch was identified as a novel predictor of new-onset PH. (Optimized Transcatheter Valvular Intervention-Transcatheter Aortic Valve Implantation [OCEAN-TAVI]; UMIN000020423).

Whether nerve block improves the quality of conscious sedation (CS) in patients undergoing transcatheter aortic valve implantation (TAVI) is unclear. This study investigated whether fascia iliaca block (FIB) reduced the remifentanil requirement and relieved pain in CS for TAVI.Methods and Results: This prospective study randomized 72 patients scheduled for elective TAVI under CS into 2 groups, with (FIB) and without (control) FIB (n=36 in each group). The sedation targeted a Bispectral Index <90 with a Richmond Agitation-Sedation Scale of -2 to -1. Dexmedetomidine (0.7 µg/kg, i.v.) combined with remifentanil (0.03 µg/kg/min, i.v.) and propofol (0.3 mg/kg/h, i.v.) was used to commence sedation. FIB using 30 mL of 0.185% ropivacaine was implemented 2 min before TAVI. Patient sedation was maintained with dexmedetomidine (0.4 µg/kg/h, i.v.) supplemented with remifentanil (0-0.02 µg/kg/min, i.v.). Remifentanil (20 µg, i.v.) was used as a rescue dose for intraprocedural pain. Compared with the control group, FIB reduced the both the total (median [interquartile range] 83.0 [65.0-98.0] vs. 34.5 [26.0/45.8)] µg; P<0.001) and continuous (25.3 [20.9/31.5] vs. 9.5 [6.8/12.5] ng/kg/min; P<0.001) doses of remifentanil administered.FIB reduced the remifentanil requirement and relieved pain in patients undergoing TAVI with CS. Therefore, FIB improved the quality of CS in TAVI.

Few reports on pre-existing left bundle branch block (LBBB) in patients undergoing transcatheter aortic valve replacement (TAVR) are currently available. Further, no present studies compare patients with new onset LBBB with those with pre-existing LBBB. This study aimed to investigate the association between pre-existing or new onset LBBB and clinical outcomes after TAVR. Using data from the Japanese multicenter registry, 5,996 patients who underwent TAVR between October 2013 and December 2019 were included. Patients were classified into 3 groups: no LBBB, pre-existing LBBB, and new onset LBBB. The 2-year clinical outcomes were compared between 3 groups using Cox proportinal hazards models and propensity score analysis to adjust the differences in baseline characteristics. Of 5,996 patients who underwent TAVR, 280 (4.6%) had pre-existing LBBB, while 1,658 (27.6%) experienced new onset LBBB. Compared with the no LBBB group, multivariable Cox regression analysis showed that pre-existing LBBB was associated not only with a higher 2-year all-cause (adjusted HR: 1.39; 95% CI: 1.06-1.82; P = 0.015) and cardiovascular (adjusted HR: 1.60; 95% CI: 1.04-2.48; P = 0.031) mortality, but also with higher all-cause (adjusted HR: 1.43, 95% CI: 1.07-1.91; P = 0.016) and cardiovascular (adjusted HR: 1.81, 95% CI:1.12-2.93; P = 0.014) mortality than the new onset LBBB group. Heart failure was the most common cause of cardiovascular death, with more heart failure deaths in the pre-existing LBBB group. Pre-existing LBBB was independently associated with poor clinical outcomes, reflecting an increased risk of cardiovascular mortality after TAVR. Patients with pre-existing LBBB should be carefully monitored.

Summary To elucidate the molecular basis of loss of self‐incompatibility in Lycopersicon , S‐RNases and HT‐proteins were analysed in seven self‐compatible (SC) and three self‐incompatible (SI) taxa. No or low stylar RNase activity was a common feature in most SC taxa examined, in contrast to the uniformly high levels of activity found in all SI species. The S‐RNase gene is most likely deleted in the four red‐fruited SC taxa ( L. esculentum, L. esculentum var. cerasiforme, L. pimpinellifolium and L. cheesmanii ) because S‐RNase genes could not be amplified from genomic DNA. S‐RNase genes could, however, be amplified from the genomes of the three green‐fruited SC taxa examined. L. chmielewskii and L. hirsutum f . glabratum show a decreased accumulation of transcripts, possibly reflecting changes in the 5′ flanking regions of the S‐RNase genes. The remaining green‐fruited SC species, L. parviflorum , has a functional S‐RNase gene in its genome that is expressed at high levels in the style, suggesting a genetic factor responsible for the low S‐RNase activity. Together these results argue for several independent mutations in the S‐RNase gene over the course of Lycopersicon diversification, and that loss of S‐RNase function is unlikely to the primary cause of the loss of self‐incompatibility. We also examined the HT‐B genes that play a role in self‐incompatibility. HT‐B transcripts were markedly reduced in the styles of all the SC taxa examined. A scenario is described where a mutation causing reduced transcription of HT‐B in an ancestral SI species was central to the loss of self‐incompatibility in Lycopersicon .

It has been reported that green tea consumption reduces the risk of coronary artery disease and cardiac events. Catechin is a major constituent of Japanese green tea and an antioxidant. Lipids and oxidization of low-density lipoprotein cholesterol (LDL-C) play important roles in atherosclerosis. Therefore, we evaluated the effect of catechin intake on the lipid profile and plasma oxidized LDL. The study population consisted of 40 healthy adult volunteers (10 men, 30 women). Catechin was extracted from green tea leaves. The subjects were randomly divided into two groups, a catechin group (n = 29) and a control group (n = 11). In the catechin group, catechin (500 mg: equivalent to 6 or 7 cups of green tea) was administered orally. Venous blood samples were obtained before eating a meal at the start and after 4 weeks without any lifestyle modification. Plasma oxidized LDL assay was performed with a sandwich-type enzyme immunoassay using anti-oxidized phosphatidylcholine monoclonal antibody. The baseline lipid profiles and tea consumptions were similar between the two groups. Plasma oxidized LDL was significantly decreased after catechin administration (from 9.56 ± 9.2 to 7.76 ± 7.7 U/mL, P = 0.005), while plasma LDL-C, triglyceride, and HDL-C concentrations did not change. Catechin decreased the plasma oxidized LDL concentration without significant change in plasma LDL concentration. The mechanism of the beneficial effects of green tea on coronary artery disease might result from a decrease in plasma oxidized LDL.

To the Editor: Presently, occurrence of late stent thrombosis (LST) after drug-eluting stent implantation is a major clinical concern. Although LST is an infrequent complication, LST can lead to serious results. A long-term follow-up study revealed recently that LST occurs at a constant rate of 0.6

Growth hormone (GH), prolactin (PRL), and placental lactogen (PL) constitute a protein family whose genes are considered to have evolved from a common ancestral gene. GHs isolated from various vertebrate species are known to possess highly conserved structural and functional features. In the present study we have cloned and sequenced flounder growth hormone (fGH) cDNA to predict the primary structure of the hormone. The preprotein of fGH is composed of 190 amino acids, and mature fGH is found to be extraordinarily small, having 171 or 173 amino acid residues. The estimated molecular masses of mature fGH are 19.4 to 19.7 kDa. This minimal size of fGH enabled an extended analysis of the essential domains and of amino acid residues required in hormone-specific activities. fGH conserves and shares 37 residues with 20 other vertebrate GHs. These common residues are seen to cluster in five distinct domains (GD1 to GD5). In human PL (hPL), which has low growth-promoting activity, 35 of these 37 residues are conserved, while the other 2 residues in the GD1 domain (Arg-16 and Leu-20) are replaced by Gln and Ala, respectively. In a less active variant of human GH, hGH-V, only 1 residue (His-21) of the 37 residues is replaced by Tyr. Besides these 3 residues, 6 other residues unique to the GHs and some PLs, that is, Ala-24 (GD1), Ser-54 (GD2), Ser-78 (GD3), Leu-106, Leu-116, and Asp-122 (GD4), appear to be important for specific binding of the GHs. The GD5 domain, at the carboxyl-terminal ends of the GHs is considered to be involved mainly in the formation and stabilization of GH molecules.

The authors previously established a transgenic mouse line in the type 1 diabetes model, NOD mouse, in which thioredoxin (TRX), a redox protein, is overexpressed in pancreatic beta cells, and found that TRX overexpression slows the progression of type 1 diabetes. Recent reports on type 2 diabetes suggest that oxidative stress also degrades the function of beta cells. To elucidate whether TRX overexpression can prevent progressive beta cell failure from oxidative stress in type 2 diabetes, the authors transferred the TRX transgene from the NOD mouse onto a mouse model of type 2 diabetes, the db/db mouse. The progression of hyperglycemia and the reduction of body weight gain and insulin content of the db/db mouse were significantly suppressed by the TRX expression. Furthermore, TRX suppressed the reduction of Pdx-1 and MafA expression in the beta cells, which may be one of the cellular mechanisms for protecting beta cells from losing their insulin-secreting capacity. These results showed that TRX can protect beta cells from destruction not only in type 1 but also in type 2 diabetes, and that they provide evidence that oxidative stress plays a crucial role in the deterioration of beta cell function during the progression of type 2 diabetes.

No detailed data regarding neointimal coverage of bare-metal stents (BMSs) at 3 months after implantation was reported to date. This investigation was designed to evaluate the neointimal coverage of BMSs compared with sirolimus-eluting stents (SESs) using optical coherence tomography. A prospective optical coherence tomographic follow-up examination was performed 3 months after stent implantation for patients who underwent BMS (n = 16) or SES implantation (n = 24). Neointimal hyperplasia (NIH) thickness on each stent strut and percentage of NIH area in each cross section were measured. Malapposition of stent struts to the vessel wall and the existence of in-stent thrombi were also evaluated. There were 5,076 struts of SESs and 2,875 struts of BMSs identified. NIH thickness and percentage of NIH area in the BMS group were higher than in the SES group (351 +/- 248 vs 31 +/- 39 mum; p <0.0001; 45.0 +/- 14% vs 10.0 +/- 4%; p <0.0001, respectively). The frequency of uncovered struts was higher in the SES group than the BMS group (15% vs 0.1%; p <0.0001). Malapposed struts were observed more frequently in the SES group than the BMS group (15% vs 1.1%; p <0.0001). In conclusion, there was no difference in incidence of in-stent thrombus between the 2 groups (14% vs 0%; p = 0.23). The present study showed almost all BMS struts to be well covered at a 3-month follow-up, suggesting that patients receiving BMS stents may not require dual-antiplatelet therapy >3 months after implantation.

Eur J Clin Invest 2011; 41 (3): 241–255 Abstract Background Urea and creatinine are widely used as biomarkers for disease. However, these parameters have been criticized as markers for several reasons. Thus, we conducted this study to identify novel biomarkers that can be used as alternatives to urea and creatinine to estimate the adequate dialysis dose by metabolomic analyses of plasma samples from patients undergoing haemodialysis. Material and methods Liquid chromatography–electrospray ionization (ESI)–time-of-flight mass spectrometry (MS) was used to analyse low molecular weight molecules present in the plasma samples of 10 patients with end-stage renal disease (ESRD) who were being treated with haemodialysis, and in 16 healthy subjects. Results In plasma samples obtained after haemodialysis, the relative quantities of 54 peaks were significantly (P < 0·05) decreased when compared with those in the plasma before haemodialysis. The candidate biomarkers were allocated to three groups. Molecules in Group A improved completely with a large variance, molecules in Group B improved partially but with a large variance, and molecules in Group C improved partially with low variance after haemodialysis. Small cohort validation study consisting of the patients with ESRD undergoing haemodialysis indicates that three candidate biomarkers in Group C would be a very useful marker to estimate adequate haemodialysis dose. Conclusions 1-Methylinosine and two unknown molecules whose m/z at ESI-positive mode are 257·1033 and 413·1359 were found as effective candidate biomarkers to estimate adequate haemodialysis dose, which has to be confirmed in prospective studies.

OBJECTIVE To determine if prediabetes is associated with atherosclerosis of coronary arteries, we evaluated the degree of coronary atherosclerosis in nondiabetic, prediabetic, and diabetic patients by using coronary angioscopy to identify plaque vulnerability based on yellow color intensity. RESEARCH DESIGN AND METHODS Sixty-seven patients with coronary artery disease (CAD) underwent angioscopic observation of multiple main-trunk coronary arteries. According to the American Diabetes Association guidelines, patients were divided into nondiabetic (n = 16), prediabetic (n = 28), and diabetic (n = 23) groups. Plaque color grade was defined as 1 (light yellow), 2 (yellow), or 3 (intense yellow) based on angioscopic findings. The number of yellow plaques (NYPs) per vessel and maximum yellow grade (MYG) were compared among the groups. RESULTS Mean NYP and MYG differed significantly between the groups (P = 0.01 and P = 0.047, respectively). These indexes were higher in prediabetic than in nondiabetic patients (P = 0.02 and P = 0.04, respectively), but similar in prediabetic and diabetic patients (P = 0.44 and P = 0.21, respectively). Diabetes and prediabetes were independent predictors of multiple yellow plaques (NYPs ≥2) in multivariate logistic regression analysis (odds ratio [OR] 10.8 [95% CI 2.09–55.6], P = 0.005; and OR 4.13 [95% CI 1.01–17.0], P = 0.049, respectively). CONCLUSIONS Coronary atherosclerosis and plaque vulnerability were more advanced in prediabetic than in nondiabetic patients and comparable between prediabetic and diabetic patients. Slight or mild disorders in glucose metabolism, such as prediabetes, could be a risk factor for CAD, as is diabetes itself.

Although transcatheter aortic valve implantation has been developing as an alternative treatment in elderly patients with high surgical risk, age-specific differences in clinical outcome have not been fully validated.Data were analyzed for 2,254 patients at least 80 years old who were enrolled between January 2010 and October 2011 in the French national transcatheter aortic valve implantation registry, FRANCE-2. Procedural and clinical outcomes defined according to the Valve Academic Research Consortium criteria were compared among subjects in three age groups: 80 to 84 years (n = 867), 85 to 89 years (n = 1,064), and at least 90 years (n = 349; range, 90 to 101 years).The self-expandable prosthesis was implanted in 710 patients, and the balloon-expandable prosthesis was implanted in 1,544 patients. No differences were observed in rates of procedural success, Valve Academic Research Consortium-defined complications, and length of hospitalization among groups. Cumulative 30-day mortalities did not change among the three groups (80 to 84 years, 10.3% versus 85 to 89 years, 9.5% versus ≥ 90 years, 11.2%; p = 0.53). Cumulative 1-year mortalities also showed no statistical differences, although the mortality rate was higher in patients 85 to 89 years old and at least 90 years old compared with those 80 to 84 years old (19.8% versus 26.1% versus 27.7%; p = 0.16). After adjustment for differential baseline characteristics and potential confounders, patient age (85 to 89 years and ≥ 90 years compared with 80 to 84 years) was not associated with increasing risk of 30-day mortality (hazard ratio, 0.92, 1.26; 95% confidence interval, 0.66 to 1.27, 0.83 to 1.94; p = 0.38, 0.28, respectively) and 1-year mortality (hazard ratio, 1.16, 1.36; 95% confidence interval, 0.90 to 1.49, 0.97 to 1.89; p = 0.25, 0.073, respectively).This study revealed acceptable clinical results of transcatheter aortic valve implantation even in very elderly populations.

The relationship between anemia, renal insufficiency, and the outcomes of TAVI patients has not been thoroughly studied. We aimed to evaluate the influence of pre- and post-procedural anemia on the incidence of renal insufficiency, especially AKI, and on the outcomes of TAVI.Data from the French national TAVI registry were collected in 3,472 patients who underwent TAVI between January 2010 and December 2012. Of these 2,137 were in the no/mild anemia group, 748 were in the moderate anemia group, and 587 were in the severe anemia group before TAVI. Furthermore, we divided the 3,472 patients into three groups according to post-procedural anemia, measured as post-procedural hemoglobin (Hb) drop: <2 g/dl (n=1,633, group 1), 2 to <4 g/dl (n=1,458, group 2), and >4 g/dl (n = 381, group 3). Procedure and outcome variables were compared.Increased severity of anemia before TAVI was associated with significantly different rates of 1-year mortality (15%, 19%, and 24%, P<0.01), with similar differences in the incidence of AKI (5%, 8%, and 10%, P<0.01). Increased severity of Hb drop was associated with significantly different rates of 1-year mortality (16%, 18%, and 23%, P<0.01), and with similar differences in the incidence of AKI (6%, 7%, and 10%, P=0.04). Both pre- and post-procedural anemia were predictors of the incidence of AKI (OR 1.82, P<0.01; OR 1.82, P<0.01, respectively) and 1-year mortality (HR 1.44, P<0.01; HR 1.50, P<0.01, respectively).Both pre- and post-procedural anemia were significantly associated AKI and 1-year mortality.

Favourable results have been reported for monitored anaesthesia care that includes local anaesthesia and conscious sedation [minimalist approach (MA)] for transfemoral transcatheter aortic valve replacement (TAVR). However, the efficacy of MA is still controversial in Japan. We describe our experience from a Japanese multicentre registry.Between October 2013 and April 2016, 1215 consecutive Japanese patients with symptomatic, severe aortic stenosis undergoing TAVR with self-expandable or balloon-expandable valves were prospectively included in the Optimized transCathEter vAlvular intervention-Transcatheter Aortic Valve Implantation (OCEAN-TAVI) registry. Of these patients, we retrospectively reviewed 921 consecutive patients who underwent elective transfemoral-TAVR. We evaluated the perioperative results of MA-TAVR and non-minimalist approach (NMA) TAVR using propensity score matching analysis.A total of 118 patients underwent MA-TAVR, and 802 patients underwent NMA-TAVR [median age 84 vs 85 years, P = 0.25; Society of Thoracic Surgeons (STS) score 7.6 vs 6.4, P = 0.01]. One hundred eighteen matched pairs were compared after propensity score matching. In-hospital mortality and stroke/transient ischaemic attack were not significantly different between the MA-TAVR and the NMA-TAVR groups (2.5% vs 0.8%, P = 0.3; 1.7% vs 0.8%, P = 0.6, respectively). Major or life-threatening bleeding and the transfusion rate were significantly lower in the MA-TAVR group (3.4% vs 17%, P = 0.003; 6.8% vs 29%, P = 0.0002, respectively). The total intensive care unit days and length of hospital stay were significantly lower in the MA-TAVR group (P ≤ 0.0002).MA-TAVR has similar results to NMA-TAVR in terms of mortality and stroke in this Japanese multicentre registry. Shorter procedure time and hospital stays were seen in the MA-TAVR group. MA-TAVR is as safe and effective as NMA-TAVR.

Abstract Objectives To compare safety, efficacy, and hemodynamics of transfemoral transcatheter aortic valve replacement (TAVR) using self‐expanding and balloon‐expandable transcatheter heart valves (THVs) in patients with a small aortic annulus. Background Few studies have directly compared TAVR outcomes using third‐generation THVs, focusing on patients with small aortic annuli. Methods In a multicenter TAVR registry, we analyzed data from 576 patients with a small annulus and who underwent transfemoral TAVR using third‐generation THVs. Propensity score matching was used to adjust baseline clinical characteristics. Results The device success rate in the overall cohort was 92.0% (Evolut R: 92.1% vs. Sapien 3:92.0%, p = 0.96). One year after TAVR, patients treated with Evolut R maintained a lower mean pressure gradient (mPG) and a higher indexed effective orifice area (iEOA) in the matched cohort {mPG: 9.0 [interquartile range (IQR): 6.0–11.9] vs. 12.0 [IQR: 9.9–16.3] mmHg, p &lt; .001; iEOA: 1.20 [IQR: 1.01–1.46] vs. 1.08 [IQR: 0.90–1.28] cm 2 /m 2 , p &lt; .001}. However, no significant differences were reported in the incidence of severe prosthesis‐patient mismatch and aortic regurgitation at 1 year. Furthermore, both groups showed comparable outcomes with no differences in terms of all‐cause mortality (log‐lank test, p = .81). Conclusions TAVR for patients with a small annulus using third‐generation THVs was associated with high device success. Evolut R seems to be superior to Sapien 3 in hemodynamic performance for patients with a small annulus and body surface area up to 1 year after TAVR. Nevertheless, all‐cause mortality at 1 year was similar between both groups.

Summary Cultivated tomato ( Lycopersicon esculentum ), a self‐compatible species, evolved from self‐incompatible (SI) species in the genus Lycopersicon following a breakdown of the self‐incompatibility system. In order to elucidate the molecular basis of this breakdown in L. esculentum , we first analysed the stylar proteins with an in‐gel assay for ribonuclease activity and 2D‐PAGE. No S‐RNase protein or its activity was detected in the style of L. esculentum . We then introduced the S6‐RNase gene from an SI relative, L. peruvianum , into L. esculentum . However, the styles of transgenic plants expressing S 6 ‐RNase at levels comparable to those found in the L. peruvianum style were unable to reject self‐pollen and L. peruvianum pollen in an allele‐specific manner. This indicated that defect in the S‐RNase expression was not the sole reason for the loss of self‐incompatibility in tomato. The asparagine‐rich HT protein, originally identified from the style of Nicotiana alata , is the other stylar factor involved in self‐incompatibility reaction. We cloned and sequenced two distinct genes encoding HT‐A and HT‐B proteins from L. peruvianum ( LpHT‐A and LpHT‐B ) and L. esculentum ( LeHT‐A and LeHT‐B ). A frame shift mutation in the coding sequence of LeHT‐A and a stop codon in the ORF of LeHT‐B were found, and no LeHT‐B transcript was detected in the style of L. esculentum . The results suggest that the breakdown of self‐incompatibility in cultivated tomato is associated with loss‐of‐function mutations in both S‐RNase and HT genes.

The formation of the lipophorin-lipopolysaccharide (LPS) complex in Bombyx mori hemolymph and its role in LPS detoxification were explored. LPS, an antibacterial protein inducer in insects, was injected into B. mori larvae. Analytical density gradient ultracentrifugation revealed that after injection the LPS peak shifts to a zone of lower density with time. The shifted peak was identified as the lipophorin-LPS complex. This complex formation was also achieved in an in vitro mixture of cell-free hemolymph and LPS at 25°C but not at 1°C. The lipophorin-LPS complex had a significantly lower capacity to elicit the mRNA of cecropin B, an antibacterial protein. The biological activity of reextracted LPS from the complex was slightly reduced in the Limulus test and no structural modification was observed in sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS-PAGE). These results suggested that the formation of lipophorin-LPS strikingly reduces the cecropin inducibility of LPS without any structural change in LPS. Similar serum lipoprotein-LPS complex formation and reduction of biological activities of LPS were also observed in mammals. We, therefore, suggest that the formation of the serum lipoprotein-LPS complex is a common pathway to inactive LPS both in insects and in mammals.

Although coronary angiograms after bare-metal stent (BMS) implantation show late luminal narrowing beyond 4 years, the detailed changes inside the BMS have not yet been fully elucidated.Serial angiographic and angioscopic examinations were performed immediately (baseline), 6 to 12 months (first follow-up), and >or=4 years (second follow-up) after stenting without target lesion revascularization in 26 segments of 26 patients who received BMS deployment for their native coronary arteries. Angioscopic observation showed atherosclerotic yellow plaque crushed out by stent struts in 22 patients (85%) and mural thrombus in 21 patients (81%) at baseline. At first follow-up, white neointimal hyperplasia was almost completely buried inside the struts, and both yellow plaque and thrombus had decreased in comparison with baseline (12% and 4%, respectively; P<0.001). The frequencies of yellow plaque and thrombus increased from the first to second follow-ups (58% and 31%, respectively; P<0.05). All of the yellow plaques in the second follow-up were located not exterior to the struts but protruding from the vessel wall into the lumen. Late luminal narrowing, defined as an increasing of percent diameter stenosis between the first and second follow-ups, was greater in segments with yellow plaque than in those without yellow plaque (18.4+/-17.3% versus 3.6+/-4.2%, respectively; P=0.011).This angiographic and angioscopic study suggests that white neointima of the BMS may often change into yellow plaque over an extended period of time, and atherosclerotic progression inside the BMS may contribute to late luminal narrowing.

Rice (Oryza sativa L.) is a model organism for the functional genomics of monocotyledonous plants since the genome size is considerably smaller than those of other monocotyledonous plants. Although highly accurate genome sequences of indica and japonica rice are available, additional resources such as full-length complementary DNA (FL-cDNA) sequences are also indispensable for comprehensive analyses of gene structure and function. We cross-referenced 28.5K individual loci in the rice genome defined by mapping of 578K FL-cDNA clones with the 56K loci predicted in the TIGR genome assembly. Based on the annotation status and the presence of corresponding cDNA clones, genes were classified into 23K annotated expressed (AE) genes, 33K annotated non-expressed (ANE) genes, and 5.5K non-annotated expressed (NAE) genes. We developed a 60mer oligo-array for analysis of gene expression from each locus. Analysis of gene structures and expression levels revealed that the general features of gene structure and expression of NAE and ANE genes were considerably different from those of AE genes. The results also suggested that the cloning efficiency of rice FL-cDNA is associated with the transcription activity of the corresponding genetic locus, although other factors may also have an effect. Comparison of the coverage of FL-cDNA among gene families suggested that FL-cDNA from genes encoding rice- or eukaryote-specific domains, and those involved in regulatory functions were difficult to produce in bacterial cells. Collectively, these results indicate that rice genes can be divided into distinct groups based on transcription activity and gene structure, and that the coverage bias of FL-cDNA clones exists due to the incompatibility of certain eukaryotic genes in bacteria.

A polytetrafluoroethylene (PTFE)-covered stent is specially used to treat coronary perforation complicating percutaneous intervention in order to prevent the aneurysm from rupturing, but until now it has not been known if endothelialization occurs inside this type of stent. A patient with a giant aneurysm of the right coronary artery underwent successful implantation of a PTFE-covered stent. Angiography at 9-month follow-up showed focal restenosis at the proximal edge of the stent and coronary angioscopy revealed restenosis as a result of thrombus formation. Absence of endothelialization in the covered stent was also detected by angioscopy and optical coherence tomography. These findings suggest that in-stent thrombosis must be prevented after PTFE-covered stent implantation.

Late vascular responses after implantation of drug-eluting stents may play a key role in steadily increasing occurrence of very late stent thrombosis have not yet been fully investigated in human beings.Serial optical coherence tomography observations at 2 and 4 years were collected for 17 patients treated with 21 sirolimus-eluting stents. Corresponding 376 cross sections within single-stent segments at intervals of 1 mm were selected for analyses, and neointimal thickness on each strut was measured. Extrastent lumen (ESL) was defined as an external lumen of the stent. Area and angle of ESL were measured. A total of 3369 and 3221 struts were identified at 2 and 4 years, respectively. From 2 to 4 years, mean neointimal thickness increased (76.8±75.6 μm versus 123.0±102.5 μm; P<0.0001), whereas frequency of patients with uncovered struts decreased (88% versus 29%; P=0.002). Although prevalence of patients that had ESL was similar (59% of 2 years versus 65% of 4 years; P=1.0), the cross sections with ESL increased (9.6% versus 15.2%; P=0.02). Moreover, area and angle of ESL increased from 2 to 4 years (0.28±0.27 mm(2) versus 0.62±0.68 mm(2) and 16.6±5.4° versus 65.1±38.4°; P<0.01, respectively). The incidence of subclinical thrombus did not decrease (24% at 2 years versus 29% at 4 years; P=1.0). All thrombi were identified in patients who had cross sections with ESL.The current serial optical coherence tomography study showed an augmentation of neointimal growth at the late phase of sirolimus-eluting stent implantation. ESL may contribute to thrombus formation and ESL of sirolimus-eluting stents expanded from 2 to 4 years.

Plants have developed several morphological and physiological strategies to adapt to phosphate stress. We analyzed the inducible transcripts associated with phosphate starvation and over-abundant phosphate supply to characterize the transcriptome in rice seedlings using the mRNA-Seq strategy. Fifty-three million reads obtained from 16 libraries under various phosphate stress and recovery treatments were uniquely mapped to the rice genome. Transcripts identified specifically tagged to 40,574 (root) and 39,748 (shoot) Rice Annotation Project (RAP) transcripts. Additionally, we detected uniquely 10,388 transcripts with no match to any RAP transcript. These transcripts that showed specific response to Pi stress include those without ORFs that may act as non-protein coding transcripts. With an accompanying browser of the transcriptome under Pi stress, a deeper understanding of the structural and functional features of both annotated and unannotated Pi stress-responsive transcripts can provide useful information in improving Pi acquisition and utilization in rice and other cereal crops.

Objective To identify clinical and electrical factors predicting delayed high‐degree atrio‐ventricular block (AVB) after transcatheter aortic valve implantation (TAVI). Background TAVI is a new technique for treating severe aortic valve stenosis in patients at high surgical risk but can be followed by high‐grade AVB requiring permanent pacing (PP). Methods and Results The study included 79 patients (82 ± 17 years, Euroscore = 23% ± 10%) free of PP need before and immediately after TAVI procedure. Delayed high‐degree AVB was defined by types 2 or 3 AVB diagnosed at least 24 hr after the index procedure. Permanent pacemaker implantation was performed for all these patients. We compared clinical and electrical variables before and after TAVI in patients with delayed AVB or not. TAVI was performed successfully in all patients. The 21 (26%) patients who exhibited delayed high‐grade AVB had significantly deeper prosthesis implantation (12 ± 4 mm vs. 9 ± 5 mm, P = 0.03) and wider post‐TAVI QRS duration (155 ± 17 msec vs. 131 ± 25 msec, P = 0.0004), with no difference in baseline QRS duration. Post‐TAVI QRS duration was the only independent predictor of post‐TAVI permanent for delayed high‐degree AVB ( P = 0.02). After a mean follow‐up of 10 ± 8 months, all 21 patients with post‐TAVI QRS ≤128 msec were free of high‐grade AVB, whereas 21/55 (38%) patients with post‐TAVI QRS &gt;128 msec had PP ( P = 0.0016). Conclusion Delayed (&gt;24 hr after the procedure) high‐grade AVB necessitating PP is common after TAVI. QRS duration measured immediately after TAVI was the best independent predictor of PP in this population. Patients with QRS ≤128 msec immediately after TAVI had no risk of requiring PP. © 2012 Wiley, Periodicals, Inc.

Decrease in blood platelet count has been described after percutaneous coronary intervention and surgical valve replacement, although no study has been performed in the setting of transcatheter aortic valve implantation (TAVI). The aim of this study was to address the incidence, mechanism, and impact of blood platelet count decrease after TAVI. One hundred forty-four consecutive patients (mean age 84 ± 7 years, 64 men) with severe symptomatic aortic stenosis who underwent TAVI from December 2007 to July 2011 were enrolled. Blood platelet count was recorded before and after aortic valve implantation. Decrease in blood platelet count was compared with in-hospital major adverse cardiovascular events (death, stroke, and major or life-threatening bleeding). Blood platelet count decreases occurred in all but 1 patient. The percentage of platelet count decrease averaged 34 ± 15% and was 24% greater than blood protein decrease. Decrease in platelet count was associated with a higher rate of prosthesis migration, longer x-ray and procedural times, and larger contrast amounts (230 ± 128 ml for the third tertile vs 170 ± 77 ml for the second and first tertiles, p = 0.0006), but no association was observed with regard to changes in bilirubin. In-hospital major adverse cardiovascular events (n = 50 [35%]) were observed more frequently in patients with severe platelet count decreases (21% for the first tertile, 35% for the second tertile, and 48% for the third tertile, p = 0.02). Finally, the percentage of blood platelet count decrease was the only predictor of in-hospital major adverse cardiovascular events (odds ratio 1.67, 95% confidence interval 1.05 to 2.67, p = 0.03). In conclusion, a decrease in platelet count is a common phenomenon after TAVI, and its severity is associated with poor outcomes. Decrease in blood platelet count has been described after percutaneous coronary intervention and surgical valve replacement, although no study has been performed in the setting of transcatheter aortic valve implantation (TAVI). The aim of this study was to address the incidence, mechanism, and impact of blood platelet count decrease after TAVI. One hundred forty-four consecutive patients (mean age 84 ± 7 years, 64 men) with severe symptomatic aortic stenosis who underwent TAVI from December 2007 to July 2011 were enrolled. Blood platelet count was recorded before and after aortic valve implantation. Decrease in blood platelet count was compared with in-hospital major adverse cardiovascular events (death, stroke, and major or life-threatening bleeding). Blood platelet count decreases occurred in all but 1 patient. The percentage of platelet count decrease averaged 34 ± 15% and was 24% greater than blood protein decrease. Decrease in platelet count was associated with a higher rate of prosthesis migration, longer x-ray and procedural times, and larger contrast amounts (230 ± 128 ml for the third tertile vs 170 ± 77 ml for the second and first tertiles, p = 0.0006), but no association was observed with regard to changes in bilirubin. In-hospital major adverse cardiovascular events (n = 50 [35%]) were observed more frequently in patients with severe platelet count decreases (21% for the first tertile, 35% for the second tertile, and 48% for the third tertile, p = 0.02). Finally, the percentage of blood platelet count decrease was the only predictor of in-hospital major adverse cardiovascular events (odds ratio 1.67, 95% confidence interval 1.05 to 2.67, p = 0.03). In conclusion, a decrease in platelet count is a common phenomenon after TAVI, and its severity is associated with poor outcomes. In recent years, transcatheter aortic valve implantation (TAVI) using stent-based prostheses has become an attractive alternative for high-risk elderly patients with symptomatic aortic stenosis.1Cribier A. Eltchaninoff H. Tron C. Bauer F. Agatiello C. Nercolini D. Tapiero S. Litzler P.Y. Bessou J.P. Babaliaros V. Treatment of calcific aortic stenosis with the percutaneous heart valve: mid-term follow-up from the initial feasibility studies: the French experience.J Am Coll Cardiol. 2006; 47: 1214-1223Abstract Full Text Full Text PDF PubMed Scopus (689) Google Scholar, 2Rodes-Cabau J. Webb J.G. Cheung A. Ye J. Dumont E. Feindel C.M. Osten M. Natarajan M.K. Velianou J.L. Martucci G. DeVarennes B. Chisholm R. Peterson M.D. Lichtenstein S.V. Nietlispach F. Doyle D. DeLarochelliere R. Teoh K. Chu V. Dancea A. Lachapelle K. Cheema A. Latter D. Horlick E. 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Clinical outcome and predictors for adverse events after transcatheter aortic valve implantation with the use of different devices and access routes.Am Heart J. 2011; 161: 1114-1124Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar Decreases in platelet counts have been observed after surgical aortic valve replacement13Hilker L. Wodny M. Ginesta M. Wollert H.G. Eckel L. Differences in the recovery of platelet counts after biological aortic valve replacement.Interact Cardiovasc Thorac Surg. 2009; 8: 70-73Crossref PubMed Scopus (42) Google Scholar, 14Repossini A. Bloch D. Muneretto C. Piccoli P. Bisleri G. Beholz S. Platelet reduction after stentless pericardial aortic valve replacement.Interact Cardiovasc Thorac Surg. 2012; 14: 434-438Crossref PubMed Scopus (20) Google Scholar, 15Steele P. Weily H. Davies H. Ppppas G. Genton E. Platelet survival time following aortic valve replacement.Circulation. 1975; 51: 358-362Crossref PubMed Scopus (30) Google Scholar and also occur after TAVI in clinical practice. However, a decrease in platelet count and its clinical impact on outcome after TAVI have never been studied. This study included 144 consecutive patients who underwent TAVI with self-expandable valves using the transfemoral approach from December 2007 to July 2011 at Henri Mondor University Hospital. The definition of severe aortic stenosis was determined by the echocardiographic findings of an aortic valve area <0.8 cm2 or 0.6 cm2/m2, a peak aortic jet velocity >4.0 m/s, or a mean aortic valve gradient >40 mm Hg. All patients were screened before TAVI to determine whether they were considered unsuitable for surgical aortic valve replacement, according to a consensus between cardiac surgeons and cardiologists. Only patients with native aortic stenoses were included in the study. All patients provided written informed consent before enrollment in the registry. The TAVI procedure was previously reported in detail.2Rodes-Cabau J. Webb J.G. Cheung A. Ye J. Dumont E. Feindel C.M. Osten M. Natarajan M.K. Velianou J.L. Martucci G. DeVarennes B. Chisholm R. Peterson M.D. Lichtenstein S.V. Nietlispach F. Doyle D. DeLarochelliere R. Teoh K. Chu V. Dancea A. Lachapelle K. Cheema A. Latter D. Horlick E. Transcatheter aortic valve implantation for the treatment of severe symptomatic aortic stenosis in patients at very high or prohibitive surgical risk: acute and late outcomes of the multicenter Canadian experience.J Am Coll Cardiol. 2010; 55: 1080-1090Abstract Full Text Full Text PDF PubMed Scopus (879) Google Scholar, 16Yamamoto M. Meguro K. Mouillet G. Bergoend E. Monin J.L. Lim P. Dubois-Rande J.L. Teiger E. Comparison of effectiveness and safety of transcatheter aortic valve implantation in patients aged >/=90 years versus <90 years.Am J Cardiol. 2012; 110: 1156-1163Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar, 17Buellesfeld L. Wenaweser P. Gerckens U. Mueller R. Sauren B. Latsios G. Zickmann B. Hellige G. Windecker S. Grube E. Transcatheter aortic valve implantation: predictors of procedural success—the Siegburg-Bern experience.Eur Heart J. 2010; 31: 984-991Crossref PubMed Scopus (92) Google Scholar, 18Webb J.G. Pasupati S. Humphries K. Thompson C. Altwegg L. Moss R. Sinhal A. Carere R.G. Munt B. Ricci D. Ye J. Cheung A. Lichtenstein S.V. Percutaneous transarterial aortic valve replacement in selected high-risk patients with aortic stenosis.Circulation. 2007; 116: 755-763Crossref PubMed Scopus (939) Google Scholar, 19Cribier A. Eltchaninoff H. Bash A. Borenstein N. Tron C. Bauer F. Derumeaux G. Anselme F. Laborde F. Leon M.B. Percutaneous transcatheter implantation of an aortic valve prosthesis for calcific aortic stenosis: first human case description.Circulation. 2002; 106: 3006-3008Crossref PubMed Scopus (2698) Google Scholar Valve implantation was performed using the retrograde approach. The Medtronic CoreValve (Medtronic, Inc., Minneapolis, Minnesota) was used for all patients. Vascular access and closure were performed by means of a suture device (Prostar XL; Abbott Vascular, Redwood City, California). Dual-antiplatelet treatment with aspirin 75 mg and clopidogrel 75 mg was started the day before the procedure and followed thereafter, except for patients requiring oral anticoagulation by vitamin K antagonist. During the procedure, unfractionated heparin was injected to maintain an activated coagulation time of >250 seconds. Blood platelet count was measured before valve implantation (baseline) and every day after the procedure until discharge. Blood samples were drawn by venipuncture every morning. Baseline and nadir platelet count after TAVI was used to determine the maximum percentage of platelet count decrease. Blood was collected into ethylenediaminetetraacetic acid Vacuette tube (Greiner Bio-One, Kremsmünster, Austria) and processed for automatic platelet numeration (Beckman Coulter, Brea, California). The normal range of platelet count values for the automatic numeration is 150 × 109/L to 500 × 109/L, and the coefficient variation is <5%. The nadir of platelet count was defined as the minimum platelet count before any blood transfusion during the hospitalization period. Clinical follow-up was carried out through clinical visits or phone calls during the hospital stay and after 30 days. Major adverse cardiovascular events (MACEs) were prospectively collected during this period. The primary outcome was in-hospital MACEs, defined as all-cause death, life-threatening and major bleeding, and stroke during the hospitalization period as defined by the Valve Academic Research Consortium classification.20Leon M.B. Piazza N. Nikolsky E. Blackstone E.H. Cutlip D.E. Kappetein A.P. Krucoff M.W. Mack M. Mehran R. Miller C. Morel M.A. Petersen J. Popma J.J. Takkenberg J.J. Vahanian A. van Es G.A. Vranckx P. Webb J.G. Windecker S. Serruys P.W. Standardized endpoint definitions for transcatheter aortic valve implantation clinical trials: a consensus report from the Valve Academic Research Consortium.J Am Coll Cardiol. 2011; 57: 253-269Abstract Full Text Full Text PDF PubMed Scopus (707) Google Scholar Device success and 30-day combined safety data were evaluated according to the Valve Academic Research Consortium criteria. The combined safety end point was defined as follows: all-cause mortality, major stroke, life-threatening bleeding, stage 3 acute kidney injury, periprocedural myocardial infarction, major vascular complications, and a repeat procedure for valve-related dysfunction. Continuous variables with normal distributions are expressed as mean ± SD and nominal variables as percentages. To compare numerical data between groups, paired and unpaired Student's t tests were used as appropriate. Nominal variables were compared using chi-square tests. Kendall's correlation was used for trend testing. Multivariate analyses were performed using linear regression. Survival time-to-event analysis was performed using Kaplan-Meier curves. Two-tailed p values <0.05 were considered as statistically significant. Patients' baseline characteristics are listed in Table 1. All patients had severe symptomatic aortic stenosis, with a mean peak aortic jet velocity of 4.3 ± 0.8 m/s, a mean aortic gradient of 47 ± 17 mm Hg, and a mean aortic valve area of 0.7 ± 0.2 cm2. After aortic valve implantation, the mean peak aortic jet velocity and mean aortic gradient decreased to 2.3 ± 2.3 and 9 ± 4 mm Hg, respectively, and the mean aortic valve area increased to 2.0 ± 0.4 cm2. Significant postprocedural aortic regurgitation (mild to severe, grade ≥2/4) was observed in 26 patients (18%).Table 1Baseline patient characteristics (n = 144)VariableValueAge (yrs)84 ± 7Men64 (44%)European System for Cardiac Operative Risk Evaluation score (%)24 ± 12Society of Thoracic Surgeons score (%)12 ± 8Aortic maximal velocity (m/s)4.3 ± 0.8Aortic valve area (cm2)0.7 ± 0.2Left ventricular ejection fraction (%)49 ± 14Diabetes mellitus35 (24%)Hypertension∗Blood pressure >140/90 mm Hg, previous diagnosis of hypertension, or use of antihypertensive medication.109 (76%)Dyslipidemia†Low-density lipoprotein >100 mg/dl or use of lipid-lowering medication.78 (54%)Previous myocardial infarction29 (13%)Previous vascular disease29 (20%)Previous cerebrovascular event17 (12%)Previous cardiac surgery20 (14%)Chronic obstructive pulmonary disease37 (26%)New York Heart Association class2.8 ± 0.6Creatinine (μmol/L)111 ± 38Estimated glomerular filtration rate (ml/min)55 ± 23Hemoglobin (g/dl)11.9 ± 1.7Platelet count (109/L)216 ± 67Data are expressed as mean ± SD or as number (percentage).∗ Blood pressure >140/90 mm Hg, previous diagnosis of hypertension, or use of antihypertensive medication.† Low-density lipoprotein >100 mg/dl or use of lipid-lowering medication. Open table in a new tab Data are expressed as mean ± SD or as number (percentage). Blood platelet count at baseline before TAVI averaged 216 × 109/L ± 67 × 109/L (range 77 × 109/L to 441 × 109/L). Decrease in platelet count after TAVI occurred in all but 1 patient. The minimum platelet count averaged 170 × 109/L ± 54 × 109/L (range 41 × 109/L to 336 × 109/L) and was observed 2.5 ± 1.1 days after TAVI (Figure 1). The decrease in platelet count averaged 34 ± 15% (18 ± 7% for the first tertile, 33 ± 4% for the second tertile, and 55 ± 10% for the third tertile). Overall, 90 patients had moderate thrombopenia (platelet count 50 × 109/L to 150 × 109/L), and only 3 had severe thrombopenia (platelet count <50 × 109/L). No patients received platelet transfusions, and dual-antiplatelet treatment was withdrawn in patients with severe thrombopenia, except for aspirin when recent stent implantation had been performed. Blood protein decrease was poorly correlated with the severity of platelet count decrease (r2 = 0.039, p = 0.02). In addition, decreases in hematocrit and blood proteins count averaged 11% and 15%, respectively, while the decrease in platelet count was systematically 24% greater than the plasmatic protein decrease (Figure 2). In addition, platelet change failed to correlate with change in hematocrit (r2 = 0.007, p = 0.30) and bilirubin (r2 = 0.004, p = 0.40). Patients with the most severe platelet count decreases (third tertile) had more complex procedures: 5 patients in the third tertile compared with none in the second and first tertiles had prosthesis displacement that required new prosthesis valve implantations in 3 patients (p = 0.04), resulting in lower procedural success in the third tertile. Moreover, patients in the third tertile had more prolonged procedural and x-ray times and larger contrast amounts (Table 2). The differences in procedural duration persisted even after excluding patients with prosthesis displacement (23 ± 13 min in the third tertile vs 17 ± 7 min in the second and first tertiles, p = 0.0008, for x-ray time, and 89 ± 32 vs 71 ± 21 min, respectively, p = 0.0001, for procedure time). Multivariate analysis demonstrated that procedural time (β = 0.23, p = 0.02) and prosthesis migration (β = 0.17, p = 0.03) were the 2 independent predictors of platelet count decrease.Figure 2Difference between changes in protein and platelet (y axis) according to changes in protein (x axis).View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table 2Population characteristics and outcomes according to platelet decrease by tertileVariablePercentage of Platelet Count Decrease by Tertilep ValueFirstSecondThirdAge (yrs)84 ± 885 ± 783 ± 80.50Creatinine (μmol/L)113 ± 44107 ± 33112 ± 350.70Hemoglobin (g/L)11.4 ± 1.512.2 ± 1.512.1 ± 1.80.02Antithrombotic treatment Aspirin34 (70%)29 (60%)26 (54%)0.20 Clopidogrel35 (71%)32 (66%)29 (60%)0.60 Vitamin K antagonist14 (31%)18 (37%)10 (21%)0.20Procedural characteristics Postdilatation6 (13%)5 (10%)6 (13%)0.80 X-ray time (minutes)17 ± 718 ± 724 ± 130.002 Procedural time (minutes)70 ± 2072 ± 2292 ± 33<0.0001 Contrast amount (ml)172 ± 77169 ± 77227 ± 1280.006 >1 prosthesis0030.04 Prosthesis migration0050.005 Aortic regurgitation ≥25 (10%)10 (21%)11 (23%)0.30Biologic characteristics Platelet count at baseline (109/L)209 ± 66219 ± 63221 ± 720.60 Platelet count nadir (109/L)172 ± 55146 ± 42108 ± 38<0.0001 Platelet count decrease (%)18 ± 733 ± 450 ± 10<0.0001 Protein decrease (%)7 ± 1510 ± 814 ± 90.01 Hematocrit decrease (%)9 ± 1917 ± 1917 ± 100.02 Bilirubin increase (%)21 ± 4844 ± 7531 ± 740.30Valve Academic Research Consortium Procedural success48 (100%)47 (98%)42 (88%)0.009 30-day combined safety end point4 (8%)4 (8%)14 (29%)0.004 Stroke1 (2%)4 (8%)5 (10%)0.20 Major and life-threatening bleeding9 (19%)14 (29%)19 (40%)0.08 Major vascular complications4 (8%)5 (10%)10 (21%)0.20 Myocardial infarction0 (0%)2 (4%)1 (2%)0.40Other complications In-hospital mortality1 (2%)3 (6%)7 (15%)0.06 30-day mortality1 (2%)4 (8%)7 (15%)0.08 MACEs10 (21%)17 (35%)23 (48%)0.02 Hemoglobin loss (g/dl)1.6 ± 1.11.9 ± 1.22.8 ± 1.6<0.0001 Red blood cell transfusion5 (10%)5 (10%)17 (35%)0.001Data are expressed as mean ± SD or as number (percentage). Open table in a new tab Data are expressed as mean ± SD or as number (percentage). Kaplan-Meier curves for survival and MACE-free survival are shown in Figure 3. In-hospital and 30-day mortality were 7% (n = 11) and 8% (n = 12), respectively. Overall, MACEs occurred in 50 patients (35%) during the hospitalization period (11 deaths, 10 strokes and 42 episodes of major bleeding; Table 2, Figure 4). Blood transfusions were delivered in 27 patients, and 8 patients required surgical hemostatic intervention. Bleeding complications, stroke, and in-hospital death were correlated with the severity of platelet count decrease (Figure 4). MACEs were greater in patients with severe platelet count decreases (20% in the first tertile, 38% in the second tertile, and 46% in the third tertile, p = 0.02; Figure 4). MACEs were observed in 0 (0%), 35 (39%), and 14 (27%) patients with severe, moderate, and no thrombopenia, respectively. MACEs remained associated with the importance of platelet count decrease even after the exclusion of patients with procedural failure (p = 0.03; Figure 5). In addition, the relation between platelet count decrease and MACEs was more significant (p = 0.008) after exclusion of the 30 “learning curve” patients (Figure 4). Finally, blood platelet count decrease was the only predictor of in-hospital MACEs (odds ratio 1.67, 95% confidence interval 1.05 to 2.67, p = 0.03, on multivariate analysis; Table 3).Figure 4Stroke (A), major bleeding (B), in-hospital mortality (C), and 30-day mortality (D) according to the severity of platelet count decrease; p values are indicated for trend test. ‡p <0.05 versus first tertile.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 5In-hospital MACEs according to platelet tertiles in all patients (A), patients with procedural success only (B), and after exclusion of the 30 “learning curve” patients (C); p values are indicated for trend test. ‡p <0.05 versus first tertile.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table 3Variables associated with major adverse cardiovascular eventsVariableAllMACEsp ValueYes (n = 50)No (n = 94)Age (yrs)84 ± 785 ± 684 ± 70.40European System for Cardiac Operative Risk Evaluation score (%)24 ± 1224 ± 1024 ± 130.90New York Heart Association class2.8 ± 0.62.8 ± 0.62.7 ± 0.70.80Creatinine (μmol/L)111 ± 38112 ± 32111 ± 410.80Hemoglobin (g/dl)11.9 ± 1.712.1 ± 1.711.8 ± 1.60.40Left ventricular ejection fraction (%)49 ± 1450 ± 1448 ± 140.50Maximal aortic velocity (m/s)4.3 ± 0.84.3 ± 0.84.3 ± 0.80.90Aortic valve area (cm2)0.7 ± 0.20.6 ± 0.20.7 ± 0.20.10Systolic pulmonary pressure (mm Hg)49 ± 1546 ± 1351 ± 160.10X-ray time (minutes)19 ± 1019 ± 919 ± 100.90Procedural time (minutes)78 ± 2784 ± 3175 ± 240.07Contrast amount (ml)189 ± 100197 ± 97186 ± 1010.50Prosthesis migration5140.50Procedural success9592970.20Aortic regurgitation ≥226 (18)17 (18)9 (18)0.90Platelet count at baseline (109/L)216 ± 67220 ± 65214 ± 680.60Platelet count nadir (109/L)140 ± 52137 ± 55144 ± 510.40Percentage decrease in platelet count34 ± 1538 ± 1432 ± 160.02Patients in tertile 333%44%27%0.03Patients in tertile 2 or 367%80%60%0.01Data are expressed as mean ± SD or as number (percentage). Open table in a new tab Data are expressed as mean ± SD or as number (percentage). Platelet count decrease has been reported after percutaneous coronary intervention21De Labriolle A. Bonello L. Lemesle G. Roy P. Steinberg D.H. Xue Z. Suddath W.O. Satler L.F. Kent K.M. Pichard A.D. Lindsay J. Waksman R. Decline in platelet count in patients treated by percutaneous coronary intervention: definition, incidence, prognostic importance, and predictive factors.Eur Heart J. 2010; 31: 1079-1087Crossref PubMed Scopus (41) Google Scholar and surgical aortic valve replacement.13Hilker L. Wodny M. Ginesta M. Wollert H.G. Eckel L. Differences in the recovery of platelet counts after biological aortic valve replacement.Interact Cardiovasc Thorac Surg. 2009; 8: 70-73Crossref PubMed Scopus (42) Google Scholar, 14Repossini A. Bloch D. Muneretto C. Piccoli P. Bisleri G. Beholz S. Platelet reduction after stentless pericardial aortic valve replacement.Interact Cardiovasc Thorac Surg. 2012; 14: 434-438Crossref PubMed Scopus (20) Google Scholar In the setting of TAVI, platelet count decrease was described in a first-in-humans study22Grube E. Laborde J.C. Gerckens U. Felderhoff T. Sauren B. Buellesfeld L. Mueller R. Menichelli M. Schmidt T. Zickmann B. Iversen S. Stone G.W. Percutaneous implantation of the CoreValve self-expanding valve prosthesis in high-risk patients with aortic valve disease: the Siegburg first-in-man study.Circulation. 2006; 114: 1616-1624Crossref PubMed Scopus (637) Google Scholar that enrolled very few patients, and to our knowledge, no other study has focused on platelet count decrease since that initial experience. Our study had 2 important results: (1) platelet count systematically decreased after TAVI, with an average decrease of 34 ± 15%, and (2) a decrease in platelet count strongly influenced patient outcome. A decrease in platelet count had been previously studied in percutaneous coronary intervention and had been shown to be associated with the use of low-osmolar contrast agents.21De Labriolle A. Bonello L. Lemesle G. Roy P. Steinberg D.H. Xue Z. Suddath W.O. Satler L.F. Kent K.M. Pichard A.D. Lindsay J. Waksman R. Decline in platelet count in patients treated by percutaneous coronary intervention: definition, incidence, prognostic importance, and predictive factors.Eur Heart J. 2010; 31: 1079-1087Crossref PubMed Scopus (41) Google Scholar In agreement with these studies, we also observed that patients with severe platelet count decreases after TAVI received more contrast agent. Hemolysis and hemodilution probably contribute little to platelet count decrease, as a poor correlation was observed between platelet count decrease and protein decrease, and no correlation was found with bilirubin. All patients received unfractionated heparin, so heparin probably does not take part in differences observed in platelet count decreases. Similarly, most patients were receiving antiplatelet treatment, and no association was observed between these treatments and decrease in platelet count. In percutaneous coronary intervention, no clear mechanism explains the association between low-osmolar contrast agents and the decrease in platelet count except a potential effect on platelet activation.23Parvez Z. Moncada R. Nonionic contrast medium: effects on blood coagulation and complement activation in vitro.Angiology. 1986; 37: 358-364Crossref PubMed Scopus (15) Google Scholar In the setting of TAVI procedures, comparison with surgical aortic valve replacement suggests that platelet activation may be involved in the mechanism of platelet count decrease. Indeed, except for extracorporeal circulation, several steps of surgical valve replacement that promote platelet activation15Steele P. Weily H. Davies H. Ppppas G. Genton E. Platelet survival time following aortic valve replacement.Circulation. 1975; 51: 358-362Crossref PubMed Scopus (30) Google Scholar, 24Badr Eslam R. Gremmel T. Schneller A. Stegfellner M. Kaider A. Mannhalter C. Lang I. Panzer S. High levels of platelet-monocyte aggregates after valve replacement for aortic stenosis: relation to soluble P-selectin and P-selectin glycoprotein ligand-1 genes.Thromb Res. 2011; 129: 453-458Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar, 25Goldsmith I.R. Blann A.D. Patel R.L. Lip G.Y. Plasma fibrinogen, soluble P-selectin, and von Willebrand factor in aortic valve disease: evidence for abnormal haemorheology, platelet activation, and endothelial dysfunction.Heart. 2000; 83: 577-578Crossref PubMed Scopus (12) Google Scholar, 26Goldsmith I.R. Blann A.D. Patel R.L. Lip G.Y. Effect of aortic valve replacement on plasma soluble P-selectin, von Willebrand factor, and fibrinogen.Am J Cardiol. 2001; 87: 107-110Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 27Leguyader A. Watanabe R. Berbe J. Boumediene A. Cogne M. Laskar M. Platelet activation after aortic prosthetic valve surgery.Interact Cardiovasc Thorac Surg. 2006; 5: 60-64Crossref PubMed Scopus (28) Google Scholar are present in the TAVI procedure: endothelial damage caused by prosthesis implantation, fibrinogen binding on metallic armatures, and shear stress modifications due to prosthesis implantation.28Nobili M. Sheriff J. Morbiducci U. Redaelli A. Bluestein D. Platelet activation due to hemodynamic shear stresses: damage accumulation model and comparison to in vitro measurements.ASAIO J. 2008; 54: 64-72Crossref PubMed Scopus (187) Google Scholar As suggested by the correlation between TAVI procedure complications (rate of prosthesis migration, contrast amount, and procedural time) and platelet count decrease, tissue injury during aortic valve implantation may play an important part in platelet activation. Platelet activation after surgical valve replacement has been shown to be predictive of worse outcomes.15Steele P. Weily H. Davies H. Ppppas G. Genton E. Platelet survival time following aortic valve replacement.Circulation. 1975; 51: 358-362Crossref PubMed Scopus (30) Google Scholar, 26Goldsmith I.R. Blann A.D. Patel R.L. Lip G.Y. Effect of aortic valve replacement on plasma soluble P-selectin, von Willebrand factor, and fibrinogen.Am J Cardiol. 2001; 87: 107-110Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar It is tempting to suggest that the association between patient outcomes and the severity of platelet count decreases is caused by severe platelet activation. Indeed, platelet activation may promote thrombosis and take part in the higher rate of stroke observed with higher platelet count decreases. In the first report of platelet count decrease after TAVI, by Grube et al,22Grube E. Laborde J.C. Gerckens U. Felderhoff T. Sauren B. Buellesfeld L. Mueller R. Menichelli M. Schmidt T. Zickmann B. Iversen S. Stone G.W. Percutaneous implantation of the CoreValve self-expanding valve prosthesis in high-risk patients with aortic valve disease: the Siegburg first-in-man study.Circulation. 2006; 114: 1616-1624Crossref PubMed Scopus (637) Google Scholar platelet count decrease was related to platelet activation. However, in that first-in-humans study, extracorporeal circulatory support, which is known to promote platelet activation and destruction, was routinely used. In our study, TAVI procedural complications were not predictive of outcomes, and platelet count decrease was the only predictor of MACEs. This may be explained by the small sample size of the population, which limits statistical power, or by the fact that platelet count decrease is a more sensitive marker of outcome because of its potential impact on bleeding and thrombotic complications. In addition, it supports the hypothesis that platelet count decrease severity reflects the intensity of platelet activation and inflammatory response induced by tissue injury related to prosthesis valve implantation. The deleterious impact of inflammation after TAVI procedure was recently reported by Sinning et al.29Sinning J.M. Scheer A.C. Adenauer V. Ghanem A. Hammerstingl C. Schueler R. Muller C. Vasa-Nicotera M. Grube E. Nickenig G. Werner N. Systemic inflammatory response syndrome predicts increased mortality in patients after transcatheter aortic valve implantation.Eur Heart J. 2012; 33: 1459-1468Crossref PubMed Scopus (119) Google Scholar In that study, the investigators reported a rate of systemic inflammation response in 40% of patients (61 of 151) after TAVI. They showed that systemic inflammation was associated with the amount of contrast used and postprocedural TAVI complications. However, they did not investigate platelet count in their study. Finally, our results underline the need to carefully monitor platelet count after TAVI, and future prospective studies are needed to better clarify the underlying mechanism and specific treatment to prevent platelet activation. The study design (retrospective and observational) carries all the limitations inherent to such an investigation, especially the lack of data that formally demonstrate the mechanism of platelet count decrease, as platelet activation parameters were not routinely recorded. Further prospective studies including platelet activity measurement are needed to confirm our hypotheses and to verify whether outcomes are related to platelet activation. The authors have no conflicts of interest to disclose.

Relationships between plaque morphology on optical coherence tomography (OCT) and biomarker levels in the patients with acute coronary syndrome (ACS) have not been fully investigated.ACS patients (n=128) were prospectively enrolled and their plasma levels of soluble lectin-like oxidized LDL receptor-1 (sLOX-1), high-sensitivity C-reactive protein (hs-CRP), and high-sensitivity troponin T (hs-TnT) were measured. Another set of 20 patients with stable angina pectoris (SAP) without plaque rupture or erosion served as controls. Among 128 ACS patients, 75 patients underwent OCT procedure to evaluate culprit plaque morphology, and were categorized into two groups; ACS with plaque rupture (ruptured ACS; R-ACS, n=54) and ACS without plaque rupture (non-ruptured ACS; N-ACS, n=21).Levels of sLOX-1 (p<0.001), hs-CRP (p=0.048) and hs-TnT (p<0.001) were significantly higher in R-ACS than SAP. Levels of sLOX-1 were also significantly higher in R-ACS than in N-ACS (p<0.001); whereas levels of hs-CRP (p=0.675), as well as those of hs-TnT (p=0.055), were comparable between R-ACS and N-ACS. Comparison of receiver operating characteristic (ROC) curves among sLOX-1, hs-CRP and hs-TnT to differentiate R-ACS from N-ACS revealed that the area under the curve (AUC) values of sLOX-1, hs-CRP and hs-TnT were 0.782, 0.531 and 0.643, respectively. ROC curves, generated for these biomarkers, to differentiate ACS with thin-cap fibroatheroma (TCFA) from those without demonstrated that the AUC values of sLOX-1, hs-CRP and hs-TnT were 0.718, 0.506 and 0.524, respectively.sLOX-1, but not hs-CRP or hs-TnT, can differentiate ACS with plaque rupture from those without, and ACS with TCFA from those without.

Objectives This study aimed to assess the feasibility of percutaneous arterial access site closure after percutaneous transfemoral transcatheter aortic valve implantation (TF‐TAVI) using single versus double Perclose ProGlide devices. Backgrounds Although suturing with the preclose technique has been widely adopted during TF‐TAVI, the optimal vascular closure strategy is still under debate. Methods Data from 279 patients who underwent TF‐TAVI, obtained from the Optimized CathEter vAlvular iNtervention (OCEAN‐TAVI) Japanese multicenter registry. Technical, procedural, and clinical outcomes were compared between the single ProGlide group ( n = 99) and double ProGlide group ( n = 180). They were also analyzed by propensity adjusted matching model (single [ n = 69] vs. double [ n = 69]). All patients were treated through a 16‐Fr to 20‐Fr eSheath. Technical success of the closure device was defined as hemostasis not requiring alternative invasive treatment. Access site‐related vascular complications, bleedings, and other procedural complications were defined according to the Valvular Academic Research Consortium‐2 (VARC‐2) criteria. Results The rates of technical success and access site‐related vascular complications were similar in the 2 groups (94.9% vs. 91.6%, p = 0.44; 5.0% vs. 7.7%, p = 0.54, respectively). The prevalence of bleeding complications did not differ between the 2 groups (1.0% vs. 3.3%, p = 0.43). Thirty‐day mortality rate also showed no difference between the 2 groups (2.0% vs. 1.1%, p = 0.95), although these events were not associated with access site failure. These results were not attenuated in the propensity matching model. Conclusions Vascular closure with a single ProGlide in TF‐TAVI could achieve equivalent, acceptable rates of technical success and procedural complications compared with the double ProGlide technique. © 2016 Wiley Periodicals, Inc.

The aim of this study was to evaluate the incidence, predictors, and outcomes of percutaneous closure device (PCD) failure during transfemoral transcatheter aortic valve implantation (TAVI) with an Edwards Sapien-XT prosthesis using an expandable sheath (eSheath). From October 2013 to April 2016, 1,215 patients who underwent TAVI were prospectively enrolled in the Optimized Transcatheter Valvular Intervention (OCEAN-TAVI) registry. Of these, 478 patients underwent transfemoral TAVI with Sapien-XT prosthesis using an eSheath and percutaneous closure with a Perclose ProGlide system. We evaluated the predictors of PCD failure and whether it affected the clinical outcomes. Patients were aged 85 years (interquartile range 82 to 88 years). PCD failure occurred in 36 patients (8%). Sheath-to-femoral artery ratio (SFAR) (per 1 increase) (odds ratio 5.40, 95% confidence interval 1.28 to 22.92, p = 0.022) predicted PCD failure in a multivariate model. The sensitivity-specificity curves identified an SFAR threshold of 1.03; the area under the curve for SFAR as a predictor of PCD failure was 0.629. The PCD failure group did not have a higher rate of 30-day mortality (0% vs 1%, p = 0.52) or mid-term (365-day) mortality (log-rank test p = 0.85) compared with the PCD success group in the Kaplan-Meier analysis. In conclusion, PCD failures occurred in 8% of the patients and were not associated with 30-day or mid-term mortality rates after percutaneous transfemoral TAVI. The SFAR threshold of 1.03 was useful for predicting PCD failures. The aim of this study was to evaluate the incidence, predictors, and outcomes of percutaneous closure device (PCD) failure during transfemoral transcatheter aortic valve implantation (TAVI) with an Edwards Sapien-XT prosthesis using an expandable sheath (eSheath). From October 2013 to April 2016, 1,215 patients who underwent TAVI were prospectively enrolled in the Optimized Transcatheter Valvular Intervention (OCEAN-TAVI) registry. Of these, 478 patients underwent transfemoral TAVI with Sapien-XT prosthesis using an eSheath and percutaneous closure with a Perclose ProGlide system. We evaluated the predictors of PCD failure and whether it affected the clinical outcomes. Patients were aged 85 years (interquartile range 82 to 88 years). PCD failure occurred in 36 patients (8%). Sheath-to-femoral artery ratio (SFAR) (per 1 increase) (odds ratio 5.40, 95% confidence interval 1.28 to 22.92, p = 0.022) predicted PCD failure in a multivariate model. The sensitivity-specificity curves identified an SFAR threshold of 1.03; the area under the curve for SFAR as a predictor of PCD failure was 0.629. The PCD failure group did not have a higher rate of 30-day mortality (0% vs 1%, p = 0.52) or mid-term (365-day) mortality (log-rank test p = 0.85) compared with the PCD success group in the Kaplan-Meier analysis. In conclusion, PCD failures occurred in 8% of the patients and were not associated with 30-day or mid-term mortality rates after percutaneous transfemoral TAVI. The SFAR threshold of 1.03 was useful for predicting PCD failures.

In this study, we sought to investigate the 2-year prognostic impact of B-type natriuretic peptide (BNP) levels at discharge, following transcatheter aortic valve replacement.We enrolled 1094 consecutive patients who underwent transcatheter aortic valve replacement between 2013 and 2016. Study patients were stratified into 2 groups according to survival classification and regression tree analysis (high versus low BNP groups). We evaluated the impact of high BNP on 2-year mortality compared with that of low BNP using a multivariable Cox model, and assessed whether this stratification would improve predictive accuracy for determining 2-year mortality by assessing time-dependent net reclassification improvement and integrated discrimination improvement. The median age of patients was 85 years (quartile 82-88), and 29.2% of the study population were men. The median Society of Thoracic Surgeons score was 6.8 (4.7-9.5), and BNP at discharge was 186 (93-378) pg/mL. All-cause mortality following discharge was 7.9% (95% CI, 5.8-9.9%) at 1 year and 15.4% (95% CI, 11.6-19.0%) at 2 years. The survival classification and regression tree analysis revealed that the discriminating BNP level to discern 2-year mortality was 202 pg/mL, and that elevated BNP had a statistically significant impact on outcomes, with an adjusted hazard ratio of 2.28 (1.36-3.82, P=0.002). The time-dependent net reclassification improvement (P=0.047) and integrated discrimination improvement (P=0.029) analysis revealed that the incorporation of BNP stratification with other clinical variables significantly improved predictive accuracy for 2-year mortality.Elevation of BNP at discharge is associated with 2-year mortality after transcatheter aortic valve replacement.

•The STS score was designed to predict 30-day mortality after cardiac surgery. •Lower mortality after transcatheter aortic valve implantation than was predicted. •High STS score is associated with an increased risk of long-term mortality. •Similar long-term mortality in patients with low and intermediate scores. The Society of Thoracic Surgeons (STS) risk model, designed to predict operative mortality after cardiac surgery, is often used for the risk assessment of patients considered for transcatheter aortic valve implantation (TAVI). We investigated the long-term prognostic value of the STS score by utilizing the data of 2588 patients undergoing TAVI from the OCEAN (Optimized CathEter vAlvular iNtervention)—TAVI Japanese multicenter registry. The patients were divided into 3 groups according to their pre-procedural STS score as follows: low-risk (STS score <4%, n = 467 [18%]), intermediate-risk (4%≤ STS score <8%, n = 1200 [46.4%]), and high-risk (8%≤ STS score, n = 921 [35.6%]). Low-risk patients were younger and were more frequently male. The prevalence of most of the comorbidities were higher in high-risk patients, while active cancer was more frequent in low-risk patients (p <0.001).The cumulative 4-year all-cause mortality rates were higher in high-risk patients (49.0%) but comparable in low-risk (22.6%) and intermediate-risk patients (28.7%) (hazard ratio [HR] for intermediate-risk versus low-risk, 1.03; 95% confidence interval [CI], 0.77 to 1.37; p = 0.85; HR for high-risk versus low-risk, 2.27; 95% CI 1.72 to 2.99; p = <0.001). Similarly, the cumulative 4-year cardiovascular mortality rates were higher in high-risk patients (20.5%) but comparable in low-risk (9.9%) and intermediate-risk patients (10.3%) (HR for intermediate-risk versus low-risk, 1.10; 95% CI, 0.68 to 1.77; p = 0.69; HR for high-risk versus low-risk, 2.33; 95% CI 1.48 to 3.67; p = <0.001). After adjustment for several confounders, STS score ≥8% was independently associated with increased long-term mortality (HR, 1.35; 95% CI, 1.08 to 1.68). In conclusion, the risk stratification according to STS score demonstrated an increased risk of long-term mortality after TAVI in high-risk patients, albeit with comparable risks in intermediate- and low-risk patients. The Society of Thoracic Surgeons (STS) risk model, designed to predict operative mortality after cardiac surgery, is often used for the risk assessment of patients considered for transcatheter aortic valve implantation (TAVI). We investigated the long-term prognostic value of the STS score by utilizing the data of 2588 patients undergoing TAVI from the OCEAN (Optimized CathEter vAlvular iNtervention)—TAVI Japanese multicenter registry. The patients were divided into 3 groups according to their pre-procedural STS score as follows: low-risk (STS score <4%, n = 467 [18%]), intermediate-risk (4%≤ STS score <8%, n = 1200 [46.4%]), and high-risk (8%≤ STS score, n = 921 [35.6%]). Low-risk patients were younger and were more frequently male. The prevalence of most of the comorbidities were higher in high-risk patients, while active cancer was more frequent in low-risk patients (p <0.001).The cumulative 4-year all-cause mortality rates were higher in high-risk patients (49.0%) but comparable in low-risk (22.6%) and intermediate-risk patients (28.7%) (hazard ratio [HR] for intermediate-risk versus low-risk, 1.03; 95% confidence interval [CI], 0.77 to 1.37; p = 0.85; HR for high-risk versus low-risk, 2.27; 95% CI 1.72 to 2.99; p = <0.001). Similarly, the cumulative 4-year cardiovascular mortality rates were higher in high-risk patients (20.5%) but comparable in low-risk (9.9%) and intermediate-risk patients (10.3%) (HR for intermediate-risk versus low-risk, 1.10; 95% CI, 0.68 to 1.77; p = 0.69; HR for high-risk versus low-risk, 2.33; 95% CI 1.48 to 3.67; p = <0.001). After adjustment for several confounders, STS score ≥8% was independently associated with increased long-term mortality (HR, 1.35; 95% CI, 1.08 to 1.68). In conclusion, the risk stratification according to STS score demonstrated an increased risk of long-term mortality after TAVI in high-risk patients, albeit with comparable risks in intermediate- and low-risk patients.

Non-esophageal eosinophilic gastrointestinal disorders (non-EoE EGIDs) are chronic inflammatory disorders with massive infiltration of eosinophils into the gastrointestinal tract. Food elimination diets are potentially effective treatments. But the existing dietary therapies have various weak points. We developed a new regimen to compensate for the shortcomings of the elemental diet and 6-food elimination diet. The new regimen consists of an amino-acid-based formula, potatoes, vegetables, fruits and restricted seasonings. We named it the "Rainbow Elimination Diet (ED)." The aims of this study were to evaluate the tolerability and safety of this diet.A retrospective medical record examination was conducted at the National Center for Child Health and Development covering the period from January 2010 through December 2018. The medical records of patients (age 2-17 y) with histologically diagnosed non-EoE EGIDs were reviewed. The tolerability, nutritional intake, symptoms, and blood test findings were evaluated.Nineteen patients were offered several kinds of food-elimination diets. Seven patients (eosinophilic gastritis: 5; gastroenteritis: 1; duodenitis: 1) were treated with Rainbow ED. Six patients were compliant with this diet. The median duration of the diet induction phase was 15 days (range 14-30). All 5 patients who had had symptoms just before the induction phase became symptom-free. The body weight decreased in 5 patients (median -0.6 kg), probably because the serum protein increased, resulting in reduced edema. All 5 patients with hypoproteinemia had elevated serum albumin (median 2.9-3.5 g/dL). The ingested nutritional elements were calculated, and most of them were sufficient, except for fat and selenium.The Rainbow ED was well-tolerated and safe for pediatric non-EoE EGIDs.

A Bombyx mori cDNA was cloned that hybridized with Hyalophora cecropia attacin probe and its nucleotide sequence was determined. This cDNA consisted of 846 nucleotides and the deduced amino acid sequence showed that the cDNA encodes an attacin precursor protein. The putative mature protein of B. mori attacin had 70.4, 68.3 and 18.8% identity in amino acid sequences with that of H. cecropia acidic and basic attacins and Sarcophaga peregrina sarcotoxin IIA, respectively. B. mori and H. cecropia attacins and S. peregrina sarcotoxin IIA had two subdomains in each G domain, suggesting that common amino acid residues in the subdomains are conserved during evolution and plays an important role in the activity of the antibacterial proteins. Expression of B. mori attacin gene was rapidly induced by the injection of Escherichia coli cells into B. mori larvae and continued at least for 48 h mainly in fat bodies and hemocytes.

The perform of chicken prolactin (PRL) deduced from the cDNA sequence contains a signal peptide of 30 amino acid residues followed by a mature PRL of 199 residues. Chicken PRL shows 77, 68, 67, 58, and 31% identity of amino acid sequence with whale, human, ovine, rat, and salmon PRLs, respectively. Elucidation of the primary structure of avian PRL enabled extended analysis of the specific and conserved amino acid residues and domains of the PRL molecules. The mammalian, teleostean, and avian PRLs share 32 common residues, and these conserved residues are observed to cluster in four distinct domains (PD1 to PD4), corresponding to four of five conserved domains of the growth hormones. Of the 32 residues, 8 residues in the PD2 and PD4 domains, including 4 cysteines, are conserved by other members of the growth hormone family, which indicates that these 8 residues may be essential for common structural features of the gene family. On the other hand, 13 other residues distributed among all four domains are conserved almost exclusively in the PRLs, suggesting that these residues are indispensable for specific binding of the PRLs to their receptors.

Renal fibrosis is the final common pathway of chronic kidney disease, and its progression predicts the degree of renal dysfunction. We investigated the renoprotective properties of pirfenidone in a remnant kidney model of chronic renal failure to determine its pharmacological potency compared to enalapril. Five-sixths nephrectomized rats were fed diet containing pirfenidone (approximately 700mg/kg/day) for 8weeks. Pirfenidone steadily inhibited the progression of proteinuria, but not to a significant degree. Pirfenidone prevented the elevation of plasma creatinine and blood urea nitrogen. At the end of the experiment, pirfenidone had reduced systolic blood pressure by means of its renoprotective effect. In a histological study, pirfenidone improved interstitial fibrosis in the renal cortex. These effects were supported by the suppression of the expression of TGF-beta and fibronectin in the mRNA of the kidney. In contrast, pirfenidone had little effect on the expression of alpha-smooth muscle actin, which is one of the proteins responsible for epithelial-mesenchymal transition. This property was confirmed by the TGF-beta-induced transdifferentiation observed in cultured normal rat kidney tubular epithelial NRK52E cells. These results suggest that pirfenidone improves the progression of chronic renal failure via its antifibrotic action, although pirfenidone has less effective TGF-beta-induced epithelial to mesenchymal transdifferentiation.

Background: Matrix metalloproteinase-9 (MMP-9) is regarded as a biomarker of plaque rupture or vulnerability and is elevated in patients with acute coronary syndrome (ACS). The aim of the present study was to evaluate the diagnostic value of MMP-9 for early ACS (≤4h of onset) and late ACS (>4h after onset), compared with high-sensitivity troponin T (hs-TnT). Methods and Results: MMP-9 and hs-TnT were measured in 200 patients with ST elevation ACS (STEACS; 115 early STEACS and 85 late STEACS patients), and 66 patients with non-ST elevation ACS (NSTEACS; 25 early NSTEACS and 41 late NSTEACS patients). Forty patients with stable angina pectoris (SAP) were enrolled as a control group. MMP-9 levels were significantly higher in patients with early STEACS (P<0.001), early NSTEACS (P<0.001), late STEACS (P<0.001) and late NSTEACS (P=0.025) than SAP. MMP-9 levels were significantly higher in patients with early STEACS (P=0.017) and early NSTEACS (P=0.034) than late STEACS and late NSTEACS, respectively. Levels of hs-TnT were significantly lower in patients with early STEACS (P<0.001) and early NSTEACS (P=0.007) than late STEACS and late NSTEACS, respectively. On receiver operating characteristic curve analysis, area under the curve of early STEACS, early NSTEACS, late STEACS and late NSTEACS was 0.880, 0.782, 0.790 and 0.648 for MMP-9, and 0.707, 0.725, 0.993 and 0.920 for hs-TnT, respectively. Conclusions: MMP-9 levels were elevated earlier than hs-TnT and had a higher diagnostic value for early ACS, but not for late ACS, reflecting plaque rupture or vulnerability. (Circ J 2011; 75: 2853-2861)

To facilitate the learning process of transcatheter aortic valve implantation (TAVI) in Japan, unique supporting systems (e.g., on-site proctor and web-based screening systems) have been developed. Nevertheless, little is known about real-world clinical outcomes after TAVI in Japan compared with their European counterparts.From the optimized catheter valvular intervention (OCEAN-TAVI, Japan) and the Institut Cardiovasculaire Paris Sud (Massy, France) registries, we evaluated a total of 134 and 178 patients, respectively, who underwent transfemoral TAVI during the same time period.Among the French cohort, about half of the patients (N = 81, 45.5%) were treated with the Edwards SAPIEN XT. Body surface area was significantly smaller in the Japanese cohort, although operative risks for both cohorts were almost the same. A greater percentage of patients in the Japanese cohort were implanted with 23 mm valves compared with the French cohort (73.1% vs. 23.0%, P < 0.001), reflecting the smaller annulus diameter (21.8 ± 1.6 vs. 23.8 ± 2.4 mm, P < 0.001). All-cause 30-day mortality (0% vs. 0.6%, P = 1.000) and 30-day combined safety endpoint based on the Valve Academic Research Consortium 2 (VARC2) criteria (9.7% vs. 11.2%, P = 0.713) were similar when limiting the analysis to patients treated with the Edwards SAPIEN XT.Despite the unfavorable aortic anatomy of the Japanese patients, their clinical outcomes after transfemoral TAVI were excellent with the same degree of safety as in an experienced European institute. This minimized learning process achieved the use of unique support systems.

No scoring system for assessing acute heart failure (AHF) has been reported.Data for 824 AHF patients were analyzed. The subjects were divided into an alive (n=750) and a dead group (n=74). We constructed a predictive scoring system based on eight significant APACHE II factors in the alive group [mean arterial pressure (MAP), pulse, sodium, potassium, hematocrit, creatinine, age, and Glasgow Coma Scale (GCS); giving each one point], defined as the APACHE-HF score. The patients were assigned to five groups by the APACHE-HF score [Group 1: point 0 (n=70), Group 2: points 1 and 2 (n=343), Group 3: points 3 and 4 (n=294), Group 4: points 5 and 6 (n=106), and Group 5: points 7 and 8 (n=11)]. A higher optimal balance was observed in the APACHE-HF between sensitivity and specificity [87.8%, 63.9%; area under the curve (AUC)=0.779] at 2.5 points than in the APACHE II (47.3%, 67.3%; AUC=0.558) at 17.5 points. The multivariate Cox regression model identified belonging to Group 5 [hazard ratio (HR): 7.764, 95% confidence interval (CI) 1.586-38.009], Group 4 (HR: 6.903, 95%CI 1.940-24.568) or Group 3 (HR: 5.335, 95%CI 1.582-17.994) to be an independent predictor of 3-year mortality. The Kaplan-Meier curves revealed a poorer prognosis, including all-cause death and HF events (death, readmission-HF), in Group 5 and Group 4 than in the other groups, in Group 3 than in Group 2 or Group 1, and in Group 2 than in Group 1.The new scoring system including MAP, pulse, sodium, potassium, hematocrit, creatinine, age, and GCS (APACHE-HF) can be used to predict adverse outcomes of AHF.

Cognitive impairment is common in patients underwent transcatheter aortic valve implantation (TAVI) and might affect procedure outcomes. This study evaluated the incidence of preprocedural cognitive impairment and its impact on clinical outcomes after TAVI. We analyzed the data of 1,111 patients (age ≥70 years) obtained from the Optimized CathEter vAlvular iNtervention (OCEAN-TAVI) registry. The cognitive performance of all patients was assessed using the Mini-Mental State Examination (MMSE) at baseline. We evaluated the 1-year cumulative mortality after TAVI according to the MMSE performance. Cognitive impairment was present in 420 (38%) of 1,111 patients. Compared with patients with normal cognition, those with cognitive impairment showed higher cumulative all-cause and noncardiovascular mortality rates at 1 year (14% vs. 8%, p = 0.001; 11% vs. 5%, p <0.001, respectively). Moreover, cognitive impairment increased the risk of mortality from sepsis (2% vs. 0.4%; hazard ratio, 4.2; 95% confidence interval, 1.3 to 13.5; p = 0.02). In adjusted models, cognitive impairment was an independent risk factor for 1-year all-cause mortality (adjusted hazard ratio, 2.1; 95% confidence interval, 1.1 to 4.0; p = 0.02). Although patients with cognitive impairment had more in-hospital adverse outcomes, including prolonged hospital stays, major bleeding and vascular complications, and acute kidney injury, than did those with normal cognition, the 30-day mortality was similar between the groups (1% in the two groups; p >0.99). In conclusion, cognitive impairment based on the MMSE score was an independent predictor of mortality at 1 year after TAVI.

The Valve Academic Research Consortium-2 has defined body mass index (BMI) <20 as indicative of frailty, which may be one of the co-morbidities not captured by traditional risk factors after transcatheter aortic valve replacement (TAVR). This study aimed to assess the impact of low BMI on clinical outcomes after TAVR. A total of 777 consecutive patients scheduled for TAVR were classified into 3 groups as BMI <20 (n = 56), 20 to 24.9 (n = 322), and ≥25 (n = 399). Procedural complications and clinical outcomes were compared among the 3 groups. They were also analyzed according to propensity-matching model A (BMI <20 [n = 50] vs ≥20 [n = 50]), model B (BMI <20 [n = 50] vs 20 to 24.9 [n = 50]), and model C (BMI <20 [n = 47] vs ≥25 [n = 47]). The differences in baseline characteristics among the 3 groups were adequately adjusted in 3 matched models. Valve Academic Research Consortium-2-defined end points and other complications were similar among the 3 groups in each model. Kaplan-Meier curves indicated no significant differences in cumulative 30-day survival (BMI <20 [91.0%] vs 20 to 24.9 [86.3%], p = 0.33; BMI <20 [91.0%] vs ≥25 [91.4%], p = 0.91, respectively) and 1-year survival (BMI <20 [74.3%] vs 20 to 24.9 [71.8%], p = 0.71; BMI <20 [74.3%] vs ≥25 [77.0%], p = 0.71; respectively). These survival rates were also similar in each of the 3 matched models. In conclusion, BMI <20 was not associated with increased early or midterm mortality. BMI <20 alone may not constitute an additional co-morbidity factor in patients who underwent TAVR.

Deep sternal wound infection (DSWI), especially in patients with diabetes mellitus (DM), is a major concern after coronary artery bypass grafting (CABG) with bilateral internal mammary artery (BIMA) grafts. We evaluated the risk of DSWI and other clinical outcomes between continuous insulin infusion therapy (CIT) and insulin sliding scale therapy (IST) in a cohort of DM patients who underwent CABG with BIMA. The clinical records of DM patients who underwent isolated CABG with BIMA were retrospectively reviewed. The study population consisted of 95 patients who received CIT and 126 patients who received IST. Furthermore, a one-to-one matched analysis based on estimated propensity scores for patients who received CIT or IST yielded two groups comprising 58 patients each. The proportion of patients with DSWI, overall survival rates and major adverse cardiac events were compared between the two groups in the overall and the propensity-matching cohort. The prevalence of DSWI requiring debridement and closure was significantly reduced in the CIT group compared with that in the IST group [1/95 (1.1%) vs 9/126 (7.1%), P = 0.031]; these results were not attenuated even after propensity-matching analysis [0/58 (0%) vs 6/58 (10.3%), P = 0.031]. The mean preoperative glucose levels were similar between the two groups (157.5 ± 54.6 vs 176.1 ± ±70 mg/dl, P = 0.063), whereas the mean glucose values were significantly lower on the first and second operative days in the CIT group than in the IST group (132.9 ± 44.1 vs 197.8 ± 78.6 mg/dl, P < 0.0001; 153.5 ± 58.8 vs 199.6 ± 89.1 mg/dl, P < 0.0001, respectively). The glucose variability levels within 24 h postoperatively were significantly higher in the IST group (46.1 ± 19.4 vs 66.4 ± 26.8 mg/dl, P < 0.0001). The 30-day and 1-year survival rates were similar between the two groups (100 vs 99.2%, P = 0.384; 96.6 vs 94.4%, P = 0.454). No results were changed in the propensity-matching models. The CIT approach reduced the variability in glucose concentration and resulted in fewer instances of DSWI after CABG with BIMA grafts.

Background There are limited data regarding the influence of liver dysfunction on outcomes of transcatheter aortic valve implantation (TAVI). Model for End-stage Liver Disease eXcluding International normalized ratio (MELD-XI) score, which was originally developed for patients with cirrhosis awaiting liver transplantation, has been reported as a predictor of heart disease. The aim of this study was to investigate the prognostic value of MELD-XI score for patients undergoing TAVI. Methods Data from the prospectively maintained Optimized transCathEter vAlvular iNtervention (OCEAN-TAVI) multicenter registry were collected in 749 patients who underwent TAVI between October 2013 and August 2015. MELD-XI score was calculated as follows: 11.76 × Ln (creatinine) + 5.11 × Ln (total bilirubin) + 9.44. Patients were categorized based on MELD-XI score > 10 or ≤10, and compared with regard to clinical characteristics and outcomes of TAVI. Results Higher MELD-XI score was associated with lower 30-day survival (95.6% vs 98.5%, P = 0.03). Kaplan–Meier analysis revealed that higher MELD-XI score also was associated with lower 6-month survival (P < 0.01). Multivariate Cox regression analysis showed that MELD-XI score was an independent predictor of 6-month cumulative mortality. Receiver operating characteristic analysis revealed that MELD-XI score showed better accuracy in predicting 6-month mortality compared with Logistic European System for Cardiac Operative Risk Evaluation, European System for Cardiac Operative Risk Evaluation II, and Society of Thoracic Surgeons scores (area under the curve = 0.67, 0.58, 0.57, and 0.60, respectively). Conclusion Evaluation of liver dysfunction according to MELD-XI score provides additional risk information for patients undergoing TAVI.

A cDNA encoding lebocin, a novel member of insect antibacterial peptides, was isolated from the fat body cDNA library of Bombyx mori larvae immunized with Escherichia coli. The cDNA was 844 bp long and had an open reading frame (ORF) containing a probable signal peptide (16 amino acids), a putative prosegment (104 amino acids) and a mature peptide (32 amino acids) followed by 27 additional amino acids at its carboxyl-terminus. Northern blot analysis showed that lebocin gene expression was inducible by bacterial injection, occured tissue-specifically in the fat bodies and continued at least for 48 h post-infection. These results suggest that lebocin has a unique precursor structure and shows typical gene expression pattern as insect antibacterial peptide.

To determine whether mast cell blocker (tranilast) improves fertility and/or semen parameters in severe oligozoospermia. Placebo-controlled single-blind clinical study. Nagoya University Hospital Andrology Clinic, Nagoya, Japan. Fifty men with sperm density < 5 × 106 sperm/mL, normal serum gonadotropins, and T, and a fertile partner were enrolled in this study. Patients were prescribed randomly 300 mg/d tranilast or a placebo, three tablets per day, for 3 months. Semen and blood samples were collected before and after therapy. Semen parameters, serum gonadotropins, T, and PRL were evaluated before and after therapy. The pregnancy rate (PR) in the mast cell blocker group was 28.6% compared with 0% in the placebo group. There was a statistical difference in the PR between groups. The mast cell blocker group had significantly higher levels of sperm density, sperm motility, and total motile sperm count. There were no differences between the mast cell blocker and placebo groups in seminal volume and normal sperm morphology. The authors conclude that mast cell blocker is clinically useful for the treatment of idiopathic severe Oligozoospermic men.

Thin cap fibroatheroma (TCFA) is considered to be a vulnerable plaque. Virtual Histology-intravascular ultrasound (VH-IVUS) can precisely identify TCFA in vivo. Intense yellow plaque on angioscopy determined by quantitative colorimetry with L a b color space corresponds with histological TCFA; in particular, a plaque of color b value >23 indicates an atheroma with a fibrous cap thickness <100 mum. In the present study, the relationship between VH-TCFA and angioscopic plaque color determined by colorimetry was investigated.Fifty-seven culprit plaques in 57 patients were evaluated by VH-IVUS and angioscopy. VH-TCFA was defined as a plaque with a necrotic core >10% of plaque area without overlying fibrous tissue, and angioscopic TCFA was a plaque with b value >23. The frequency of angioscopic TCFA was higher in the VH-TCFA group than in the VH-non-TCFA group (74% vs 23%, P=0.0002). Moreover, yellow color intensity (b value) significantly correlated with plaque classification on VH-IVUS. When TCFA detected with angioscopy was used as the gold standard, the sensitivity, specificity, and accuracy for TCFA with VH-IVUS was 68%, 81%, and 75%, respectively.VH-TCFA strongly correlated with angioscopic TCFA determined by a quantitative analysis with colorimetry.

Background Although several clinical trials have shown the superior efficacy and safety of second-generation everolimus-eluting stents (EES) in comparison with first-generation paclitaxel-eluting stents (PES), the differences in the vascular healing process between EES and PES in a human coronary artery during an early stage are unknown. Methods A prospective optical coherence tomography (OCT) observation was performed for 25 EES in 21 patients and 27 PES in 21 patients at 6 months after implantation. Cross-sections within single-stent segments were analyzed at intervals of 1 mm. The neointimal (NI) thickness on each strut was measured. Uncovered struts (NI thickness=0 μm), malapposed struts, NI area (%), uncovered strut ratio >0.3 (UCSR; number of uncovered struts/number of total struts) per cross-section, and in-stent thrombus were evaluated. Results A total of 5198 EES struts in 514 cross-sections and 4243 PES struts in 469 cross-sections were identified. NI thickness and its area were smaller for EES than PES (80.0±84.8 μm vs. 117.9±140.0 μm and 19.1±8.9% vs. 23.7±11.5%, respectively; P<0.001). The frequencies of uncovered struts and malapposed struts were lower in EES compared to PES (2.3% vs. 5.2% and 2.1% vs. 5.7%, respectively; P<0.001). Patients who had cross-sections of UCSR >0.3 and thrombi were identified less frequently in EES than in PES group (5% vs. 57%; P<0.001, and 19% vs. 48%; P=0.05, respectively). Conclusions Six-month OCT examination showed a favorable vessel healing response after the implantation of EES, demonstrating less in-stent late loss as well as fewer uncovered struts and better stent apposition to the vessel wall in comparison with PES.

Transcatheter aortic valve implantation (TAVI) has been reported to be advantageous over surgical aortic valve replacement owing to the low incidence of prosthesis-patient mismatch (PPM) and large effective orifice area (EOA). However, data on TAVI for extremely small annuli are limited. The present study aimed to compare post-procedural hemodynamics and morphology between 20-mm and 23-mm Sapien XT (SXT) transcatheter heart valves (THVs) with extremely small annuli (<314mm2).All patients with severe aortic stenosis treated with TAVI at eight Japanese centers between October 2013 and January 2016 were prospectively included in the Optimized CathEter vAlvular iNtervention (OCEAN-TAVI) registry. In the overall cohort of 20-mm (19 patients) and 23-mm SXTs (492 patients) with extremely small annuli, the patient groups were matched one-to-one using propensity scores, and post-procedural echocardiography and multidetector computed tomography data were compared for 18 matched patients from each group (matched cohort).In the matched cohort, the mean gradient was higher (15.4±4.1 vs. 12.2±4.8mmHg, p=0.04), EOA was lower (1.22±0.25 vs. 1.44±0.37cm2, p=0.02) and THV area was lower (245.6±19.1 vs. 298.5±33.3mm2, p<0.01) in the 20-mm group than in the 23-mm group. However, all patients in both groups were asymptomatic. Although moderate PPM was more prevalent in the 20-mm group than in the 23-mm group (31.6% vs. 7.9%, p<0.01), the incidence of severe PPM was low and similar between the groups (0% vs. 0.4%, p=1.00) in the overall cohort.A 20-mm SXT in patients who require a small bioprosthesis leads to favorable short-term outcomes.

This study aimed to compare the clinical outcomes of patients undergoing transfemoral transcatheter aortic valve implantation (TAVI) via a percutaneous or surgical cut-down approach.Between October 2013 and July 2015, 586 patients underwent transfemoral TAVI according to the Optimized CathEter vAlvular iNtervention (OCEAN)-TAVI registry (percutaneous approach, n=305; surgical cut-down approach, n=281). After propensity matching, 166 patients underwent transfemoral TAVI via each approach. Major vascular complications, as defined per the Valve Academic Research Consortium-2 criteria, were found less frequently in patients who underwent a percutaneous approach (15.1% vs. 27.1%, p<0.01), and femoral artery injuries requiring surgical repair were mostly the result of a closure device failure (seven cases, 4.2%). In these patients, major bleeding was less (7.2% vs. 16.9%, p=0.01) and blood transfusion less frequent (21.1% vs. 38.0%, p<0.01); therefore, cases of acute kidney injury (AKI) were rare (6.0% vs. 15.1%, p<0.01).Transfemoral TAVI using the percutaneous approach proved safe and feasible and resulted in fewer major vascular complications, bleeding and AKI events compared to the surgical cut-down approach.

Current guidelines recommend dual antiplatelet therapy for the first 1 to 6 months after transcatheter aortic valve replacement (TAVR); however, recent studies have reported better outcomes with single antiplatelet therapy than with dual antiplatelet therapy in the occurrence of bleeding events, while not increasing thrombotic events. However, no data exist about optimal single antiplatelet therapy following TAVR.Patients who underwent TAVR between October 2013 and May 2017 were enrolled from the OCEAN-TAVI Japanese multicenter registry (Optimized Transcatheter Valvular Intervention). After excluding 1759 patients, 829 who received aspirin (100 mg/d) or clopidogrel (75 mg/d) after TAVR were identified and stratified according to the presence or absence of anticoagulation. Propensity score matching was performed to adjust the baseline characteristics between the aspirin and clopidogrel groups. Outcomes of interest were all-cause and cardiovascular deaths, stroke, and life-threatening or major bleeding within 2 years following TAVR.After propensity score matching, 98 and 157 pairs of patients without and with anticoagulation, respectively, were identified. Falsification end points of pneumonia, urinary tract infection, and hip fracture were evaluated, and their rates were not different between groups. All-cause deaths were not statistically different between the groups in patients with (aspirin, 17.5%; clopidogrel, 11.1%; log-rank P=0.07) and without (aspirin, 29.6%; clopidogrel, 20.1%; log-rank P=0.15) anticoagulation at 2 years post-TAVR, whereas clopidogrel was associated with a lower cardiovascular mortality at 2 years in patients with (aspirin, 8.5%; clopidogrel, 2.7%; log-rank P=0.03) and without (aspirin, 18.0%; clopidogrel, 5.2%; log-rank P=0.02) anticoagulation.We demonstrated that clopidogrel monotherapy was associated with a lower incidence of cardiovascular death compared with aspirin monotherapy during the 2-year follow-up after TAVR regardless of anticoagulation use.URL: https://upload.umin.ac.jp; Unique identifier: UMIN000020423.

Background Limited data are available about clinical outcomes and residual mitral regurgitation (MR) after transcatheter edge-to-edge repair in the large Asian-Pacific cohort. Methods and Results From the Optimized Catheter Valvular Intervention (OCEAN-Mitral) registry, a total of 2150 patients (primary cause of 34.6%) undergoing transcatheter edge-to-edge repair were analyzed and classified into 3 groups according to the residual MR severity at discharge: MR 0+/1+, 2+, and 3+/4+. The mortality and heart failure hospitalization rates at 1 year were 12.3% and 15.0%, respectively. Both MR and symptomatic improvement were sustained at 1 year with MR ≤2+ in 94.1% of patients and New York Heart Association functional class I/II in 95.0% of patients. Compared with residual MR 0+/1+ (20.4%) at discharge, both residual MR 2+ (30.2%; P < 0.001) and 3+/4+ (32.4%; P = 0.007) were associated with the higher incidence of death or heart failure hospitalization (adjusted hazard ratio [HR], 1.59; P < 0.001, and adjusted HR, 1.73; P = 0.008). New York Heart Association class III/IV at 1 year was more common in the MR 3+/4+ group (20.0%) than in the MR 0+/1+ (4.6%; P < 0.001) and MR 2+ (6.4%; P < 0.001) groups, and the proportion of New York Heart Association class I is significantly higher in the MR 1+ group (57.8%) than in the MR 2+ group (48.3%; P = 0.02). Conclusions The OCEAN-Mitral registry demonstrated favorable clinical outcomes and sustained MR reduction at 1 year in patients undergoing transcatheter edge-to-edge repair. Both residual MR 2+ and 3+/4+ after transcatheter edge-to-edge repair at discharge were associated with worse clinical outcomes compared with residual MR 0+/1+. Registration Information https://upload.umin.ac.jp. Identifier: UMIN000023653.

The experiments reported here demonstrate for the first time that the isolated human seminiferous tubule is capable of undergoing contraction after exposure to noradrenaline and acetylcholine. Isoproterenol produces a relaxation of the seminiferous tubule. It is indicated that there are the adrenergic alpha and beta receptors and muscarinic receptors in the myoid cells of human seminiferous tubules.

To evaluate the effects of ligature of the internal spermatic artery at varicocelectomy on fertility, we conducted a prospective randomized study for comparison of two surgical methods (artery-ligated and artery-preserved). A total of 66 infertile patients with palpable varicocele was randomly assigned to an artery-ligated or artery-preserved group at varicocelectomy and the change in seminal characteristics and testis volume was prospectively investigated. Sperm density and motility improved significantly in the artery-ligated group. There was significant improvement in sperm density in the artery-preserved group, but motility did not reach the level of statistical significance in this group. The significant change in testis volume was not observed in both groups. Seven (23.3%) of 30 patients in the artery-ligated group and 5 (13.9%) of 36 men in the artery-preserved group managed to impregnate their partners. The difference was not statistically significant. In spite of the advocative advantage of artery preservation, our present study did not show any significant difference between artery-ligating and artery-preserving varicocelectomy when improvements in semen quality and pregnancy rate were assessed. Thus, artery-ligated varicocelectomy is warranted with regard to post-operative fertility in the patients with clinical varicocele.

Progression of neointimal stent coverage (NSC) and changes in thrombus were evaluated serially by coronary angioscopy for up to 2 years after sirolimus-eluting stent (SES) implantation.Serial angioscopic observations were performed in 20 segments of 20 patients at baseline, and at 6 months and 2 years after SES implantation. NSC was classified as follows: 0, uncovered struts; 1, visible struts through thin neointima; or 2, no visible struts. In each patient, maximum and minimum NSC was evaluated. Existence of thrombus was also examined.The maximum NSC increased from 6 months to 2 years (1.2 (0.4) vs 1.8 (0.4), respectively, p = 0.005), while the minimum NSC did not change (0.7 (0.5) vs 0.8 (0.4), respectively, p = 0.25). The prevalence of patients with uncovered struts did not decrease from 6 months to 2 years (35% vs 20%, respectively, p = 0.29). Although there were no thrombus-related adverse events, new thrombus formation was found in one patient (5%) at the 6-month, and in four patients (20%) at the 2-year follow-up evaluations. Frequencies of thrombus inside the SES at baseline, 6 months and 2 years did not differ one from another (40%, 40% and 30%, respectively; p = NS).Neointimal growth inside the SES progressed heterogeneously. Uncovered struts persisted in 20% of the patients for up to 2 years and subclinical thrombus formation was not a rare phenomenon.

It recently has been hypothesized that a larger late loss may have a protective role against stent thrombosis. The relationship between angiographic late loss and the presence of thrombus based on angioscopic findings within paclitaxel-eluting stents (PES) and sirolimus-eluting stents (SES) was investigated in this study.Prospective 6-month follow-up angiographic and angioscopic examinations were performed on 18 patients for PES and on 20 patients for SES. Late loss was measured by quantitative coronary angiography. Angioscopic neointimal stent coverage (NSC) grade was classified as follows: 0=uncovered struts without neointima, 1=visible struts through thin neointima, and 2=no visible struts. In each patient, maximum NSC, minimum NSC, and the existence of thrombus were evaluated. Late loss and maximum NSC were greater in PES than in SES (0.38+/-0.43 versus 0.10+/-0.23 mm; P=0.02 and P=0.0004, respectively). Late loss was correlated with maximum NSC (grade 0, 0.06+/-0.01 mm; grade 1, 0.10+/-0.05 mm; and grade 2, 0.48+/-0.46 mm), whereas there was no correlation between late loss and minimum NSC. The prevalence of patients with uncovered struts did not differ (44% of PES, 40% of SES; P=0.78). In-stent thrombus was found more frequently in PES than in SES (72% versus 40%, P=0.046) despite no occurrence of stent thrombosis. Only within PES were thrombi found in the segments of NSC grade 2 associated with large late loss.The present study suggests that angiographic large late loss was not associated with a low risk of in-stent thrombus.

There is a hypothesis that advanced neointimal stent coverage may protect against stent thrombosis. In the present study, differences in neointimal growth and prevalence of in-stent thrombus between paclitaxel- and sirolimus-eluting stent (PES and SES) were evaluated by optical coherence tomography (OCT).Follow-up angiographic and OCT examinations at approximately 6 months were performed for 40 patients (20 PES, 20 SES). Late loss was measured by quantitative coronary angiography. Neointimal hyperplasia (NIH) thickness on stent struts was measured by cross-sectional OCT images at 1 mm intervals. After measuring the NIH area in each cross-section, NIH volume was calculated as integral of NIH area within the stent. Late loss, NIH thickness, and NIH volume were greater for PES than for SES (0.42 +/-0.44 vs 0.13 +/-0.12 mm, 118 +/-141 vs 31 +/-39 mum, 53.2 +/-30.5 vs 24.3 +/-14.0 mm(3); P<0.05, respectively). In-stent thrombus was found more frequently in PES than in SES (50 vs 15%; P=0.02).Although the degree of neointimal growth in PES was generally greater, in-stent thrombus was more common compared with SES. Presence of thrombus in first-generation drug-eluting stents was not related to advanced neointimal growth.

The AngioSculpt scoring balloon catheter (AngioScore, Inc., Fremont, California) has recently been developed for percutaneous intervention in coronary and peripheral arteries. This device is composed of two major components, a minimally compliant balloon and three nitinol wore. The three wires encapsulate the low-compliant balloon in a spiral configuration. The concept is for the spiral wires to score the lumen surface during balloon expansion. However, the precise mechanisms and efficacy of this scoring technology in humans had not yet to be determined. In this case, both a de novo coronary lesion and an in-stent restenosis lesion were treated with the scoring balloon and were subsequently observed via optical coherence tomography (OCT) with high-resolution images ( approximately 15 microm). OCT clearly demonstrated the effects of this device on plaque and neointimal hyperplasia scoring, as well as its ability to achieve sufficient lumen sizes after coronary artery dilatation.

Background: The association between elevated malondialdehyde-modified low-density lipoprotein (MDA-LDL) and plaque instability in patients with coronary artery disease (CAD) is suspected but not established. The aim of the present study was therefore to investigate the association between serum MDA-LDL and plaque characteristics on angioscopy. Methods and Results: A total of 37 consecutive patients with CAD and single-vessel disease who underwent pre-interventional angioscopy, were studied. Using angioscopy at the target lesions, the presence of yellow plaque and complex plaque was examined. Moreover, we evaluated the yellow intensity, which has been shown to have an inverse correlation with the fibrous-cap thickness of the plaques, with quantitative colorimetry to identify a thin-cap atheroma. Serum MDA-LDL in patients with thin-cap atheroma diagnosed on quantitative colorimetry was significantly higher than in patients without thin-cap atheroma (P<0.0009). Univariate logistic regression indicated that serum MDA-LDL was a predictor for thin-cap atheroma (odds ratio [OR], 1.48; 95% confidence interval [CI]: 1.10–1.97; P=0.003) and for complex plaque (OR, 1.22; 95% CI: 1.00–1.48; P=0.046). On multivariate logistic regression serum MDA-LDL was the only independent predictor for thin-cap atheroma (OR, 1.48; 95% CI: 1.10–1.97; P=0.011). Conclusions: Using angioscopy and quantitative colorimetry, elevated MDA-LDL was confirmed to be associated with thin-cap atheroma in CAD patients. (Circ J 2012; 76: 2211–2217)

Transcatheter aortic valve replacement (TAVR) improves clinical symptoms in most patients with severe aortic stenosis (AS). However, some patients do not benefit from the symptom-reducing effects of TAVR. We assessed the predictors and clinical outcomes of poor symptomatic improvement (SI) after TAVR.A total of 1749 patients with severe symptomatic AS undergoing transfemoral TAVR were evaluated using the Japanese multicentre TAVR registry. Poor SI was defined as readmission for heart failure (HF) within 1 year after TAVR or New York Heart Association (NYHA) class ≥3 after 1 year. A logistic regression model was used to identify predictors of poor SI. One-year landmark analysis after TAVR was used to evaluate the association between poor SI and clinical outcomes.Among the overall population (mean age, 84.5 years; female, 71.3%; mean STS score, 6.3%), 6.6% were categorised as having poor SI. Atrial fibrillation, chronic obstructive pulmonary disease, Clinical Frailty Scale ≥4, chronic kidney disease and moderate to severe mitral regurgitation were independent predictors of poor SI. One-year landmark analysis demonstrated that poor SI had a higher incidence of all-cause death and readmission for HF compared with SI (p<0.001). Poor SI with preprocedural NYHA class 2 had a worse outcome than SI with preprocedural NYHA class ≥3.Poor SI was associated with worse outcomes 1 year after the procedure. It had a greater impact on clinical outcomes than baseline symptoms. TAVR may be challenging for patients with many predictors of poor SI.This registry, associated with the University Hospital Medical Information Network Clinical Trials Registry, was accepted by the International Committee of Medical Journal Editors (UMIN-ID: 000020423).

Two genomic DNAs encoding cecropin B (CecB), an antibacterial protein from Bombyx mori, were cloned and sequenced. The number of CecB genes was estimated to be more than four copies per haploid by genomic Southern blotting. Two genes, CecB1 and CecB2, were located tandemly within 12 kb in the same orientation. These two genes encoded identical amino acids, though 15 nucleotides (nt) were different in the coding region and the intron size varied. About 90% of the nt spanning 800 by in the 5′-untranslated region (UTR) were identical between the two genes. This 5′-flanking region contained characteristic sequences such as a repetitive element of B. mori (Bml), an interleukin-6 response element (IL-6 RE), and two putative lipopolysaccharide (LPS) response elements (LPS RE). An electrophoretic mobility shift assay (EMSA) showed that the fat body contains at least three different nuclear proteins inducible by bacteria which bind to the 5′-UTR, suggesting that these proteins may be involved in CecB expression triggered by bacteria.