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Background: Tricuspid valve (TV) geometry gained attention when the prognostic significance of tricuspid regurgitation (TR) was determined. However, the TV geometric characteristics in Barlow disease (BD) have not been elucidated. This study aimed to clarify the difference in TV morphology between BD and fibroelastic deficiency (FED) and the effect of its geometry on residual TR after tricuspid annuloplasty (TAP) using three-dimensional (3D) transesophageal echocardiography., Methods: Based on the mitral valve (MV) morphology defined by 3D transesophageal echocardiography, 106 patients with degenerative MV disease were classified into BD (n = 42) and FED (n = 64). Three-dimensional images of the TV were analyzed using a quantification software to compare the geometrical parameters. Among them, 35 patients (17 with BD and 18 with FED) underwent concomitant TAP during MV surgery, and the residual TR after TAP was evaluated within 1 month., Results: TV annulus area, billowing height, and billowing volume were greater in BD than in FED (10.8 ± 2.9 vs 9.2 ± 2.4 cm 2 , 4.6 ± 1.6 vs 2.3 ± 1.1 mm, and 1.3 ± 0.8 vs 0.3 ± 0.3 mL; all P < .01). In contrast, TV tenting height and tenting volume were smaller in BD than in FED (2.6 ± 1.5 vs 4.4 ± 2.4 mm and 0.3 ± 0.4 vs 0.9 ± 1.0 mL; both P < .01). These morphologic differences in TV were similar to those in MV. There was a strong correlation between MV billowing volume and TV billowing volumes (R = 0.83, P < .01). The prevalence of significant residual TR after TAP was greater in BD than in FED (35% vs 0%, P < .01). Moderate correlations between TV billowing height and volume and residual TR after TAP were observed (R = 0.47 and 0.49, respectively, both P < .01)., Conclusions: Patients with BD exhibited larger TV annulus area and billowing than FED patients. These results suggest that degenerative changes in the TV apparatus in BD patients are similar to that seen in the MV apparatus. These findings should be taken into consideration when a TV surgery is required., (Copyright © 2020 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Clinical outcomes after percutaneous coronary intervention (PCI) for severely calcified lesions remain poor. The purpose of this study was to investigate the neointimal response after everolimus-eluting stents (EES) for severely calcified lesions treated with rotational atherectomy (RA) using optical coherence tomography (OCT).We retrospectively analyzed 34 lesions in which PCI was performed with EES deployment following RA and OCT was performed immediately after PCI and at follow-up (nine months). The EES was either durable-polymer (DP) EES (22 lesions) or bioabsorbable polymer (BP) -EES (12 lesions). Strut coverage and malapposition were evaluated at 1-mm intervals of cross-section (CS) by serial OCT analysis. Malapposed strut was defined as having the distance from luminal border > 100 μm.A total of 11,823 struts immediately after PCI and 11,720 struts at follow-up were analyzed. Immediately after PCI, the strut-level analysis showed no significant differences in the percentage of malapposed struts between the DP-EES group and the BP-EES group. At follow-up, the BP-EES group showed a more prevalent covered strut compared with the DP-EES group (strut-level analysis: 95% versus 97%, P = 0.045; CS-level analysis: 97% versus 100%, P < 0.01; lesion-level analysis: 27% versus 83%, P < 0.01, respectively).In severely calcified lesions requiring RA, the BP-EES group achieved better neointimal coverage than the DP-EES group at nine months. Additional prospective studies are needed.

Objective: This study aimed to assess the sex differences in clinical presentation and outcomes of Japanese patients with ruptured aortic aneurysm (rAA) using a large nationwide claims-based database in Japan., Methods: We identified patients hospitalized in certified teaching hospitals in Japan with rAA between April 1, 2012, and March 31, 2015. Patients' characteristics and in-hospital outcomes were compared between men and women. The Barthel index was used for evaluating functional status at discharge by examining the ability to perform basic daily activities., Results: Of 7086 eligible patients, 32.3% (2291/7086) were women. Women were older than men (81.9 years vs 76.1 years; P < .001), had higher prevalence of coma at admission (33.2% vs 25.2%; P < .001), and were less likely to undergo emergency operation including endovascular aneurysm repair (35.7% vs 51.1%; P < .001). The unadjusted mortality rate (62.5% vs 52.0%; P < .001) and Barthel index at discharge (78.7 vs 86.1; P < .001) were significantly worse in women than in men. However, multilevel mixed-effect logistic regression analyses showed that female sex itself was not an independent predictor for in-hospital death (odds ratio [OR], 0.90; 95% confidence interval [CI], 0.78-1.04; P = .17). Older age, coma at admission, and vasopressor use were detected as independent predictors for in-hospital death. The same results were confirmed for each rupture site. Stratified analyses showed that older women (threshold, 80 years; OR, 0.81; 95% CI, 0.66-0.98; P = .028) and those who underwent emergency operation (OR, 0.75; 95% CI, 0.61-0.93; P = .009) showed significantly better outcomes than men., Conclusions: In a univariate analysis, female patients with rAA showed worse mortality than men because of their older age, more severe clinical presentation, and low emergency operation rate. However, after adjustment for covariates, female sex itself was not associated with increased mortality., (Copyright © 2019 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Stenting for severely calcified lesions has a higher risk of stent restenosis or stent failure than stenting for lesions without calcification, and stenting for complex lesions including ostial or bifurcation lesions sometimes causes plaque shift which leads to side branch occlusion. A calcified nodule (CN) is considered one of the culprits for stable angina or acute coronary syndrome. However, the optimal strategy for this lesion is not well clarified. We report a patient who presented stable angina with a CN at the ostial left circumflex artery. In this case, pretreatment with excimer laser coronary atherectomy (ELCA) and scoring balloon dilatation followed by drug-coated balloon (DCB) dilatation successfully prevented plaque shift caused by stenting in the acute phase. In addition, it also maintained the patency in the late phase. Furthermore, we observed the CN lesions at preprocedural, postprocedural, and late phase by optical coherence tomography. ELCA, which has a unique debulking technique, and scoring balloon dilatation followed by DCB dilatation might offer an alternative treatment for ostial CN lesions instead of stenting. 〈 Learning objective: The optimal strategy for severely calcified lesions with calcified nodule is controversial because the prevalence of calcified nodule is rare and stent failure is more common in calcified lesions. In particular, regarding a calcified nodule located in ostial left circumflex coronary artery lesion, excimer laser coronary atherectomy and scoring balloon dilatation followed by drug-coated balloon may give an alternative treatment to avoid stenting.〉., (© 2020 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Rationale and Objectives: We have developed a technique to measure ventilation heterogeneity (VH) on low dose chest CT scan that we hypothesize may be associated with the development of lung nodules, and perhaps cancer. If true, such an analysis may improve screening by identifying regional areas of higher risk., Materials and Methods: Using the National Lung Screening Trial database, we identified a small subset of those participants who were labeled as having a positive screening test at 1 year (T1) but not at baseline (T0). We isolated the region in which the nodule would form on the T0 scan ("target region") and measured VH as the standard deviation of the linear dimension of a virtual cubic airspace based on measurement of lung attenuation within the region., Results: We analyzed 24 cases, 9 with lung cancer and 15 with a benign nodule. We found that the VH of the target region was nearly statistically greater than that of the corresponding contralateral control region (0.168 [0.110-0.226] vs. 0.112 [0.083-0.203], p = 0.051). The % emphysema within the target region was greater than that of the corresponding contralateral control region (1.339 [0.264-4.367] vs. 1.092 [0.375-4.748], p = 0.037). There was a significant correlation between the % emphysema and the VH of the target region (rho = +0.437, p = 0.026)., Conclusion: Our study provides the first data in support of increased local VH being associated with subsequent lung nodule formation. Further work is necessary to determine whether this technique can enhance screening for lung cancer by low dose chest CT scan., (Copyright © 2019 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) and hypertrophic cardiomyopathy (HCM) implanted with implantable cardioverter-defibrillators (ICDs) may show a large decrease in R-wave amplitude during long-term follow-up. However, it is unclear whether this decrease is higher in these patients than in those without structural heart disease. This study investigated ICD-lead intracardiac parameters over a long duration in patients with ARVC and HCM and compared these parameters with those of a control group. We included 50 patients (mean age, 55.2 ± 17.2 years; 26% female) with ICD leads in the right ventricular apex, and compared 7 ARVC and 14 HCM patients with 29 control patients without structural heart disease. ICD-lead parameters, including R-wave amplitude, pacing threshold, and impedance during follow-up, were compared. The difference in these parameters between the time of implantation and year 5 were also compared. There were no significant differences in R-wave amplitude at implantation among the 3 groups. The change in R-wave amplitude between the time of implantation and year 5 was significantly greater in the ARVC group (-3.3 ± 5.4 mV, P = 0.012) in comparison to the control group (1.3 ± 2.8 mV); the HCM group showed no significant difference (-0.4 ± 2.3 mV, P = 0.06). Thus, in the ARVC group, R-wave amplitude at year 5 was significantly lower than that in the control group (5.7 ± 4.8 mV versus 12.5 ± 4.5 mV, P = 0.001). In ARVC patients with ICDs, ventricular sensing is likely to deteriorate during long-term follow-up; however, in HCM patients, sensing may not deteriorate.

The latest chemical management policies require toxicological evaluation of marketed but untested chemicals. Furthermore, in Europe, for animal welfare reasons sales of cosmetics and raw materials for which animal experiments were conducted were totally banned, in 2013. Responding to these regulatory trends, a strong demand exists to develop new in vitro test methods and to improve in silico prediction models for safety assessments. In recent years, the development of adverse outcome pathways (AOPs) has been actively promoted in the Organisation for Economic Co-operation and Development (OECD). Since it is difficult to replace a particular in vivo animal test with a single in vitro test method or in silico prediction model, integrated approaches to testing and assessment (IATA) have been studied based on AOP information. With regard to skin sensitization, several in vitro test methods that measure key events of AOP have been established, and integrated strategies using in vitro tests have been examined using AOP. Currently, numerous AOPs are under development for a wide range of complex toxicity endpoints in the OECD AOP program. The AOPs are expected to contribute to the development of many accurate in vitro test methods and to establish IATA as well as to evaluate safety in humans of many substances, including household chemicals, food-related chemicals, cosmetics, and pharmaceuticals.

Excimer laser coronary angioplasty (ELCA) is a unique revascularization modality that can vaporize plaque and thrombus. Compared to thrombus aspiration therapy, ELCA is reported to provide better microcirculation and reduced peripheral embolism in treatment for acute coronary syndrome. Excimer laser catheters come in various sizes, and we sought to compare the 0.9- and 1.4-mm-diameter catheters. We retrospectively enrolled 90 acute myocardial infarction (AMI) patients who underwent primary percutaneous coronary intervention with excimer laser from August 2013 to March 2017 in our hospital. Patients were grouped by diameter of catheter that had been used, the 0.9 mm group (n = 51) and 1.4 mm group (n = 39). We evaluated myocardial perfusion, procedural success rate, short-term outcome, lesion crossability, and complications between the two groups. The percentage of patients whose final thrombolysis in myocardial infarction (TIMI) grade was 3 (0.9 mm 86.3% vs 1.4 mm 89.7% p = 0.75) and final myocardial blush grade (MBG) was 3 (0.9 mm 72.5% vs 1.4 mm 69.2% p = 0.82) was similarly high for both groups. Procedural success rate, in-hospital major adverse cardiac events (MACE), lesion crossability, and complications were also similar. This study showed that efficacy of 0.9 and 1.4 mm excimer laser catheter was equivalent in ELCA for AMI patients. If one takes into account lesion crossability, debulking effects, and the stunned platelets phenomenon, the 0.9 mm excimer laser catheter is sufficient for ELCA in AMI patients.

Mesenchymal stromal (stem) cells (MSCs) are increasingly demonstrated to ameliorate experimentally induced lung injuries through disease-specific anti-inflammatory actions, thus suggesting that different in vivo inflammatory environments can influence MSC actions. To determine the effects of different representative inflammatory lung conditions, human bone marrow-derived MSCs (hMSCs) were exposed to in vitro culture conditions from bronchoalveolar lavage fluid (BALF) samples obtained from patients with either the acute respiratory distress syndrome (ARDS) or with other lung diseases including acute respiratory exacerbations of cystic fibrosis (CF) (non-ARDS). hMSCs were subsequently assessed for time- and BALF concentration-dependent effects on mRNA expression of selected pro- and anti-inflammatory mediators, and for overall patterns of gene and mRNA expression. Both common and disease-specific patterns were observed in gene expression of different hMSC mediators, notably interleukin (IL)-6. Conditioned media obtained from non-ARDS BALF-exposed hMSCs was more effective in promoting an anti-inflammatory phenotype in monocytes than was conditioned media from ARDS BALF-exposed hMSCs. Neutralizing IL-6 in the conditioned media promoted generation of anti-inflammatory monocyte phenotype. This proof of concept study suggest that different lung inflammatory environments potentially can alter hMSC behaviors. Further identification of these interactions and the driving mechanisms may influence clinical use of MSCs for treating lung diseases.

BACKGROUND Previous case reports have shown that regardless of the etiology, multiple channel structures can be treated successfully by routine percutaneous coronary intervention. However, there are no general recommendations for intervention because multiple channel structures are complex and rarely diagnosed. CASE REPORT A 71-year-old male was admitted to our hospital due to bronchial pneumonia. After admission, the patient experienced acute decompensated heart failure. Coronary angiogram revealed 3 diseased vessels with heavy calcification. Although the patient's syntax score was high, we performed percutaneous coronary intervention (PCI) on each vessel based on his request and in consideration of his dementia. After PCI for the left circumflex and descending arteries, we performed PCI for the right coronary artery (RCA) using optical frequency domain imaging (OFDI). A multiple channel structure and calcified nodule were observed by OFDI. We performed rotational atherectomy (RA) on the RCA, and the 2 structures were ablated. After RA, we dilated the lesions with a scoring balloon and deployed a drug-eluting stent. CONCLUSIONS RA was effective in ablating partition walls of the multiple channel structure observed using OFDI.

Background: The long-term safety of first-generation drug-eluting stent (DES) in acute coronary syndrome (ACS) was controversial., Purpose: The purpose of this study was to establish 5-year real-world data regarding the long-term efficacy and safety of second-generation DES in Japanese patients with ACS., Methods: The Tokyo-MD PCI study is a multicenter, observational cohort study enrolling consecutive patients who underwent everolimus-eluting stent (EES) implantation. The 5-year clinical events were compared between the ACS group ( n  = 644) and the stable coronary artery disease (SCAD) group ( n  = 1255). The primary efficacy endpoint was ischemia-driven target lesion revascularization (TLR), and the primary safety endpoint was the composite of all-cause death or myocardial infarction (MI)., Results: The median follow-up duration was 5.4 years. The cumulative incidence of ischemia-driven TLR was similar between ACS and SCAD (1 year: 3.0% versus 2.7%; P =0.682, 1-5 years: 2.7% versus 2.9%; P =0.864). The cumulative incidence of all-cause death or MI within 1 year was significantly higher in ACS than in SCAD (7.4% versus 3.8%; P < 0.001); however, ACS did not increase the risk of all-cause death or MI after adjusting confounders (adjusted hazard ratio, 1.260; 95% confidence interval, 0.774-2.053; P =0.352). From 1 to 5 years, the cumulative incidence of all-cause death or MI was not significantly different between ACS and SCAD (11.6% versus 11.4%; P =0.706). The cumulative incidence of very late stent thrombosis was low and similar between ACS and SCAD (0.2% versus 0.2%; P =0.942)., Conclusion: This real-world registry suggested that EES has comparable long-term efficacy and safety in patients with ACS and SCAD., Competing Interests: The authors have no conflicts of interest with regard to this study., (Copyright © 2019 Shunji Yoshikawa et al.)

Background: Malnutrition is associated with a poor prognosis in heart failure, angina pectoris, and peripheral artery disease. However, the clinical importance of the preprocedural nutrition status of patients requiring pacemaker implantation (PMI) for bradycardia is unclear., Methods: We retrospectively enrolled 521 patients (median 79 years) who underwent their first PMI between January 1, 2012 and June 30, 2017. The nutrition status before implantation was assessed by the geriatric nutritional risk index (GNRI). The association between the preprocedural GNRI-based nutritional status and all-cause mortality was investigated., Results: GNRI-based high (GNRI <82) and moderate (GNRI 82 to <92) malnutrition status were found in 9.2% and 34.0%, respectively. During a median follow-up of 1178 days, 71 patients died. The mortality rate, which was analyzed using survival curves, was significantly stratified by the GNRI-based malnutrition status [high: 52.0% (25/48), moderate: 16.9% (30/177), low: 5.4% (16/296), p<0.001). On a multivariate Cox-proportional hazard analysis, GNRI-based high malnutrition status independently predicted all-cause death (hazard ratio: 4.49, 95% confidence interval: 2.59-7.80, p<0.001). A sensitivity analysis based on the controlling nutritional status score showed consistent results. On a receiver operating characteristic curve analysis, GNRI had a high predictive value for all-cause mortality (area under the curve, 0.78, 95% confidence interval: 0.72-0.84, p<0.001)., Conclusions: Preprocedural malnutrition was significantly associated with poor outcomes of patients who underwent PMI. Assessing the nutritional status in advance is important for risk stratification, and improving the nutritional status may be an option for managing these patients., (Copyright © 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Objective: The aim of the study was to investigate the impact of chronic kidney disease (CKD) on the 5-year clinical outcomes of everolimus-eluting stent (EES) implantation., Background: Recent studies have demonstrated the safety and efficacy of EES. However, limited information exists on the long-term clinical outcomes associated with CKD., Methods: The Tokyo-MD PCI study is a multi-center observational study designed to describe the clinical outcomes of unselected patients after EES implantation. In this subanalysis, patients on maintenance hemodialysis were excluded, and patients with (n = 316) or without (n = 1,424) CKD were evaluated for their 5-year incidence rates of major adverse cardiac events (MACEs), defined as death, non-fatal myocardial infarction, ischemia driven target lesion revascularization (ID-TLR), and stent thrombosis (ST)., Results: The mean and median follow-up duration were 1,391 ± 557 days and 1,769 days (interquartile range, 1,012-1,800 days), respectively. Although the incidence of ID-TLR and ST was similar between patients with and without CKD (4.9% vs. 3.7%, P = 0.26, 0.5% vs. 1.0%, P = 0.20, respectively), cardiac death and MACE were significantly higher in patients with CKD than in those without CKD (6.5% vs. 2.9%, P = 0.007, 26.9% vs. 14.0%, P < 0.001, respectively). In multivariate analysis, CKD was an independent predictor of MACE (hazard ratio 1.22 [95% confidence interval 1.04-1.43], P = 0.01)., Conclusions: Patients with CKD had similar ID-TLR and ST rates as those without CKD at 5 years after EES implantation. The risk of long-term MACEs appeared to be associated with CKD., (© 2019 Wiley Periodicals, Inc.)

Background: Subcutaneous implantable cardioverter-defibrillators (S-ICDs) are an established therapy for preventing sudden cardiac death. However, a considerable number of patients still undergo inappropriate shocks even after conventional preimplantation electrocardiographic (ECG) screening., Objective: This study aimed to elucidate the additional effect of diurnal variations in the QRS complex and T waves of 24-hour Holter screening on S-ICD eligibility., Methods: Patients with transvenous ICDs who did not need pacing were selected for the study. The ECG was recorded by placing the electrodes to simulate the 3 sensing vectors of the S-ICD, with the patient in the standing and supine positions (conventional), during exercise, and during 24-hour Holter screening. We investigated the additional discrimination of diurnal variations in patients ineligible for S-ICDs as well as characteristics of those patients., Results: Of the 86 patients (82% men; mean age 54±16 years) analyzed by all 3 screenings, 2 (2.3%) and 3 (3.4%) were considered ineligible by conventional and exercise screening, respectively. An additional 21 patients (24.4%) were found ineligible through Holter screening. A multivariate logistic regression analysis demonstrated that Brugada syndrome and an increased QRS duration per millisecond were associated with ineligibility (odds ratio 5.74; 95% confidence interval 1.74-20.2; P = .003 and odds ratio 1.04; 95% confidence interval 1.01-1.07; P = .007, respectively). T-wave oversensing was mostly observed during 0-6 AM, but no significant diurnal variations were observed in the incorrect QRS profiles., Conclusion: The detection of diurnal variations through Holter monitoring in addition to conventional screening is expected to be useful for determining S-ICD eligibility., (Copyright © 2019 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: While the evaluation of burr speed was discussed regarding platelet aggregation, the association between platform speed and acute lumen gain of rotational atherectomy remains unknown., Methods: Through the evaluation of the potential of low-speed rotational atherectomy (LSRA) in in-vitro experiments, minimum lumen diameter (MLD) and minimum lumen area (MLA) after conventional high-speed rotational atherectomy (HSRA group) and those after LSRA following HSRA (LSRA+HSRA group) treated by 1.5 mm burrs were measured by optical frequency domain imaging (OFDI) in 30 consecutive human lesions., Results: The in-vitro experiments demonstrated that MLD and MLA after LSRA+HSRA were significantly larger (MLD: LSRA+HSRA=1.50 ±0.05 mm, HSRA= 1.43 ±0.05 mm, p=0.015; MLA: LSRA+HSRA= 1.90 ±0.17 mm 2 , HSRA= 1.71±0.11 mm 2 , and p= 0.037), requiring more crossing attempts (LSRA= 134 ±20 times, HSRA= 72 ±11 times, and p< 0.001). In human studies, there was no significance in reference vessel diameter and lesion length before the procedure between two groups. MLDs after LSRA+HSRA were significantly larger than those in HSRA (LSRA+HSRA= 1.22 ±0.16 mm, HSRA= 1.07 ±0.14 mm, and p= 0.0078), while MLAs after LSRA+HSRA tended to be larger (LSRA+HSRA= 1.79 ±0.51 mm 2 , HSRA= 1.55 ±0.47 mm 2 , and p= 0.19). There was no significance in the occurrence of in-hospital complication, including slow flow or no reflow, major dissection, and procedural myocardial infarction, between LSRA+HSRA and HSRA., Conclusions: LSRA can achieve larger lumen gain compared, whereas HSRA can pass calcified lesions easily. Combination of LSRA and HSRA is a safe and feasible strategy for severely calcified lesions in clinical practice., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2019 Takanobu Yamamoto et al.)

Competing Interests: The authors have no financial conflicts of interest.

Objectives: We aimed to compare the results of neointimal modification before drug-coated balloon (DCB) treatment with excimer laser coronary atherectomy (ELCA) plus scoring balloon predilation versus scoring balloon alone in patients presenting with in-stent restenosis (ISR)., Background: Treatment of ISR with ELCA typically results in superior acute gain by neointima debulking. However, the efficacy of combination therapy of ELCA and DCB remains unknown., Methods: A total of 42 patients (44 ISR lesions) undergoing DCB treatment with ELCA plus scoring balloon (ELCA group, n = 18) or scoring balloon alone (non-ELCA group, n = 24) were evaluated via serial assessment by optical coherence tomography (OCT) performed before, after intervention, and at 6 months., Results: Although there was significantly greater frequency of diffuse restenosis and percent diameter stenosis (%DS) after intervention in the ELCA group, comparable result was shown in %DS, late lumen loss, and binary angiographic restenosis at follow-up. On OCT analysis, a decreased tendency in the minimum lumen area and a significant decrease in the minimum stent area were observed in the ELCA group between 6-month follow-up and after intervention (-0.89 ± 1.36 mm 2 vs. -0.09 ± 1.25 mm 2 , p = 0.05, -0.49 ± 1.48 mm 2 vs. 0.28 ± 0.78 mm 2 , p = 0.03, respectively). The changes in the neointimal area were similar between the groups, and target lesion revascularization showed comparable rates at 1 year (11.1% vs. 11.4%, p = 0.85)., Conclusions: Despite greater %DS after intervention, ELCA before DCB had possible benefit for late angiographic and clinical outcome., Competing Interests: The authors have no associations with industry that could constitute conflicts of interest., (Copyright © 2019 Toru Miyazaki et al.)

Little is known about the impact of the relationship built between interventionists and their participants on weight loss. Our objective is to determine whether stronger early (i.e., 4 weeks) participant-interventionist bond is associated with significantly greater weight loss success and treatment adherence. Three hundred and ninety-eight participants received an online group behavioral weight control program over 18 months. Weight was measured objectively at baseline and at 6 and 18 months. At 4 weeks, participants completed the Working Alliance Inventory (WAI) bonding subscale, which measures the collaborative bond with the interventionist. Adherence (i.e., session attendance and online self-monitoring diary completion) was recorded by the interventionists. Participant-interventionist bond at 4 weeks was significantly associated with weight loss at 6 months (t(322) = -2.14, p = .03) but not at 18 months (t(290) = 0.53, p = .60). The model indicated that participant-interventionist bond at 4 weeks was a significant predictor of adherence at 6 months (b = .063, standard error [SE] = .30, p = .04), and 6 month adherence was a significant predictor of weight loss at 6 months (b = -.594, SE = .049, p < .0001). The indirect effect of the WAI-Bond subscale was significant (b = -.037, p = .03, 95% confidence interval: -.074, -.002) and accounted for 54% of the total effect of participant-interventionist bond on weight loss. However, the total weight loss explained by WAI-Bond subscale was small (0.04 kg). Participant-interventionist bond between participant and interventionist is an early predictor of treatment adherence and weight loss success at 6 months; however, the degree of weight loss explained by participant-interventionist bond is small and was not maintained at 18 months., (© Society of Behavioral Medicine 2018. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective The aim of this study was to assess the relationship between hypercholesterolemia (HC) and clinical events through a percutaneous coronary intervention (PCI) registry. HC is a well-known independent risk factor for long-term cardiovascular events after PCI. However, it has been reported to be associated with a lower risk of adverse events in patients with cancer or acute coronary syndrome. Methods We analyzed the relationship between HC and adverse events in patients treated with everolimus-eluting stents (EESs) through the Tokyo-MD PCI study (an all-comer, multicenter, observational registry). The propensity score method was applied to select two groups with similar baseline characteristics. Results The unadjusted population included 1,536 HC patients and 330 non-HC patients. Propensity score matching yielded 314 matched pairs. After baseline adjustment, the outcomes of HC patients were significantly better than those of the non-HC patients with respect to the primary endpoint, which was a combination of mortality from all causes, nonfatal myocardial infarction (MI), nonfatal neurological events, and major bleeding [hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.39-0.81; p=0.002], and the secondary endpoints, which included a combination of mortality from all causes, nonfatal MI, and nonfatal neurological events (HR 0.59, 95% CI 0.39-0.88; p=0.01), and major bleeding (HR 0.42, 95% CI 0.20-0.88; p=0.02). A subgroup analysis showed age as an interaction factor for the primary endpoint (interaction p=0.035). Conclusion HC was associated with better outcomes in patients who underwent EES implantation, even after baseline adjustment.

Background: Long-term clinical outcomes of permanent polymer everolimus-eluting stent (PP-EES) implantation after rotational atherectomy (RA) have not been fully evaluated. We sought to investigate the long-term clinical outcomes of PP-EES implantation after RA and assess the impact of hemodialysis on this treatment strategy., Methods: Patients who underwent percutaneous coronary intervention (PCI) with PP-EES at 22 institutions between January 2010 and December 2011 were enrolled in this multicenter, observational trial. From a total of 1918 registered patients, 113 patients with 115 de-novo lesions who underwent PCI with PP-EES following RA were retrospectively analyzed. The primary endpoint was a major adverse cardiac event (MACE) defined as the composite of cardiac death, non-fatal myocardial infarction (MI), and clinically driven target lesion revascularization (TLR)., Results: Long-term follow-up was available for 112 patients (99.1%). The median follow-up period was 2.9 (interquartile range 1.9-3.6) years. The mean age of the patients was 72.3 ± 8.8 years and 64 patients (56.6%) had chronic kidney disease (≥stage 3, 42 on hemodialysis). The cumulative incidences of MACE, non-fatal MI, and TLR were 22.1%, 5.3%, and 10.6%, respectively. Cox's proportional hazards analysis showed that the independent predictors of TLR were hemodialysis and chronic total occlusion. (HR, 14.1; 95% CI, 1.74-155.5; p = 0.01, HR, 9.01; 95% CI, 1.34-62.5; p = 0.02)., Conclusions: PP-EES implantation after lesion modification by RA is considered to be a feasible treatment strategy for heavily calcified lesions. Hemodialysis and chronic total occlusion appeared to be associated with TLR., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Being overweight has been identified as independent risk factors for coronary artery disease. However, overweight patients have been reported frequently to have better mortality outcomes, and there is little data showing they are at a disadvantage regarding secondary prevention of cardiovascular events. We analyzed the influence of being overweight (defined as body mass index > 25 kg/m 2 ) on adverse events in patients who underwent everolimus-eluting stent (EES) implantation using a multicenter registry with a maximum follow-up of 3 years. Propensity score matching was done for adjusting baseline characteristics. We defined primary end points as major adverse cardiac and cerebrovascular events (MACCE: a composite of mortality from all causes, nonfatal myocardial infarction, and nonfatal stroke) and "MACCE excluding non-cardiac mortality". Other adverse events were analyzed as key secondary end points. Out of 1918 patients, 450 pairs were obtained through propensity score matching. Overweight patients were superior to non-overweight patients regarding MACCE (event rates: 8.2 vs. 13.8% in overweight vs. non-overweight, respectively; log-rank p = 0.009) and "MACCE excluding non-cardiac mortality" (5.9 vs. 10.1%, p = 0.03). On secondary end points, not only did overweight patients have significantly fewer major bleeding events (2.2 vs. 4.8%, p = 0.02), but they also had smaller adverse event rates for almost all such events; the differences were not statistically significant. Overweight patients had better outcomes for MACCE, even on excluding non-cardiac mortalities. No result was supportive of an evident advantage to non-overweight EES-implanted patients in terms of secondary prevention of cardiovascular events.

Syphilis is a sexually transmitted disease caused by Treponema pallidum. Syphilitic aortitis might coexist in a dysfunctional aortic valve, but the etiology remains unclear, because microbiological diagnosis is difficult. A 62-year-old man with low-grade fever was diagnosed with aortitis and infective endocarditis, due to Treponema pallidum infection, using polymerase chain reaction analysis. This case suggests that syphilis might cause infective endocarditis., (Copyright © 2018 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Objectives: To evaluate the effectiveness of the proximal optimization technique (POT) to prevent longitudinal stent elongation., Background: The mechanism of stent elongation, which occurs after post-balloon dilation, is still unclear., Methods: A total of 103 lesions treated with optical coherence tomography guided coronary intervention between May 2013 and November 2017 were retrospectively analyzed. Lesions were divided according to the circumferential degree of malapposition at the stent edge immediately after deployment into well-apposed group (<180°) and malapposed group (≥180°). Post-dilation was performed from distal to proximal within the stent until August 2016 (non-POT cohort), and POT was applied thereafter (POT cohort). In the POT cohort, post-dilation was done at the proximal portion of the stent with sufficiently large balloon to minimize malapposition followed by distal dilatations. Stent elongation length was defined as the change in stent length from stent deployment to after post-dilatation., Results: In the non-POT cohort, 72 lesions, including 54 lesions in the well-apposed group and 18 in the malapposed group were analyzed. Stent elongation length was significantly longer in the malapposed group than in the well-apposed group (1.51 ± 1.34 mm vs 0.13 ± 0.84 mm, P < 0.01). In the POT cohort, 31 lesions including 21 in the well-apposed group and 10 in the malapposed group were analyzed. Stent elongation length was not significantly different between the groups (-0.09 ± 0.91 mm vs 0.30 ± 0.99 mm, P = 0.29)., Conclusions: Malapposition of the stent edge is responsible for longitudinal stent elongation caused by post-dilatation. POT appeared to effectively prevent longitudinal stent elongation., (© 2018 Wiley Periodicals, Inc.)

Background: Takayasu arteritis (TAK) is an autoimmune systemic arteritis of unknown pathogenesis. Genome-wide association studies revealed that single-nucleotide polymorphisms in the MLX gene encoding the MLX (Max-like protein X) transcription factor are significantly associated with TAK in Japanese patients. MLX single-nucleotide polymorphism rs665268 is a missense mutation causing the Q139R substitution in the DNA-binding site of MLX., Methods: To elucidate the hypothesis that the single-nucleotide polymorphism of the MLX gene plays a critical role in the development of TAK, we conducted clinical and laboratory analyses., Results: We show that rs665268 significantly correlated with the severity of TAK, including the number of arterial lesions and morbidity of aortic regurgitation; the latter may be attributed to the fact that MLX mRNA expression was mostly detected in the aortic valve. Furthermore, the Q139R mutation caused structural changes in MLX, which resulted in enhanced formation of a heterodimer with MondoA, upregulation of TXNIP (thioredoxin-interacting protein) expression, and increase in the activity of the NLRP3 (NACHT, LRR, and PYD domains-containing protein 3) inflammasome and cellular oxidative stress. Furthermore, autophagy, which negatively regulates inflammasome activation, was suppressed by the Q139R mutation in MLX. The MLX-Q139R mutant significantly induced macrophage proliferation and macrophage-endothelium interaction, which was abolished by the treatment with SBI-477, an inhibitor of MondoA nuclear translocation. Our findings suggest that the Q139R substitution in MLX plays a crucial role in the pathogenesis of TAK., Conclusions: MLX-Q139R mutation plays a crucial role in the pathogenesis of TAK through promoting inflammasome formation.

Skin sensitization is a toxicity endpoint of widespread concern, for which the mechanistic understanding and concurrent necessity for non-animal testing approaches have evolved to a critical juncture, with many available options for predicting sensitization without using animals. Cosmetics Europe and the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods collaborated to analyze the performance of multiple non-animal data integration approaches for the skin sensitization safety assessment of cosmetics ingredients. The Cosmetics Europe Skin Tolerance Task Force (STTF) collected and generated data on 128 substances in multiple in vitro and in chemico skin sensitization assays selected based on a systematic assessment by the STTF. These assays, together with certain in silico predictions, are key components of various non-animal testing strategies that have been submitted to the Organization for Economic Cooperation and Development as case studies for skin sensitization. Curated murine local lymph node assay (LLNA) and human skin sensitization data were used to evaluate the performance of six defined approaches, comprising eight non-animal testing strategies, for both hazard and potency characterization. Defined approaches examined included consensus methods, artificial neural networks, support vector machine models, Bayesian networks, and decision trees, most of which were reproduced using open source software tools. Multiple non-animal testing strategies incorporating in vitro, in chemico, and in silico inputs demonstrated equivalent or superior performance to the LLNA when compared to both animal and human data for skin sensitization.

Late gadolinium enhancement (LGE) with cardiac magnetic resonance (CMR) imaging has demonstrated the capability of stratifying hypertrophic cardiomyopathy (HCM). Stress perfusion test of CMR can quantify myocardial perfusion reserve (MPR), but its clinical role is not determined. The purpose of this study was to investigate the relationship between MPR and LGE in patients with HCM. A total of 61 consecutive cases underwent complete evaluation with electrocardiography and CMR [cine imaging, coronary MR angiography (MRA), and stress perfusion testing with LGE]. HCM cases were diagnosed by the Japanese conventional guideline prior to this CMR study. Mild LVH was defined as more than 13 mm in maximum LV wall thickness at end diastole on the cine imaging of the CMR. MPR was calculated as the ratio of stress/rest myocardial blood flow using an intensity curve on the stress perfusion test. Cases with ischemic heart disease were excluded from the study based on clinical history and coronary MRA. There were 37 HCM and 24 mild LVH cases (average age: 60.5 ± 10.9 vs. 64.8 ± 10.8; male: 62.2 vs. 75.0%, respectively, non-significant). MPR in HCM was lower than in LVH (1.5 ± 0.5 vs. 2.2 ± 0.9, p < 0.001) and normal subjects (2.4 ± 0.9, p < 0.001). MPR in HCM with LGE (N = 34) was lower than in HCM without LGE (N = 3) (1.4 ± 0.5 vs. 2.1 ± 0.2, p = 0.014). Multiple regression analysis verified that LGE was the strongest predictor of MPR among multiple clinical parameters, including LVH, LV dysfunction (ejection fraction < 50%), and the presence of negative T wave (p < 0.001). MPR was impaired in HCM with LGE compared with HCM without LGE. The clinical role of MPR on CMR needs to be clarified by further research.

Cosmetics Europe, the European Trade Association for the cosmetics and personal care industry, is conducting a multi-phase program to develop regulatory accepted, animal-free testing strategies enabling the cosmetics industry to conduct safety assessments. Based on a systematic evaluation of test methods for skin sensitization, five non-animal test methods (DPRA (Direct Peptide Reactivity Assay), KeratinoSens TM , h-CLAT (human cell line activation test), U-SENS TM , SENS-IS) were selected for inclusion in a comprehensive database of 128 substances. Existing data were compiled and completed with newly generated data, the latter amounting to one-third of all data. The database was complemented with human and local lymph node assay (LLNA) reference data, physicochemical properties and use categories, and thoroughly curated. Focused on the availability of human data, the substance selection resulted nevertheless resulted in a high diversity of chemistries in terms of physico-chemical property ranges and use categories. Predictivities of skin sensitization potential and potency, where applicable, were calculated for the LLNA as compared to human data and for the individual test methods compared to both human and LLNA reference data. In addition, various aspects of applicability of the test methods were analyzed. Due to its high level of curation, comprehensiveness, and completeness, we propose our database as a point of reference for the evaluation and development of testing strategies, as done for example in the associated work of Kleinstreuer et al. We encourage the community to use it to meet the challenge of conducting skin sensitization safety assessment without generating new animal data.

5-Hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) have beneficial effects in patients with heart failure (HF), regardless of serum cholesterol levels. However, their synergic effects with angiotensin II receptor blocker (ARB) remain to be established. We assessed the existence and potential underlying mechanisms of the effects of combined ARB [losartan (LOS)] and statin [simvastatin (SIM)] on cardiac function in rats and mice with load-induced HF. Salt-loaded Dahl salt-sensitive (DS) rats were treated with vehicle, LOS, SIM, or LOS + SIM for 8 weeks. To mimic load-induced HF in vitro , cultured neonatal rat cardiomyocytes (NRCM) were cyclically stretched. We also investigated the effect of LOS + SIM on pressure overload-induced HF using mice with transverse aortic constriction (TAC). LOS + SIM improved left ventricular (LV) function and reduced LV hypertrophy more than the monotherapies in both salt-loaded DS rats and TAC-operated mice. LV-tissue increases in Rho kinase and matrix metalloproteinase-9 activity were decreased to a greater extent by LOS + SIM than by LOS and SIM monotherapies. Plasma levels of Exp-3174, a LOS metabolite, were higher in LOS + SIM-treated DS rats than in LOS-treated rats. Stretch-induced hypertrophy of NRCM pretreated with SIM + Exp-3174 was significantly attenuated from that with LOS, Exp-3174, SIM, or LOS + SIM. SIM administration significantly enhanced mitophagy in mouse hearts after TAC. However, LOS + SIM reduced mitophagy, and the salutary effect of SIM in mouse hearts after TAC was abolished in AT1R -/- mice. In conclusion, LOS and SIM have beneficial myocardial effects on load-induced HF via differential pleiotropic effects. Thus, combination therapy of these drugs thus has potential as a therapeutic strategy for HF.

It is important to predict the potential of cosmetic ingredients to cause skin sensitization, and in accordance with the European Union cosmetic directive for the replacement of animal tests, several in vitro tests based on the adverse outcome pathway have been developed for hazard identification, such as the direct peptide reactivity assay, KeratinoSens™ and the human cell line activation test. Here, we describe the development of an artificial neural network (ANN) prediction model for skin sensitization risk assessment based on the integrated testing strategy concept, using direct peptide reactivity assay, KeratinoSens™, human cell line activation test and an in silico or structure alert parameter. We first investigated the relationship between published murine local lymph node assay EC3 values, which represent skin sensitization potency, and in vitro test results using a panel of about 134 chemicals for which all the required data were available. Predictions based on ANN analysis using combinations of parameters from all three in vitro tests showed a good correlation with local lymph node assay EC3 values. However, when the ANN model was applied to a testing set of 28 chemicals that had not been included in the training set, predicted EC3s were overestimated for some chemicals. Incorporation of an additional in silico or structure alert descriptor (obtained with TIMES-M or Toxtree software) in the ANN model improved the results. Our findings suggest that the ANN model based on the integrated testing strategy concept could be useful for evaluating the skin sensitization potential., (Copyright © 2017 John Wiley & Sons, Ltd.)

Acute kidney injury (AKI) after transcatheter aortic valve implantation (TAVI) is associated with increased mortality. As significant hemodynamic improvement may occur with relief of aortic stenosis, we hypothesized that TAVI patients may demonstrate the opposite phenomena: acute kidney recovery (AKR). We studied the incidence and predictors of AKR in post-TAVI patients. A total of 366 consecutive patients underwent TAVI (January 2012 to January 2017) at a single center. We defined AKR as a 25% improvement in glomerular filtration rate (GFR) at 48 hours after TAVI. AKI-creatinine (Cr) was defined as an increase in Cr of ≥0.3 mg/dl at 48 hours. Patients were categorized in 3 groups: AKR (≥25% increase in GFR), unchanged GFR, and AKI-GFR (inverse definition of AKR, ≥25% decrease in GFR). Multivariable logistic regression defined independent predictors of AKR. AKR occurred in 1/3 of patients. AKI-Cr occurred in 13% of patients, whereas AKI-GFR occurred similarly in 15%. AKR and AKI occurred most frequently in patients with chronic kidney disease (CKD: GFR ≤ 60 ml/min/1.73 m 2 ). Independent predictors of AKR-GFR by multivariable analysis were male gender, lack of chronic β-blocker utilization, and presence of CKD. Notably, left ventricular dysfunction and contrast volume were not predictive of AKR. Transfusion occurred less frequently among patients with AKR compared with patients with AKI-GFR (11% vs 26%, p = 0.03). Death occurred in 0% of AKR patients versus 9.3% of AKI-GFR patients (p <0.01). In conclusion, this is the first report of AKR after TAVI. Patients with CKD, male gender, and lack of pre-TAVI beta blockade were more likely to demonstrate AKR., (Published by Elsevier Inc.)

The objective of this study was to assess the prostate cancer screening practices of Vermont primary care physicians and compare them with a prior study in 2001. An electronic survey was created and emailed to all currently practicing primary care physicians in Vermont. Data was stratified by practice length, practice location, university affiliation, and internal medicine versus family practice. Surveys were received from 123 (27.2%) primary care physicians. 27.7% of physicians in practice <10 years recommended prostate specific antigen (PSA) testing, compared with 55.9% of those practicing ≥10 years (p = 0.006). Of those who modified their recommendations in the past 5 years, 96.1% reported that the United States Preventive Services Task Force (USPSTF) 2012 statement influenced them. Respondents who continued to use PSA testing were less likely to stop screening after age 80 compared with those surveyed in 2001 (51% in 2014 vs. 74% in 2001; p <0.001). Primary care physicians in practice for 10 or more years were more likely to recommend PSA-based screening than those in practice for less time. The USPSTF statement discouraging PSA-based screening for prostate cancer has had significant penetrance among Vermont primary care physicians.

Context: Acculturation is the phenomenon of the attitudinal changes of individuals who come into continuous contact with another culture. Despite the long history of Japanese immigration to America, little is known about the impact of acculturation on perceptions of a good death., Objectives: To examine differences in perceptions of a good cancer death among Japanese Americans (JA/A), Japanese living in America (J/A), and the Japanese living in Japan (J/J)., Methods: We administered surveys among JA/A and J/A and used historical J/J data for reference. Primary endpoint was the proportion of respondents who expressed the necessity of core and optional items of the Good Death Inventory. Group differences ≥20% were deemed clinically important., Results: In total, 441 survey responses in America and 2548 in Japan were obtained. More than 80% of respondents consistently considered nine of 10 core items necessary without significant group differences. No core item reached a ≥20% group difference. Three of the eight optional items reached ≥20% group difference: fighting against disease until one's last moment (49%, P < 0.0001; 52%, P < 0.0001; and 73% in JA/A, J/A, and J/J, respectively), knowing what to expect about one's condition in the future (83%, P < 0.0001; 80%, P < 0.0001; and 58%, respectively), and having faith (64%, P = 0.0548; 43%, P = 0.0127; and 38%, respectively)., Conclusion: Although most core items of a good death were preserved throughout the levels of acculturation, perceptions of some optional items shifted away from Japanese attitudes as individuals became more acculturated. Understanding of different levels of acculturation may help clinicians provide culturally sensitive end-of-life care., (Copyright © 2017 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Aim: The aim of this study was to assess the acute and mid-term effects of drug-coated balloon (DCB) in terms of the healing process of non-flow-limiting dissections and changes in the neointimal area after DCB treatment using frequency domain optical coherence tomography (FD-OCT)., Patients and Methods: Thirty-six consecutive patients with in-stent restenosis pretreated with a scoring balloon were evaluated (19 and 17 patients with and without a DCB, respectively). FD-OCT was performed before and after each procedure during percutaneous coronary intervention and at 6 months of follow-up., Results: Clinical characteristics and baseline FD-OCT findings were comparable between the two groups. No patient required stent implantation because of low-pressure DCB-related dissections. In the acute phase, the DCB distributed paclitaxel to the vessel wall without increasing dissections. The DCB did not reduce the neointimal area by itself. At 6 months, more dissections healed in the DCB group (-4.5±2.3 vs. -2.7±1.3, P=0.02). The DCB group showed less change in the neointimal area (-0.04±0.92 vs. 1.06±1.57 mm, P=0.03)., Conclusion: The low-pressure DCB was not intended to expand the lumen, but instead to attach paclitaxel to the vessel wall by using FD-OCT examination. The DCB reduced the number of dissections and prevented neointimal proliferation during the mid-term follow-up.

Significant progress has been made in the development and validation of non-animal test methods for skin sensitization assessment. At present, three of the four key events of the Adverse Outcome Pathway (AOP) are assessable by OECD-accepted in vitro methods. The fourth key event describes the immunological response in the draining lymph node where activated dendritic cells present major histocompatibility complex-bound chemically modified peptides to naive T cells, thereby priming the proliferation of antigen-specific T cells. Despite substantial efforts, modelling and assessing this adaptive immune response to sensitizers with in vitro T cell assays still represents a challenge. The Cosmetics Europe Skin Tolerance Task Force organized a workshop, bringing together academic researchers, method developers, industry representatives and regulatory stakeholders to review the scientific status of T cell-based assays, foster a mutual scientific understanding and conceive new options to assess T cell activation. Participants agreed that current T cell assays have come a long way in predicting immunogenicity, but that further investment and collaboration is required to simplify assays, optimize their sensitivity, better define human donor-to-donor variability and evaluate their value to predict sensitizer potency. Furthermore, the potential role of T cell assays in AOP-based testing strategies and subsequent safety assessment concepts for cosmetic ingredients was discussed. It was agreed that it is currently difficult to anticipate uses of T cell assay data for safety assessment and concluded that experience from case studies on real-life risk assessment scenarios is needed to further consider the usefulness of assessing the fourth AOP key event.

Purpose: To evaluate the usefulness of serum lipoprotein(a) as a biomarker of clinical outcomes after endovascular therapy (EVT) for atherosclerotic aortoiliac lesions., Methods: Serum lipoprotein(a) concentrations were measured at admission in 189 consecutive patients (median age 72 years; 160 men) with peripheral artery disease who underwent EVT for aortoiliac occlusive disease. The patients were dichotomized into 2 groups based on serum lipoprotein(a) levels ≤40 mg/dL (LOW; n=135) or >40 mg/dL (HIGH; n=54). After EVT, the incidences of major adverse limb events (MALE) were analyzed. Predictors of MALE were sought with a Cox proportional hazards analysis; results are presented as the hazard ratio (HR) and 95% confidence interval., Results: At the median follow-up of 33 months (interquartile range 11, 54), MALE occurred in 44 (23.3%) patients. The MALE-free survival estimate was significantly lower in patients in the HIGH group (55.6% vs 85.2%, p<0.001). Independent predictors of MALE after EVT were hemodialysis (HR 2.23, 95% CI 1.04 to 4.78, p=0.039) and high lipoprotein(a) levels (HR 2.80, 95% CI 1.44 to 5.45, p=0.003)., Conclusion: High lipoprotein(a) levels were associated with a higher incidence of MALE after EVT for patients with aortoiliac lesions.

Advanced glycation end-products (AGEs) play a role in the pathophysiology of diabetes mellitus (DM) and possibly hypertension (HTN). In experimental DM, AGEs accumulate in myocardium. Little is known about AGEs in human myocardium. We quantified abundance, localization, and functional correlates of the AGE carboxymethyl lysine (CML) in left ventricular (LV) myocardium from patients undergoing coronary bypass grafting (CBG). Immunoelectron microscopy was used to quantify CML in epicardial biopsies from 98 patients (71 M, 27 F) with HTN, HTN + DM or neither (controls), all with normal LV ejection fraction. Myofilament contraction-relaxation function was measured in demembranated myocardial strips. Echocardiography was used to quantify LV structure and function. We found that CML was abundant within cardiomyocytes, but minimally associated with extracellular collagen. CML counts/ μ m 2 were 14.7% higher in mitochondria than the rest of the cytoplasm ( P  < 0.001). There were no significant sex or diagnostic group differences in CML counts [controls 45.6 ± 3.6/ μ m 2 (±SEM), HTN 45.8 ± 3.6/ μ m 2 , HTN + DM 49.3 ± 6.2/ μ m 2 ; P  = 0.85] and no significant correlations between CML counts and age, HgbA1c or myofilament function indexes. However, left atrial volume was significantly correlated with CML counts ( r  = 0.41, P  = 0.004). We conclude that in CBG patients CML is abundant within cardiomyocytes but minimally associated with collagen, suggesting that AGEs do not directly modify the stiffness of myocardial collagen. Coexistent HTN or HTN + DM do not significantly influence CML abundance. The correlation of CML counts with LAV suggests an influence on diastolic function independent of HTN, DM or sex whose mechanism remains to be determined., (© 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Background: There are no biological markers to predict the onset of acute kidney injury (AKI) in patients with acute decompensated heart failure (ADHF). Liver-type fatty acid-binding protein (L-FABP) levels are markedly upregulated in the proximal tubules after renal ischemia. We investigated whether urinary L-FABP is a suitable marker to predict AKI in ADHF patients., Methods: We examined 281 consecutive patients with ADHF. Serum creatinine (Cr) and L-FABP levels were measured at admission and 24 and 48 h after admission., Results: AKI developed in 104 patients (37%). Urinary L-FABP levels at admission were significantly higher in patients with AKI than in those without (33.0 vs. 5.2 μg/g Cr; p < 0.001). Multivariate analysis showed that baseline urinary L-FABP level was an independent predictor of AKI in ADHF patients (odds ratio 1.08, 95% confidence interval 1.05-1.12; p < 0.001). Receiver operating characteristic analysis showed that baseline urinary L-FABP level exhibited 94.2% sensitivity and 87.0% specificity at a cutoff value of 12.5 μg/g Cr., Conclusions: Urinary L-FABP level is useful for predicting the onset of AKI in patients with ADHF. The results of our study could help clinicians diagnose AKI in ADHF patients earlier, leading to possible improvements in the treatment of this group of patients.

Background: Takayasu arteritis (TA) is an autoimmune arteritis of unknown etiology. Currently, the erythrocyte sedimentation rate (ESR) and serum C-reactive protein (CRP) levels are widely used to monitor disease activity of TA. However, sometimes it is difficult to reflect inflammatory symptoms in either CRP or ESR values, especially in TA patients with immunosuppressive therapies. Therefore, higher-accuracy biomarkers for evaluating disease activity need to be explored., Methods and Results: We examined 21 Japanese patients diagnosed with TA; 17 TA patients were treated with prednisone with or without additional immunosuppressive therapies and the remaining 4 patients were treated with infliximab, a human monoclonal anti-tumor necrosis factor (TNF)-α antibody. In active phase, the serum levels of both TNF-α and interleukin (IL)-6 were significantly higher than in healthy subjects, as is the case with both the levels of CRP and ESR. In contrast, the levels of both IL-12 and IL-23 remained in the normal range. Both TNF-α and IL-6 levels were markedly decreased in response to therapies, on equality with both CRP and ESR levels. Regarding the TA patients treated with infliximab, both CRP and IL-6 levels tended to be decreased after infliximab therapy. Conversely, TNF-α level after infliximab therapy was higher than before therapy., Conclusion: Both TNF-α and IL-6 levels, but not IL-12 or IL-23 levels, in the serum could be potent biomarkers that can reflect the activity of TA., (Copyright © 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Chronic aortic regurgitation (AR) induces mitral valve (MV) leaflet enlargement, although, its mechanism still remains unclear. This study aimed to clarify the influence of AR jet directions on the MV apparatus in patients with chronic AR. This study included 69 consecutive patients with severe chronic AR and 17 controls who underwent three-dimensional (3D) transesophageal echocardiography (TEE). The anterior mitral leaflet (AML), posterior mitral leaflet (PML) and MV annulus areas were measured at mid-diastole. All AR patients were classified into the posterior (Group A, n = 38) or non-posterior (Group B, n = 31) group based on the AR jet directions. Both two groups revealed the increased total leaflet areas compared with the controls. No significant differences in the left ventricular volumes, PML or MV annulus area were observed between Group A and B; however, Group A had the larger AML area and greater AML/PML area ratio than Group B (both P < 0.01). The multivariate analysis indicated that the posterior AR jet was independently associated with the AML/PML area (P < 0.01). 3D TEE depicted geometric differences in the MV apparatus between the different types of AR jet directions. These results may be helpful in understanding the mechanism of MV leaflet remodeling in chronic AR.

Background: Relaxation characteristics and Ca 2+ homeostasis have not been studied in isolated myocardium from patients with hypertensive heart disease (HHD) and heart failure with preserved ejection fraction (HFpEF). Prolonged myocardial relaxation is believed to play an important role in the pathophysiology of these conditions. In this study, we evaluated relaxation parameters, myocardial calcium (Ca 2+ ), and sodium (Na + ) handling, as well as ion transporter expression and tested the effect of Na + -influx inhibitors on relaxation in isolated myocardium from patients with HHD and HFpEF., Methods and Results: Relaxation characteristics were studied in myocardial strip preparations under physiological conditions at stimulation rates of 60 and 180 per minute. Intracellular Ca 2+ and Na + were simultaneously assessed using Fura-2 and AsanteNATRIUMGreen-2, whereas elemental analysis was used to measure total myocardial concentrations of Ca, Na, and other elements. Quantitative polymerase chain reaction was used to measure expression levels of key ion transport proteins. The lusitropic effect of Na + -influx inhibitors ranolazine, furosemide, and amiloride was evaluated. Myocardial left ventricular biopsies were obtained from 36 control patients, 29 HHD and 19 HHD+HFpEF. When compared with control patients, half maximal relaxation time (RT 50 ) at 60 per minute was prolonged by 13% in HHD and by 18% in HHD+HFpEF (both P <0.05). Elevated resting Ca 2+ levels and a tachycardia-induced increase in diastolic Ca 2+ were associated with incomplete relaxation and an increase in diastolic tension in HHD and HHD+HFpEF. Na + levels were not increased, and expression levels of Ca 2+ - or Na + -handling proteins were not altered. Na + -influx inhibitors did not improve relaxation or prevent incomplete relaxation at high stimulation rates., Conclusions: Contraction and relaxation are prolonged in isolated myocardium from patients with HHD and HHD+HFpEF. This leads to incomplete relaxation at higher rates. Elevated calcium levels in HFpEF are neither a result of an impaired Na + gradient nor expression changes in key ion transporters and regulatory proteins., (© 2017 American Heart Association, Inc.)

Inactivation of genes in the transforming growth factor (TGF)-β/SMAD signaling pathway is a well-known step for the progression of colorectal cancers (CRCs). Genetic mutations can occur in the precursors, and the combined prevalence of SMAD4, SMAD2, and SMAD3 mutations was seen in up to 50% of CRCs. High levels of serum TGF-β1 were reported in patients with CRC and were associated with poor clinical outcome. PPM1A is an important inhibitory regulator in the TGF-β signaling pathway and contributes to terminating the TGF-β/SMAD signaling activity. We recently showed that PPM1A expression was lost in approximately 45% of pancreatic ductal adenocarcinomas and loss of PPM1A was associated with worse overall survival. Genome-wide analyses from The Cancer Genome Atlas revealed that abnormal TGF-β signaling pathway is among the most common molecular changes in CRC. The complexity of the TGF-β signaling pathway is its dual function as a tumor suppressor and tumor-promoting factor, depending on the cellular and molecular context. In this study, we simultaneously investigated the protein expression pattern of 3 regulators in the TGF-β/SMAD signaling pathway, including SMAD4, PPM1A, and TGF-β1, and their clinicopathological correlations in CRCs by immunohistochemistry. We observed that loss of SMAD4 and PPM1A was seen in 37.8% and 7.3% of CRCs, respectively. Loss of SMAD4, lymphovascular invasion, and distant metastasis were independently associated with worse overall survival in multivariate analysis. However, loss of PPM1A was associated with worse overall survival with less statistical strength. Our findings would provide new insights into the pathophysiological function of different components in the TGF-β signaling pathway in CRC., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Hemophilia B Leyden is a unique subtype of hemophilia B, characterized by increasing factor IX activity (FIX:C) after puberty and a lower normal range of FIX:C throughout adulthood. However, to date, no Japanese case has been reported. Here, we report a case of hemophilia B Leyden in a 22-year-old male. He suffered from subgaleal hematoma, and was subsequently diagnosed with hemophilia B (FIX:C 0.2%) in the neonatal period. Both his parents are Japanese. There was no history of hemophilia in his family. FIX:C gradually increased with age (8% at age = 1; 14% at age = 7; 19% at age = 12; 32% at age = 18). FIX:C is within the range 30-40% in recent several years. He once required administration of FIX concentrate against traumatic tongue bleeding at 7 years of age. Genotyping analysis of FIX was performed after informed consent at 21 years of age, and a point mutation (c.-35G>A) was detected. This mutation has been reported previously as the Leyden mutation. Although it has been reported that hemophilia B Leyden is seen in 1.9% of patients with hemophilia B, the present case is the first report of hemophilia B Leyden from Japan.

Objective: The objective of this study was to clarify the incidence and predictors of early and late target lesion revascularization (TLR) after everolimus-eluting stent (EES) implantation in actual clinical practice., Background: Several clinical studies have reported the incidence and predictors of TLR after EES implantation. However, detailed features of early and late TLR are unknown., Methods: We analyzed the clinical data of patients who underwent EES implantation between January 2010 and December 2011 at 22 institutions in Japan (Tokyo-MD PCI study). Patients who underwent ischemia-driven TLR (ID-TLR) were grouped according to the number of years elapsed since stent placement, and incidence and correlations between clinical factors were analyzed., Results: Statistical analysis was performed for 1,899 patients and 2,305 lesions. The mean age was 70.0 ± 9.9 years, and the median follow-up period was 1,281 days (IQR: 762-1,440 days). The incidence of ID-TLR was 2.7% at 1 year and 5.4% at 4 years. After 2 years, the ID-TLR rates plateaued. The independent predictors of ID-TLR occurring within 2 years were hemodialysis, triple vessel disease, restenotic lesion, and ostial lesions. The independent predictors of ID-TLR between 2 and 4 years were diabetes mellitus and peripheral artery disease., Conclusion: The ID-TLR rates leveled off after 2 years. Furthermore, the predictors of ID-TLR that occurred within 2 years of EES implantation differed from those that occurred later than 2 years. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

The progression of coronary atherosclerosis has been influenced by the presence of chronic kidney disease (CKD). This study investigated the impact of CKD stages on coronary plaque components observed on optical coherence tomography (OCT). We investigated 296 native coronary lesions with stable angina pectoris treated with stent implantation. All lesions were divided into the three groups according to the values of estimated glomerular filtration rate (eGFR, mL min -1  1.73 m -2 ): the non-CKD group (eGFR ≥60, n = 142), CKD group (15 ≤ eGFR < 60, n = 126), and end-stage kidney disease (ESKD) group (eGFR <15 and/or hemodialysis, n = 28). Among the groups, plaque morphologies at the narrowest culprit sites on OCT were evaluated. The CKD group had a larger lipid arc [207.5 (88.3-264.5) vs. 159.3 (73.3-227.7) degrees, P = 0.037] and longer lipid length [2.4 (0.0-5.7) vs. 0.0 (0.0-4.7) mm, P = 0.017] than the non-CKD group. The ESKD group had a thinner fibrous cap [120 (70-258) vs. 170 (100-270) μm, P = 0.044], higher prevalence of plaque rupture (28.6 vs. 12.3 %, P = 0.038), and larger calcification arc [124.8 (0.0-194.3) vs. 0.0 (0.0-125.4) degrees, P = 0.025] than the non-ESKD group (CKD + non-CKD groups). The presence of CKD was related to the growth of lipidic plaques. Furthermore, the advancement in the CKD stage to ESKD affected the occurrence of plaque rupture or progression of calcification.

Background: Long-term dual antiplatelet therapy (DAPT) for patients treated with coronary stents has been reported to be effective. However the effectiveness of long-term DAPT for everolimus-eluting stent (EES) implanted patients has been controversial. We assessed the major adverse cardiac and cerebral events (MACCE: a composite of death, myocardial infarction, or cerebral arterial disease) in patients free from MACCE during the first 2 years after EES implantation., Methods and Results: A total of 1918 patients who underwent successful percutaneous coronary intervention (PCI) with EES at 22 centers in Japan in 2010-2011 were enrolled, and 742 patients were free from MACCE for 2 years. We divided these MACCE-free patients into two groups: those who received DAPT for >2 years (Over-2-Year DAPT: n=591), and those who received DAPT for ≤2 years (Under-2-Year DAPT: n=151). We performed the landmark analysis that began at 2 years and evaluated at 3 years after PCI about the occurrence of MACCE, major bleeding, stent thrombosis, and restenosis between these groups, both with and without baseline adjustment by propensity score matching (n=145 in both groups)., Results: Fifty MACCE cases were reported (Over-2-Year DAPT, 38; Under-2-Year DAPT, 12), with no significant differences between the 2 groups (log-rank test, p=0.19). Even after baseline adjustment, there were no differences in MACCE occurrence (Over-2-Year DAPT, 8; Under-2-Year DAPT, 11, p=0.19); 15 cases of major bleeding, 5 of restenosis, and 2 of stent thrombosis were observed after 2-years' follow-up, with no statistical differences between the groups, although the event numbers were too low for comparison., Conclusion: Continuing DAPT for >2 years did not prevent MACCE in patients free from MACCE during initial 2 years after EES implantation. Few events of major bleeding, stent thrombosis, and restenosis were observed, with no statistical differences., (Copyright © 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: When drug-induced coronary spasm provocation tests are performed, a washout period of >48h for calcium channel blockers (CCBs) is uniformly recommended. However, each CCB has a distinct half-life, and little is known about the influence of prior oral administration of CCBs on acetylcholine provocation test to evaluate coronary vasomotor reaction., Methods and Results: We examined 245 consecutive patients with suspected vasospastic angina who had undergone acetylcholine provocation test. Of those patients, 29 patients had been on amlodipine, an ultra-long term acting CCB (group A), 34 on other CCBs (group O), and 182 patients on no CCB (group N). After CCBs had been withheld > 48h, we performed acetylcholine provocation, which resulted in 152 positive, 36 intermediate, and 57 negative reactions. We evaluated coronary artery tone calculated as follows: (luminal diameter after nitrate-baseline luminal diameter)÷(luminal diameter after nitrate)×100 (%). In group A patients, coronary artery tone was lower (A:9.1±6.9% vs. O:11.7±8.3% vs. N:12.1±8.5%, p=0.0011) and the positive rate of acetylcholine provocation test was lower than group O and group N (A:41% vs. O:68% vs. N:64%, p=0.047). Multivariate logistic analysis showed that taking amlodipine until 2days before acetylcholine provocation test was a significant inverse predictor for acetylcholine-provoked coronary spasm (odds ratio 0.327; 95% confidence interval 0.125-0.858, p=0.023)., Conclusions: Residual vasodilatory effects of ultra-long acting CCB may decrease coronary artery tone and the vasoconstrictive reaction to acetylcholine suggesting that a 2-day pre-test drug holiday may not be long enough., (Copyright © 2017 Elsevier B.V. All rights reserved.)