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Background: Fulminant myocarditis presentation (FMP) is a rare and severe presentation of myocarditis. The natural history of FMP and its clinical features associated with poor outcomes are incompletely understood because there is a lack of generalizable evidence. Methods: This multicenter retrospective cohort study included patients hospitalized with histologically proven myocarditis who underwent catecholamine or mechanical support from 235 cardiovascular training hospitals across Japan between April 2012 and March 2017. Clinical features and the prognostic predictors of death or heart transplantation within 90 days on the basis of clinical and pathologic findings were determined using the Kaplan-Meier method, log-rank test, and Cox regression analysis. Results: This study included 344 patients with histologically proven FMP (median age, 54 years; 40% female). The median follow-up was 600 days (interquartile range, 36 to 1599 days) and the cumulative risk of death or heart transplantation at 90 days was 29% (n=98). Results from multivariable Cox regression analysis showed that older age, nonsinus rhythm, low left ventricular wall motion ( Conclusions: The results from analyses of data from this multicenter registry demonstrated that patients with FMP are at a higher risk of death or heart transplantation in real-world settings. These observations inform which clinical and pathologic findings may be useful for prognostication in FMP. Registration: URL: https://www.umin.ac.jp/ctr ; Unique identifier: UMIN000039763.

The effect of body weight (BW) on bleeding and ischemic events has not been adequately evaluated in real-world percutaneous coronary intervention (PCI) practice.Methods and Results:12,690 consecutive patients undergoing first PCI in the CREDO-Kyoto registry cohort-2 were divided into 3 groups according to tertiles of BW stratified by sex (male; Tertile 1 [60.0 kg], 2 [60.0-68.0 kg], and 3 [68.0 kg], and female; Tertile 1 [47.9 kg], 2 [47.9-55.8 kg], and 3 [55.8 kg]). Cumulative 5-year incidences of the primary bleeding (GUSTO moderate/severe) and ischemic (myocardial infarction/ischemic stroke) endpoints increased incrementally with decrease in BW in both strata (male Tertiles 1, 2, and 3: 13.7%, 10.3%, and 8.0%, P0.001, and 13.9%, 11.3%, and 10.2%, P0.001; female Tertiles 1, 2, and 3: 17.9%, 12.9%, and 10.1%, P0.001, and 17.9%, 12.9%, and 10.1%, P0.001). Compared with Tertile 3, the adjusted risks of Tertile 1 for the primary bleeding and ischemic endpoints remained significant in the female stratum (hazard ratio (HR): 1.45, 95% confidence interval (CI): 1.14-1.87, P=0.003, and HR:1.49, 95% CI:1.13-1.95, P=0.004), but not in the male stratum (HR:1.10, 95% CI:0.92-1.32, P=0.31, and HR:1.06, 95% CI:0.90-1.27, P=0.47).Cumulative incidences of bleeding and ischemic events increased incrementally as BW decreased in both men and women. The adjusted risks of underweight relative to overweight for bleeding and ischemic events were significant only in women.

Background There are no data comparing transcatheter aortic valve implantation (TAVI) with surgical aortic valve replacement (SAVR) outcomes in real clinical practice in Japan. Methods and results We combined 2 independent registries, the K-TAVI Registry (a 6-center prospective registry of consecutive patients who underwent TAVI) and the CURRENT AS Registry (a large, 27-center registry of 3,815 consecutive patients with severe aortic stenosis [AS]). In the K-TAVI Registry, 338 patients underwent TAVI with SAPIEN XT balloon-expandable valves from October 2013 to January 2016, whereas in the CURRENT AS Registry 237 patients with severe AS underwent SAVR from January 2003 to December 2011. Propensity score matching was conducted, with final cohort comprising 306 patients. The cumulative 2-year incidence of all-cause death and heart failure (HF) hospitalization did not differ significantly between the TAVI and SAVR groups (13.7% vs. 12.4% [P=0.81] and 7.9% vs 3.9% [P=0.13], respectively). After adjusting for residual confounders, there were no significant differences between the TAVI and SAVR groups in the risk for all-cause death (hazard ratio [HR] 0.74; 95% confidence interval [CI] 0.35-1.58; P=0.43) or HF hospitalization (HR 1.27; 95% CI 0.40-4.59; P=0.69). Conclusions These findings from 2 independent Japanese registries suggest that the 2-year risk of all-cause mortality and HF does not differ significantly between TAVI and SAVR groups in real-world practice in Japan.

BACKGROUND This study aimed to evaluate the effect of the initial aortic valve replacement (AVR) strategy relative to a conservative strategy on long-term outcomes stratified by age among asymptomatic patients with severe aortic stenosis (AS).Methods and Results:Among 1,808 asymptomatic severe AS patients in the CURRENT AS registry, there were 1,166 patients aged ≥75 years (initial AVR: n=124, and conservative: n=1,042), and 642 patients with age

Objectives: The aim of this study was to investigate the prognostic impact of the decline in left ventricular ejection fraction (LVEF) at 1-year follow-up in patients with severe aortic stenosis (AS) managed conservatively. Background: No previous study has explored the association between LVEF decline during follow-up and clinical outcomes in patients with severe AS. Methods: Among 3, 815 patients with severe AS enrolled in the multicenter CURRENT AS (Contemporary Outcomes After Surgery and Medical Treatment in Patients With Severe Aortic Stenosis) registry in Japan, 839 conservatively managed patients who underwent echocardiography at 1-year follow-up were analyzed. The primary outcome measure was a composite of AS-related deaths and hospitalization for heart failure. Results: There were 91 patients (10.8%) with >10% declines in LVEF and 748 patients (89.2%) without declines. Left ventricular dimensions and the prevalence of valve regurgitation and atrial fibrillation or flutter significantly increased in the group with declines in LVEF. The cumulative 3-year incidence of the primary outcome measure was significantly higher in the group with declines in LVEF than in the group with no decline (39.5% vs. 26.5%; p < 0.001). After adjusting for confounders, the excess risk of decline in LVEF over no decline for the primary outcome measure remained significant (hazard ratio: 1.98; 95% confidence interval: 1.29 to 3.06). When stratified by LVEF at index echocardiography (≥70%, 60% to 69%, and 10% declines in LVEF at 1 year after diagnosis had worse AS-related clinical outcomes than those without declines in LVEF under conservative management. (Contemporary Outcomes After Surgery and Medical Treatment in Patients With Severe Aortic Stenosis Registry; UMIN000012140)

Aims Early aortic valve replacement (AVR) might be beneficial in selected high-risk asymptomatic patients with severe aortic stenosis (AS), considering their poor prognosis when managed conservatively. This study aimed to develop and validate a clinical scoring system to predict AS-related events within 1 year after diagnosis in asymptomatic severe AS patients. Methods and results We analysed 1274 asymptomatic severe AS patients derived from a retrospective multicentre registry enrolling consecutive patients with severe AS in Japan (CURRENT AS registry), who were managed conservatively and completed 1-year follow-up without AVR. From a randomly assigned derivation set (N = 849), we developed CURRENT AS risk score for the AS-related event (a composite of AS-related death and heart failure hospitalization) within 1 year using a multivariable logistic regression model. The risk score comprised independent risk predictors including left ventricular ejection fraction Conclusion The CURRENT-AS risk score integrating clinical and echocardiographic factors well-predicted the risk of AS-related events at 1 year in asymptomatic patients with severe AS and was validated internally.

Background Patients with severe aortic stenosis (AS) might be at high risk for adverse cardiovascular events at the time of non-cardiac surgery.Methods and Results:The current study population included 348 patients who underwent elective non-cardiac surgery under general or spinal anesthesia during the follow up of 3,815 patients in the CURRENT AS (Contemporary outcomes after sURgery and medical tREatmeNT in patients with severe Aortic Stenosis) registry. There were 187 patients with untreated severe AS at time of surgery (untreated severe AS group) and 161 patients who had undergone aortic valve replacement (AVR) before surgery (prior AVR group), including 23 patients with prophylactic AVR. The primary outcome measure was 30-day mortality after non-cardiac surgery. At 30 days after non-cardiac surgery, 8 patients (4.3%) died in the untreated severe AS group, while no patients died in the prior AVR group (P=0.008). The causes of death were cardiovascular in 6 out of 8 patients. Mortality at 30 days was higher in untreated severe AS patients with AS-related symptoms before surgery than in those without AS-related symptoms (7.2% vs. 3.1%). Higher surgical risk estimates of the non-cardiac surgery incrementally increased the risk of 30-day mortality in patients with untreated severe AS, though the difference was not statistically significant (low-risk: 0%, intermediate-risk: 4.3%, and high-risk: 6.6 %, P=0.46). Conclusions Symptomatic and asymptomatic severe AS might be associated with higher risk of 30-day mortality if untreated before elective intermediate- and high-risk non-cardiac surgery, while no patient with prior AVR died after elective non-cardiac surgery.

Background: Clinical profiles of acute heart failure (AHF) complicating severe aortic stenosis (AS) remain unclear. Methods and Results: From a Japanese multicenter registry enrolling consecutive patients with severe AS, 3, 813 patients were categorized into the 3 groups according to the symptom of heart failure (HF); No HF (n=2, 210), chronic HF (CHF) (n=813) and AHF defined as hospitalized HF at enrolment (n=790). Median follow-up was 1, 123 days with 93% follow-up rate at 2 years. Risk factors for developing AHF included age, female sex, lower body mass index, untreated coronary artery stenosis, anemia, history of HF, left ventricular ejection fraction

Background:There is discordance regarding the effect of symptom status before aortic valve replacement (AVR) on long-term outcome after AVR in severe aortic stenosis (AS). Methods and Results:The CURRENT AS registry is a multicenter retrospective registry enrolling 3, 815 consecutive patients with severe AS. Among 1, 196 patients managed with the initial AVR strategy, long-term clinical outcomes were compared between the symptomatic patients (n=905), and asymptomatic patients (n=291). Median follow-up interval was 1337 days with a 91% follow-up rate at 2 years. AVR was performed in 886 patients (98%) in the symptomatic group and in 287 patients (99%) in the asymptomatic group. Symptomatic patients were older and more often had comorbidities than asymptomatic patients with similar echocardiographic AS severity. The cumulative 5-year incidences of all-cause death and heart failure (HF) hospitalization were significantly higher in symptomatic patients than in asymptomatic patients (25.6% vs. 15.4%, P=0.001, and 14.2% vs. 3.8%, P

Two randomized control trials demonstrated that transcatheter aortic valve implantation was associated with 1-2 year clinical outcomes comparable or even superior to surgical aortic valve replacement (SAVR) in low surgical risk patients with severe aortic stenosis (AS). However, no previous study has reported the clinical outcomes after SAVR in Japanese patients with low surgical risk. From 3815 consecutive patients enrolled in the CURRENT AS registry, we retrieved 220 patients who underwent SAVR in reference to the inclusion and exclusion criteria of the PARTNER 3 trial. Age and surgical risk score in the current study population were comparable to those in the PARTNER 3 trial (Age: 75 years versus 74 years, and STS-PROM score: 2.3 versus 1.9). The cumulative incidence of a composite all-cause death or stroke was comparable between the current study population and the SAVR patients in the PARTNER 3 trial both at 30-day (2.3% versus 3.3%), and at 1-year (4.1% versus 4.9%). The clinical outcomes of SAVR in low surgical risk patients with severe AS selected from a real world Japanese registry according to the inclusion and exclusion criteria of the PARTNER 3 trial was favorable and numerically comparable to those of SAVR patients in the PARTNER 3 trial.

Background: Transcatheter aortic valve implantation (TAVI) is criticized by some as an expensive treatment in super-elder patients with limited life expectancy. However, there is a knowledge gap regarding the magnitude of clinical benefit provided by TAVI in comparison with conservative management in patients with severe aortic stenosis (AS) in real clinical practice, which would be important in the decision making for TAVI. Methods: We combined two independent registries, namely CURRENT AS and K-TAVI registries. CURRENT AS was a multicenter registry enrolling 3815 consecutive patients with severe AS irrespective to treatment modalities between January 2003 and December 2011. K-TAVI was a multicenter, prospective registry including 449 consecutive patients with severe AS, who underwent TAVI with SAPIEN XT balloon-expandable valves between October 2013 and June 2016. In these 2 registries, 449 patients received TAVI and 894 patients were managed with conservative strategy. We conducted propensity score matching and finally obtained a cohort of 556 patients (278 patients for each group) for the analysis. The primary outcome measures were all-cause death and heart failure (HF) hospitalization at 2-year. Results: The cumulative 2-year incidences of all-cause death and HF hospitalization were significantly lower in the TAVI group than in the conservative group (16.8% versus 36.6%, P, 竹治, 泰明, 谷口, 智彦, 森本, 剛, 齋藤, 成達, 安藤, 献児, 白井, 伸一, 新井, 善雄, 坂口, 元一, 福, 康志, 川瀬, 裕一, 小宮, 達彦, 江原, 夏彦, 北井, 豪, 小山, 忠明, 渡邉, 真, 渡部, 宏俊, 塩見, 紘樹, 南野-牟田, 恵里, 松田, 真太郎, 夜久, 英憲, 芳川, 裕亮, 山﨑, 和裕, 川東, 正英, 坂本, 和久, 田村, 俊寛, 三宅, 誠, 阪口, 仁寿, 村田, 耕一郎, 中井, 真尚, 泉, 知里, 稲田, 司, 竹内, 泰代, 山根, 啓一郎, 田村, 崇, 豊福, 守, 石井, 充, 猪子, 森明, 池田, 智之, 石井, 克尚, 堀田, 幸造, 陣内, 俊和, 東谷, 暢也, 犬塚, 康孝, 湊谷, 謙司, 木村, 剛

Background There has not been a previous report on the long-term outcomes of those patients who refuse aortic valve replacement (AVR) despite physicians' recommendations.Methods and Results:Among 3,815 consecutive patients with severe aortic stenosis (AS) enrolled in the CURRENT AS registry, the study population comprised 2,005 symptomatic patients, who were subdivided into 3 groups by their treatment strategy and the reasons for conservative strategy (Initial AVR group: n=905; Patient rejection group: n=256; Physician judgment group, n=844). The primary outcome measure was a composite of aortic valve-related death and heart failure hospitalization. Patients in the patient rejection group as compared with those in the physician judgment group were younger, and had less comorbidities, and lower surgical risk scores. The cumulative 5-year incidence of the primary outcome measure in the patient rejection group was markedly higher than that in the initial AVR group, and was similar to that in the physician judgment group (60.7%, 19.0%, and 66.4%, respectively). Conclusions Patient rejection was the reason for non-referral to AVR in nearly one-quarter of the symptomatic patients with severe AS who were managed conservatively. The dismal outcome in patients who refused AVR was similar to that in patients who were not referred to AVR based on physician judgment despite less comorbidities and lower surgical risk scores in the former than in the latter.

Background The annual incidence of sudden death has been reported to be low (AS ), and there is a paucity of data on the risk factors of sudden death in patients with severe AS . Methods and Results We evaluated the incidence and risk factors of sudden death during the median follow‐up period of 1334 days in the Contemporary Outcomes After Surgery and Medical Treatment in Patients With Severe Aortic Stenosis (CURRENT AS) registry enrolling 3815 consecutive patients with severe AS between 2003 and 2011. The mean age was 78 years, and the prevalences of male sex and prior myocardial infarction were 38% and 8%, respectively. Sudden death occurred in 175 patients without aortic valve replacement. The cumulative 5‐year incidences of sudden death, censored at aortic valve replacement, which accounted for the competing risk, were 9.2% in symptomatic patients and 7.2% (1.4%/year) in asymptomatic patients ( P HR ] 3.63; 95% confidence interval [ CI ] 2.42‐5.43), prior myocardial infarction ( HR 2.11; 95% CI 1.28‐3.50), body mass index HR 1.51; 95% CI 1.03‐2.21), peak aortic jet velocity ≥5 m/s ( HR 1.76; 95% CI 1.12‐2.78), and left ventricular ejection fraction HR 1.52; 95% CI 1.08‐2.14). Conclusions The incidence of sudden death in asymptomatic patients with severe AS might be higher than that reported in previous reports. Several baseline clinical and echocardiographic characteristics were associated with increased risk of sudden death. Clinical Trial Registration URL : www.umin.ac.jp/ctr/index.htm . Unique identifier: UMIN 000012140.

[Aim]To investigate the effect of malignancy on the outcomes of patients with severe aortic stenosis (AS) and the management strategy for AS with malignancy. [Methods and results]Using data of 3815 patients with severe AS in a retrospective multicentre registry [CURRENT AS (Contemporary outcomes after sURgery and medical tREatmeNT in patients with severe Aortic Stenosis) registry], we compared 3-year clinical outcomes among three groups based on malignancy status: with malignancy currently under treatment including best supportive care (malignancy group), with a history of malignancy without any current treatment (past history group), or without history of malignancy (no malignancy group). Patients in the malignancy group (n = 124) were more often men and had higher prevalence of low body mass index, recurrence of malignancy, anaemia, and asymptomatic status, despite comparable surgical risks and echocardiographic parameters. The malignancy group or the past history group (n = 389) had significantly higher risk for all-cause death [hazard ratio (HR) 2.49, 95% CI (95% confidence interval) 1.98–3.14; HR 1.23, 95% CI 1.04–1.46] and for malignancy-related death (HR 16.2, 95% CI 10.64–24.54; HR 3.66, 95% CI 2.43–5.52) than that of the no malignancy group (n = 3302). The excess risk for aortic valve-related death was not observed in the malignancy group (HR 0.79, 95% CI 0.48–1.29) and was lower in the past history group (HR 0.72, 95% CI 0.53–0.96). In the malignancy group, the treatment strategy (surgery: n = 16, conservative management: n = 108) was determined based on the clinical status of AS or life expectancy. [Conclusions]Malignancy had marked effect on all-cause death and malignancy-related death in patients with severe AS. History of malignancy also had a smaller but significant effect on mortality.

It is unknown how much different are the clinical outcomes between asymptomatic and symptomatic patients with severe aortic stenosis (AS). In the CURRENT AS registry enrolling 3,815 consecutive patients with severe AS, we compared the long-term outcomes between 1808 asymptomatic and 1215 symptomatic patients (exertional dyspnea: N = 813, syncope: N = 136, and angina: N = 266) without heart failure (HF) hospitalization. Symptomatic patients had greater AS severity, and more depressed left ventricular function than asymptomatic patients without much difference in other baseline characteristics. During a median follow-up of 3.2 years, aortic valve replacement (AVR) was performed in 62% of symptomatic patients, and 38% of asymptomatic patients. The cumulative 5-year incidences for the primary outcome measure (a composite of aortic valve-related death or HF hospitalization) was higher in symptomatic patients than in asymptomatic patients (32.3% versus 27.6%, P

Whether patients with severe aortic stenosis (AS) die because of AS-related causes is an important issue for the management of these patients. We used data from CURRENT AS registry, a Japanese multicenter registry, to assess the causes of death in severe AS patients and to identify the factors associated with non-cardiac mortality. We enrolled 3815 consecutive patients with a median follow-up of 1176 days; the 1449 overall deaths comprised 802 (55.3%) from cardiac and 647 (44.7%) from non-cardiac causes. Heart failure (HF) (25.7%) and sudden death (13.0%) caused the most cardiac deaths, whereas infection (13.0%) and malignancy (11.1%) were the main non-cardiac causes. According to treatment strategies, infection was the most common cause of non-cardiac death, followed by malignancy, in both the initial aortic valve replacement (AVR) cohort (N = 1197), and the conservative management cohort (N = 2618). Both non-cardiac factors (age, male, body mass index

The aim of this study was to evaluate the prognostic impact of left ventricular ejection fraction (LVEF) in patients with severe aortic stenosis (AS).The prognostic impact of LVEF in severe AS remains controversial.Among 3,815 consecutive patients with severe AS enrolled in the CURRENT AS (Contemporary Outcomes After Surgery and Medical Treatment in Patients With Severe Aortic Stenosis) registry, the present study population consisted of 3,794 patients after excluding 21 patients without LVEF data. Patients were divided into 4 groups according to LVEF at index echocardiography (50%, 50% to 59%, 60% to 69%, and ≥70%; conservative strategy: n = 388, n = 390, n = 1,025, and n = 800; initial aortic valve replacement strategy: n = 206, n = 170, n = 375, and n = 440). Echocardiographic data were site reported, and there was no echocardiography core laboratory.In the conservative group, the cumulative 5-year incidence of the primary outcome measure (a composite of aortic valve-related death or heart failure hospitalization) was significantly higher in patients with LVEFs 50% and 50% to 59% than in those with LVEFs 60% to 69% and ≥70% (72.3%, 58.4%, 38.7%, and 35.0%, respectively, p 0.001), whereas in the initial aortic valve replacement group, the negative effect of low LVEF was markedly attenuated (20.2%, 20.3%, 17.7%, and 12.4%, respectively, p = 0.03). After adjusting for confounders, LVEF 50% (hazard ratio: 1.82; 95% confidence interval: 1.44 to 2.28; p 0.001) and 50% to 59% (hazard ratio: 1.77; 95% confidence interval: 1.42 to 2.20; p 0.001) but not 60% to 69% (hazard ratio: 1.14; 95% confidence interval: 0.94 to 1.39; p = 0.17) were independently associated with poorer outcomes compared with LVEF ≥70% (reference) in the conservative group. In the initial aortic valve replacement group, the adjusted risk for the primary outcome measure was not significantly different across the 4 LVEF groups.This study demonstrates that survival in patients with severe AS is impaired when LVEF is 60%, and these findings have implications for decision making with regard to the timing of surgical intervention.

Background There are limited data regarding the risk stratification based on peak aortic jet velocity (Vmax) in patients with severe aortic stenosis ( AS ). Methods and Results Among 3815 consecutive patients with severe AS enrolled in the CURRENT AS (Contemporary Outcomes After Surgery and Medical Treatment in Patients With Severe Aortic Stenosis) registry, the study population consisted of 1075 conservatively managed patients with Vmax ≥4.0 m/s and left ventricular ejection fraction ≥50%. The study patients were subdivided into 3 groups based on Vmax (group 1, 4.0 ≤ Vmax AS ‐related events (aortic valve–related death or heart failure hospitalization) was incrementally higher with increasing Vmax (entire population; 38.0%, 49.4%, and 62.8%, P P =0.008; and asymptomatic patients; 29.4%, 38.9%, and 47.7%, P =0.005). After adjusting for confounders, the excess risk of group 2 and group 3 relative to group 1 for AS ‐related events remained significant (hazard ratio, 1.39; 95% CI , 1.07–1.81; P =0.02, and hazard ratio, 1.53; 95% CI , 1.17–2.00; P =0.002, respectively). The effect size of group 3 relative to group 1 for AS ‐related events in asymptomatic patients (N=479) was similar to that in symptomatic patients (N=596; hazard ratio, 1.59; 95% CI , 1.01–2.52; P =0.047, and hazard ratio, 1.67; 95% CI , 1.16–2.40, P =0.008, respectively), and there was no significant overall interaction between the symptomatic status and the effect of the Vmax categories on AS ‐related events (interaction, P =0.88). Conclusions In conservatively managed severe AS patients with preserved left ventricular ejection fraction, increasing Vmax was associated with incrementally higher risk for AS ‐related events. However, the cumulative 5‐year incidence of the AS ‐related events remained very high even in asymptomatic patients with less greater Vmax.

There is a paucity of data on the sex differences in the prevalence, clinical presentation, and prognosis of aortic stenosis (AS).Methods and Results:A total of 3,815 consecutive patients with severe AS were enrolled in the multicenter CURRENT AS registry between January 2003 and December 2011. The registry included 1,443 men (38%) and 2,372 women (62%). Women were much older than men (79±10 vs. 75±10 years, P0.0001), and the ratio of women to men increased with age. The cumulative 5-year incidence of all-cause death was significantly higher in men than in women (47% vs. 41%, P=0.003), although women were more symptomatic and much older. The 5-year mortality was similar between men and women at age65 years (16% vs. 15%, P=0.99), whereas it was significantly higher in men than in women at age ≥65 years (65-74 years, 38% vs. 19%, P0.0001; 75-84 years, 55% vs. 34%, P0.0001; ≥85 years: 82% vs. 72%, P=0.03).A large Japanese multicenter registry of consecutive patients with severe AS included a much higher proportion of women than men, with the female:male sex ratio increasing with age. The 5-year mortality rate of women was lower than that of men. Lower 5-year mortality rates in women were consistently seen across all age groups65 years.

ObjectivesWe sought to evaluate the prognostic impact of the B-type natriuretic peptide (BNP) levels in patients with asymptomatic severe aortic stenosis (AS), who were not referred for aortic valve replacement (AVR).MethodsWe used data from a Japanese multicentre registry, the Contemporary outcomes after sURgery and medical tREatmeNT in patients with severe Aortic Stenosis Registry, which enrolled 3815 consecutive patients with severe AS. Of those, 387 asymptomatic patients who were not referred for AVR without left ventricular dysfunction and very severe AS were subdivided into four groups based on their BNP levels (BNP300 pg/mL, n=50).ResultsThe cumulative 5-year incidence of AS-related events (aortic valve-related death or heart failure hospitalisation) was incrementally higher with increasing BNP level (14.2%, 29.6%, 46.3% and 47.0%, pConclusionsIncreased BNP level was associated with a higher risk for AS-related adverse events in patients with asymptomatic severe AS with normal left ventricular ejection fraction who were not referred for AVR. Asymptomatic patients with BNP levels of Trail registration numberUMIN000012140.

Congenital contractural arachnodactyly (CCA) is a rare connective tissue disorder characterized by marfanoid habitus with camptodactyly. However, cardiac features have rarely been documented in adults. We herein report a sporadic case of CCA in a 20-year-old woman who developed decompensated dilated cardiomyopathy. The patient did not have any mutations in the FBN1 or FBN2 genes, which are most commonly associated with Marfan syndrome and CCA, respectively. Although whether these two diseases are caused by a mutation(s) in the same gene or two different genes remains unknown, this case provides new clinical insight into the cardiovascular management of CCA.

Aquaporin-2 (AQP2) is responsible for the concentration of urine in the kidney collecting tubule under the regulation of vasopressin. The mRNA level of this water channel in polydipsic STR/N mice was extremely reduced compared with that in normal ICR mice. In male mice, reduction of the AQP2 mRNA level was not evident at 3 wk of age, at which time water intake was not increased. At 10 wk of age, however, the AQP2 mRNA level was reduced to 10% of that in control mice, whereas water intake was increased by 36%. At 44 wk, the water intake became five times that of the control ICR mice, and the AQP2 mRNA level in these polydipsic mice was only ∼5% of control. Similar changes were observed in the AQP2 protein level, suggesting that the mRNA level of AQP2 reflects the protein level of AQP2. These inverse changes in the AQP2 mRNA level and water intake were also evident in female mice. The data imply that polydipsia in STR/N mice may have affected AQP2 mRNA transcription in the kidney, resulting in reduced AQP2 expression, which would contribute to a reduction in overretention of water.

The expression and localization of aquaporins (AQP1-AQP5), members of the water channel family, in the developing rat submandibular gland were analysed using RT-PCR, Northern blotting and immunohistochemistry to explore their relation to the development of this salivary gland. RT-PCR analysis revealed unique expression patterns of each AQP. AQP1 was expressed constitutively during prenatal development, whereas the expression of AQP5 became more intense in the course of development from embryonic day 16.5 (E16) to E20. These expression patterns concurred with the results of Northern blot analysis. AQP3 and AQP4 mRNAs in the prenatal development were not detected in Northern blots, although they were detected by RT-PCR. During postnatal development, AQP5 and AQP1 mRNAs were expressed continuously, but no message for AQP3 or AQP4 was detected. AQP2 mRNA was not detected during either prenatal or postnatal development in this tissue. Immunohistochemical studies revealed that AQP5 was first localized at the apical membrane of proacinar cells at E18, and then became clearly distributed at the apical membrane of acinar cells in accordance with the differentiation and establishment of the mature acini. In addition, some vasculature also showed immunoreactivity for AQP5. AQP1 was immunolocalized in the blood vessels, including capillaries, of the gland throughout development. These observations suggest the existence of transcriptional regulation of rat AQP5, which is one of the most probable regulators of saliva production and secretion, during the establishment of the functional submandibular salivary gland.

We investigated the effects of decerebration on long-term variations in arterial blood pressure during paradoxical sleep (PS) in cats. In normal cats, the blood pressure decreased during the transition from slow wave sleep to PS and maintained its lower level throughout PS for several days after surgery. After this early postoperative stage, however, the arterial hypotension was replaced by tonic and phasic rises in blood pressure during PS. Such long-term changes in blood pressure were completely abolished when the brain stem was transected at the ponto-mesencepholic junction, and the cats consistently exhibited a sustained fall in blood pressure throughout the survival periods of 1 month or more.

Using a new telemetric system for arterial blood pressure recordings, we have investigated long-term postoperative changes in blood pressure during sleep in freely moving cats. Particular attention was paid to the transitional periods at the beginning and end of paradoxical sleep (PS), as well as to the relationships between the blood pressure and ponto-geniculo-occipital (PGO) waves. In the initial postoperative stage lasting 2 to 5 days, the blood pressure decreased during the transition from slow wave sleep (SWS) to PS and maintained its lower level until the end of PS. In contrast, in the later chronic stage, the blood pressure increased tonically during the transition from SWS to PS and maintained its higher level throughout PS on which several phasic rises in blood pressure were superimposed. A significant increase in arterial pressure during the transitional period began shortly after the first appearance of PGO waves. On the other hand, significant phasic rises in arterial pressure during PS shortly preceded the onset of PGO wave bursts.

The temporospatial expression of PACE4, a member of the mammalian subtilisin-like proprotein convertase family involved in the activation of growth/differentiation factors, was investigated by in situ hybridization during the development of the rat submandibular gland (SMG). At the initiation stage (day 15.5 of gestation; E15), PACE4 was intensely expressed in the submandibular epithelium, but weakly expressed in the mesenchymal cells. At E16 when the branching morphogenesis becomes obvious, the expression of PACE4 in the mesenchyme was further decreased, although its level in the submandibular epithelium had not changed remarkably from that at E15. During the next stage of embryonic development (E17-E20), PACE4 was expressed in the cells derived from the submandibular epithelium, which include the proacinar, terminal tubular, and presumptive ductal cells. In the perinatal SMG, PACE4 was still expressed intensely in the terminal portion of the SMG containing the proacinar and terminal tubular cells, whereas its expression in the ductal cells was obviously decreased at the second postnatal day (P2) and at P6. Acinar cells expressing no PACE4 appeared, and their numbers increased following their development (P9-P20). At P30 when the PACE4 expression in the acinar cells was completely suppressed, its expression in the ductal cells became intense again. This temporospatially regulated expression of PACE4 suggests its apparent association with the proliferation, differentiation, and establishment of functional acinar and ductal cells of the SMG.

By Western blot analysis, the expression level of aquaporin (AQP) 5 in the submandibular gland (SMG) was found to be different among individual rats of the Sprague-Dawley (SD) strain. Such differences were observed for AQP5 but not for AQP1 and consequently the SD strain was divided into two groups, one expressing a high level of AQP5 and the other a low one. The difference in average intensity of expression between the two groups was more than twofold. Immunohistochemical analysis of the SMG demonstrated that the AQP5 protein was localized in the basal and apical/lateral plasma membrane of acinar cells in rats expressing the high level of AQP5. In the rat expressing the low level, however, this channel protein was localized strongly in the apical/lateral plasma membrane, but only very weakly in the basal membrane of the acinar cells. Such a diverse localization of AQP5 was confirmed by Western blotting as well. Breeding between brother and sister was repeated for two times within high expressers and low expressers to obtain the third generation progenies (F2); the AQP5 level of the SMG in the third generation (F2 rats) from high expressers was significantly higher than the F2 from low expressers. Our present study suggests the existence of genetic variation in the expression of a water channel protein, AQP5, in rats.

Objective Chemoradiotherapy is a popular definitive therapy for esophageal carcinoma among many patients and oncologists. Although the complete response rates are high and short-term survival is favorable after chemoradiotherapy, persistent or recurrent locoregional disease is frequent. Salvage surgery is the sole curative intent treatment option for this course of the disease. The present study evaluates the safety and value of salvage esophagectomy for locoregional failure after high-dose definitive chemoradiotherapy for esophageal squamous cell carcinoma. Methods We reviewed 59 consecutive patients with thoracic esophageal squamous cell carcinoma who underwent salvage esophagectomy after definitive chemoradiotherapy. All patients received more than 60 Gy of radiation plus concurrent chemotherapy for curative intent. The data were compared with those of patients who received esophagectomy without preoperative therapy. Results Postoperative morbidity and mortality rates were increased among patients who underwent salvage esophagectomy compared with those who underwent esophagectomy without preoperative therapy (mean hospital stay, 38 vs 33 days; anastomotic leak rates, 31% vs 25%; respiratory complication rates, 31% vs 20%; reintubation within 1 week, 2% vs 2%; hospital mortality rates, 8% vs 2%). Tracheobronchial necrosis and gastric conduit necrosis were highly lethal complications after salvage esophagectomy; 3-year postoperative survivals were 38% and 58%, respectively. Conclusion Patients who underwent salvage esophagectomy after definitive high-dose chemoradiotherapy had increased morbidity and mortality. Nevertheless, this is acceptable in view of the potential long-term survival after salvage esophagectomy. Such treatment should be considered for carefully selected patients at specialized centers.

Background Current guidelines generally recommend watchful waiting until symptoms emerge for aortic valve replacement (AVR) in asymptomatic patients with severe aortic stenosis (AS). Objectives The study sought to compare the long-term outcomes of initial AVR versus conservative strategies following the diagnosis of asymptomatic severe AS. Methods We used data from a large multicenter registry enrolling 3,815 consecutive patients with severe AS (peak aortic jet velocity >4.0 m/s, or mean aortic pressure gradient >40 mm Hg, or aortic valve area