Peripheral Venous Pressure Measurements to Evaluate Congestion in Heart Failure.

BACKGROUND: Accurate bedside assessment of congestion in the management of patients with heart failure remains challenging. As a continuous conduit of circulating fluid, systemic congestion represented by high right atrial pressure (RAP) may be reflected by peripheral venous pressure (PVP). We evaluated the reliability of PVP measurements for assessing congestion beyond conventional clinical assessments. METHODS AND RESULTS: We performed conventional congestion assessments and PVP measurements in 95 patients undergoing pulmonary artery catheterization. PVP was measured via the 22-gauge peripheral venous access placed in the upper extremity. The median RAP and PVP was 7 (interquartile range [IQR]: 5-11) mmHg and 9 (IQR: 7-12) mmHg, respectively, with a mean bias of 1.8 ± 2.6 mmHg. PVP exhibited a strong linear correlation with RAP (Spearman R = 0.81; P < 0.001). PVP demonstrated greater discriminatory power for both RAP ≤ 8 mmHg (area under the curve [AUC]: 0.91 [95% confidence interval: 0.85-0.97]; sensitivity: 75%; specificity: 87%) and RAP > 12 mmHg (AUC: 0.98 [0.95-1.00]; sensitivity: 88%; specificity: 95%) than edema, jugular venous pressure, pulmonary congestion on chest radiograph, B-type natriuretic peptide levels, and inferior vena cava diameter. CONCLUSIONS: PVP measured via peripheral venous access strongly correlates with invasively obtained RAP. PVP measurements may improve current bedside assessments of congestion.

Prognostic Value of the Severity of Clinical Congestion in Patients Hospitalized for Decompensated Heart Failure: Findings From the Japanese KCHF Registry.

BACKGROUND: Congestion is a leading cause of hospitalization and a major therapeutic target in patients with heart failure (HF). Clinical practice in Japan is characterized by a long hospital stay, which facilitates more extensive decongestion during hospitalization. We herein examined the time course and prognostic impact of clinical congestion in a large contemporary Japanese cohort of HF. METHODS AND RESULTS: Peripheral edema, jugular venous pressure, and orthopnea were graded on a standardized 4-point scale (0-3) in 3787 hospitalized patients in a Japanese cohort of HF. Composite Congestion Scores (CCS) on admission and at discharge were calculated by summing individual scores. The primary outcome was a composite of all-cause death or HF hospitalization. The median admission CCS was 4 (interquartile range, 3-6). Overall, 255 patients died during the median hospitalization length of 16 days, and 1395 died or were hospitalized for HF over a median postdischarge follow-up of 396 days. The cumulative 1-year incidence of the primary outcome increased at higher tertiles of congestion on admission (32.5%, 39.3%, and 41.0% in the mild [CCS ≤3], moderate [CCS = 4 or 5], and severe [CCS ≥6] congestion groups, respectively, log-rank P < .001). The adjusted hazard ratios of moderate and severe congestion relative to mild congestion were 1.205 (95% confidence interval [CI], 1.065-1.365; P = .003) and 1.247 (95% CI, 1.103-1.410; P < .001), respectively. Among 3445 patients discharged alive, 85% had CCS of 0 (complete decongestion) and 15% had a CCS of 1 or more (residual congestion) at discharge. Although residual congestion predicted a risk of postdischarge death or HF hospitalization (adjusted hazard ratio, 1.314 [1.145-1.509]; P < .001), the admission CCS correlated with the risk of postdischarge death or HF hospitalization, even in the complete decongestion group. No correlation was observed for postdischarge death or HF hospitalization between residual congestion at discharge and admission CCS (P for the interaction = .316). CONCLUSIONS: In total, 85% of patients were discharged with complete decongestion in Japanese clinical practice. Clinical congestion, on admission and at discharge, was of prognostic value. The severity of congestion on admission was predictive of adverse outcomes, even in the absence of residual congestion. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT02334891 (NCT02334891) https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000017241 (UMIN000015238).

Sex Differences in Clinical Outcomes After Percutaneous Coronary Intervention.

BACKGROUND: There is a scarcity of studies comparing the clinical outcomes after percutaneous coronary intervention (PCI) for women and men stratified by the presentation of acute coronary syndromes (ACS) or stable coronary artery disease (CAD).Methods and Results: The study population included 26,316 patients who underwent PCI (ACS: n=11,119, stable CAD: n=15,197) from the CREDO-Kyoto PCI/CABG registry Cohort-2 and Cohort-3. The primary outcome was all-cause death. Among patients with ACS, women as compared with men were much older. Among patients with stable CAD, women were also older than men, but with smaller difference. The cumulative 5-year incidence of all-cause death was significantly higher in women than in men in the ACS group (26.2% and 17.9%, log rank P<0.001). In contrast, it was significantly lower in women than in men in the stable CAD group (14.2% and 15.8%, log rank P=0.005). After adjusting confounders, women as compared with men were associated with significantly lower long-term mortality risk with stable CAD but not with ACS (hazard ratio [HR]: 0.75, 95% confidence interval [CI]: 0.69-0.82, P<0.001, and HR: 0.92, 95% CI: 0.84-1.01, P=0.07, respectively). There was a significant interaction between the clinical presentation and the mortality risk of women relative to men (interaction P=0.002). CONCLUSIONS: Compared with men, women had significantly lower adjusted mortality risk after PCI among patients with stable CAD, but not among those with ACS.

Polypharmacy and Bleeding Outcomes After Percutaneous Coronary Intervention.

BACKGROUND: Polypharmacy was reported to be associated with major bleeding in various populations. However, there are no data on polypharmacy and its association with bleeding in patients undergoing percutaneous coronary intervention (PCI).Methods and Results: Among 12,291 patients in the CREDO-Kyoto PCI Registry Cohort-3, we evaluated the number of medications at discharge and compared major bleeding, defined as Bleeding Academic Research Consortium Type 3 or 5 bleeding, across tertiles (T1-3) of the number of medications. The median number of medications was 6, and 88.0% of patients were on ≥5 medications. The cumulative 5-year incidence of major bleeding increased incrementally with increasing number of medications (T1 [≤5 medications] 12.5%, T2 [6-7] 16.5%, and T3 [≥8] 20.4%; log-rank P<0.001). After adjusting for confounders, the risks for major bleeding of T2 (hazard ratio [HR] 1.21; 95% confidence interval [CI] 1.08-1.36; P=0.001) and T3 (HR 1.27; 95% CI 1.12-1.45; P<0.001) relative to T1 remained significant. The adjusted risks of T2 and T3 relative to T1 were not significant for a composite of myocardial infarction or ischemic stroke (HR 0.95 [95% CI 0.83-1.09; P=0.47] and HR 1.06 [95% CI 0.91-1.23; P=0.48], respectively). CONCLUSIONS: In a real-world population of patients undergoing PCI, approximately 90% were on ≥5 medications. Increasing number of medications was associated with a higher adjusted risk for major bleeding, but not ischemic events.

Bleeding Outcomes After Percutaneous Coronary Intervention in the Past Two Decades in Japan　- From the CREDO-Kyoto Registry Cohort-2 and Cohort-3.

BACKGROUND: Optimal intensity is unclear for P2Y12receptor blocker therapy after percutaneous coronary intervention (PCI) in real-world clinical practice.Methods and Results: From the CREDO-Kyoto Registry, the current study population consisted of 25,419 patients (Cohort-2: n=12,161 and Cohort-3: n=13,258) who underwent their first PCI. P2Y12receptor blocker therapies were reduced dose of ticlopidine (200 mg/day), and global dose of clopidogrel (75 mg/day) in 87.7% and 94.8% of patients in Cohort-2 and Cohort-3, respectively. Cumulative 3-year incidence of GUSTO moderate/severe bleeding was significantly higher in Cohort-3 than in Cohort-2 (12.1% and 9.0%, P<0.0001). After adjusting 17 demographic factors and 9 management factors potentially related to the bleeding events other than the type of P2Y12receptor blocker, the higher bleeding risk in Cohort-3 relative to Cohort-2 remained significant (hazard ratio (HR): 1.52 95% confidence interval (CI) 1.37-1.68, P<0.0001). Cohort-3 compared with Cohort-2 was not associated with lower adjusted risk for myocardial infarction/ischemic stroke (HR: 0.96, 95% CI: 0.87-1.06, P=0.44). CONCLUSIONS: In this historical comparative study, Cohort-3 compared with Cohort-2 was associated with excess bleeding risk, which might be at least partly explained by the difference in P2Y12receptor blockers.

Concomitant Mitral Regurgitation in Severe Aortic Stenosis　- A Report From the CURRENT AS Registry.

BACKGROUND: The clinical significance of concomitant mitral regurgitation (MR) has not been well addressed in patients with severe aortic stenosis (AS).Methods and Results:We analyzed 3,815 patients from a retrospective multicenter registry of severe AS in Japan (CURRENT AS registry). We compared the clinical outcomes between patients with moderate/severe MR and with none/mild MR according to the initial treatment strategy (initial aortic valve replacement [AVR] or conservative strategy). The primary outcome measure was a composite of aortic valve-related death or heart failure hospitalization. At baseline, moderate/severe MR was present in 227/1,197 (19%) patients with initial AVR strategy and in 536/2,618 (20%) patients with a conservative strategy. The crude cumulative 5-year incidence of the primary outcome measure was significantly higher in patients with moderate/severe MR than in those with none/mild MR, regardless of the initial treatment strategy (25.2% vs. 14.4%, P<0.001 in the initial AVR strategy, and 63.3% vs. 40.7%, P<0.001 in the conservative strategy). After adjusting confounders, moderate/severe MR was not independently associated with higher risk for the primary outcome measure in the initial AVR strategy (hazard ratio [HR] 1.11, 95% confidence interval [CI] 0.67-1.83, P=0.69), and in the conservative strategy (HR 1.13, 95% CI 0.93-1.37, P=0.22). CONCLUSIONS: Concomitant moderate/severe MR was not independently associated with higher risk for the primary outcome measure regardless of the initial treatment strategy.

Effects of Acute Coronary Syndrome and Stable Coronary Artery Disease on Bleeding and Ischemic Risk After Percutaneous Coronary Intervention.

BACKGROUND: Data evaluating the effects of acute coronary syndrome (ACS) relative to stable coronary artery disease (CAD) on bleeding risk after percutaneous coronary intervention (PCI) are scarce.Methods and Results:From the CREDO-Kyoto Registry Cohort-3, 13,258 patients undergoing first PCI (5,521 ACS; 7,737 stable CAD) were identified. Patients were further stratified according to ACS presentation and Academic Research Consortium High Bleeding Risk (HBR): ACS/HBR: n=2,502; ACS/no-HBR: n=3,019; stable CAD/HBR: n=3,905; and stable CAD/no-HBR: n=3,832. The primary bleeding endpoint was Bleeding Academic Research Consortium 3/5 bleeding, whereas the primary ischemic endpoint was myocardial infarction (MI)/ischemic stroke. Compared with stable CAD, ACS was associated with a significantly higher adjusted risk for bleeding (hazard ratio [HR] 1.85; 95% confidence interval [CI] 1.68-2.03; P<0.0001), with a markedly higher risk within 30 days (HR 4.24; 95% CI 3.56-5.06; P<0.0001). Compared with the stable CAD/no-HBR group, the ACS/HBR, no-ACS/HBR, and ACS/no-HBR groups were associated with significantly higher adjusted risks for bleeding, with HRs of 3.05 (95% CI 2.64-3.54; P<0.0001), 1.89 (95% CI 1.66-2.15; P<0.0001), and 1.69 (95% CI 1.45-1.98; P<0.0001), respectively. There was no excess adjusted risk of the ACS relative to stable CAD group for MI/ischemic stroke (HR 1.07; 95% CI 0.94-1.22; P=0.33). CONCLUSIONS: Bleeding risk after PCI depended on both ACS presentation and HBR, with a significant effect of ACS within 30 days.

Long-Term Impact of Diabetes Mellitus on Initially Conservatively Managed Patients With Severe Aortic Stenosis.

BACKGROUND: Although diabetes mellitus (DM) is a common comorbidity of aortic stenosis (AS), clinical evidence about the long-term effect of DM on patients with AS is insufficient.Methods and Results:Data were acquired from CURRENT AS, a large Japanese multicenter registry that enrolled 3,815 patients with severe AS. Patients without initial valve replacement were defined as the conservative group; among them, 621 (23.4%) had DM, whereas 1997 did not. The DM group was further divided into 2 groups according to insulin treatment (insulin-treated DM, n=130; non-insulin treated DM, n=491). The primary outcome was a composite of aortic valve (AV)-related death and heart failure (HF) hospitalization. Secondary outcomes were AV-related death, HF hospitalization, all-cause death, cardiovascular death, sudden death, and surgical or transcatheter AV replacement during follow up. As a result, DM was associated with higher risk for the primary outcome (52.8% vs. 42.9%, P<0.001), with a statistically significant adjusted hazard ratio (HR 1.33, 95% confidence interval: 1.14-1.56, P<0.001). All secondary outcomes were not significantly different between DM and non-DM patients after adjusting for confounding factors, except for HF hospitalization. Insulin use was not associated with higher incidence of primary or secondary outcome. CONCLUSIONS: In initially conservatively managed patients with AS, DM was independently associated with higher risk for a composite of AV-related death or HF hospitalization; however, insulin use was not associated with poor outcomes.

Effects of Body Weight on Bleeding and Ischemic Events in Patients Undergoing Percutaneous Coronary Intervention　- From the CREDO-Kyoto Registry Cohort-2.

BACKGROUND: 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%, P<0.001, and 13.9%, 11.3%, and 10.2%, P<0.001; female Tertiles 1, 2, and 3: 17.9%, 12.9%, and 10.1%, P<0.001, and 17.9%, 12.9%, and 10.1%, P<0.001). 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). CONCLUSIONS: 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.

Age-Related Differences in the Effects of Initial Aortic Valve Replacement vs. Conservative Strategy on Long-Term Outcomes in Asymptomatic Patients With Severe Aortic Stenosis.

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 <75 years (initial AVR: n=167, and conservative: n=475). Median follow-up interval was 1,280 (interquartile range [IQR]: 1,012-1,611) days, and 1461 (IQR: 1,132-1,886) days in patients aged ≥ and <75 years, respectively. The favorable effect of the initial AVR strategy relative to conservative strategy for heart failure (HF) hospitalization was seen regardless of the age stratum (≥75 years: adjusted hazard ratio [HR] 0.13, 95% confidence interval [CI] 0.05-0.34, and <75 years: HR 0.37, 95% CI 0.14-0.99, interaction P=0.35). However, the lower mortality risk of the initial AVR strategy relative to conservative strategy was significant in patients aged ≥75 years, but not in patients <75 years, with significant interaction (HR 0.35, 95% CI 0.20-0.61, and HR 0.69, 95% CI 0.41-1.16, interaction P=0.016). CONCLUSIONS: The benefit of initial AVR in reducing HF hospitalization in asymptomatic patients with severe AS was consistently seen regardless of age. The magnitude of mortality benefit of initial AVR was greater in super-elder patients than in non-super-elder patients.

Transcatheter Aortic Valve Implantation vs. Surgical Aortic Valve Replacement for Severe Aortic Stenosis in Real-World Clinical Practice.

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.

MicroRNA-33 Controls Adaptive Fibrotic Response in the Remodeling Heart by Preserving Lipid Raft Cholesterol.

RATIONALE: Heart failure and atherosclerosis share the underlying mechanisms of chronic inflammation followed by fibrosis. A highly conserved microRNA (miR), miR-33, is considered as a potential therapeutic target for atherosclerosis because it regulates lipid metabolism and inflammation. However, the role of miR-33 in heart failure remains to be elucidated. OBJECTIVE: To clarify the role of miR-33 involved in heart failure. METHODS AND RESULTS: We first investigated the expression levels of miR-33a/b in human cardiac tissue samples with dilated cardiomyopathy. Increased expression of miR-33a was associated with improving hemodynamic parameters. To clarify the role of miR-33 in remodeling hearts, we investigated the responses to pressure overload by transverse aortic constriction in miR-33-deficient (knockout [KO]) mice. When mice were subjected to transverse aortic constriction, miR-33 expression levels were significantly upregulated in wild-type left ventricles. There was no difference in hypertrophic responses between wild-type and miR-33KO hearts, whereas cardiac fibrosis was ameliorated in miR-33KO hearts compared with wild-type hearts. Despite the ameliorated cardiac fibrosis, miR-33KO mice showed impaired systolic function after transverse aortic constriction. We also found that cardiac fibroblasts were mainly responsible for miR-33 expression in the heart. Deficiency of miR-33 impaired cardiac fibroblast proliferation, which was considered to be caused by altered lipid raft cholesterol content. Moreover, cardiac fibroblast-specific miR-33-deficient mice also showed decreased cardiac fibrosis induced by transverse aortic constriction as systemic miR-33KO mice. CONCLUSION: Our results demonstrate that miR-33 is involved in cardiac remodeling, and it preserves lipid raft cholesterol content in fibroblasts and maintains adaptive fibrotic responses in the remodeling heart.

Reasons for Choosing Conservative Management in Symptomatic Patients With Severe Aortic Stenosis　- Observations From the CURRENT AS Registry.

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.

Early Surgery vs. Surgery After Watchful Waiting for Asymptomatic Severe Aortic Stenosis.

BACKGROUND: There is no large-scale study comparing postoperative mortality after aortic valve replacement (AVR) for asymptomatic severe aortic stenosis (AS) between initial treatment with AVR vs. eventual AVR after conservative management. Methods and Results: We analyzed data from a multicenter registry enrolling 3,815 consecutive patients with severe AS. Of 1,808 asymptomatic patients, 286 patients initially underwent AVR (initial AVR group), and 377 patients were initially managed conservatively and eventually underwent AVR (AVR after watchful waiting group). Mortality after AVR was compared between the 2 groups. Subgroup analysis according to peak aortic jet velocity (Vmax) at diagnosis was also conducted. There was no significant difference between the 2 groups in 5-year overall survival (OS; 86.0% vs. 84.1%, P=0.34) or cardiovascular death-free survival (DFS; 91.3% vs. 91.1%, P=0.61), but on subgroup analysis of patients with Vmax ≥4.5 m/s at diagnosis, the initial AVR group was superior to the AVR after watchful waiting group in both 5-year OS (88.4% vs. 70.6%, P=0.003) and cardiovascular DFS (91.9% vs. 81.7%, P=0.023). CONCLUSIONS: Asymptomatic severe AS patients who underwent AVR after watchful waiting had a postoperative survival rate similar to those who initially underwent AVR. In a subgroup of patients with Vmax ≥4.5 m/s at diagnosis, however, the AVR after watchful waiting group had worse postoperative survival rate than the initial AVR group.

Acute Heart Failure in Patients With Severe Aortic Stenosis　- Insights From the CURRENT AS Registry.

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 <50%, presence of any combined valvular disease, peak aortic jet velocity ≥5 m/s and tricuspid regurgitation pressure gradient ≥40 mmHg, and negative risk factors included dyslipidemia, history of percutaneous coronary intervention and hemodialysis. Respective cumulative 5-year incidences of all-cause death and HF hospitalization in No HF, CHF and AHF groups were 37.1%, 41.8% and 61.8% (P<0.001) and 20.7%, 33.8% and 52.3% (P<0.001). Even in the initial aortic valve replacement (AVR) stratum, AHF was associated with excess 5-year mortality risk relative to No HF and CHF (adjusted hazard ratio [HR] 1.64; 95% confidence interval [CI]: 1.14-2.36, P=0.008; adjusted HR 1.47; 95% CI: 1.03-2.11, P=0.03, respectively). CONCLUSIONS: AHF complicating severe AS was associated with an extremely dismal prognosis, which could not be fully resolved by AVR. Careful management to avoid the development of AHF is crucial.

Five-Year Clinical Outcome of Asymptomatic vs. Symptomatic Severe Aortic Stenosis After Aortic Valve Replacement.

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<0.001, respectively). On landmark analysis at 30 days after AVR, the differences in mortality and HF hospitalization between the 2 groups were mainly observed beyond 30 days. CONCLUSIONS: When managed with the initial AVR strategy, the long-term outcomes of symptomatic severe AS were worse than those of asymptomatic severe AS. Early AVR strategy might be recommended in some selected asymptomatic severe AS patients with reasonable operative risk.

Sex Differences in Severe Aortic Stenosis　- Clinical Presentation and Mortality.

BACKGROUND: 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, P<0.0001), 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 age <65 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%, P<0.0001; 75-84 years, 55% vs. 34%, P<0.0001; ≥85 years: 82% vs. 72%, P=0.03). CONCLUSIONS: 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 groups >65 years.

Auxiliary roles of nardilysin in the early diagnosis of acute coronary syndrome: a prospective cohort study, the Nardi-ACS study.

Acute coronary syndrome (ACS) includes myocardial infarction (MI) and unstable angina (UA). MI is defined by elevated necrosis markers, preferably high-sensitivity cardiac troponins (hs-cTn). However, it takes hours for cTn to become elevated after coronary occlusion; therefore, difficulties are associated with diagnosing early post-onset MI or UA. The aim of this prospective cohort study was to examine the diagnostic ability of serum nardilysin (NRDC) for the early detection of ACS. This study consisted of two sequential cohorts, the Phase I cohort, 435 patients presenting to the emergency room (ER) with chest pain, and the Phase II cohort, 486 patients with chest pain who underwent coronary angiography. The final diagnosis was ACS in 155 out of 435 patients (35.6%) in the phase I and 418 out of 486 (86.0%) in the phase II cohort. Among 680 patients who presented within 24 h of onset, 466 patients (68.5%) were diagnosed with ACS. Serum NRDC levels were significantly higher in patients with ACS than in those without ACS. The sensitivity of NRDC in patients who presented within 6 h after the onset was higher than that of hsTnI, and the AUC of NRDC within 1 h of the onset was higher than that of hsTnI (0.718 versus 0.633). Among hsTnI-negative patients (300 of 680 patients: 44.1%), 136 of whom (45.3%) were diagnosed with ACS, the sensitivity and the NPV of NRDC were 73.5 and 65.7%, respectively. When measured in combination with hsTnI, NRDC plays auxiliary roles in the early diagnosis of ACS.

Prognostic significance of baseline low-density lipoprotein cholesterol in patients undergoing coronary revascularization; a report from the CREDO-Kyoto registry.

BACKGROUND: The impact of very low baseline levels of low-density lipoprotein cholesterol (LDL-C) on patients with coronary artery disease remains unclear. METHOD: We enrolled 39,439 patients of the pooled population from the CREDO-Kyoto registries Cohorts 1, 2, and 3. The study population consisted of 33,133 patients who had undergone their first coronary revascularization. We assessed the risk for mortality and cardiovascular events according to quintiles of the baseline LDL-C levels. RESULTS: Patients in the very low LDL-C quintile (<85 mg/dL) had more comorbidities than those in the other quintiles. Lower LDL-C levels were strongly associated with anemia, thrombocytopenia, and end-stage renal disease. The cumulative 4-year incidence of all-cause death increased as LDL-C levels decreased (very low: 19.4 %, low: 14.5 %, intermediate: 11.1 %, high: 10.0 %, and very high: 9.2 %; p < 0.001), which was driven by both the early and late events. After adjusting for baseline characteristics, the adjusted risks of the very low and low LDL-C quintiles relative to the intermediate LDL-C quintile remained significant for all-cause death (very low: HR 1.29, 95 % CI 1.16-1.44, p < 0.001; low: HR 1.15, 95 % CI 1.03-1.29, p = 0.01). The excess adjusted risks of the lowest LDL-C quintile relative to the intermediate LDL-C quintile were significant for clinical outcomes such as cardiovascular death (HR 1.17, 95 % CI 1.01-1.35), non-cardiovascular death (HR 1.35, 95 % CI 1.15-1.60), sudden death (HR 1.44, 95 % CI 1.01-2.06), and heart failure admission (HR 1.11 95 % CI 1.01-1.22), while there was no excess risk for the lowest LDL-C quintile relative to the intermediate LDL-C quintile for myocardial infarction and stroke. CONCLUSIONS: Lower baseline LDL-C levels were associated with more comorbidities and a significantly higher risk of death, regardless of cardiovascular or non-cardiovascular causes, in patients who underwent coronary revascularization.

Relationship between atrial fibrillation and a liver fibrogenesis marker in patients with acute heart failure.

BACKGROUND: Hemodynamic disturbance in heart failure (HF) induces extra-cardiac organ injury. Atrial fibrillation (AF) is common in patients with HF. The relationship between AF and organ injury in HF remains unclear. We investigated the relationship between AF and the liver fibrosis marker, type IV collagen 7S (P4NP 7S) in patients with HF. METHODS AND RESULTS: From a pooled dataset of 3 observational cohorts of hospitalized HF, 720 patients in whom P4NP 7S was measured before discharge were included. Median P4NP 7S were 5.1, 5.3, and 6.2 ng/mL in the sinus rhythm (SR) (n = 368), paroxysmal AF (n = 67), and persistent AF (n = 285) groups, respectively (P < 0.001). In the multiple linear regression analysis, the significant association with P4NP 7S was found for persistent AF (P < 0.001). The cumulative 1-year incidence of the primary composite endpoint of cardiac death and HF hospitalization were 27.6, 24.1, and 34.5% in the SR, paroxysmal AF, and persistent AF groups, respectively (Log-rank P = 0.07) and 25.3 and 34.5% in the low (below median) and high P4NP 7S groups, respectively (Log-rank P = 0.005). The adjusted risks of persistent AF versus SR and high P4NP 7S versus low P4NP 7S for the primary endpoint were 1.38 (95% confidence interval 1.02-1.89) and 1.52 (1.14-2.03), respectively. When patients were divided based on a combination of AF and P4NP 7S, concomitant persistent AF and high P4NP 7S portended a dismal prognosis. CONCLUSION: AF is associated with an increase in the liver fibrosis marker. Co-presence of persistent AF and P4NP 7S may portend adverse clinical outcomes.