Shintaro Matsuda

Initial Surgical Versus Conservative Strategies in Patients With Asymptomatic Severe Aortic Stenosis.

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 <1.0 cm(2)) between January 2003 and December 2011. Among 1,808 asymptomatic patients, the initial AVR and conservative strategies were chosen in 291 patients, and 1,517 patients, respectively. Median follow-up was 1,361 days with 90% follow-up rate at 2 years. The propensity score-matched cohort of 582 patients (n = 291 in each group) was developed as the main analysis set for the current report. RESULTS Baseline characteristics of the propensity score-matched cohort were largely comparable, except for the slightly younger age and the greater AS severity in the initial AVR group. In the conservative group, AVR was performed in 41% of patients during follow-up. The cumulative 5-year incidences of all-cause death and heart failure hospitalization were significantly lower in the initial AVR group than in the conservative group (15.4% vs. 26.4%, p = 0.009; 3.8% vs. 19.9%, p < 0.001, respectively). CONCLUSIONS The long-term outcome of asymptomatic patients with severe AS was dismal when managed conservatively in this real-world analysis and might be substantially improved by an initial AVR strategy. (Contemporary Outcomes After Surgery and Medical Treatment in Patients With Severe Aortic Stenosis Registry; UMIN000012140).

Nardilysin Is Required for Maintaining Pancreatic β-Cell Function.

Type 2 diabetes (T2D) is associated with pancreatic β-cell dysfunction, manifested by reduced glucose-stimulated insulin secretion (GSIS). Several transcription factors enriched in β-cells, such as MafA, control β-cell function by organizing genes involved in GSIS. Here we demonstrate that nardilysin (N-arginine dibasic convertase; Nrd1 and NRDc) critically regulates β-cell function through MafA. Nrd1−/− mice showed glucose intolerance and severely decreased GSIS. Islets isolated from Nrd1−/− mice exhibited reduced insulin content and impaired GSIS in vitro. Moreover, β-cell-specific NRDc-deficient (Nrd1delβ) mice showed a diabetic phenotype with markedly reduced GSIS. MafA was specifically downregulated in islets from Nrd1delβ mice, whereas overexpression of NRDc upregulated MafA and insulin expression in INS832/13 cells. Chromatin immunoprecipitation assay revealed that NRDc is associated with Islet-1 in the enhancer region of MafA, where NRDc controls the recruitment of Islet-1 and MafA transcription. Our findings demonstrate that NRDc controls β-cell function via regulation of the Islet-1–MafA pathway.

Causes of Death in Patients with Severe Aortic Stenosis: An Observational study

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 <22, diabetes, prior history of stroke, dialysis, anemia, and malignancy) and cardiac factors (atrial fibrillation, ejection fraction <68%, and the initial AVR strategy) were associated with non-cardiac death. These findings highlight the importance of close monitoring of non-cardiac comorbidities, as well as HF and sudden death, to improve the mortality rate of severe AS patients.

High- Versus Low-Gradient Severe Aortic Stenosis: Demographics, Clinical Outcomes, and Effects of the Initial Aortic Valve Replacement Strategy on Long-Term Prognosis

Background— There is considerable debate on the management of patients with low-gradient severe aortic stenosis (LG-AS), defined as aortic valve area <1 cm2 with peak aortic jet velocity ⩽4.0 m/s, and mean aortic pressure gradient ⩽40 mm Hg. Methods and Results— In the CURRENT AS registry (Contemporary Outcomes After Surgery and Medical Treatment in Patients With Severe Aortic Stenosis), there were 2097 patients (initial aortic valve replacement [AVR] strategy: n=977, and conservative strategy: n=1120) with high-gradient severe aortic stenosis (HG-AS) and 1712 patients (initial AVR strategy: n=219, and conservative strategy: n=1493) with LG-AS. AVR was more frequently performed in HG-AS patients than in LG-AS patients (60% versus 28%) during the entire follow-up. In the comparison between the initial AVR and conservative groups, the propensity score–matched cohorts were developed in both HG-AS (n=887 for each group) and LG-AS (n=218 for each group) strata. The initial AVR strategy when compared with the conservative strategy was associated with markedly lower risk for a composite of aortic valve–related death or heart failure hospitalization in both HG-AS and LG-AS strata (hazard ratio, 0.30; 95% confidence interval, 0.25–0.37; P<0.001 and hazard ratio, 0.46; 95% confidence interval, 0.32–0.67; P<0.001, respectively). Among 1358 patients with LG-AS with preserved left ventricular ejection fraction, the initial AVR strategy was associated with a better outcome than the conservative strategy (adjusted hazard ratio, 0.37; 95% confidence interval, 0.23–0.59; P<0.001). Conclusions— The initial AVR strategy was associated with better outcomes than the conservative strategy in both HG-AS and LG-AS patients, although AVR was less frequently performed in LG-AS patients than in HG-AS patients. The favorable effect of initial AVR strategy was also seen in patients with LG-AS with preserved left ventricular ejection fraction. Clinical Trial Registration— URL: http://www.umin.ac.jp/ctr/index.htm. Unique identifier: UMIN000012140.

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.

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.

Nardilysin is a promising biomarker for the early diagnosis of acute coronary syndrome

BACKGROUND Biomarkers for detection of transient myocardial ischemia in patients with unstable angina (UA) or for very early diagnosis of acute myocardial infarction (AMI) are not currently available. METHODS AND RESULTS We performed two sequential screenings of autoantibodies elevated shortly after the onset of acute coronary syndrome (ACS), and focused on metalloendopeptidase nardilysin (NRDC) among 19 identified candidate antigens. In a retrospective analysis among 93 ACS and 117 non-ACS patients, the serum level of NRDC was significantly increased in patients with ACS compared with that in patients with non-ACS (2073.5±189.8pg/ml versus 775.7±63.4pg/ml, P<0.0001). The area under the curve of NRDC for the diagnosis of ACS was 0.822 by the receiver operating characteristic curves analysis. In the time course analysis in 43 consecutive ACS patients (AMI: N=35 and UA: N=8), serum concentration of NRDC was significantly increased even in UA patients with a peak serum NRDC levels reached at admission both in AMI and UA patients. In a mouse model of AMI, we found an acute increase in serum NRDC and reduced NRDC expression in ischemic regions shortly after coronary artery ligation. NRDC expression was also reduced in infarcted regions in human autopsy samples from AMI patients. Moreover, the short treatment of primary culture of rat cardiomyocytes with H2O2 or A23187 induced NRDC secretion without cell toxicity. CONCLUSION NRDC is a promising biomarker for the early detection of ACS, even in UA patients without elevation of necrosis markers.

Asymptomatic versus Symptomatic Patients with Severe Aortic Stenosis

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 < 0.001). After adjusting for AVR and other variables, the greater risk of symptomatic relative to asymptomatic patients for the primary outcome measure was significant (hazard ratio 1.64, 95% confidence interval 1.41–1.96, P < 0.001). In conclusions, the excess risk of symptomatic relative to asymptomatic patients with severe AS for the aortic valve-related event was significant. However, the prevalence of AVR in symptomatic patients was not optimal.

Genome-wide profiling of nardilysin target genes reveals its role in epigenetic regulation and cell cycle progression.

Post-translational histone modifications, such as acetylation and methylation, are prerequisites for transcriptional regulation. The metalloendopeptidase nardilysin (Nrdc) is a H3K4me2-binding protein that controls thermoregulation and β-cell functions through its transcriptional coregulator function. We herein combined high-throughput ChIP-seq and RNA-seq to achieve the first genome-wide identification of Nrdc target genes. A ChIP-seq analysis of immortalized mouse embryo fibroblasts (iMEF) identified 4053 Nrdc-binding sites, most of which were located in proximal promoter sites (2587 Nrdc-binding genes). Global H3K4me2 levels at Nrdc-binding promoters slightly increased, while H3K9ac levels decreased in the absence of Nrdc. Among Nrdc-binding genes, a comparative RNA-seq analysis identified 448 candidates for Nrdc target genes, among which cell cycle-related genes were significantly enriched. We confirmed decreased mRNA and H3K9ac levels at the promoters of individual genes in Nrdc-deficient iMEF, which were restored by the ectopic introduction of Nrdc. Reduced mRNA levels, but not H3K9ac levels were fully restored by the reintroduction of the peptidase-dead mutant of Nrdc. Furthermore, Nrdc promoted cell cycle progression at multiple stages, which enhanced cell proliferation in vivo. Collectively, our integrative studies emphasize the importance of Nrdc for maintaining a proper epigenetic status and cell growth.