Shintaro Matsuda - Academia.edu (original) (raw)
Papers by Shintaro Matsuda
Proceedings for Annual Meeting of The Japanese Pharmacological Society, 2022
Brown adipose tissue (BAT) is a major organ responsible for diet-induced thermogenesis, a phenome... more Brown adipose tissue (BAT) is a major organ responsible for diet-induced thermogenesis, a phenomenon which converts excess energy intake into heat. Previous studies suggested that hepatocytes regulate diet-induced thermogenesis in response to changes in nutritional status. However, it is not clear how hepatocytes are involved in diet-induced thermogenesis. Here, we demonstrate that liver nardilysin (NRDC) expression changes by nutritional state; it increases by fasting and decreases by re-feeding. Moreover, liver NRDC decreases upon high-fat diet (HFD) feeding. We have previously demonstrated that mice systemically deficient in a metallopeptidase nardilysin (NRDC) show reduced fat mass, enhanced energy expenditure and BAT activity. To clarify the liver-specific role of NRDC in diet-induced thermogenesis and energy metabolism, we established hepatocyte-specific Nrdc deficient mice (LKO). In HFD-fed state, the body weight gain was significantly suppressed, while glucose tolerance and insulin sensitivity were significantly improved in LKO. Measurement in metabolic cage demonstrated unchanged food intake and physical activity, while increased oxygen consumption rate and heat generation in LKO. BAT in LKO showed less fat accumulation and increased thermogenic genes such as UCP1 and PGC1a. Together, these results suggest that hepatic NRDC regulates diet-induced thermogenesis via BAT activity.
The FASEB Journal, 2020
Cardiac sympathetic innervation is critically involved in the regulation of circulatory dynamics.... more Cardiac sympathetic innervation is critically involved in the regulation of circulatory dynamics. However, the molecular mechanism for the innervation patterning has remained elusive. Here, we demonstrate that nardilysin (NRDC, Nrdc), an enhancer of ectodomain shedding, regulates cardiac sympathetic innervation. Nardilysin‐deficient (Nrdc−/−) mice show hypoplastic hearts, hypotension, bradycardia, and abnormal sympathetic innervation patterning. While the innervation of left ventricle (LV) of wild‐type mice is denser in the subepicardium than in the subendocardium, Nrdc−/− LV lacks such a polarity and is uniformly and more abundantly innervated. At the molecular level, the full‐length form of p75 neurotrophin receptor (p75NTR, Ngfr) is increased in Nrdc−/− LV due to the reduced ectodomain shedding of p75NTR. Importantly, the reduction of p75NTR rescued the abnormal innervation phenotype of Nrdc−/− mice. Moreover, sympathetic neuron‐specific, but not cardiomyocyte‐specific deletion o...
The Molecular Biology Society of Japan, 2016
The Molecular Biology Society of Japan, 2016
The Molecular Biology Society of Japan, 2015
Nardilysin (NRDC; N-arginine dibasic convertase) is a metalloprotease of the M16 family. We repor... more Nardilysin (NRDC; N-arginine dibasic convertase) is a metalloprotease of the M16 family. We reported that NRDC is a protease having localization-dependent multiple functions. NRDC-deficient mice (Nrdc-/-) showed wide range of phenotypes such as hypomyelination, hypothermia, and bradycardia. In this study, we have explored a role of NRDC in the regulation of heart rate. (1) Pharmacological blocking of autonomic nervous system revealed that an intrinsic heart rate of Nrdc-/was significantly reduced compared with that of wild-type mice. (2) In Nrdc-/hearts, mRNA levels of Cav3.1 and HCN1/4, ion channels responsible for sinus automaticity, were significantly reduced. (3) Funny (If) current and T-type Ca current measured in the sinus node cells were markedly reduced in Nrdc-/cells, indicating that the functions of Cav3.1 and HCN1/4 are impaired. (4) Gene knockdown of NRDC in primary rat ventricular myocyte led to the reduction of mRNA level of HCN1/4. (5) Chromatin immunoprecipitation-PCR analysis showed that NRDC binds to the promoter region of Cav3.1 and HCN1/4, suggesting the direct involvement of NRDC in transcriptional regulation of these ion channels. (6) Atrium-specific Nrdc-/-(Sarcolipin-Cre) showed mild bradycardia and reduced Cav3.1 mRNA expression. (7) In silico simulation model of Human iPS cell-derived sinus node cells recapitulated the bradycardia in NRDC-deficient cells. Together, our results indicated that NRDC in cardiomyocyte controls heart rate through the transcriptional regulation of ion channels critical for sinus automaticity.
Hiroki Shiomi, M.D., Takeshi Morimoto, M.D, PhD., Shoji Kitaguchi, M.D., Yoshihisa Nakagawa, M.D.... more Hiroki Shiomi, M.D., Takeshi Morimoto, M.D, PhD., Shoji Kitaguchi, M.D., Yoshihisa Nakagawa, M.D., Katsuhisa Ishii, M.D., Yoshisumi Haruna, M.D, PhD, Itaru Takamisawa, M.D., Makoto Motooka, M.D., Kazuhiro Nakao, M.D., Shintaro Matsuda, M.D., Satoru Mimoto, M.D., Yutaka Aoyama, M.D., Teruki Takeda, M.D., Koichiro Murata, M.D., Masaharu Akao, M.D., Tsukasa Inada, M.D., Hiroshi Eizawa, M.D., Eiji Momona, M.D., Kojiro Awano, M.D., Manabu Shirotani, M.D., Yutaka Furukawa, M.D., Kazushige Kadota, M.D., Katsumi Miyauchi, M.D., Masaru Tanaka, M.D., Yuichi Noguchi, M.D., Sunao Nakamura, M.D., Satoshi Yasuda, M.D., Shunichi Miyazaki, M.D., Hiroyuki Daida, M.D., Kazuo Kimura, M.D., Yuji Ikari, M.D., Haruo Hirayama, M.D, PhD, Tetsuya Sumiyoshi, M.D., Takeshi Kimura, M.D.
The Molecular Biology Society of Japan, 2016
Circulation Journal
on behalf of the CURRENT AS Registry Investigators Background: Although diabetes mellitus (DM) is... more on behalf of the CURRENT AS Registry Investigators 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.
Circulation Journal
(AHA) guidelines, concomitant mitral valve repair or replacement is recommended for patients with... more (AHA) guidelines, concomitant mitral valve repair or replacement is recommended for patients with severe primary MR (Class I) and mitral valve repair is described as a reasonable option for M itral regurgitation (MR) often coexists with severe aortic stenosis (AS). 1,2 The prevalence of concomitant moderate or severe MR has been reported in 13% 3 to 33% 4 of patients undergoing surgical aortic valve replacement (SAVR) and in 20-30% of patients undergoing transcatheter aortic valve replacement (TAVR). 2 In the current American College of Cardiology Editorial p ????
Journal of the American Heart Association
Background-Data are scarce on the role of aortic valve area (AVA) to identify those patients with... more Background-Data are scarce on the role of aortic valve area (AVA) to identify those patients with asymptomatic severe aortic stenosis (AS) who are at high risk of adverse events. We sought to explore the prognostic impact of AVA in asymptomatic patients with severe AS in a large observational database. 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 present study included 1309 conservatively managed asymptomatic patients with left ventricular ejection fraction ≥50%. The study patients were subdivided into 3 groups based on AVA (group 1: AVA >0.80 cm 2 , N=645; group 2: 0.8 cm 2 ≥AVA >0.6 cm 2 , N=465; and group 3: AVA ≤0.6 cm 2 , N=199). The prevalence of very severe AS patients (peak aortic jet velocity ≥5 m/s or mean aortic pressure gradient ≥60 mm Hg) was 2.0%, 5.8%, and 26.1% in groups 1, 2, and 3, respectively. The cumulative 5-year incidence of AVR was not different across the 3 groups (39.7%, 43.7%, and 39.9%; P=0.43). The cumulative 5-year incidence of the primary outcome measure (a composite of aortic valve-related death or heart failure hospitalization) was incrementally higher with decreasing AVA (24.1%, 29.1%, and 48.1%; P<0.001). After adjusting for confounders, the excess risk of group 3 and group 2 relative to group 1 for the primary outcome measure remained significant (hazard ratio, 2.21, 95% CI, 1.56-3.11, P<0.001; and hazard ratio, 1.34, 95% CI, 1.01-1.78, P=0.04, respectively). Conclusions-AVA ≤0.6 cm 2 would be a useful marker to identify those high-risk patients with asymptomatic severe AS, who might benefit from early AVR.
Journal of the American Heart Association, Feb 5, 2019
BackgroundData are scarce on the role of aortic valve area (AVA) to identify those patients with ... more BackgroundData are scarce on the role of aortic valve area (AVA) to identify those patients with asymptomatic severe aortic stenosis (AS) who are at high risk of adverse events. We sought to explore the prognostic impact of AVA in asymptomatic patients with severe AS in a large observational database.Methods and ResultsAmong 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 present study included 1309 conservatively managed asymptomatic patients with left ventricular ejection fraction ≥50%. The study patients were subdivided into 3 groups based on AVA (group 1: AVA >0.80 cm2, N=645; group 2: 0.8 cm2 ≥AVA >0.6 cm2, N=465; and group 3: AVA ≤0.6 cm2, N=199). The prevalence of very severe AS patients (peak aortic jet velocity ≥5 m/s or mean aortic pressure gradient ≥60 mm Hg) was 2.0%, 5.8%, and 26.1% in groups 1, 2, and 3, respectively. The cumulative 5‐year incidence of AVR was not different across the 3 groups (39.7%, 43.7%, and 39.9%; P=0.43). The cumulative 5‐year incidence of the primary outcome measure (a composite of aortic valve–related death or heart failure hospitalization) was incrementally higher with decreasing AVA (24.1%, 29.1%, and 48.1%; P<0.001). After adjusting for confounders, the excess risk of group 3 and group 2 relative to group 1 for the primary outcome measure remained significant (hazard ratio, 2.21, 95% CI, 1.56–3.11, P<0.001; and hazard ratio, 1.34, 95% CI, 1.01–1.78, P=0.04, respectively).ConclusionsAVA ≤0.6 cm2 would be a useful marker to identify those high‐risk patients with asymptomatic severe AS, who might benefit from early AVR.Clinical Trial RegistrationURL: www.umin.ac.jp. Unique identifier: UMIN000012140.
Proceedings for Annual Meeting of The Japanese Pharmacological Society
Thermogenesis is enhanced not only by cold exposure but also by feeding, which is considered as a... more Thermogenesis is enhanced not only by cold exposure but also by feeding, which is considered as a partial defense mechanism against obesity. However, the molecular mechanism of diet-induced thermogenesis has remained unclear. Here we found that metallopeptidase nardilysin (NRDC) expression in liver is increased by fasting and decreased by re-feeding in wild-type mice. To elucidate the liver-specific role of NRDC in energy metabolism, we established hepatocyte-specific NRDC deficient mice (LKO). These mice showed intriguing phenotypes including 1) elevation of thermogenic genes in BAT, 2) decrease in lipid accumulation in BAT, and 3) increase in whole-body energy expenditure. These results suggested that the loss of NRDC in hepatocyte enhances adaptive thermogenesis in BAT by an inter-organ metabolic network. Notably, the phenotypic difference between control and LKO was completely eliminated by hepatic vagotomy or elevation of ambient temperature to thermoneutral range (30℃). Furthermore, LKO showed a significant increase in skin blood flow of the plantar at room temperature (23℃), suggesting that heat dissipation is enhanced in LKO. Taken together, these results indicate that hepatic NRDC regulates skin blood flow, thus heat dissipation via nervous system. BAT thermogenesis was then enhanced to compensate for the heat loss. In conclusion, NRDC, a novel sensor of nutrition, mediates diet-induced thermogenesis.
Proceedings for Annual Meeting of The Japanese Pharmacological Society
Proceedings for Annual Meeting of The Japanese Pharmacological Society
Nardilysin (NRDC; N-arginine dibasic convertase) is a metalloprotease of the M16 family. We repor... more Nardilysin (NRDC; N-arginine dibasic convertase) is a metalloprotease of the M16 family. We reported that NRDC is a protease having localization-dependent multiple functions; an enhancer of ectodomain shedding in the extracellular space and a transcriptional coregulator in the nucleus. NRDC-deficient mice (Nrdc-/-) showed wide range of phenotypes such as hypomyelination, hypothermia, and bradycardia. In this study, we have explored a role of NRDC in the regulation of heart rate, and obtained the following results. (1) Pharmacological blocking of autonomic nervous system revealed that an intrinsic heart rate of Nrdc-/was significantly reduced compared with that of wild-type mice. (2) In Nrdc-/hearts, mRNA levels of Cav3.1 and HCN1/4, ion channels responsible for sinus automaticity, were significantly reduced. (3) Funny (If) current and T-type Ca current measured in the sinus node cells were markedly reduced in Nrdc-/cells, indicating that the functions of Cav3.1 and HCN1/4 are impaired. (4) Gene knockdown of NRDC in primary rat ventricular myocyte led to the reduction of mRNA level of HCN1/4. (5) Chromatin immunoprecipitation-PCR analysis showed that NRDC binds to the promoter region of Cav3.1 and HCN1/4, suggesting the direct involvement of NRDC in transcriptional regulation of these ion channels. (6) Atrium-specific Nrdc-/-(obtained by mating Nrdc floxed mouse with Sarcolipin-Cre mouse) showed mild bradycardia and reduced Cav3.1 mRNA expression. (7) In silico simulation model of human iPS cell-derived sinus node cells recapitulated the bradycardia in NRDC-deficient cells. Together, our results indicated that NRDC in cardiomyocyte controls heart rate through the transcriptional regulation of ion channels critical for sinus automaticity.
Proceedings for Annual Meeting of The Japanese Pharmacological Society, 2022
Brown adipose tissue (BAT) is a major organ responsible for diet-induced thermogenesis, a phenome... more Brown adipose tissue (BAT) is a major organ responsible for diet-induced thermogenesis, a phenomenon which converts excess energy intake into heat. Previous studies suggested that hepatocytes regulate diet-induced thermogenesis in response to changes in nutritional status. However, it is not clear how hepatocytes are involved in diet-induced thermogenesis. Here, we demonstrate that liver nardilysin (NRDC) expression changes by nutritional state; it increases by fasting and decreases by re-feeding. Moreover, liver NRDC decreases upon high-fat diet (HFD) feeding. We have previously demonstrated that mice systemically deficient in a metallopeptidase nardilysin (NRDC) show reduced fat mass, enhanced energy expenditure and BAT activity. To clarify the liver-specific role of NRDC in diet-induced thermogenesis and energy metabolism, we established hepatocyte-specific Nrdc deficient mice (LKO). In HFD-fed state, the body weight gain was significantly suppressed, while glucose tolerance and insulin sensitivity were significantly improved in LKO. Measurement in metabolic cage demonstrated unchanged food intake and physical activity, while increased oxygen consumption rate and heat generation in LKO. BAT in LKO showed less fat accumulation and increased thermogenic genes such as UCP1 and PGC1a. Together, these results suggest that hepatic NRDC regulates diet-induced thermogenesis via BAT activity.
The FASEB Journal, 2020
Cardiac sympathetic innervation is critically involved in the regulation of circulatory dynamics.... more Cardiac sympathetic innervation is critically involved in the regulation of circulatory dynamics. However, the molecular mechanism for the innervation patterning has remained elusive. Here, we demonstrate that nardilysin (NRDC, Nrdc), an enhancer of ectodomain shedding, regulates cardiac sympathetic innervation. Nardilysin‐deficient (Nrdc−/−) mice show hypoplastic hearts, hypotension, bradycardia, and abnormal sympathetic innervation patterning. While the innervation of left ventricle (LV) of wild‐type mice is denser in the subepicardium than in the subendocardium, Nrdc−/− LV lacks such a polarity and is uniformly and more abundantly innervated. At the molecular level, the full‐length form of p75 neurotrophin receptor (p75NTR, Ngfr) is increased in Nrdc−/− LV due to the reduced ectodomain shedding of p75NTR. Importantly, the reduction of p75NTR rescued the abnormal innervation phenotype of Nrdc−/− mice. Moreover, sympathetic neuron‐specific, but not cardiomyocyte‐specific deletion o...
The Molecular Biology Society of Japan, 2016
The Molecular Biology Society of Japan, 2016
The Molecular Biology Society of Japan, 2015
Nardilysin (NRDC; N-arginine dibasic convertase) is a metalloprotease of the M16 family. We repor... more Nardilysin (NRDC; N-arginine dibasic convertase) is a metalloprotease of the M16 family. We reported that NRDC is a protease having localization-dependent multiple functions. NRDC-deficient mice (Nrdc-/-) showed wide range of phenotypes such as hypomyelination, hypothermia, and bradycardia. In this study, we have explored a role of NRDC in the regulation of heart rate. (1) Pharmacological blocking of autonomic nervous system revealed that an intrinsic heart rate of Nrdc-/was significantly reduced compared with that of wild-type mice. (2) In Nrdc-/hearts, mRNA levels of Cav3.1 and HCN1/4, ion channels responsible for sinus automaticity, were significantly reduced. (3) Funny (If) current and T-type Ca current measured in the sinus node cells were markedly reduced in Nrdc-/cells, indicating that the functions of Cav3.1 and HCN1/4 are impaired. (4) Gene knockdown of NRDC in primary rat ventricular myocyte led to the reduction of mRNA level of HCN1/4. (5) Chromatin immunoprecipitation-PCR analysis showed that NRDC binds to the promoter region of Cav3.1 and HCN1/4, suggesting the direct involvement of NRDC in transcriptional regulation of these ion channels. (6) Atrium-specific Nrdc-/-(Sarcolipin-Cre) showed mild bradycardia and reduced Cav3.1 mRNA expression. (7) In silico simulation model of Human iPS cell-derived sinus node cells recapitulated the bradycardia in NRDC-deficient cells. Together, our results indicated that NRDC in cardiomyocyte controls heart rate through the transcriptional regulation of ion channels critical for sinus automaticity.
Hiroki Shiomi, M.D., Takeshi Morimoto, M.D, PhD., Shoji Kitaguchi, M.D., Yoshihisa Nakagawa, M.D.... more Hiroki Shiomi, M.D., Takeshi Morimoto, M.D, PhD., Shoji Kitaguchi, M.D., Yoshihisa Nakagawa, M.D., Katsuhisa Ishii, M.D., Yoshisumi Haruna, M.D, PhD, Itaru Takamisawa, M.D., Makoto Motooka, M.D., Kazuhiro Nakao, M.D., Shintaro Matsuda, M.D., Satoru Mimoto, M.D., Yutaka Aoyama, M.D., Teruki Takeda, M.D., Koichiro Murata, M.D., Masaharu Akao, M.D., Tsukasa Inada, M.D., Hiroshi Eizawa, M.D., Eiji Momona, M.D., Kojiro Awano, M.D., Manabu Shirotani, M.D., Yutaka Furukawa, M.D., Kazushige Kadota, M.D., Katsumi Miyauchi, M.D., Masaru Tanaka, M.D., Yuichi Noguchi, M.D., Sunao Nakamura, M.D., Satoshi Yasuda, M.D., Shunichi Miyazaki, M.D., Hiroyuki Daida, M.D., Kazuo Kimura, M.D., Yuji Ikari, M.D., Haruo Hirayama, M.D, PhD, Tetsuya Sumiyoshi, M.D., Takeshi Kimura, M.D.
The Molecular Biology Society of Japan, 2016
Circulation Journal
on behalf of the CURRENT AS Registry Investigators Background: Although diabetes mellitus (DM) is... more on behalf of the CURRENT AS Registry Investigators 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.
Circulation Journal
(AHA) guidelines, concomitant mitral valve repair or replacement is recommended for patients with... more (AHA) guidelines, concomitant mitral valve repair or replacement is recommended for patients with severe primary MR (Class I) and mitral valve repair is described as a reasonable option for M itral regurgitation (MR) often coexists with severe aortic stenosis (AS). 1,2 The prevalence of concomitant moderate or severe MR has been reported in 13% 3 to 33% 4 of patients undergoing surgical aortic valve replacement (SAVR) and in 20-30% of patients undergoing transcatheter aortic valve replacement (TAVR). 2 In the current American College of Cardiology Editorial p ????
Journal of the American Heart Association
Background-Data are scarce on the role of aortic valve area (AVA) to identify those patients with... more Background-Data are scarce on the role of aortic valve area (AVA) to identify those patients with asymptomatic severe aortic stenosis (AS) who are at high risk of adverse events. We sought to explore the prognostic impact of AVA in asymptomatic patients with severe AS in a large observational database. 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 present study included 1309 conservatively managed asymptomatic patients with left ventricular ejection fraction ≥50%. The study patients were subdivided into 3 groups based on AVA (group 1: AVA >0.80 cm 2 , N=645; group 2: 0.8 cm 2 ≥AVA >0.6 cm 2 , N=465; and group 3: AVA ≤0.6 cm 2 , N=199). The prevalence of very severe AS patients (peak aortic jet velocity ≥5 m/s or mean aortic pressure gradient ≥60 mm Hg) was 2.0%, 5.8%, and 26.1% in groups 1, 2, and 3, respectively. The cumulative 5-year incidence of AVR was not different across the 3 groups (39.7%, 43.7%, and 39.9%; P=0.43). The cumulative 5-year incidence of the primary outcome measure (a composite of aortic valve-related death or heart failure hospitalization) was incrementally higher with decreasing AVA (24.1%, 29.1%, and 48.1%; P<0.001). After adjusting for confounders, the excess risk of group 3 and group 2 relative to group 1 for the primary outcome measure remained significant (hazard ratio, 2.21, 95% CI, 1.56-3.11, P<0.001; and hazard ratio, 1.34, 95% CI, 1.01-1.78, P=0.04, respectively). Conclusions-AVA ≤0.6 cm 2 would be a useful marker to identify those high-risk patients with asymptomatic severe AS, who might benefit from early AVR.
Journal of the American Heart Association, Feb 5, 2019
BackgroundData are scarce on the role of aortic valve area (AVA) to identify those patients with ... more BackgroundData are scarce on the role of aortic valve area (AVA) to identify those patients with asymptomatic severe aortic stenosis (AS) who are at high risk of adverse events. We sought to explore the prognostic impact of AVA in asymptomatic patients with severe AS in a large observational database.Methods and ResultsAmong 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 present study included 1309 conservatively managed asymptomatic patients with left ventricular ejection fraction ≥50%. The study patients were subdivided into 3 groups based on AVA (group 1: AVA >0.80 cm2, N=645; group 2: 0.8 cm2 ≥AVA >0.6 cm2, N=465; and group 3: AVA ≤0.6 cm2, N=199). The prevalence of very severe AS patients (peak aortic jet velocity ≥5 m/s or mean aortic pressure gradient ≥60 mm Hg) was 2.0%, 5.8%, and 26.1% in groups 1, 2, and 3, respectively. The cumulative 5‐year incidence of AVR was not different across the 3 groups (39.7%, 43.7%, and 39.9%; P=0.43). The cumulative 5‐year incidence of the primary outcome measure (a composite of aortic valve–related death or heart failure hospitalization) was incrementally higher with decreasing AVA (24.1%, 29.1%, and 48.1%; P<0.001). After adjusting for confounders, the excess risk of group 3 and group 2 relative to group 1 for the primary outcome measure remained significant (hazard ratio, 2.21, 95% CI, 1.56–3.11, P<0.001; and hazard ratio, 1.34, 95% CI, 1.01–1.78, P=0.04, respectively).ConclusionsAVA ≤0.6 cm2 would be a useful marker to identify those high‐risk patients with asymptomatic severe AS, who might benefit from early AVR.Clinical Trial RegistrationURL: www.umin.ac.jp. Unique identifier: UMIN000012140.
Proceedings for Annual Meeting of The Japanese Pharmacological Society
Thermogenesis is enhanced not only by cold exposure but also by feeding, which is considered as a... more Thermogenesis is enhanced not only by cold exposure but also by feeding, which is considered as a partial defense mechanism against obesity. However, the molecular mechanism of diet-induced thermogenesis has remained unclear. Here we found that metallopeptidase nardilysin (NRDC) expression in liver is increased by fasting and decreased by re-feeding in wild-type mice. To elucidate the liver-specific role of NRDC in energy metabolism, we established hepatocyte-specific NRDC deficient mice (LKO). These mice showed intriguing phenotypes including 1) elevation of thermogenic genes in BAT, 2) decrease in lipid accumulation in BAT, and 3) increase in whole-body energy expenditure. These results suggested that the loss of NRDC in hepatocyte enhances adaptive thermogenesis in BAT by an inter-organ metabolic network. Notably, the phenotypic difference between control and LKO was completely eliminated by hepatic vagotomy or elevation of ambient temperature to thermoneutral range (30℃). Furthermore, LKO showed a significant increase in skin blood flow of the plantar at room temperature (23℃), suggesting that heat dissipation is enhanced in LKO. Taken together, these results indicate that hepatic NRDC regulates skin blood flow, thus heat dissipation via nervous system. BAT thermogenesis was then enhanced to compensate for the heat loss. In conclusion, NRDC, a novel sensor of nutrition, mediates diet-induced thermogenesis.
Proceedings for Annual Meeting of The Japanese Pharmacological Society
Proceedings for Annual Meeting of The Japanese Pharmacological Society
Nardilysin (NRDC; N-arginine dibasic convertase) is a metalloprotease of the M16 family. We repor... more Nardilysin (NRDC; N-arginine dibasic convertase) is a metalloprotease of the M16 family. We reported that NRDC is a protease having localization-dependent multiple functions; an enhancer of ectodomain shedding in the extracellular space and a transcriptional coregulator in the nucleus. NRDC-deficient mice (Nrdc-/-) showed wide range of phenotypes such as hypomyelination, hypothermia, and bradycardia. In this study, we have explored a role of NRDC in the regulation of heart rate, and obtained the following results. (1) Pharmacological blocking of autonomic nervous system revealed that an intrinsic heart rate of Nrdc-/was significantly reduced compared with that of wild-type mice. (2) In Nrdc-/hearts, mRNA levels of Cav3.1 and HCN1/4, ion channels responsible for sinus automaticity, were significantly reduced. (3) Funny (If) current and T-type Ca current measured in the sinus node cells were markedly reduced in Nrdc-/cells, indicating that the functions of Cav3.1 and HCN1/4 are impaired. (4) Gene knockdown of NRDC in primary rat ventricular myocyte led to the reduction of mRNA level of HCN1/4. (5) Chromatin immunoprecipitation-PCR analysis showed that NRDC binds to the promoter region of Cav3.1 and HCN1/4, suggesting the direct involvement of NRDC in transcriptional regulation of these ion channels. (6) Atrium-specific Nrdc-/-(obtained by mating Nrdc floxed mouse with Sarcolipin-Cre mouse) showed mild bradycardia and reduced Cav3.1 mRNA expression. (7) In silico simulation model of human iPS cell-derived sinus node cells recapitulated the bradycardia in NRDC-deficient cells. Together, our results indicated that NRDC in cardiomyocyte controls heart rate through the transcriptional regulation of ion channels critical for sinus automaticity.