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1. Smooth muscle protein 22α-Cre recombination in resting cardiac fibroblasts and hematopoietic precursors

Author

Shinya Ikeda, Sachiko Sugioka, Takeshi Kimura, and Noboru Ashida

Subjects
Medicine, Science
Abstract

Abstract The Cre-loxP system has been widely used for cell- or organ-specific gene manipulation, but it is important to precisely understand what kind of cells the recombination takes place in. Smooth muscle 22α (SM22α)-Cre mice have been utilized to alter genes in vascular smooth muscle cells (VSMCs), activated fibroblasts or cardiomyocytes (CMs). Moreover, previous reports indicated that SM22α-Cre is expressed in adipocytes, platelets or myeloid cells. However, there have been no report of whether SM22α-Cre recombination takes place in nonCMs in hearts. Thus, we used the double-fluorescent Cre reporter mouse in which GFP is expressed when recombination occurs. Immunofluorescence analysis demonstrated that recombination occurred in resting cardiac fibroblasts (CFs) or macrophages, as well as VSMCs and CMs. Flow cytometry showed that some CFs, resident macrophages, neutrophils, T cells, and B cells were positive for GFP. These results prompted us to analyze bone marrow cells, and we observed GFP-positive hematopoietic precursor cells (HPCs). Taken together, these results indicated that SM22α-Cre-mediated recombination occurs in resting CFs and hematopoietic cell lineages, including HPCs, which is a cautionary point when using SM22α-Cre mice.

Published
2022
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3. Effects of constitutively active IKKβ on cardiac development

Author

Sachiko Sugioka, Shinya Ikeda, Masayuki Harada, Masako Kishihata, Isehaq Al-Huseini, Takeshi Kimura, and Noboru Ashida

Subjects
Mice, Myocardium, Bone Morphogenetic Proteins, NF-kappa B, Biophysics, Animals, Heart, Cell Biology, T-Box Domain Proteins, Molecular Biology, Biochemistry, I-kappa B Kinase, Transcription Factors
Abstract

NF-κB is a major transcription factor regulating cell survival, organ development and inflammation, but its role in cardiac development has been inadequately explored. To examine this function, we generated mice in which IKKβ, an essential kinase for NF-κB activation, was constitutively activated in embryonic cardiomyocytes. For this purpose, we used smooth muscle-22α (SM22α)-Cre mice, which are frequently used for gene recombination in embryonic cardiomyocytes. Embryonic hearts of SM22αCre-CA (constitutively active) IKKβ

Published
2022
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4. Concomitant Mitral Regurgitation in Severe Aortic Stenosis - A Report From the CURRENT AS Registry

Author

Yasutaka Inuzuka, Kenji Ando, Katsuhisa Ishii, Masaharu Akao, Yutaka Hirano, Manabu Shirotani, Takeshi Morimoto, Toshihiko Saga, Takeshi Maruo, Yukihito Sato, Masanobu Ohya, Shinji Miki, Takeshi Kitai, Kotaro Shiraga, Hiroki Sakamoto, Yutaka Furukawa, Junichiro Nishizawa, Yasuyo Takeuchi, Mitsuru Ishii, Ichiro Kouchi, Hiroshi Eizawa, Shouji Kitaguchi, Yuko Morikami, Keiichiro Yamane, Tomoyuki Ikeda, Tatsuya Ogawa, Yuichi Kawase, Michiya Hanyu, Eiji Shinoda, Chiyo Maeda, Takeshi Kimura, Tomoya Onodera, Takao Kato, Shintaro Matsuda, Makoto Miyake, Norio Kanamori, Mitsuru Kitano, Tsukasa Inada, Eri Minamino-Muta, Moriaki Inoko, Akihiro Komasa, Kazushige Kadota, Tatsuhiko Komiya, Genichi Sakaguchi, Kenji Minatoya, Tadaaki Koyama, Hiroyuki Nakajima, Sachiko Sugioka, Shigeru Ikeguchi, Kazuya Nagao, Yoshihiro Kato, Koji Ueyama, Yoshihisa Nakagawa, Kazuo Yamanaka, Mamoru Toyofuku, Toshikazu Jinnai, Ryosuke Murai, Hirokazu Mitsuoka, Yasushi Fuku, Takashi Tamura, Tomohiko Taniguchi, Mitsuo Matsuda, Chisato Izumi, Keiichi Fujiwara, Current As Registry Investigators, Masashi Kato, Nobuya Higashitani, Shunichi Miyazaki, Fumio Yamazaki, Takenobu Shimada, Takeshi Aoyama, Kozo Hotta, Senri Miwa, Hiroshi Mabuchi, Atsushi Iwakura, Yoshihiro Himura, Shogo Nakayama, and Koichiro Murata

Subjects
medicine.medical_specialty, Severity of Illness Index, Aortic valve replacement, Internal medicine, Medicine, Humans, Registries, Retrospective Studies, Heart Valve Prosthesis Implantation, Mitral regurgitation, business.industry, Incidence (epidemiology), Hazard ratio, Mitral Valve Insufficiency, General Medicine, Aortic Valve Stenosis, medicine.disease, Confidence interval, Stenosis, Treatment Outcome, Concomitant, Heart failure, Aortic Valve, Cardiology, Cardiology and Cardiovascular Medicine, business
Abstract

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

Published
2021

5. Prognostic Impact of Aortic Valve Area in Conservatively Managed Patients With Asymptomatic Severe Aortic Stenosis With Preserved Ejection Fraction

Author

Norio Kanamori, Tomohiko Taniguchi, Takeshi Morimoto, Hirotoshi Watanabe, Hiroki Shiomi, Kenji Ando, Koichiro Murata, Takeshi Kitai, Yuichi Kawase, Chisato Izumi, Makoto Miyake, Hirokazu Mitsuoka, Masashi Kato, Yutaka Hirano, Shintaro Matsuda, Kazuya Nagao, Tsukasa Inada, Hiroshi Mabuchi, Yasuyo Takeuchi, Keiichiro Yamane, Mamoru Toyofuku, Mitsuru Ishii, Eri Minamino‐Muta, Takao Kato, Moriaki Inoko, Tomoyuki Ikeda, Akihiro Komasa, Katsuhisa Ishii, Kozo Hotta, Nobuya Higashitani, Yoshihiro Kato, Yasutaka Inuzuka, Chiyo Maeda, Toshikazu Jinnai, Yuko Morikami, Naritatsu Saito, Kenji Minatoya, Takeshi Aoyama, Takeshi Kimura, Ryuzo Sakata, Masao Imai, Junichi Tazaki, Toshiaki Toyota, Hirooki Higami, Tetsuma Kawaji, Shinichi Shirai, Kengo Korai, Takeshi Arita, Shiro Miura, Kyohei Yamaji, Kitae Kim, Keiichiro Iwasaki, Hiroshi Miyawaki, Ayumi Misao, Akimune Kuwayama, Masanobu Ohya, Takenobu Shimada, Hidewo Amano, Masashi Amano, Yusuke Takahashi, Yusuke Yoshikawa, Shunsuke Nishimura, Maiko Kuroda, Tetsu Mizoguchi, Takafumi Yokomatsu, Akihiro Kushiyama, Hidenori Yaku, Toshimitsu Watanabe, Sachiko Sugioka, Naoki Takahashi, Kohei Fukuchi, Teruki Takeda, Tomoko Sakaguchi, Keiko Maeda, Masayuki Yamaji, Motoyoshi Maenaka, Yutaka Tadano, Makoto Motooka, Ryusuke Nishikawa, Mitsunori Kawato, Minako Kinoshita, Kenji Aida, Kousuke Takahashi, Euihong Ko, Nobutoyo Masunaga, Hisashi Ogawa, Moritake Iguchi, Takashi Unoki, Kensuke Takabayashi, Yasuhiro Hamatani, Yugo Yamashita, Shuhei Tsuji, Soji Nishio, Jyunya Seki, Miho Yamada, Akira Kawamoto, Kouji Sogabe, Michiya Tachiiri, Yukiko Matsumura, Chihiro Ota, Kenji Minakata, Michiya Hanyu, Fumio Yamazaki, Tadaaki Koyama, Tatsuhiko Komiya, Kazuo Yamanaka, Noboru Nishiwaki, Hiroyuki Nakajima, Motoaki Ohnaka, Hiroaki Osada, Katsuaki Meshii, Toshihiko Saga, Masahiko Onoe, Hitoshi Kitayama, Shogo Nakayama, Genichi Sakaguchi, Atsushi Iwakura, Kotaro Shiraga, Koji Ueyama, Keiichi Fujiwara, Atsushi Fukumoto, Senri Miwa, Junichiro Nishizawa, Mitsuru Kitano, Kenji Nakatsuma, and Tomoki Sasa

Subjects
medicine.medical_specialty, Aortic Valve Replacement/Transcather Aortic Valve Implantation, aortic valve stenosis, 030204 cardiovascular system & hematology, Severity of Illness Index, Asymptomatic, 03 medical and health sciences, 0302 clinical medicine, Aortic valve replacement, Internal medicine, medicine, asymptomatic, echocardiography, Humans, aortic valve replacement, 030212 general & internal medicine, Adverse effect, Original Research, Heart Valve Prosthesis Implantation, Ejection fraction, business.industry, Background data, Stroke Volume, Prognosis, medicine.disease, Stenosis, Aortic valve area, Valvular Heart Disease, Aortic Valve, Aortic valve stenosis, Asymptomatic Diseases, Cardiology, medicine.symptom, Cardiology and Cardiovascular Medicine, business, aortic valve area
Abstract

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 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, See Editorial by Tribouilloy et al

Published
2019
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6. Prognostic Impact of Left Ventricular Ejection Fraction in Patients With Severe Aortic Stenosis

Author

Tomohiko Taniguchi, Takeshi Morimoto, Hiroki Shiomi, Kenji Ando, Norio Kanamori, Koichiro Murata, Takeshi Kitai, Kazushige Kadota, Chisato Izumi, Kenji Nakatsuma, Tomoki Sasa, Hirotoshi Watanabe, Yasuhide Kuwabara, Takeru Makiyama, Koh Ono, Satoshi Shizuta, Takao Kato, Naritatsu Saito, Kenji Minatoya, Takeshi Kimura, Masao Imai, Junichi Tazaki, Toshiaki Toyota, Hirooki Higami, Tetsuma Kawaji, Shinichi Shirai, Kengo Kourai, Takeshi Arita, Shiro Miura, Kyohei Yamaji, Takeshi Aoyama, Tomoya Onodera, Yutaka Furukawa, Kitae Kim, Yuichi Kawase, Keiichiro Iwasaki, Hiroshi Miyawaki, Ayumi Misao, Akimune Kuwayama, Masanobu Ohya, Takenobu Shimada, Hidewo Amano, Yoshihisa Nakagawa, Makoto Miyake, Masashi Amano, Yusuke Takahashi, Yusuke Yoshikawa, Shunsuke Nishimura, Maiko Kuroda, Manabu Shirotani, Hirokazu Mitsuoka, Shinji Miki, Tetsu Mizoguchi, Masashi Kato, Takafumi Yokomatsu, Akihiro Kushiyama, Hidenori Yaku, Toshimitsu Watanabe, Shunichi Miyazaki, Yutaka Hirano, Mitsuo Matsuda, Shintaro Matsuda, Sachiko Sugioka, Tsukasa Inada, Kazuya Nagao, Naoki Takahashi, Kohei Fukuchi, Tomoyuki Murakami, Hiroshi Mabuchi, Teruki Takeda, Tomoko Sakaguchi, Keiko Maeda, Masayuki Yamaji, Motoyoshi Maenaka, Yutaka Tadano, Hiroki Sakamoto, Yasuyo Takeuchi, Makoto Motooka, Ryusuke Nishikawa, Hiroshi Eizawa, Keiichiro Yamane, Mitsunori Kawato, Minako Kinoshita, Kenji Aida, Takashi Tamura, Mamoru Toyofuku, Kousuke Takahashi, Euihong Ko, Masaharu Akao, Mitsuru Ishii, Nobutoyo Masunaga, Hisashi Ogawa, Moritake Iguchi, Takashi Unoki, Kensuke Takabayashi, Yasuhiro Hamatani, Yugo Yamashita, Moriaki Inoko, Eri Minamino-Muta, Yoshihiro Himura, Tomoyuki Ikeda, Katsuhisa Ishii, Akihiro Komasa, Yukihito Sato, Kozo Hotta, Shuhei Tsuji, Yuji Hiraoka, Nobuya Higashitani, Ichiro Kouchi, Yoshihiro Kato, Shigeru Ikeguchi, Yasutaka Inuzuka, Soji Nishio, Jyunya Seki, Eiji Shinoda, Miho Yamada, Akira Kawamoto, Chiyo Maeda, Takashi Konishi, Toshikazu Jinnai, Kouji Sogabe, Michiya Tachiiri, Yukiko Matsumura, Chihiro Ota, Shoji Kitaguchi, Yuko Morikami, Ryuzo Sakata, Kenji Minakata, Michiya Hanyu, Fumio Yamazaki, Tadaaki Koyama, Tatsuhiko Komiya, Kazuo Yamanaka, Noboru Nishiwaki, Hiroyuki Nakajima, Motoaki Ohnaka, Hiroaki Osada, Katsuaki Meshii, Toshihiko Saga, Masahiko Onoe, Shogo Nakayama, Genichi Sakaguchi, Atsushi Iwakura, Kotaro Shiraga, Koji Ueyama, Keiichi Fujiwara, Atsushi Fukumoto, Masaki Park, Junichiro Nishizawa, and Mitsuru Kitano

Subjects
Male, medicine.medical_specialty, Time Factors, macromolecular substances, 030204 cardiovascular system & hematology, Conservative Treatment, Risk Assessment, Severity of Illness Index, Ventricular Function, Left, 03 medical and health sciences, 0302 clinical medicine, Primary outcome, Japan, Risk Factors, Internal medicine, medicine, Humans, In patient, cardiovascular diseases, 030212 general & internal medicine, Registries, Aged, Retrospective Studies, Aged, 80 and over, Heart Failure, Heart Valve Prosthesis Implantation, Ejection fraction, Medical treatment, business.industry, Incidence (epidemiology), Stroke Volume, Aortic Valve Stenosis, medicine.disease, Echocardiography, Doppler, Hospitalization, Stenosis, Treatment Outcome, Heart failure, cardiovascular system, Cardiology, Disease Progression, Population study, Female, Cardiology and Cardiovascular Medicine, business, circulatory and respiratory physiology
Abstract

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.

Published
2017

7. Prognostic Impact of Peak Aortic Jet Velocity in Conservatively Managed Patients With Severe Aortic Stenosis: An Observation From the CURRENT AS Registry

Author

Kenji Nakatsuma, Tomohiko Taniguchi, Takeshi Morimoto, Hiroki Shiomi, Kenji Ando, Norio Kanamori, Koichiro Murata, Takeshi Kitai, Yuichi Kawase, Chisato Izumi, Makoto Miyake, Hirokazu Mitsuoka, Masashi Kato, Yutaka Hirano, Shintaro Matsuda, Tsukasa Inada, Kazuya Nagao, Tomoyuki Murakami, Yasuyo Takeuchi, Keiichiro Yamane, Mamoru Toyofuku, Mitsuru Ishii, Eri Minamino‐Muta, Takao Kato, Moriaki Inoko, Tomoyuki Ikeda, Akihiro Komasa, Katsuhisa Ishii, Kozo Hotta, Nobuya Higashitani, Yoshihiro Kato, Yasutaka Inuzuka, Chiyo Maeda, Toshikazu Jinnai, Yuko Morikami, Naritatsu Saito, Kenji Minatoya, Takeshi Kimura, Masao Imai, Junichi Tazaki, Toshiaki Toyota, Hirooki Higami, Tetsuma Kawaji, Shinichi Shirai, Kengo Korai, Takeshi Arita, Shiro Miura, Kyohei Yamaji, Kitae Kim, Keiichiro Iwasaki, Hiroshi Miyawaki, Ayumi Misao, Akimune Kuwayama, Masanobu Ohya, Takenobu Shimada, Hidewo Amano, Masashi Amano, Yusuke Takahashi, Yusuke Yoshikawa, Shunsuke Nishimura, Maiko Kuroda, Tetsu Mizoguchi, Takafumi Yokomatsu, Akihiro Kushiyama, Hidenori Yaku, Toshimitsu Watanabe, Sachiko Sugioka, Naoki Takahashi, Kohei Fukuchi, Hiroshi Mabuchi, Teruki Takeda, Tomoko Sakaguchi, Masayuki Yamaji, Motoyoshi Maenaka, Yutaka Tadano, Makoto Motooka, Ryusuke Nishikawa, Mitsunori Kawato, Minako Kinoshita, Kenji Aida, Kousuke Takahashi, Euihong Ko, Nobutoyo Masunaga, Hisashi Ogawa, Moritake Iguchi, Takashi Unoki, Kensuke Takabayashi, Yasuhiro Hamatani, Yugo Yamashita, Shuhei Tsuji, Soji Nishio, Jyunya Seki, Miho Yamada, Akira Kawamoto, Kouji Sogabe, Michiya Tachiiri, Yukiko Matsumura, Chihiro Ota, Ryuzo Sakata, Kenji Minakata, Michiya Hanyu, Fumio Yamazaki, Tadaaki Koyama, Tatsuhiko Komiya, Kazuo Yamanaka, Noboru Nishiwaki, Motoaki Ohnaka, Hiroaki Osada, Katsuaki Meshii, Toshihiko Saga, Hitoshi Kitayama, Shogo Nakayama, Genichi Sakaguchi, Atsushi Iwakura, Kotaro Shiraga, Koji Ueyama, Keiichi Fujiwara, Atsushi Fukumoto, Senri Miwa, Junichiro Nishizawa, Mitsuru Kitano, Hirotoshi Watanabe, and Tomoki Sasa

Subjects
Male, Aortic valve, Time Factors, Hemodynamics, Kaplan-Meier Estimate, 030204 cardiovascular system & hematology, Severity of Illness Index, Ventricular Function, Left, 0302 clinical medicine, Japan, Risk Factors, Registries, 030212 general & internal medicine, Original Research, Aged, 80 and over, Stroke volume, clinical outcomes, Hospitalization, Treatment Outcome, medicine.anatomical_structure, Aortic Valve, Aortic valve stenosis, Cardiology, Female, Cardiology and Cardiovascular Medicine, peak aortic jet velocity, medicine.medical_specialty, 03 medical and health sciences, Internal medicine, Severity of illness, medicine, Humans, Aged, Proportional Hazards Models, Retrospective Studies, Heart Failure, Chi-Square Distribution, business.industry, aortic stenosis, Stroke Volume, Retrospective cohort study, Aortic Valve Stenosis, medicine.disease, Surgery, Stenosis, Valvular Heart Disease, Heart failure, Asymptomatic Diseases, business
Abstract

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.

Published
2017
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