Papers - Katsumata, Yoshinori

Narrow QRS tachycardia

Aizawa Y., Takatsuki S., Inagawa K., Katsumata Y., Nishiyama T., Kimura T., Nishiyama N., Sato Y., Fukumoto K., Tanimoto Y., Tanimoto K., Fukuda K.

Herz 39 ( 2 ) 276 - 278 2014

ISSN  0340-9937

• Access to Document (DOI)

Narrow QRS tachycardia

Aizawa Y., Takatsuki S., Inagawa K., Katsumata Y., Nishiyama T., Kimura T., Nishiyama N., Sato Y., Fukumoto K., Tanimoto Y., Tanimoto K., Fukuda K.

Herz 39 ( 2 ) 276 - 278 2014

ISSN  0340-9937

• Access to Document (DOI)

Serum Inflammation Markers Predicting Successful Initial Catheter Ablation for Atrial Fibrillation

Kimura Takehiro, Takatsuki Seiji, Inagawa Kohei, Katsumata Yoshinori, Nishiyama Takahiko, Nishiyama Nobuhiro, Fukumoto Kotaro, Aizawa Yoshiyasu, Tanimoto Yoko, Tanimoto Kojiro, Fukuda Keiichi

Heart Lung and Circulation 23 ( 7 ) 636 - 643 2014

ISSN  1443-9506

　View Summary

<p>Background: We investigated various serum inflammatory markers to predict ablation responders who have no atrial fibrillation (AF) relapse after the initial ablation. Methods: Forty-four consecutive AF patients (age: 59 ± 8 years, paroxysmal: 31, CHADS₂: 1.1 ± 1.1) who underwent an initial pulmonary vein isolation were investigated. Various serum inflammatory markers, such as adiponectin, ANP, BNP, 1CTP, F1+2, hs-CRP, IL-6, intact P1NP, MDA-LDL, MMP-2, TGF-β, TIMP-2, and TNF-α, were evaluated prior to ablation. AF relapse was defined as AF documented in telemonitoring electrocardiograms twice a day during 9.7 ± 2.4 months of follow-up with three months of a blanking-period. Results: A total of 29 patients (paroxysmal: 21) maintained sinus rhythm after the initial catheter ablation. These ablation responders had significantly lower MMP-2 (Sinus vs. Relapsed: 748 ± 132.7 vs. 841.2 ± 152.4 ng/mL, P=0.042) and TNF-α (1.1 ± 0.4 vs. 1.8 ± 1.7 pg/mL, P=0.046) levels prior to ablation. A BNP-adjusted Cox multivariate regression analysis revealed that the independent predictive factor for AF recurrence was high MMP-2 levels (&gt;766 ng/mL) accompanied by high TNF-α levels (&gt;1.2 pg/mL). Conclusions: The levels of MMP-2 and TNF-α might be useful for predicting initial AF catheter ablation responders.</p>

• Access to Document (DOI)

Thrombus Formation in the Left Atrial Appendage During Catheter Ablation for Atrial Fibrillation Under Sufficient Heparinization

Kimura Takehiro, Takatsuki Seiji, Tanimoto Kojiro, Katsumata Yoshinori, Nishiyama Takahiko, Inagawa Kohei, Nishiyama Nobuhiro, Tanimoto Yoko, Aizawa Yoshiyasu, Fukuda Keiichi

Canadian Journal of Cardiology 30 ( 4 )  2014

ISSN  0828-282X

• Access to Document (DOI)

Efficacy and safety of bepridil for prevention of ICD shocks in patients with Brugada syndrome and idiopathic ventricular fibrillation

Aizawa Yoshiyasu, Yamakawa Hiroyuki, Takatsuki Seiji, Katsumata Yoshinori, Nishiyama Takahiko, Kimura Takehiro, Nishiyama Nobuhiro, Fukumoto Kotaro, Tanimoto Yoko, Tanimoto Kojiro, Mitamura Hideo, Ogawa Satoshi, Fukuda Keiichi

International Journal of Cardiology 168 ( 5 ) 5083 - 5085 2013.10

ISSN  0167-5273

• Access to Document (DOI)

Efficacy and safety of bepridil for prevention of ICD shocks in patients with Brugada syndrome and idiopathic ventricular fibrillation

Aizawa Yoshiyasu, Yamakawa Hiroyuki, Takatsuki Seiji, Katsumata Yoshinori, Nishiyama Takahiko, Kimura Takehiro, Nishiyama Nobuhiro, Fukumoto Kotaro, Tanimoto Yoko, Tanimoto Kojiro, Mitamura Hideo, Ogawa Satoshi, Fukuda Keiichi

International Journal of Cardiology 168 ( 5 ) 5083 - 5085 2013.10

ISSN  0167-5273

• Access to Document (DOI)

Temporal dynamics of cardiac immune cell accumulation following acute myocardial infarction

Yan Xiaoxiang, Anzai Atsushi, Katsumata Yoshinori, Matsuhashi Tomohiro, Ito Kentaro, Endo Jin, Yamamoto Tsunehisa, Takeshima Akiko, Shinmura Ken, Shen Weifeng, Fukuda Keiichi, Sano Motoaki

Journal of Molecular and Cellular Cardiology 62   24 - 35 2013.09

ISSN  0022-2828

　View Summary

<p>Acute myocardial infarction (MI) causes sterile inflammation, which is characterized by recruitment and activation of innate and adaptive immune system cells. Here we delineate the temporal dynamics of immune cell accumulation following MI by flow cytometry. Neutrophils increased immediately to a peak at 3days post-MI. Macrophages were numerically the predominant cells infiltrating the infarcted myocardium, increasing in number over the first week post-MI. Macrophages are functionally heterogeneous, whereby the first responders exhibit high expression levels of proinflammatory mediators, while the late responders express high levels of the anti-inflammatory cytokine IL-10; these macrophages can be classified into M₁ and M₂ macrophages, respectively, based on surface-marker expression. M₁ macrophages dominated at 1-3days post-MI, whereas M₂ macrophages represented the predominant macrophage subset after 5days. The M₂ macrophages expressed high levels of reparative genes in addition to proinflammatory genes to the same levels as in M₁ macrophages. The predominant subset of dendritic cells (DCs) was myeloid DC, which peaked in number on day 7. Th1 and regulatory T cells were the predominant subsets of CD4⁺ T cells, whereas Th2 and Th17 cells were minor populations. CD8⁺ T cells, γδT cells, B cells, natural killer (NK) cells and NKT cells peaked on day 7 post-MI. Timely reperfusion reduced the total number of leukocytes accumulated in the post-MI period, shifting the peak of innate immune response towards earlier and blunting the wave of adaptive immune response. In conclusion, these results provide important knowledge necessary for developing successful immunomodulatory therapies.</p>

• Access to Document (DOI)

Temporal dynamics of cardiac immune cell accumulation following acute myocardial infarction

Yan Xiaoxiang, Anzai Atsushi, Katsumata Yoshinori, Matsuhashi Tomohiro, Ito Kentaro, Endo Jin, Yamamoto Tsunehisa, Takeshima Akiko, Shinmura Ken, Shen Weifeng, Fukuda Keiichi, Sano Motoaki

Journal of Molecular and Cellular Cardiology 62   24 - 35 2013.09

ISSN  0022-2828

　View Summary

<p>Acute myocardial infarction (MI) causes sterile inflammation, which is characterized by recruitment and activation of innate and adaptive immune system cells. Here we delineate the temporal dynamics of immune cell accumulation following MI by flow cytometry. Neutrophils increased immediately to a peak at 3days post-MI. Macrophages were numerically the predominant cells infiltrating the infarcted myocardium, increasing in number over the first week post-MI. Macrophages are functionally heterogeneous, whereby the first responders exhibit high expression levels of proinflammatory mediators, while the late responders express high levels of the anti-inflammatory cytokine IL-10; these macrophages can be classified into M₁ and M₂ macrophages, respectively, based on surface-marker expression. M₁ macrophages dominated at 1-3days post-MI, whereas M₂ macrophages represented the predominant macrophage subset after 5days. The M₂ macrophages expressed high levels of reparative genes in addition to proinflammatory genes to the same levels as in M₁ macrophages. The predominant subset of dendritic cells (DCs) was myeloid DC, which peaked in number on day 7. Th1 and regulatory T cells were the predominant subsets of CD4⁺ T cells, whereas Th2 and Th17 cells were minor populations. CD8⁺ T cells, γδT cells, B cells, natural killer (NK) cells and NKT cells peaked on day 7 post-MI. Timely reperfusion reduced the total number of leukocytes accumulated in the post-MI period, shifting the peak of innate immune response towards earlier and blunting the wave of adaptive immune response. In conclusion, these results provide important knowledge necessary for developing successful immunomodulatory therapies. © 2013 Elsevier Ltd.</p>

• Access to Document (DOI)

Anatomical characteristics of the left atrial appendage in cardiogenic stroke with low CHADS2 scores

Kimura Takehiro, Takatsuki Seiji, Inagawa Kohei, Katsumata Yoshinori, Nishiyama Takahiko, Nishiyama Nobuhiro, Fukumoto Kotaro, Aizawa Yoshiyasu, Tanimoto Yoko, Tanimoto Kojiro, Jinzaki Masahiro, Fukuda Keiichi

Heart Rhythm 10 ( 6 ) 921 - 925 2013.06

ISSN  1547-5271

　View Summary

<p>BACKGROUND Strokes develop even in patients with low CHADS₂ scores, and the left atrial appendage (LAA) is the embolic source 90% of the time. We focused on the LAA morphology as a new predictor of strokes. OBJECTIVE To clarify the anatomical characteristics of the LAA for risk stratification of strokes in patients with nonvalvular atrial fibrillation (AF) who have low CHADS₂ scores. METHODS Among 80 patients who underwent catheter ablation of AF with contrast-enhanced computed tomography, the LAA characteristics were compared between 30 patients with histories of strokes and 50 age-matched controls. The LAA anatomy was classified into 4 types-"cactus," "cauliflower," "chicken wing," and "windsock"- discriminated by the computed tomography measurements of the length, angle, and number of lobes of the LAA. RESULTS The average CHADS₂ score did not differ significantly between patients with stroke and controls (0.8 ± 0.8 vs 0.6 ± 0.7; P = .277). Eight (26.7%) patients with stroke had CHA₂DS₂-VASc scores of 0. The left atrial size, LAA flow velocity, left ventricular function, and serum brain natriuretic peptide level were also unable to predict strokes. However, a "cauliflower" LAA, defined as a main lobe of less than 4 cm long without forked lobes, was significantly more common in patients with stroke (odds ratio 3.857; 95% confidence interval 1.482-10.037; P = .005). The CHA ₂DS₂-VASc score-adjusted logistic regression analysis revealed the cauliflower LAA as an independent predictor of a stroke (odds ratio 3.355; 95% confidence interval 1.243-9.055; P = .017). CONCLUSIONS The LAA anatomy might be useful for predicting strokes in patients with nonvalvular AF who have low CHADS₂ scores.</p>

• Access to Document (DOI)

Anatomical characteristics of the left atrial appendage in cardiogenic stroke with low CHADS2 scores

Kimura Takehiro, Takatsuki Seiji, Inagawa Kohei, Katsumata Yoshinori, Nishiyama Takahiko, Nishiyama Nobuhiro, Fukumoto Kotaro, Aizawa Yoshiyasu, Tanimoto Yoko, Tanimoto Kojiro, Jinzaki Masahiro, Fukuda Keiichi

Heart Rhythm 10 ( 6 ) 921 - 925 2013.06

ISSN  1547-5271

　View Summary

<p>BACKGROUND Strokes develop even in patients with low CHADS₂ scores, and the left atrial appendage (LAA) is the embolic source 90% of the time. We focused on the LAA morphology as a new predictor of strokes. OBJECTIVE To clarify the anatomical characteristics of the LAA for risk stratification of strokes in patients with nonvalvular atrial fibrillation (AF) who have low CHADS₂ scores. METHODS Among 80 patients who underwent catheter ablation of AF with contrast-enhanced computed tomography, the LAA characteristics were compared between 30 patients with histories of strokes and 50 age-matched controls. The LAA anatomy was classified into 4 types-"cactus," "cauliflower," "chicken wing," and "windsock"- discriminated by the computed tomography measurements of the length, angle, and number of lobes of the LAA. RESULTS The average CHADS₂ score did not differ significantly between patients with stroke and controls (0.8 ± 0.8 vs 0.6 ± 0.7; P = .277). Eight (26.7%) patients with stroke had CHA₂DS₂-VASc scores of 0. The left atrial size, LAA flow velocity, left ventricular function, and serum brain natriuretic peptide level were also unable to predict strokes. However, a "cauliflower" LAA, defined as a main lobe of less than 4 cm long without forked lobes, was significantly more common in patients with stroke (odds ratio 3.857; 95% confidence interval 1.482-10.037; P = .005). The CHA ₂DS₂-VASc score-adjusted logistic regression analysis revealed the cauliflower LAA as an independent predictor of a stroke (odds ratio 3.355; 95% confidence interval 1.243-9.055; P = .017). CONCLUSIONS The LAA anatomy might be useful for predicting strokes in patients with nonvalvular AF who have low CHADS₂ scores. © 2013 Heart Rhythm Society. All rights reserved.</p>

• Access to Document (DOI)

Storms of ventricular fibrillation responsive to isoproterenol in an idiopathic ventricular fibrillation patient demonstrating complete right bundle branch block

Aizawa Yoshiyasu, Takatsuki Seiji, Inagawa Kohei, Katsumata Yoshinori, Nishiyama Takahiko, Kimura Takehiro, Nishiyama Nobuhiro, Fukumoto Kotaro, Tanimoto Yoko, Tanimoto Kojiro, Ogawa Satoshi, Fukuda Keiichi

International Heart Journal 54 ( 4 ) 240 - 242 2013

ISSN  1349-2365

　View Summary

<p>A 45-year-old male was admitted to our hospital after successful resuscitation of cardiac arrest. Ventricular fbrilla-tion (VF) had occurred during breakfast and was defbrillated by an automated external defbrillator operated by emergency medical service staff. On admission, his ECG demonstrated complete right bundle branch block as the sole abnormality. Intensive examination could not detect any structural disease leading to a diagnosis of idiopathic VF and implantation of an ICD. VF storm occurred one month after hospital discharge and beta-blocker, amiodarone, and sedative administration had no effect on VF. Likewise, catheter ablation for triggering premature ventricular beats failed to control the VF storm. The VF storm then subsided in the following weeks and the patient was discharged on amiodarone. A half month later VF storm recurred and the patient was admitted again. This time, isoproterenol infusion was effective in suppressing VF, and thereafter the patient was administered bepridil and followed up without recurrence of VF for 1.5 years. From these benefcial effects, the VF of the patient was suggested to share common arrhythmogenic characteristics to those of Brugada syndrome or J-wave associated VF.</p>

Storms of ventricular fibrillation responsive to isoproterenol in an idiopathic ventricular fibrillation patient demonstrating complete right bundle branch block

Aizawa Yoshiyasu, Takatsuki Seiji, Inagawa Kohei, Katsumata Yoshinori, Nishiyama Takahiko, Kimura Takehiro, Nishiyama Nobuhiro, Fukumoto Kotaro, Tanimoto Yoko, Tanimoto Kojiro, Ogawa Satoshi, Fukuda Keiichi

International heart journal 54 ( 4 ) 240 - 242 2013

ISSN  1349-2365

　View Summary

<p>A 45-year-old male was admitted to our hospital after successful resuscitation of cardiac arrest. Ventricular fbrilla-tion (VF) had occurred during breakfast and was defbrillated by an automated external defbrillator operated by emergency medical service staff. On admission, his ECG demonstrated complete right bundle branch block as the sole abnormality. Intensive examination could not detect any structural disease leading to a diagnosis of idiopathic VF and implantation of an ICD. VF storm occurred one month after hospital discharge and beta-blocker, amiodarone, and sedative administration had no effect on VF. Likewise, catheter ablation for triggering premature ventricular beats failed to control the VF storm. The VF storm then subsided in the following weeks and the patient was discharged on amiodarone. A half month later VF storm recurred and the patient was admitted again. This time, isoproterenol infusion was effective in suppressing VF, and thereafter the patient was administered bepridil and followed up without recurrence of VF for 1.5 years. From these benefcial effects, the VF of the patient was suggested to share common arrhythmogenic characteristics to those of Brugada syndrome or J-wave associated VF.</p>

PGD ₂-CRTH2 pathway promotes tubulointerstitial fibrosis

Ito Hideyuki, Yan Xiaoxiang, Nagata Nanae, Aritake Kosuke, Katsumata Yoshinori, Matsuhashi Tomohiro, Nakamura Masataka, Hirai Hiroyuki, Urade Yoshihiro, Asano Koichiro, Kubo Masato, Utsunomiya Yasunori, Hosoya Tatsuo, Fukuda Keiichi, Sano Motoaki

Journal of the American Society of Nephrology 23 ( 11 ) 1797 - 1809 2012.10

ISSN  1046-6673

　View Summary

<p>Urinary excretion of lipocalin-type PGD ₂ synthase (L-PGDS), which converts PG H ₂ to PGD ₂, increases in early diabetic nephropathy. In addition, L-PGDS expression in the tubular epithelium increases in adriamycin-induced nephropathy, suggesting that locally produced L-PGDS may promote the development of CKD. In this study, we found that L-PGDS-derived PGD ₂ contributes to the progression of renal fibrosis via CRTH2-mediated activation of Th2 lymphocytes. In a mouse model, the tubular epithelium synthesized L-PGDS de novo after unilateral ureteral obstruction (UUO). L-PGDS-knockout mice and CRTH2-knockout mice both exhibited less renal fibrosis, reduced infiltration of Th2 lymphocytes into the cortex, and decreased production of the Th2 cytokines IL-4 and IL-13. Furthermore, oral administration of a CRTH2 antagonist, beginning 3 days after UUO, suppressed the progression of renal fibrosis. Ablation of IL-4 and IL-13 also ameliorated renal fibrosis in the UUO kidney. Taken together, these data suggest that blocking the activation of CRTH2 by PGD ₂ might be a strategy to slow the progression of renal fibrosis in CKD.</p>

• Access to Document (DOI)

PGD ₂-CRTH2 pathway promotes tubulointerstitial fibrosis

Ito Hideyuki, Yan Xiaoxiang, Nagata Nanae, Aritake Kosuke, Katsumata Yoshinori, Matsuhashi Tomohiro, Nakamura Masataka, Hirai Hiroyuki, Urade Yoshihiro, Asano Koichiro, Kubo Masato, Utsunomiya Yasunori, Hosoya Tatsuo, Fukuda Keiichi, Sano Motoaki

Journal of the American Society of Nephrology 23 ( 11 ) 1797 - 1809 2012.10

ISSN  1046-6673

　View Summary

<p>Urinary excretion of lipocalin-type PGD ₂ synthase (L-PGDS), which converts PG H ₂ to PGD ₂, increases in early diabetic nephropathy. In addition, L-PGDS expression in the tubular epithelium increases in adriamycin-induced nephropathy, suggesting that locally produced L-PGDS may promote the development of CKD. In this study, we found that L-PGDS-derived PGD ₂ contributes to the progression of renal fibrosis via CRTH2-mediated activation of Th2 lymphocytes. In a mouse model, the tubular epithelium synthesized L-PGDS de novo after unilateral ureteral obstruction (UUO). L-PGDS-knockout mice and CRTH2-knockout mice both exhibited less renal fibrosis, reduced infiltration of Th2 lymphocytes into the cortex, and decreased production of the Th2 cytokines IL-4 and IL-13. Furthermore, oral administration of a CRTH2 antagonist, beginning 3 days after UUO, suppressed the progression of renal fibrosis. Ablation of IL-4 and IL-13 also ameliorated renal fibrosis in the UUO kidney. Taken together, these data suggest that blocking the activation of CRTH2 by PGD ₂ might be a strategy to slow the progression of renal fibrosis in CKD. Copyright © 2012 by the American Society of Nephrology.</p>

• Access to Document (DOI)

Induction of cardiomyocyte-like cells in infarct hearts by gene transfer of Gata4, Mef2c, and Tbx5

Inagawa Kohei, Miyamoto Kazutaka, Yamakawa Hiroyuki, Muraoka Naoto, Sadahiro Taketaro, Umei Tomohiko, Wada Rie, Katsumata Yoshinori, Kaneda Ruri, Nakade Koji, Kurihara Chitose, Obata Yuichi, Miyake Koichi, Fukuda Keiichi, Ieda Masaki

Circulation Research 111 ( 9 ) 1147 - 1156 2012.10

ISSN  0009-7330

　View Summary

<p>RATIONALE: After myocardial infarction (MI), massive cell death in the myocardium initiates fibrosis and scar formation, leading to heart failure. We recently found that a combination of 3 cardiac transcription factors, Gata4, Mef2c, and Tbx5 (GMT), reprograms fibroblasts directly into functional cardiomyocytes in vitro. OBJECTIVE: To investigate whether viral gene transfer of GMT into infarcted hearts induces cardiomyocyte generation. METHODS AND RESULTS: Coronary artery ligation was used to generate MI in the mouse. In vitro transduction of GMT retrovirus converted cardiac fibroblasts from the infarct region into cardiomyocyte-like cells with cardiac-specific gene expression and sarcomeric structures. Injection of the green fluorescent protein (GFP) retrovirus into mouse hearts, immediately after MI, infected only proliferating noncardiomyocytes, mainly fibroblasts, in the infarct region. The GFP expression diminished after 2 weeks in immunocompetent mice but remained stable for 3 months in immunosuppressed mice, in which cardiac induction did not occur. In contrast, injection of GMT retrovirus into α-myosin heavy chain (αMHC)-GFP transgenic mouse hearts induced the expression of αMHC-GFP, a marker of cardiomyocytes, in 3% of virus-infected cells after 1 week. A pooled GMT injection into the immunosuppressed mouse hearts induced cardiac marker expression in retrovirus-infected cells within 2 weeks, although few cells showed striated muscle structures. To transduce GMT efficiently in vivo, we generated a polycistronic retrovirus expressing GMT separated by 2A "self-cleaving" peptides (3F2A). The 3F2A-induced cardiomyocyte-like cells in fibrotic tissue expressed sarcomeric α-actinin and cardiac troponin T and had clear cross striations. Quantitative RT-PCR also demonstrated that FACS-sorted 3F2A-transduced cells expressed cardiac-specific genes. CONCLUSIONS: GMT gene transfer induced cardiomyocyte-like cells in infarcted hearts.</p>

• Access to Document (DOI)

Induction of cardiomyocyte-like cells in infarct hearts by gene transfer of Gata4, Mef2c, and Tbx5

Inagawa Kohei, Miyamoto Kazutaka, Yamakawa Hiroyuki, Muraoka Naoto, Sadahiro Taketaro, Umei Tomohiko, Wada Rie, Katsumata Yoshinori, Kaneda Ruri, Nakade Koji, Kurihara Chitose, Obata Yuichi, Miyake Koichi, Fukuda Keiichi, Ieda Masaki

Circulation Research 111 ( 9 ) 1147 - 1156 2012.10

ISSN  0009-7330

　View Summary

<p>RATIONALE: After myocardial infarction (MI), massive cell death in the myocardium initiates fibrosis and scar formation, leading to heart failure. We recently found that a combination of 3 cardiac transcription factors, Gata4, Mef2c, and Tbx5 (GMT), reprograms fibroblasts directly into functional cardiomyocytes in vitro. OBJECTIVE: To investigate whether viral gene transfer of GMT into infarcted hearts induces cardiomyocyte generation. METHODS AND RESULTS: Coronary artery ligation was used to generate MI in the mouse. In vitro transduction of GMT retrovirus converted cardiac fibroblasts from the infarct region into cardiomyocyte-like cells with cardiac-specific gene expression and sarcomeric structures. Injection of the green fluorescent protein (GFP) retrovirus into mouse hearts, immediately after MI, infected only proliferating noncardiomyocytes, mainly fibroblasts, in the infarct region. The GFP expression diminished after 2 weeks in immunocompetent mice but remained stable for 3 months in immunosuppressed mice, in which cardiac induction did not occur. In contrast, injection of GMT retrovirus into α-myosin heavy chain (αMHC)-GFP transgenic mouse hearts induced the expression of αMHC-GFP, a marker of cardiomyocytes, in 3% of virus-infected cells after 1 week. A pooled GMT injection into the immunosuppressed mouse hearts induced cardiac marker expression in retrovirus-infected cells within 2 weeks, although few cells showed striated muscle structures. To transduce GMT efficiently in vivo, we generated a polycistronic retrovirus expressing GMT separated by 2A "self-cleaving" peptides (3F2A). The 3F2A-induced cardiomyocyte-like cells in fibrotic tissue expressed sarcomeric α-actinin and cardiac troponin T and had clear cross striations. Quantitative RT-PCR also demonstrated that FACS-sorted 3F2A-transduced cells expressed cardiac-specific genes. CONCLUSIONS: GMT gene transfer induced cardiomyocyte-like cells in infarcted hearts. © 2012 American Heart Association, Inc.</p>

• Access to Document (DOI)

Deleterious effect of the IL-23/IL-17A axis and γδT cells on left ventricular remodeling after myocardial infarction.

Yan Xiaoxiang, Shichita Takashi, Katsumata Yoshinori, Matsuhashi Tomohiro, Ito Hideyuki, Ito Kentaro, Anzai Atsushi, Endo Jin, Tamura Yuichi, Kimura Kensuke, Fujita Jun, Shinmura Ken, Shen Weifeng, Yoshimura Akihiko, Fukuda Keiichi, Sano Motoaki

Journal of the American Heart Association 1 ( 5 )  2012.10

　View Summary

<p>Left ventricular (LV) remodeling leads to chronic heart failure and is a main determinant of morbidity and mortality after myocardial infarction (MI). At the present time, therapeutic options to prevent LV remodeling are limited. We created a large MI by permanent ligation of the coronary artery and identified a potential link between the interleukin (IL)-23/IL-17A axis and γδT cells that affects late-stage LV remodeling after MI. Despite the finsinf that infarct size 24 hours after surgery was similar to that in wild-type mice, a deficiency in IL-23, IL-17A, or γδT cells improved survival after 7 days, limiting infarct expansion and fibrosis in noninfarcted myocardium and alleviating LV dilatation and systolic dysfunction on day 28 post-MI. M(1) macrophages and neutrophils were the major cellular source of IL-23, whereas &gt;90% of IL-17A-producing T cells in infarcted heart were CD4(-) TCRγδ(+) (γδT) cells. Toll-like receptor signaling and IL-1β worked in concert with IL-23 to drive expansion and IL-17A production in cardiac γδT cells, whereas the sphingosine-1-phosphate receptor and CCL20/CCR6 signaling pathways mediated γδT cell recruitment into infarcted heart. IL-17A was not involved in the acute inflammatory response, but it functioned specifically in the late remodeling stages by promoting sustained infiltration of neutrophils and macrophages, stimulating macrophages to produce proinflammatory cytokines, aggravating cardiomyocyte death, and enhancing fibroblast proliferation and profibrotic gene expression. The IL-23/IL-17A immune axis and γδT cells are potentially promising therapeutic targets after MI to prevent progression to end-stage dilated cardiomyopathy.</p>

• Access to Document (DOI)

Deleterious effect of the IL-23/IL-17A axis and γδT cells on left ventricular remodeling after myocardial infarction.

Yan Xiaoxiang, Shichita Takashi, Katsumata Yoshinori, Matsuhashi Tomohiro, Ito Hideyuki, Ito Kentaro, Anzai Atsushi, Endo Jin, Tamura Yuichi, Kimura Kensuke, Fujita Jun, Shinmura Ken, Shen Weifeng, Yoshimura Akihiko, Fukuda Keiichi, Sano Motoaki

Journal of the American Heart Association 1 ( 5 )  2012.10

　View Summary

<p>Left ventricular (LV) remodeling leads to chronic heart failure and is a main determinant of morbidity and mortality after myocardial infarction (MI). At the present time, therapeutic options to prevent LV remodeling are limited. We created a large MI by permanent ligation of the coronary artery and identified a potential link between the interleukin (IL)-23/IL-17A axis and γδT cells that affects late-stage LV remodeling after MI. Despite the finsinf that infarct size 24 hours after surgery was similar to that in wild-type mice, a deficiency in IL-23, IL-17A, or γδT cells improved survival after 7 days, limiting infarct expansion and fibrosis in noninfarcted myocardium and alleviating LV dilatation and systolic dysfunction on day 28 post-MI. M(1) macrophages and neutrophils were the major cellular source of IL-23, whereas &gt;90% of IL-17A-producing T cells in infarcted heart were CD4(-) TCRγδ(+) (γδT) cells. Toll-like receptor signaling and IL-1β worked in concert with IL-23 to drive expansion and IL-17A production in cardiac γδT cells, whereas the sphingosine-1-phosphate receptor and CCL20/CCR6 signaling pathways mediated γδT cell recruitment into infarcted heart. IL-17A was not involved in the acute inflammatory response, but it functioned specifically in the late remodeling stages by promoting sustained infiltration of neutrophils and macrophages, stimulating macrophages to produce proinflammatory cytokines, aggravating cardiomyocyte death, and enhancing fibroblast proliferation and profibrotic gene expression. The IL-23/IL-17A immune axis and γδT cells are potentially promising therapeutic targets after MI to prevent progression to end-stage dilated cardiomyopathy.</p>

• Access to Document (DOI)

Biphasic time course of the changes in aldosterone biosynthesis under high-salt conditions in dahl salt-sensitive rats

Morizane Shintaro, Mitani Fumiko, Ozawa Kae, Ito Kentaro, Matsuhashi Tomohiro, Katsumata Yoshinori, Ito Hideyuki, Yan Xiaoxiang, Shinmura Ken, Nishiyama Akira, Honma Seijiro, Suzuki Takeshi, Funder John W., Fukuda Keiichi, Sano Motoaki

Arteriosclerosis, Thrombosis, and Vascular Biology 32 ( 5 ) 1194 - 1203 2012.05

ISSN  1079-5642

　View Summary

<p>Objective-: The comorbidity of excess salt and elevated plasma aldosterone has deleterious effects in cardiovascular disease. We evaluated the mechanisms behind the paradoxical increase in aldosterone biosynthesis in relation to dietary intake of salt. Methods And Results-: Dahl salt-sensitive (Dahl-S) and salt-resistant (Dahl-R) rats were fed a high-salt diet, and plasma and tissue levels of aldosterone in the adrenal gland and heart were quantified by liquid chromatography-electrospray ionization-tandem mass spectrometry. In Dahl-S rats, we found that the delayed and paradoxical increase in aldosterone biosynthesis after the initial and appropriate response to high salt. The late rise in aldosterone biosynthesis was accompanied by upregulation of CYP11B2 expression in the zona glomerulosa and increased adrenal angiotensin II levels and renin-angiotensin system components. It preceded the appearance of left ventricular systolic dysfunction and renal insufficiency. Blockade of angiotensin AT1 receptors reversed the paradoxical increase in aldosterone biosynthesis. In contrast, Dahl-R rats maintained the initial suppression of aldosterone biosynthesis. Aldosterone levels in the heart closely paralleled those in the plasma and adrenal gland and disappeared after bilateral adrenalectomy. Conclusion-: Chronic salt overload in Dahl-S rats stimulates aberrant aldosterone production via activation of the local renin-angiotensin system in the adrenal gland, thereby creating the comorbidity of excess salt and elevated plasma aldosterone.</p>

• Access to Document (DOI)

Biphasic time course of the changes in aldosterone biosynthesis under high-salt conditions in dahl salt-sensitive rats

Morizane Shintaro, Mitani Fumiko, Ozawa Kae, Ito Kentaro, Matsuhashi Tomohiro, Katsumata Yoshinori, Ito Hideyuki, Yan Xiaoxiang, Shinmura Ken, Nishiyama Akira, Honma Seijiro, Suzuki Takeshi, Funder John W., Fukuda Keiichi, Sano Motoaki

Arteriosclerosis, Thrombosis, and Vascular Biology 32 ( 5 ) 1194 - 1203 2012.05

ISSN  1079-5642

　View Summary

<p>Objective-: The comorbidity of excess salt and elevated plasma aldosterone has deleterious effects in cardiovascular disease. We evaluated the mechanisms behind the paradoxical increase in aldosterone biosynthesis in relation to dietary intake of salt. Methods And Results-: Dahl salt-sensitive (Dahl-S) and salt-resistant (Dahl-R) rats were fed a high-salt diet, and plasma and tissue levels of aldosterone in the adrenal gland and heart were quantified by liquid chromatography-electrospray ionization-tandem mass spectrometry. In Dahl-S rats, we found that the delayed and paradoxical increase in aldosterone biosynthesis after the initial and appropriate response to high salt. The late rise in aldosterone biosynthesis was accompanied by upregulation of CYP11B2 expression in the zona glomerulosa and increased adrenal angiotensin II levels and renin-angiotensin system components. It preceded the appearance of left ventricular systolic dysfunction and renal insufficiency. Blockade of angiotensin AT1 receptors reversed the paradoxical increase in aldosterone biosynthesis. In contrast, Dahl-R rats maintained the initial suppression of aldosterone biosynthesis. Aldosterone levels in the heart closely paralleled those in the plasma and adrenal gland and disappeared after bilateral adrenalectomy. Conclusion-: Chronic salt overload in Dahl-S rats stimulates aberrant aldosterone production via activation of the local renin-angiotensin system in the adrenal gland, thereby creating the comorbidity of excess salt and elevated plasma aldosterone. © 2012 American Heart Association, Inc.</p>

• Access to Document (DOI)