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Lentiviral Vector-mediated SERCA2 Gene Transfer Prevents Cardiac Dysfunction in Rats:The New Storategy of Gene Therapy for Sever Heart Failure
The 9th Annual Scientific Meeting
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JHFS
S277
O-009
O-011
Assessment of Left Ventricular Dyssynchrony Using Two-dimensional Strain Echocardiography(2D-Strain): Comparison Between Radial and Longitudinal Approach AZUSA FURUGEN, NAOKI MATSUDA, SONOKO SAITOH, KYOMI TANIMOTO, NAOKO ISHIZUKA, MORIO SYOHDA, HIROSHI KASANUKI Department of Cardiology, Tokyo Women’s Medical University, Tokyo, Japan
Repeated Thermal Therapy Improves the Abnormality of Sympathetic Nervous System in Chronic Heart Failure
2D-Strain is a new echocardiographic technique and allows both evaluations of radial and longitudinal LV dyssynchrony. We investigated usefulness of radial approach in predicting responders to Cardiac resynchronization therapy(CRT). Methods: 28 patients with heart failure and wide QRS ⬎120msec underwent 2D-Strain before CRT. Intervals from the onset of QRS configuration to peak-radial-strain(Tr) and peak-longitudinal-strain(Tl) were measured at 6-LV basal segments. Differences of Tr between opposite sites in LV were calculated: Tr-septal-to-lateral(Tr-S-L); Tr-anteroseptal-to-posterior(TrAS-P); Tr-anterior-to-inferior(Tr-A-I). Differences of Tl in the same sites were also calculated: Tl-S-L; Tl-AS-P; Tl-A-I. Responder to CRT was defined as a patient who had a reduction in LVEDV by ⬎10%, increase in LVEF by ⬎5% and improvement of NYHA class at 6 months after CRT. Results: Tr-S-L, Tr-AS-P and Tr-A-P were significantly longer than TlS-L, Tl-AS-P, and Tl-A-P, respectively. Significant but weak correlation was observed between Tr-S-L and Tl-S-L, Tr-AS-P and Tl-AS-P, and TrA-I and Tl-A-I. Responders to CRT were 20 patients (71%). The areas of ROC curves in predicting responders for Tr-S-L, Tr-AS-P and Tr-A-I were larger than those of Tl-S-L, Tl-AS-P and Tl-A-I, respectively. The area of ROC curve was the largest for Tr-S-L with a sensitivity of 80% and specificity of 75%, at a cut-off of 198ms. Conclusion: LV radial-dyssynchrony assessed with 2D-Strain echo may be better indicator than longitudinal-dyssynchrony in selection of CRT candidate.
Purpose: In patients with chronic heart failure (CHF), the increased sympathetic nervous activity develops cardiac dysfunction. We developed the thermal therapy which is a different design from the traditional sauna. We reported that thermal therapy using 60ºC dry sauna improves hemodynamics, vascular endothelial function and clinical symptoms in patients with CHF. The present study aims to investigate whether repeated thermal therapy improves sympathetic nervous activity in patients with CHF. Method: Thirty patients with CHF due to dilated cardiomyopathy were randomized into thermal therapy or non-treated groups and thermal therapy group was taken sauna daily for 2 weeks. To analyze sympathetic nervous activity, we measured plasma concentration of norepinephrine and standard deviation of normal to normal intervals (SDNN) by 24-hr Holter ECG recordings. Result: Two-week thermal therapy improved NYHA functional class, left ventricular ejection fraction estimated by echocardiography, cardiothoracic ratio of chest X-ray and plasma brain-natriuretic peptide concentration. After 2-week thermal therapy, the plasma concentration of norepinephrine significantly decreased and SDNN increased compared to those before treatment (norepinephrine: 497⫾173 to 365⫾140 pg/ml, P⬍0.01, SDNN: 113⫾8 to 142⫾10 ms, P⬍0.01). On the other hand, there were no significant changes in those of non-treated group (norepinephrine: 414⫾42 to 455⫾84 pg/ml, SDNN: 111⫾10 to 112⫾11 ms). Conclusion: Repeated thermal therapy decreased sympathetic nervous activity and improved cardiac function in CHF.
O-010
O-012
Impact of End-tidal Carbon Dioxide on Responsiveness to Oxygen Therapy in Patients with Central Sleep Apnea
Lentiviral Vector-mediated SERCA2 Gene Transfer Prevents Cardiac Dysfunction in Rats:The New Storategy of Gene Therapy for Sever Heart Failure KAZUO NIWANO1, MASASHI ARAI1, NORIMICHI KOITABASHI1, YASUHIRO IKEDA2, HIROYUKI MIYOSHI3, SHIRO HARA1, ATAI WATANABE1, MASAHIKO KURABAYASHI1 1 Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Maebashi, Japan, 2Department of Medical Bioregulation, Molecular Biology, Yamaguchi University School of Medicine, Japan, 3Subteam for Manipulation of Cell fate, BioResource Center, RIKEN Tsukuba Institute, Japan
KOICHIRO SUGIMURA1, TSUYOSHI SHINOZAKI1, SHIGEFUMI FUKUI1, HIROMASA OGAWA2, JUN WATANABE1, KUNIO SHIRATO1 1 Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, 2Department of Infection and Respiratory Disease, Tohoku University Graduate School of Medicine Background: Nocturnal oxygen therapy (OT) improves central sleep apnea in patients with chronic heart failure (CHF). There are, however, nonresponders to OT. This study aimed to find factors contributing to the responsiveness to OT. Methods: Sleep study was performed in 10 central sleep apnea patients (apnea-hypopnea index, AHI 33⫾12 /h, age 71⫾10, ejection fraction 39⫾10%). To predict the percentage reduction of AHI by OT, multiple regression analysis was performed with variables of the ejection fraction, BNP, baseline AHI, central chemosensitivity, circulation time and endtidal CO2. Results: The percentage reduction of AHI was determined by only endtidal CO2 (r⫽0.82, p⬍0.005). Conclusion: Low end-tidal CO2 predicts the ineffectiveness to OT in patients with CHF and central sleep apnea.
YOSHIYUKI IKEDA, MASAAKI MIYATA, TSUYOSHI FUKUDOME, TAKURO SHINSATO, TAKURO KUBOZONO, TAKASHI KIHARA, YUTAKA OTSUJI, CHUWA TEI Department of Cardiovascular, Respiratory and Metabolic Medicine, Graduate School of Medicine, Kagoshima University, Kagoshima, Japan
Reduced expression of sarcoplasmic reticulum (SR) Ca2⫹-ATPase (SERCA2) impairs calcium handling in the cardiac myocytes and contributes importantly to contractile dysfunction of the heart. Unlike adenovirus- or adenoassociated vectors, lentivirus can stably integrate into host genome of terminally differentiated cardiac myoctes and thus induces permanent gene expression. We developed lentivirus-based SERCA2 gene transfer system using hypothermic intracoronary delivery method and examined its effect on the cardiac contractile function in rat heart failure model. Transfection of Lenti-GFP vector (1×1011 IU/300g BW) revealed that the transgene was preferentially delivered into heart but far less abundant into liver and spleen. The therapeutic effect of Lenti-SERCA2 vector was compared with the Lenti-beta-Gal control vector in the failure heart induced by myocardial infarction (MI) in rat. Using echocardiography, LentiSERCA2 group rats showed a significant increase in fractional shortening by 10% compared with Lenti-beta-Gal group rats from 30 to 90 days after gene transfer. Although SERCA2 mRNA and protein were elevated after gene transfer, mRNA levels for other SR genes were not affected. In addition, the expression of BNP mRNA expression was significantly decreased in Lenti-SERCA2 group rats. Our study showed that the introduced SERCA2a gene was successfully integrated into hearts by using lentivirus system, and supports the premise that a lentivirus-based, SERCA2 gene therapy improves human heart failure.
•
JHFS
S277
O-009
O-011
Assessment of Left Ventricular Dyssynchrony Using Two-dimensional Strain Echocardiography(2D-Strain): Comparison Between Radial and Longitudinal Approach AZUSA FURUGEN, NAOKI MATSUDA, SONOKO SAITOH, KYOMI TANIMOTO, NAOKO ISHIZUKA, MORIO SYOHDA, HIROSHI KASANUKI Department of Cardiology, Tokyo Women’s Medical University, Tokyo, Japan
Repeated Thermal Therapy Improves the Abnormality of Sympathetic Nervous System in Chronic Heart Failure
2D-Strain is a new echocardiographic technique and allows both evaluations of radial and longitudinal LV dyssynchrony. We investigated usefulness of radial approach in predicting responders to Cardiac resynchronization therapy(CRT). Methods: 28 patients with heart failure and wide QRS ⬎120msec underwent 2D-Strain before CRT. Intervals from the onset of QRS configuration to peak-radial-strain(Tr) and peak-longitudinal-strain(Tl) were measured at 6-LV basal segments. Differences of Tr between opposite sites in LV were calculated: Tr-septal-to-lateral(Tr-S-L); Tr-anteroseptal-to-posterior(TrAS-P); Tr-anterior-to-inferior(Tr-A-I). Differences of Tl in the same sites were also calculated: Tl-S-L; Tl-AS-P; Tl-A-I. Responder to CRT was defined as a patient who had a reduction in LVEDV by ⬎10%, increase in LVEF by ⬎5% and improvement of NYHA class at 6 months after CRT. Results: Tr-S-L, Tr-AS-P and Tr-A-P were significantly longer than TlS-L, Tl-AS-P, and Tl-A-P, respectively. Significant but weak correlation was observed between Tr-S-L and Tl-S-L, Tr-AS-P and Tl-AS-P, and TrA-I and Tl-A-I. Responders to CRT were 20 patients (71%). The areas of ROC curves in predicting responders for Tr-S-L, Tr-AS-P and Tr-A-I were larger than those of Tl-S-L, Tl-AS-P and Tl-A-I, respectively. The area of ROC curve was the largest for Tr-S-L with a sensitivity of 80% and specificity of 75%, at a cut-off of 198ms. Conclusion: LV radial-dyssynchrony assessed with 2D-Strain echo may be better indicator than longitudinal-dyssynchrony in selection of CRT candidate.
Purpose: In patients with chronic heart failure (CHF), the increased sympathetic nervous activity develops cardiac dysfunction. We developed the thermal therapy which is a different design from the traditional sauna. We reported that thermal therapy using 60ºC dry sauna improves hemodynamics, vascular endothelial function and clinical symptoms in patients with CHF. The present study aims to investigate whether repeated thermal therapy improves sympathetic nervous activity in patients with CHF. Method: Thirty patients with CHF due to dilated cardiomyopathy were randomized into thermal therapy or non-treated groups and thermal therapy group was taken sauna daily for 2 weeks. To analyze sympathetic nervous activity, we measured plasma concentration of norepinephrine and standard deviation of normal to normal intervals (SDNN) by 24-hr Holter ECG recordings. Result: Two-week thermal therapy improved NYHA functional class, left ventricular ejection fraction estimated by echocardiography, cardiothoracic ratio of chest X-ray and plasma brain-natriuretic peptide concentration. After 2-week thermal therapy, the plasma concentration of norepinephrine significantly decreased and SDNN increased compared to those before treatment (norepinephrine: 497⫾173 to 365⫾140 pg/ml, P⬍0.01, SDNN: 113⫾8 to 142⫾10 ms, P⬍0.01). On the other hand, there were no significant changes in those of non-treated group (norepinephrine: 414⫾42 to 455⫾84 pg/ml, SDNN: 111⫾10 to 112⫾11 ms). Conclusion: Repeated thermal therapy decreased sympathetic nervous activity and improved cardiac function in CHF.
O-010
O-012
Impact of End-tidal Carbon Dioxide on Responsiveness to Oxygen Therapy in Patients with Central Sleep Apnea
Lentiviral Vector-mediated SERCA2 Gene Transfer Prevents Cardiac Dysfunction in Rats:The New Storategy of Gene Therapy for Sever Heart Failure KAZUO NIWANO1, MASASHI ARAI1, NORIMICHI KOITABASHI1, YASUHIRO IKEDA2, HIROYUKI MIYOSHI3, SHIRO HARA1, ATAI WATANABE1, MASAHIKO KURABAYASHI1 1 Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Maebashi, Japan, 2Department of Medical Bioregulation, Molecular Biology, Yamaguchi University School of Medicine, Japan, 3Subteam for Manipulation of Cell fate, BioResource Center, RIKEN Tsukuba Institute, Japan
KOICHIRO SUGIMURA1, TSUYOSHI SHINOZAKI1, SHIGEFUMI FUKUI1, HIROMASA OGAWA2, JUN WATANABE1, KUNIO SHIRATO1 1 Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, 2Department of Infection and Respiratory Disease, Tohoku University Graduate School of Medicine Background: Nocturnal oxygen therapy (OT) improves central sleep apnea in patients with chronic heart failure (CHF). There are, however, nonresponders to OT. This study aimed to find factors contributing to the responsiveness to OT. Methods: Sleep study was performed in 10 central sleep apnea patients (apnea-hypopnea index, AHI 33⫾12 /h, age 71⫾10, ejection fraction 39⫾10%). To predict the percentage reduction of AHI by OT, multiple regression analysis was performed with variables of the ejection fraction, BNP, baseline AHI, central chemosensitivity, circulation time and endtidal CO2. Results: The percentage reduction of AHI was determined by only endtidal CO2 (r⫽0.82, p⬍0.005). Conclusion: Low end-tidal CO2 predicts the ineffectiveness to OT in patients with CHF and central sleep apnea.
YOSHIYUKI IKEDA, MASAAKI MIYATA, TSUYOSHI FUKUDOME, TAKURO SHINSATO, TAKURO KUBOZONO, TAKASHI KIHARA, YUTAKA OTSUJI, CHUWA TEI Department of Cardiovascular, Respiratory and Metabolic Medicine, Graduate School of Medicine, Kagoshima University, Kagoshima, Japan
Reduced expression of sarcoplasmic reticulum (SR) Ca2⫹-ATPase (SERCA2) impairs calcium handling in the cardiac myocytes and contributes importantly to contractile dysfunction of the heart. Unlike adenovirus- or adenoassociated vectors, lentivirus can stably integrate into host genome of terminally differentiated cardiac myoctes and thus induces permanent gene expression. We developed lentivirus-based SERCA2 gene transfer system using hypothermic intracoronary delivery method and examined its effect on the cardiac contractile function in rat heart failure model. Transfection of Lenti-GFP vector (1×1011 IU/300g BW) revealed that the transgene was preferentially delivered into heart but far less abundant into liver and spleen. The therapeutic effect of Lenti-SERCA2 vector was compared with the Lenti-beta-Gal control vector in the failure heart induced by myocardial infarction (MI) in rat. Using echocardiography, LentiSERCA2 group rats showed a significant increase in fractional shortening by 10% compared with Lenti-beta-Gal group rats from 30 to 90 days after gene transfer. Although SERCA2 mRNA and protein were elevated after gene transfer, mRNA levels for other SR genes were not affected. In addition, the expression of BNP mRNA expression was significantly decreased in Lenti-SERCA2 group rats. Our study showed that the introduced SERCA2a gene was successfully integrated into hearts by using lentivirus system, and supports the premise that a lentivirus-based, SERCA2 gene therapy improves human heart failure.