| Project/Area Number |
16K10071
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Multi-year Fund |
|---|
| Section | 一般 |
|---|
| Research Field |
Pediatrics
|
|---|
| Research Institution | Kyoto Prefectural University of Medicine |
|---|
Principal Investigator |
奥村 謙一 京都府立医科大学, 医学(系)研究科(研究院), 助教 (10349699)
|
|---|
| Project Period (FY) |
2016-04-01 – 2019-03-31
|
| Project Status |
Discontinued (Fiscal Year 2018)
|
| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2016: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
|
|---|
| Keywords | 肺高血圧 / 心拍抑制作用 / 心筋線維化 / 心拍抑制 / 右室心機能 / 肺高血圧治療 / 右室機能 / 心室相互作用 |
|---|
| Outline of Annual Research Achievements |
Background: Beta-blockers improve biventricular dysfunction in experimental pulmonary arterial hypertension (PAH), but heart rate reduction (HRR) versus non-chronotropic beta-blocker effects is unknown. We investigated HRR, using the If current inhibitor ivabradine, on biventricular function in experimental PAH comparing results to the adrenergic-receptor blocker carvedilol.
Methods and Results: Rats were randomized to: 1) Sham controls, 2) monocrotaline (MCT) PAH, 3) MCT-PAH + ivabradine. Results were compared to previously reported carvedilol treated PAH rats. Oral ivabradine (10mg/kg/d) and carvedilol (15mg/kg/d) were started 2-weeks after MCT and continued for 3-weeks until terminal experiment. Echocardiography was assessed at baseline and at terminal experiment with pressure-volume hemodynamics. Right (RV) and left ventricular hypertrophy, fibrosis and its molecular signaling were analyzed by western blots. Despite similar severely elevated RV systolic pressures, ivabradine reduced biventricular fibrosis area (RV: 13.4±6.5 vs 6.7±2.6 %, p<0.001), transforming growth factor β (TGFβ) (RV TGFβ/ glyceraldehyde 3-phosphate dehydrogenase (GAPDH) ratio; 1.16±0.39 vs. 0.7±0.54, p<0.05) and connective tissue growth factor (CTGF) (RV CTGF/GAPDH ratio: 0.49±0.06 vs 0.28±0.12, p<0.05).
Conclusions: HRR improves biventricular fibrosis and function in experimental PAH independent of adrenergic receptor blockade. If blockers to modulate heart rate in PAH warrants further study as a promising strategy utilizing beta blockers benefits while avoiding negative inotrope.
|
