2019 Fiscal Year Research-status Report
Understanding the pathogenesis of right heart failure in pulmonary arterial hypertension
| Project/Area Number |
19K16498
|
|---|
| Research Institution | National Cardiovascular Center Research Institute |
|---|
Principal Investigator |
ワディンガム マーク.トーマス 国立研究開発法人国立循環器病研究センター, 病院, 特任研究員 (70822211)
|
|---|
| Project Period (FY) |
2019-04-01 – 2022-03-31
|
| Keywords | Heart Failure / Right Ventricle / Pulmonary Hypertension / Myocardium / Myofilament / Sarcomere |
|---|
| Outline of Annual Research Achievements |
The aim for this component of the proposal was to investigate the series of events at the level of the right ventricle (RV) cardiomyocyte myofilaments that occur over the time-course of pulmonary arterial hypertension (PAH). To achieve this aim, the Sugen 5416/chronic hypoxia (SuHx) rat model of PAH was utilized. Global RV function and myofilament function was simultaneously assessed at 3 weeks (SuHx 3wk) and 6 weeks (SuHx 6wk) after the induction of PAH.
It was found that in both PAH groups, there was a time-dependent increase in RV size and RV systolic pressure, demonstrating an increase in the severity of PAH between the SuHx 3wk and SuHx 6wk groups. At the level of the myofilament, it was demonstrated that myosin mass transfer was reduced in the deep myocardium of the SuHx 6wk group.
|
| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
In year 1, I planned to characterise global RV function and RV myofilament function across the pathophysiological spectrum of PAH using the SuHx rat model. As described above, the SuHx rat model of PAH demonstrates progressive global RV remodelling and dysfunction in addition to similar changes at the level of sarcomere and myofilament. Therefore, our model has been well characterised and the final studies (SuHx 10wk) are due for completion in summer 2020.
|
| Strategy for Future Research Activity |
In the next series of experiments, it is planned to carry out an "intervention study", whereby rats will be induced with PAH (SuHx model) and immediately after induction, will be treated with agents that are able to inhibit sympathetic nervous system (SNS) activity. In these studies, it is planned to use the ghrelin analog, hexarelin OR the serotonin selective re-uptake inhibitor, paroxetine. These drugs have been shown to inhibit SNS activity or sensitize the myocardium to the SNS messengers respectively, and have demonstrated to improve heart function in other models of chronic heart failure.
|
| Causes of Carryover |
Parts of the molecular biological analysis planned for FY2019 will be conducted after the final planned experiments for FY2019 are completed in summer 2020.
|
