2020 Fiscal Year Research-status Report
Understanding the pathogenesis of right heart failure in pulmonary arterial hypertension
| Project/Area Number |
19K16498
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| Research Institution | National Cardiovascular Center Research Institute |
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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)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Keywords | Pulmonary Hypertension / Heart Failure / Right Ventricle / Myofilament / Sarcomere / Sympathetic Nervous Sys. / SSRIs |
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| Outline of Annual Research Achievements |
Using the model characterisation data obtained in FY2019, the effects of a selective serotonin re-uptake inhibitor (SSRI), paroxetine, were examined in the Sugen 5416/10% O2 chronic hypoxia (SuHx) model of pulmonary hypertension (PH). Briefly, after induction of PH, rats were returned to normoxic conditions for 2 weeks. SuHx rats then received either paroxetine (5mg/kg/day) or vehicle via an osmotic pump implanted subcutaneously for 4 weeks.
It was found that paroxetine treatment was associated with improved right ventricular (RV) systolic function and pulmonary vascular compliance in the PH rats, despite no overt reduction in pulmonary pressures. Moreover, modest improvements in RV diastolic function were also observed in PH rats that received the paroxetine treatment.
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| Current Status of Research Progress |
Current Status of Research Progress
3: Progress in research has been slightly delayed.
Reason
It was planned to conduct synchrotron x-ray diffraction experiments in the in situ beating rat heart to understand if the beneficial effects of paroxetine on RV function in PH is associated with changes at the level of the sarcomere. However, due to the COVID-19 global pandemic and the necessary restrictions, only limited access to SPring-8 Synchrotron (Hyogo, Japan) was offered in 2020. This precluded these experiments being conducted in FY2020 as per the experiment plan.
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| Strategy for Future Research Activity |
It is now planned to investigate if using the SSRI, paroxetine, can prevent the development of RV dysfunction throughout the development of PH. To achieve this, a prevention study will be conducted whereby rats will receive paroxetine from the time that PH is induced until the end of the study.
Moreover, biochemical analysis of RV tissues will continue to establish if paroxetine treatment in the intervention study exhibited any beneficial effects directly upon the RV myofilaments (e.g. increase in phosphorylation or reduction of oxidative modifications) or other processes within the cardiomyocytes such as energetics, metabolism or calcium handling. Analysis of lung tissue will also be conducted to establish if paroxetine could also reduce lung remodelling, inflammation and vasoconstrictor factors that are associated with the initiation and progression of PH.
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| Causes of Carryover |
Funds were reserved for travel and SPring-8 experiments that could not be conducted in FY2020 due to the impact of the COVID-19 pandemic. The remaining funds will be utilised in FY2021 to support SPring-8 experiments (pending approval for access) in addition to further biochemical analysis of rat heart and lung tissues collected during FY2020.
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Research Products
(1 results)
