Differential Biventricular Remodeling and Fibrosis Caused by Pulmonary Regurgitation Versus Combined Regurgitation and Stenosis: Transcriptome Analysis, Pharmocotherapy, and Clinical Implication

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Project title/計畫英文名

Project Number/計畫編號

MOST105-2628-B002-044-MY3

Translated Name/計畫中文名

肺動脈逆流與狹窄引致之差異性左右心室重塑與纖維化：轉錄體分析、藥物治療、與臨床意義

Project Principal Investigator/計畫主持人

CHUN-AN CHEN

Co-Investigator(s)/共同執行人

KAI-CHIEN YANG
MAO-YUAN SU

Funding Organization

Ministry of Science and Technology

Department/Unit

Pediatrics

Start date/計畫起

01-08-2016

Expected Completion/計畫迄

31-07-2017

摘要：法洛氏四重症術後併發的肺動脈逆流，是惡化患者心臟功能的重要問題。本團隊過去研究發現，若同時合併輕度肺動脈狹窄，反而能減輕肺動脈逆流對心臟擴大與纖維化的不良影響。然而，這些發現皆來自於回溯性分析，特別是廣泛性心肌纖維化的評估仍有方法學上的不足。此外，我們雖然在已穩定建立的小鼠肺動脈逆流與狹窄模式中觀察到了與臨床患者相似的差異性心室重塑現象，但其中的分子機轉，以及藥物治療的潛在效果與差異性，仍屬未知。本研究第一個目的是以前瞻性的研究設計，針對肺動脈逆流分率≥25%的法洛氏四重症術後患者，透過核磁共振T1 mapping 技術以及同時間的血比容，評估廣泛性心肌纖維化，探討不同右心室負荷異常的患者中纖維化程度上可能的差異與臨床意義。本研究第二個目的是以這兩種不同右心室負荷異常的小鼠，在右心室負荷異常長達六個月之後，分析心肌中轉錄體(transcriptome)的特異與差別表現，特別是著重在長鏈非編碼核醣核酸(long noncoding RNA)的差異性表現，期能作為未來研究的標的。本研究第三個目的是以這兩種不同右心室負荷異常的小鼠，探討使用血管張力素受體阻斷劑(angiotensin receptor blocker, ARB)與乙型阻斷劑(β blocker)對於心室重塑、運動功能、心肌纖維化、以及特定RNA 表現的影響。
Abstract: Chronic and significant pulmonary regurgitation (PR) is a major complicationlate after tetralogy of Fallot repair (rTOF). Our previous study has demonstrated theprotective effect of concomitant mild pulmonary stenosis (PS) in patients withsignificant PR in terms of ventricular remodeling and diffuse fibrosis. Nonetheless, allthese studies are retrospective in study design, and there is significant methodologicallimitation in the calculation of diffuse fibrosis. Besides, we have established stablemice models of PR and PS, and similar to clinical cases, presenting with differentialventricular remodeling. However, little is known about the underlying molecularmechanisms and the potential effect of pharmacotherapy.The first aim of this project is to prospectively investigate the extent of diffusemyocardial fibrosis by measuring biventricular extracellular volume index (ECV) inrTOF patients with significant PR and combined PR + mild PS using T1 mappingtechnique. Potential relationships between myocardial ECV and ventricularremodeling, hemodynamic load, and clinical parameters will be explored.The second aim of this project is to explore myocardial long noncoding RNAs(lncRNAs) expression profiles associated with different types of abnormal rightventriculr loadings in our established mouse models, which have been subject tospecific hemodynamic burden for 6 months.The third aim of this project is to evaluate the efficacy and potential differentialeffects of angiotensin receptor blocker (ARB) and β blocker on biventricular reverseremodeling, exercise capacity, diffuse fibrosis, and target gene expressions in mousemodels of PR and combined PR + mild PS.

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Differential Biventricular Remodeling and Fibrosis Caused by Pulmonary Regurgitation Versus Combined Regurgitation and Stenosis: Transcriptome Analysis, Pharmocotherapy, and Clinical Implication

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