肺動脈高血壓是一種由於肺動脈壓力過高引起的肺部血管疾病，病程會持續進展最終導致右心衰竭。而肺動脈壓力高低取決於肺血管阻力、肺血流量和左心房壓力，這三個發病原因不論是在哪一個環節出現問題，肺動脈長期持續處於高壓狀態，代償性地造成肺血管增加，使肺動脈血管發生結構和功能改變，肺血管內膜增生、變厚，肺血管中層壞死、失去彈性。儘管近幾年藥物的開發已大幅改善肺動高壓的預後，但其牽涉到其尚未明朗且複雜的病理生理機制變化，以致目前已上市的抗肺動脈高壓的藥物僅作用在於延緩疾病進程，使該疾病仍無法治癒，死亡率仍高居不下。sildenafil是用於治療肺動脈高壓的常見藥物之一，根據過去文獻指出其能夠幫助改善肺動脈高壓病患的預後，但在其長期臨床試驗報告指出仍有部分病患的臨床需求得不到很好滿足，因此對抗肺動脈高血壓藥物開發仍有極大的需求。近幾年的臨床研究發現肺動脈高壓的嚴重程度與血液中醛固酮(Aldosterone)濃度成正比，因而被視為肺動脈高血壓發展藥物新的方向。隨著肺動脈高壓疾病病程的進展，醛固酮的合成增加會促進肺動脈血管結構非可逆性的嚴重破壞。我們因而推測醛固酮調節對肺動脈高壓病程的預後有一定的影響力，了解醛固酮在肺動脈高壓形成下如何調節及影響右心衰竭，可為肺動脈高壓增加新的治療契機。鹽皮質激素受體拮抗劑(Mineralocorticoid receptor antagonists) 包括spironolactone、eplerenone，是常見的醛固酮拮抗劑，臨床上常被用來治療心衰竭引起的水腫問題。在我們的研究中利用spironolactone和eplerenone去治療經由Aortocaval fistula形成手術而引起肺動高壓的大鼠，觀察大鼠心肺功能與肺動脈血管結構的變化。我們發現，有肺動脈高壓的大鼠在經過四周的合併使用sildenafil和eplerenone治療後，對右心室結構有顯著的改善，而此在單獨使用sildenafil的大鼠身上並未出現。因此我們進一步利用回溯性研究分析肺動脈高壓的患者在既有sildenafil藥物治療下，追蹤在spironolactone的輔助治療六個月下，病患病況和心肺功能的變化。我們發現接受spironolactone治療的實驗組病患相較於未使用的對照組病患，實驗組在6分鐘步行距離及NYHA功能性分級表現上皆有顯著的改善。因此我們認為在可能有sildenafil藥物阻抗性的肺動脈高壓患者上，鹽皮質激素受體拮抗劑的輔助療可減輕疾病症狀並改善其心肺功能。

Pulmonary arterial hypertension (PAH) is a lethal and progressive disease associated with the elevated pressures in the pulmonary arteries ultimately leading to right heart failure as poor prognosis outcomes. The pressure of pulmonary artery depends on the pulmonary vascular resistance, blood flow and left atrial pressure. When PAH occurs, chronic progression of this disease compensatorily contributes to increased pulmonary blood flow, which is often observed in congenital heart disease. The irreversible malformation of pulmonary vasculature, including vascular proliferation, remodeling, fibrosis or even obstruction, can be as well observed in the progression of PAH.
Although the drug invention on PAH does enhance the prognosis, there are further needs for the research and development of medicines on PAH due to its unknown and complex mechanism and high mortality. Sildenafil, one of the specific treatments on PAH, has been proved to benefit on the prognosis of PAH. However, the previous long-term clinical studies about sildenafil indicate that a portion of patients with PAH may have resistance to this medicine. Besides, elevated levels of plasma aldosterone have been recently documented to correlate with the severity of functional capacity in patients with PAH. Thus, we propose that increased aldosterone modulates the progression of PAH leading to the irreversible injuries of structure of pulmonary vasculatures, promotion of right heart failure as well as poor prognosis. Mineralocorticoid receptor (MR) antagonists (spironolactone and eplerenone), also known as aldosterone antagonists, are used on patients of heart failure to improve the symptom of edema. Herein, in our study, spironolactone and eplerenone are utilized on a flow-induced animal model of PAH developed by creating aortocaval (AC) on rats to investigate the cardiopulmonary function and changes in pulmonary arterial structures. We find that the rats with artificial AC fistula which received the combination of eplerenone and sildenafil were observed with improved function of right ventricle. However, these changes didn’t appear on rats with the single treatment of sildenafil. We further did a retrospective cohort, involving adult patients who had received sildenafil as the standard treatments, with or without spironolactone, for comparison. We find out that patients, dosage with spironolactone, did improve significantly in terms of exercise and functional capacity after 6-month. The other group of sildenafil alone treatment, patients had deteriorated in functional capacity after 6-month follow-up. Thus, we expect that MR antagonists can improve cardiopulmonary function under the resistance to sildenafil.

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