Clinical Implications of Pulmonary Hypertension associated with Down Syndrome

Abstract

Childrens with Down syndrome (DS) has a greater risk of pulmonary arterial hypertension (PAH) than the general pediatric patients. The reasons of PAH are mainly due to probably genetic backgrounds, specific structure of pulmonary vascular wall, certain types of congenital heart diseases, and partly due to pulmonary hypoplasia, upper and lower airway obstructive diseases, chronic infection, and neuro-muscular underdevelopment. Exposure to increased left to right shunt results in increased sheer stress on pulmonary endothelial cells and may induce endothelial dysfunction followed by irreversible pulmonary arterial remodeling. The pathological changes are characterized by endothelial cell proliferation and thickening of pulmonary arterial vessel wall due to mechanical responses to thinner medial smooth muscle cell (SMC) layer and pulmonary hypoplasia (under development of alveoli). DS patients has decreased production of prostacycline and Nitrate, but elevated endothelin-1 and thromboxane. Perioperative periods, DS may develop post ICR PAH crisis, poorer response to nitric oxide (NO) inhalation, and prolonged PAH status. For better management of DS patients, it is crucial to evaluate systemic complications with pediatric cardiologists, pulmonologists, neurologists, and adult cardiologists. At the cardiac catheterization, pulmonary arterial resistance is a kee-data for assessing the severity of PAH, and response to vasodilating agents for preventing postoperative PAH crisis, and for indication of intracardiac repair. The advanced therapy with recently developed pulmonary vasodilating agents seems to be effective for DS patients. Operative risk is not so high even in DS patients except patients with severe AVSD compared to non-DS patients. Optimal timing and modalities for evaluation are essential. 要 旨 Down 症候群 （DS） に伴う遺伝子異常は研究の途上であり，Alzheimer 病を基本とした神経系細胞の研究に比べ， CRELD1 や GATA4 関連心奇形，肺動脈の組織変化に関連する経路の研究はやや乏しい感がある．基本的には，お おむね房室中隔欠損 （AVSD） に伴う肺動脈性肺高血圧 （pulmonary arterial hypertension：PAH） のリスクに関してはコ ンセンサスが得られているが，臨床医として適切な検査時期，多彩な PAH 増悪因子，そして治療介入時期の判断 を間違わなければ，非 DS と同程度の手術成績が得られることに関しては全く同感である．特に呼吸器系の低形 成は肺気腫に類似した組織像であり，肺血管壁の構築もストレスに対して肥厚しやすく，二次性または合併症 PAH への進展が懸念される．発見後 150 年，染色体異常確認後 50 年が過ぎたこの症候群についてはさらなる研 究成果の臨床への応用が，DS 患者に多くの光を与えるであろう． Key words: Down syndrome, pulmonary hyperten-sion, congenital heart disease, atrio-ventricular septal defect, nitric oxide