CAJ | 학술논문

目的：探讨器质性心脏基础疾病左心衰竭合并妊娠时，左心室功能的变化及其肥厚重构的病理分子变化。方法微创主动脉弓缩窄（TAC）建立左心衰竭小鼠，诱导其妊娠，于妊娠晚期超声心动图（TTE）评估心脏结构和功能的变化、病理方法评估测心肌肥厚、间质纤维化以及毛细血管密度，监测器官重量、胎鼠体重、数量以评估左心室反应及其肥厚重构的变化以及对胎鼠的影响。结果重度缩窄sTAC组的妊娠率是62.5%，妊娠期间的死亡率是8.7%，中度缩窄mTAC及假手术组所有小鼠怀孕无死亡，三组中胎鼠的数量和平均体重并无统计学差异（P＞0.05）；怀孕sTAC小鼠的LVFS%有明显下降（21.6±1.18 vs.15.9±1.41，P＜0.05），且左心室收缩末期内径（LVESD）、左心室舒张末期内径（LVEDD）进一步扩大（P＜0.01）；而妊娠sTAC小鼠的LVFS%略有下降至18.1±1.67（P＞0.05），其左心室腔并未有进一步明显扩张，且扩张的幅度明显小于未妊娠sTAC小鼠；mTAC小鼠的超声指标均未见明显变化；HE染色发现sTAC组未妊娠小鼠心肌细胞横径明显大于妊娠小鼠（62.04±0.98 vs.48.46±1.33，P＜0.05），后者与mTAC妊娠小鼠的心肌细胞横径无明显差异（P＞0.05）；无论妊娠和非妊娠 sTAC 小鼠，均显示明显的间质纤维化（P＜0.05）；而 mTAC组和假手术组的纤维化程度均＜1%，mTAC 或 sTAC 小鼠，无论有无妊娠，毛细血管密度均有明显下降（P＜0.05），未怀孕sTAC小鼠低于怀孕sTAC小鼠（1675.02±41.15 vs.1 916.91±48.04， P＜0.05）。结论妊娠伴随的心血管系统变化会诱使已经衰竭心脏功能进一步恶化，但顺利妊娠分娩仍是完全可能的，其心肌肥厚重构反而轻于未妊娠时，可能机制是高水平的雌激素部分抵消了妊娠状态对心功能的不利影响，延缓心肌肥厚重构的进展，从而有利于心脏收缩功能的保存。目的：探討器質性心髒基礎疾病左心衰竭閤併妊娠時，左心室功能的變化及其肥厚重構的病理分子變化。方法微創主動脈弓縮窄（TAC）建立左心衰竭小鼠，誘導其妊娠，于妊娠晚期超聲心動圖（TTE）評估心髒結構和功能的變化、病理方法評估測心肌肥厚、間質纖維化以及毛細血管密度，鑑測器官重量、胎鼠體重、數量以評估左心室反應及其肥厚重構的變化以及對胎鼠的影響。結果重度縮窄sTAC組的妊娠率是62.5%，妊娠期間的死亡率是8.7%，中度縮窄mTAC及假手術組所有小鼠懷孕無死亡，三組中胎鼠的數量和平均體重併無統計學差異（P＞0.05）；懷孕sTAC小鼠的LVFS%有明顯下降（21.6±1.18 vs.15.9±1.41，P＜0.05），且左心室收縮末期內徑（LVESD）、左心室舒張末期內徑（LVEDD）進一步擴大（P＜0.01）；而妊娠sTAC小鼠的LVFS%略有下降至18.1±1.67（P＞0.05），其左心室腔併未有進一步明顯擴張，且擴張的幅度明顯小于未妊娠sTAC小鼠；mTAC小鼠的超聲指標均未見明顯變化；HE染色髮現sTAC組未妊娠小鼠心肌細胞橫徑明顯大于妊娠小鼠（62.04±0.98 vs.48.46±1.33，P＜0.05），後者與mTAC妊娠小鼠的心肌細胞橫徑無明顯差異（P＞0.05）；無論妊娠和非妊娠 sTAC 小鼠，均顯示明顯的間質纖維化（P＜0.05）；而 mTAC組和假手術組的纖維化程度均＜1%，mTAC 或 sTAC 小鼠，無論有無妊娠，毛細血管密度均有明顯下降（P＜0.05），未懷孕sTAC小鼠低于懷孕sTAC小鼠（1675.02±41.15 vs.1 916.91±48.04， P＜0.05）。結論妊娠伴隨的心血管繫統變化會誘使已經衰竭心髒功能進一步噁化，但順利妊娠分娩仍是完全可能的，其心肌肥厚重構反而輕于未妊娠時，可能機製是高水平的雌激素部分牴消瞭妊娠狀態對心功能的不利影響，延緩心肌肥厚重構的進展，從而有利于心髒收縮功能的保存。
목적：탐토기질성심장기출질병좌심쇠갈합병임신시，좌심실공능적변화급기비후중구적병리분자변화。방법미창주동맥궁축착（TAC）건립좌심쇠갈소서，유도기임신，우임신만기초성심동도（TTE）평고심장결구화공능적변화、병리방법평고측심기비후、간질섬유화이급모세혈관밀도，감측기관중량、태서체중、수량이평고좌심실반응급기비후중구적변화이급대태서적영향。결과중도축착sTAC조적임신솔시62.5%，임신기간적사망솔시8.7%，중도축착mTAC급가수술조소유소서부잉무사망，삼조중태서적수량화평균체중병무통계학차이（P＞0.05）；부잉sTAC소서적LVFS%유명현하강（21.6±1.18 vs.15.9±1.41，P＜0.05），차좌심실수축말기내경（LVESD）、좌심실서장말기내경（LVEDD）진일보확대（P＜0.01）；이임신sTAC소서적LVFS%략유하강지18.1±1.67（P＞0.05），기좌심실강병미유진일보명현확장，차확장적폭도명현소우미임신sTAC소서；mTAC소서적초성지표균미견명현변화；HE염색발현sTAC조미임신소서심기세포횡경명현대우임신소서（62.04±0.98 vs.48.46±1.33，P＜0.05），후자여mTAC임신소서적심기세포횡경무명현차이（P＞0.05）；무론임신화비임신 sTAC 소서，균현시명현적간질섬유화（P＜0.05）；이 mTAC조화가수술조적섬유화정도균＜1%，mTAC 혹 sTAC 소서，무론유무임신，모세혈관밀도균유명현하강（P＜0.05），미부잉sTAC소서저우부잉sTAC소서（1675.02±41.15 vs.1 916.91±48.04， P＜0.05）。결론임신반수적심혈관계통변화회유사이경쇠갈심장공능진일보악화，단순리임신분면잉시완전가능적，기심기비후중구반이경우미임신시，가능궤제시고수평적자격소부분저소료임신상태대심공능적불리영향，연완심기비후중구적진전，종이유리우심장수축공능적보존。
Objective To assess cardiac structural responses and the pathological changes of left ventricule (LV) under the compromised conditions of transverse aortic constriction (TAC) induced left heart failure during pregnancy. Methods Based on the successfully established model of pressure overload induced LVH, all operated mice were mated to find out whether these mTAC (moderate TAC) or sTAC (severe TAC) mice can get pregnant or even survive the pregnancy. TTE was deployed again to examine the contractile function of the heart. LV tissues were stained to analyze the interstitial fibrosis, capillary density, and myocyte width to evaluate the status of hypertrophic responses and cardiac remodeling. Maternal and fetal outcomes including maternal death rate, litter size, average body weight of pups were calculated to evaluate the effect of LVH or heart failure on the growth and maturity of mouse fetus in pregnant mice. Results 62.5% of all sTAC mice finally became pregnant with a death rate of 8.7%, while in mTAC group, all mice got pregnant and survived, without maternal death. TTE examination demonstrated that LVFS% in sTAC mice decreased further, especially in non-pregnant sTAC mice, the LVFS% was depressed significantly from 21.6±1.18 to 15.9±1.41 (P<0.05), and LV parameters including LVESD and LVEDD increased substantially to (3.73±0.20)mm (P<0.01) and (4.41± 0.18)mm (P<0.01), respectively, which showed an progressively impaired LV contractile function and dilated LV lumen. While LVEDD and LVESD also had noticeable increases in sTAC pregnant mice, but the increases were not statistically significant (P>0.05), LVFS%decreased to 18.1±1.67 but no statistical difference (P>0.05) was found. LVFS%, LVEDD and LVESD of mTAC mice didn't have significant changes. Fetal outcomes showed that no significant difference in litter size and average body weight of pups were found in each group, yet, sTAC mice with pathological LV hypertrophy carried more pups with lower average body weight, compared with normal sham operated mice. According to pathological HE staining and quantitative analysis, myocyte sizes of sTAC mice without pregnancy were significantly larger than those in sTAC pregnant mice (62.04±0.98 vs. 48.46±1.33, P<0.05), or in mTAC pregnant mice (62.04±0.98 vs. 45.98±0.98, P<0.05), respectively. Yet no significant difference were found between sTAC pregnant mice and mTAC pregnant mice (45.98±0.98 vs. 48.46±1.33, P>0.05). In sham operated and mTAC mice, the area of collagen deposition was less than 1%, but in sTAC mice, no matter pregnant or not, the area of myocardial fibrosis markedly increased to 12.03±1.48 and 11.13±0.89, respectively (P<0.05), and there was no significant difference between them (P>0.05). Lectin stainings showed a significantly reduced microvascular density in sTAC or mTAC mice, no matter pregnant or not. Yet in sTAC group, the capillary density of pregnant mice were significantly higher than non-pregnant mice (1 916.91±48.04 vs. 1 675.02±41.15, P<0.05), but lower than that in mTAC mice (1 916.91±48.04 vs. 2 074.07±40.83, P<0.05). Conclusions There was no doubt that pregnancy was well tolerated even under the depressed conditions, although the heart functions deteriorated greatly. It seemed that cardiovascular changes during pregnancy didn’t exert substantially adverse influences as cardiac remodeling process was attenuated and contractile function preserved in pregnant TAC mice. An important explanation might be potential cardiopreotective effects of estrogen, which could limit the progress of hypertrophic remodeling and protect the impaired heart from further deterioration.