Walsh-Wilkinson Élisabeth, Drolet Marie-Claude, Le Houillier Charlie, Roy Ève-Marie, Arsenault Marie, Couet Jacques
Université Laval, Groupe de recherche sur les valvulopathies, Centre de recherche, Institut universitaire de cardiologie et de pneumologie de Quebec, Québec, Québec, Canada.
PeerJ. 2019 Aug 5;7:e7461. doi: 10.7717/peerj.7461. eCollection 2019.
Men and women differ in their susceptibility to cardiovascular disease, though the underlying mechanism has remained elusive. Heart disease symptoms, evolution and response to treatment are often sex-specific. This has been studied in animal models of hypertension or myocardial infarction in the past but has received less attention in the context of heart valve regurgitation. The aim of the study was to evaluate the development of cardiac hypertrophy (CH) in response to left ventricle (LV) volume overload (VO) caused by chronic aortic valve regurgitation (AR) in male and female rats treated or not with angiotensin II receptor blocker (ARB), valsartan. We studied eight groups of Wistar rats: male or female, AR or sham-operated (sham) and treated or not with valsartan (30 mg/kg/day) for 9 weeks starting one week before AR surgical induction. As expected, VO from AR resulted for both male and female rats in significant LV dilation (39% vs. 40% end-diastolic LV diameter increase, respectively; < 0.0001) and CH (53% vs. 64% heart weight increase, respectively; < 0.0001) compared to sham. Sex differences were observed in LV wall thickening in response to VO. In untreated AR males, relative LV wall thickness (a ratio of wall thickness to end-diastolic diameter) was reduced compared to sham, whereas this ratio in females remained unchanged. ARB treatment did not prevent LV dilation in both male and female animals but reversed LV wall thickening in females. Systolic and diastolic functions in AR animals were altered similarly for both sexes. ARB treatment did not improve systolic function but helped normalizing diastolic parameters such as left atrial mass and E wave slope in female AR rats. Increased LV gene expression of and was normalized by ARB treatment in AR females but not in males. Other hypertrophy gene markers ( and ) were not modulated by ARB treatment. The same was true for genes related to LV extracellular matrix remodeling ( and ). In summary, ARB treatment of rats with severe AR blocked the female-specific hypertrophic response characterized by LV chamber wall thickening. LV dilation, on the other hand, was not significantly decreased by ARB treatment. This also indicates that activation of the angiotensin II receptor is probably more involved in the early steps of LV remodeling caused by AR in females than in males.
男性和女性对心血管疾病的易感性存在差异，但其潜在机制仍不清楚。心脏病的症状、发展过程及对治疗的反应往往具有性别特异性。过去曾在高血压或心肌梗死的动物模型中对此进行过研究，但在心脏瓣膜反流的背景下受到的关注较少。本研究的目的是评估在接受或未接受血管紧张素II受体阻滞剂（ARB）缬沙坦治疗的雄性和雌性大鼠中，慢性主动脉瓣反流（AR）引起的左心室（LV）容量超负荷（VO）导致的心脏肥大（CH）的发展情况。我们研究了八组Wistar大鼠：雄性或雌性、AR组或假手术（sham）组，并且在AR手术诱导前一周开始，对其进行为期9周的缬沙坦（30 mg/kg/天）治疗或不治疗。正如预期的那样，与假手术组相比，AR导致的VO使雄性和雌性大鼠的左心室均出现显著扩张（舒张末期左心室直径分别增加39%和40%；P<0.0001）和心脏肥大（心脏重量分别增加53%和64%；P<0.0001）。在对VO的反应中，观察到左心室壁增厚存在性别差异。在未治疗的AR雄性大鼠中，与假手术组相比，相对左心室壁厚度（壁厚度与舒张末期直径的比值）降低，而雌性大鼠的该比值保持不变。ARB治疗并未阻止雄性和雌性动物的左心室扩张，但逆转了雌性动物的左心室壁增厚。AR动物的收缩和舒张功能在两性中均有类似改变。ARB治疗并未改善收缩功能，但有助于使雌性AR大鼠的舒张参数（如左心房质量和E波斜率）恢复正常。ARB治疗使AR雌性大鼠左心室中增加的[具体基因1]和[具体基因2]基因表达恢复正常，但对雄性大鼠无效。其他肥大基因标志物（[具体基因3]和[具体基因4]）未受ARB治疗的调节。与左心室细胞外基质重塑相关的基因（[具体基因5]和[具体基因6]）也是如此。总之，ARB治疗严重AR大鼠可阻断以左心室腔壁增厚为特征的雌性特异性肥大反应。另一方面，ARB治疗并未显著降低左心室扩张。这也表明，血管紧张素II受体的激活在雌性AR引起的左心室重塑早期阶段可能比在雄性中更起作用。
