Muñoz-Pacheco Paloma, Ortega-Hernández Adriana, Caro-Vadillo Alicia, Casanueva-Eliceiry Sebastian, Aragoncillo Paloma, Egido Jesús, Fernández-Cruz Arturo, Gómez-Garre Dulcenombre
aVascular Biology Research Laboratory, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos bDepartment of Animal Medicine and Surgery, School of Veterinary Science, Universidad Complutense de Madrid cDepartment of Pathology, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos dLaboratory of Renal and Vascular Pathology, IIS-Fundación Jiménez Díaz, Universidad Autónoma eFacultad de Medicina, Department of Internal Medicine, Hospital Clínico San Carlos, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Madrid, Spain *In memoriam.
J Hypertens. 2013 Nov;31(11):2309-18; discussion 2319. doi: 10.1097/HJH.0b013e328364abd6.
The addition of an aldosterone receptor antagonist on top of current optimal therapy (based on angiotensin II inhibition) has demonstrated an important clinical benefit in heart failure patients with systolic dysfunction. Whether this finding also applies to heart failure patients with preserved systolic function is unknown. Therefore, we have studied the effect of adding eplerenone to standard pharmacological heart failure therapy (angiotensin-converting enzyme inhibitor/angiotensin receptor blocker and diuretic and β-blocker) in the progression of heart failure in spontaneously hypertensive heart failure (SHHF) rats.
Two-month-old SHHF rats were randomized to receive no treatment (SHHF group), a standard heart failure therapy (quinapril-torasemide-carvedilol; ST-SHHF group), or the combination of eplerenone and standard heart failure therapy (Eple+ST-SHHF group) for 20 months. Untreated SHHF was characterized by progressive left ventricular hypertrophy, fibrosis, and myocardial contractile and relaxation abnormalities, leading to pulmonary congestion. Despite similar blood pressure control, the addition of eplerenone to standard heart failure therapy further prevented left ventricular hypertrophy, contractile and relaxation alterations, and pulmonary congestion than standard heart failure therapy alone. ST-SHHF and Eple + ST-SHHF rats showed similar inhibition of structural extracellular matrix proteins collagen I, collagen III and fibronectin and metalloproteinase (MMP)-2, MMP-7, MMP-12, and MMP-13. However, only the coadministration of eplerenone with standard heart failure therapy normalized the expression of matricellular proteins thrombospondin 1, tenascin C, periostin, and secreted protein acidic rich in cysteine/osteonectin to values comparable to normotensive rats.
In a hypertensive heart failure rat model, the addition of eplerenone to conventional heart failure therapy further improves cardiac structural and functional parameters, delaying the progression of heart failure. These beneficial effects of eplerenone were associated with normalization of matricellular protein expression.
在当前最佳治疗（基于血管紧张素II抑制）基础上加用醛固酮受体拮抗剂已在收缩功能障碍的心力衰竭患者中显示出重要的临床益处。这一发现是否也适用于收缩功能保留的心力衰竭患者尚不清楚。因此，我们研究了在自发性高血压心力衰竭（SHHF）大鼠心力衰竭进展过程中，在标准药理学心力衰竭治疗（血管紧张素转换酶抑制剂/血管紧张素受体阻滞剂、利尿剂和β受体阻滞剂）基础上加用依普利酮的效果。
将2月龄的SHHF大鼠随机分为不治疗组（SHHF组）、标准心力衰竭治疗组（喹那普利-托拉塞米-卡维地洛；ST-SHHF组）或依普利酮与标准心力衰竭治疗联合组（依普利酮+ST-SHHF组），治疗20个月。未经治疗的SHHF表现为进行性左心室肥厚、纤维化以及心肌收缩和舒张异常，导致肺淤血。尽管血压控制相似，但与单独的标准心力衰竭治疗相比，在标准心力衰竭治疗基础上加用依普利酮能进一步预防左心室肥厚、收缩和舒张改变以及肺淤血。ST-SHHF组和依普利酮+ST-SHHF组对细胞外基质蛋白I型胶原、III型胶原和纤连蛋白以及金属蛋白酶（MMP）-2、MMP-7、MMP-1
在高血压心力衰竭大鼠模型中，在传统心力衰竭治疗基础上加用依普利酮可进一步改善心脏结构和功能参数，延缓心力衰竭进展。依普利酮的这些有益作用与基质细胞蛋白表达的正常化有关。
