Ocaranza Maria Paz, Jalil Jorge E, Altamirano Rodrigo, de León Ana, Moya Jackeline, Lonis Alejandra, Gabrielli Luigi, Nab Paul Mac, Córdova Samuel, Paredes Alejandro, Vergara Ismael, Bittner Alex, Sabat Karime, Pastorini Karla
Pontificia Universidad Católica de Chile, School of Medicine, Department of Cardiovascular Diseases, Santiago, Chile.
Center for New Drugs for Hypertension (CENDHY), Pontificia Universidad Católica de Chile, Santiago, Chile.
Front Pharmacol. 2021 Apr 23;12:565724. doi: 10.3389/fphar.2021.565724. eCollection 2021.
Reverse remodeling is a clinically relevant endpoint in heart failure with reduced ejection fraction (HFrEF). Rho-kinase (ROCK) signaling cascade activation correlates with cardiac remodeling and left ventricular (LV) systolic dysfunction in HFrEF patients. Cardiac resynchronization therapy (CRT) is effective in HFrEF, especially when there is a left bundle block, as this treatment may stimulate reverse remodeling, thereby improving quality of life and prolonging survival for patients with this severe condition. Here, we evaluate the hypothesis that ROCK activation is reduced after effective CRT in HFrEF. ROCK activation in circulating leukocytes was evaluated in 28 HFrHF patients, using Western blot (myosin light chain phosphatase subunit 1 phosphorylation, MYPT1p/t), before and three months after initiation of CRT. LV systolic function and remodeling were assessed by echocardiography. Three months after CRT, LV ejection fraction increased an average of 14.5% ( < 0.001) in 13 patients (responders), while no change was observed in 15 patients (non-responders). End-systolic diameter decreased 16% ( < 0.001) in responders, with no change in non-responders. ROCK activation in PBMCs decreased 66% in responders ( < 0.05) but increased 10% in non-responders (NS). LV end-diastolic diameter was also 5.2 mm larger in non-responders vs. responders ( = 0.058). LV ejection fraction, systolic diameter, and ROCK activation levels were similar in both groups at baseline. In HFrEF patients, 3 months of effective CRT induced reverse myocardial remodeling, and ROCK activation was significantly decreased in circulating leukocytes. Thus, decreased ROCK activation in circulating leukocytes may reflect reverse cardiac remodeling in patients with heart failure.
逆向重构是射血分数降低的心力衰竭（HFrEF）的一个临床相关终点。Rho激酶（ROCK）信号级联激活与HFrEF患者的心脏重构和左心室（LV）收缩功能障碍相关。心脏再同步治疗（CRT）对HFrEF有效，尤其是在存在左束支传导阻滞时，因为这种治疗可能会刺激逆向重构，从而改善这种严重疾病患者的生活质量并延长生存期。在此，我们评估这样一个假设：在HFrEF患者中，有效的CRT治疗后ROCK激活会降低。在28例HFrHF患者中，在开始CRT治疗前及治疗三个月后，使用蛋白质印迹法（肌球蛋白轻链磷酸酶亚基1磷酸化，MYPT1p/t）评估循环白细胞中的ROCK激活情况。通过超声心动图评估左心室收缩功能和重构。CRT治疗三个月后，13例患者（反应者）的左心室射血分数平均增加了14.5%（<0.001），而15例患者（无反应者）未观察到变化。反应者的收缩末期直径减少了16%（<0.001），无反应者则无变化。反应者外周血单核细胞中的ROCK激活降低了66%（<0.05），而无反应者增加了10%（无统计学意义）。无反应者的左心室舒张末期直径比反应者大5.2毫米（P = 0.058）。两组在基线时的左心室射血分数、收缩直径和ROCK激活水平相似。在HFrEF患者中，3个月的有效CRT诱导了心肌逆向重构，并且循环白细胞中的ROCK激活显著降低。因此，循环白细胞中ROCK激活的降低可能反映了心力衰竭患者的心脏逆向重构。
