Iborra-Egea Oriol, Aimo Alberto, Martini Nicola, Galvez-Monton Carolina, Burchielli Silvia, Panichella Giorgia, Passino Claudio, Emdin Michele, Bayes-Genis Antoni
ICREC (Heart Failure and Cardiac Regeneration) Research Programme, Health Sciences Research Institute Germans Trias i Pujol (IGTP), Barcelona, Spain.
Hospital Universitari Germans Trias i Pujol, Badalona, Spain.
Front Cardiovasc Med. 2022 Jul 11;9:887248. doi: 10.3389/fcvm.2022.887248. eCollection 2022.
Left ventricular (LV) remodeling consists in maladaptive changes in cardiac geometry and function following an insult such as ST-segment elevation myocardial infarction (STEMI). Interventions able to prevent LV remodeling after a STEMI are expected to improve the outcome of this condition. Paroxetine has inhibitory effects on GRK2, also known as beta-adrenergic receptor kinase 1 (ADRBK1). This drug does not yield beneficial effects on LV remodeling in patients with STEMI and LV ejection fraction ≤ 45%.
We compared the molecular effects of paroxetine and drugs for neurohormonal antagonism (beta-blockers, angiotensin converting enzyme inhibitors/angiotensin receptor blockers, mineralocorticoid receptor antagonists), using a bioinformatic approach integrating transcriptomic data in a swine model of post-MI and available evidence from the literature and massive public databases.
Among standard therapies for MI, beta-blockers are the only ones acting directly upon GKR2, but the mechanism of action overlaps with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers with respect to the AT2R-mediated anti-hypertensive response. Moreover, beta-blockers could have anti-fibrotic and anti-inflammatory effects through the regulation of myocyte-specific enhancer factors, endothelins and chemokines.
The additive benefit of paroxetine on the background of the standard therapy for STEMI, which includes beta-blockers, is expected to be limited. Nonetheless, paroxetine becomes particularly interesting when a beta-blocker is contraindicated (for example, in hypotensive individuals) or poorly tolerated.
左心室（LV）重塑是指在诸如ST段抬高型心肌梗死（STEMI）等损伤后心脏几何形状和功能的适应性改变。能够预防STEMI后左心室重塑的干预措施有望改善这种疾病的预后。帕罗西汀对GRK2具有抑制作用，GRK2也称为β-肾上腺素能受体激酶1（ADRBK1）。该药物对STEMI且左心室射血分数≤45%的患者的左心室重塑没有产生有益影响。
我们使用一种生物信息学方法，整合心肌梗死后猪模型中的转录组数据以及来自文献和大量公共数据库的现有证据，比较了帕罗西汀与神经激素拮抗剂（β受体阻滞剂、血管紧张素转换酶抑制剂/血管紧张素受体阻滞剂、盐皮质激素受体拮抗剂）的分子效应。
在心肌梗死的标准治疗方法中，β受体阻滞剂是唯一直接作用于GKR2的药物，但其作用机制在AT2R介导的抗高血压反应方面与血管紧张素转换酶抑制剂/血管紧张素受体阻滞剂重叠。此外，β受体阻滞剂可通过调节心肌细胞特异性增强因子、内皮素和趋化因子产生抗纤维化和抗炎作用。
在包括β受体阻滞剂在内的STEMI标准治疗背景下，帕罗西汀的附加益处预计有限。然而，当β受体阻滞剂禁忌（例如，在低血压个体中）或耐受性差时，帕罗西汀就变得特别有意义。
