Key result
Beta-blockers may blunt the anti-remodeling benefit of paroxetine post-MI via overlapping GRK2 inhibition.
Why the study?
Paroxetine inhibits GRK2 but fails to show beneficial effects on LV remodeling in patients with STEMI and LVEF ≤ 45%, prompting investigation into its molecular interactions with standard neurohormonal therapies.
Does paroxetine provide additive anti-remodeling effects on top of standard neurohormonal antagonists in post-MI models?
Does paroxetine provide additive anti-remodeling effects on top of standard neurohormonal antagonists in post-MI models?
Bioinformatic analysis reveals that beta-blockers and paroxetine share overlapping inhibitory effects on GRK2, explaining why paroxetine may lack additive anti-remodeling benefits in post-MI patients on standard therapy.
Background: 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%. Methods: 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. Results: 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. Conclusion: 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.
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Iborra‐Egea et al. (2022) studied Post-myocardial infarction left ventricular remodeling. Paroxetine and beta-blockers was evaluated on Molecular interactions and pathways targeted by beta-blockers and paroxetine (GRK2 signaling). Bioinformatic analysis reveals that beta-blockers and paroxetine have overlapping inhibitory effects on GRK2, suggesting the anti-remodeling benefit of paroxetine after myocardial infarction is blunted by standard beta-blocker therapy.
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