Unveiling the Heart's Vulnerability: How Pde4 Inhibition Can Intensifies Myocardial Injury

Objective: The dysregulation of beta-receptor signaling in heart diseases, like arrhythmias and heart failure, is a concern due to sustained elevation of cAMP levels, impacting cardiac function. Phosphodiesterase (PDEs) regulate cAMP levels, with PDE4 linked to chronotropic signaling through beta-receptors. Apremilast, a PDE4 inhibitor used in psoriasis, theoretically could heighten arrhythmia risk by prolonging catecholamine effects and increasing cardiac workload. In our study, we sought to confirm this theory, exploring PDE4 inhibition's impact on cardiomyocytes, especially in ischemic heart disease scenarios where it might exacerbate myocardial injury during acute ischemic events. Design and method: Male albino Wistar rats were randomly distributed into 7 groups – Normal control, ISO control, ISO+ 2.5mg/kg AP, ISO + 5mg/kg AP, ISO + 10mg/kg AP, ISO + 20mg/kg AP and 20mg/kg AP perse. Corresponding doses of Apremilast were administered to the animals for a period of 21 days. On the 20th and 21st day, isoproterenol was administered at a dose of 85 mg/kg to induce myocardial necrosis. Hemodynamic parameters, histopathological and ultrastructural appearances, levels of oxidative stress markers, inflammatory cytokines, and apoptotic markers across the groups were investigated on 22nd day from the blood and myocardium after surgery. Results: Pretreatment with AP before inducing myocardial necrosis using ISO led to notable hemodynamic instability and no improvement during surgery. These groups showed increased damage, evident in hemodynamic measures, oxidant-antioxidant balance, and cardiac injury markers. Inflammatory and apoptotic proteins were notably elevated after AP followed by ISO administration compared to the ISO-Control group, indicating heightened adverse effects. A subsequent pilot study focusing on AP's direct impact on cardiomyocytes revealed 21 days administration resulting in hemodynamic instability, histopathological and ultrastructural damage, increased cardiac injury markers, and elevated inflammatory and apoptotic proteins in rats, indicating detrimental effects on the heart. Conclusions: Apremilast may cause myocardial injury and exacerbate myocardial necrosis in rats. Hence, there are concerns of AP use in patients with concomitant ischemic heart disease.