Apremilast Improves Endothelial Glycocalyx Integrity, Vascular and Left Ventricular Myocardial Function in Psoriasis

Abstract

The phosphodiesterase 4 inhibitor apremilast is used for the treatment of psoriasis. We investigated the effects of apremilast on endothelial glycocalyx, vascular and left ventricular (LV) myocardial function in psoriasis. One hundred and fifty psoriatic patients were randomized to apremilast (n = 50), anti-tumor necrosis factor-α (etanercept; n = 50), or cyclosporine (n = 50). At baseline and 4 months post-treatment, we measured: (1) Perfused boundary region (PBR), a marker of glycocalyx integrity, in sublingual microvessels with diameter 5-25 μm using a Sidestream Dark Field camera (GlycoCheck). Increased PBR indicates damaged glycocalyx. Functional microvascular density, an index of microvascular perfusion, was also measured. (2) Pulse wave velocity (PWV-Complior) and (3) LV global longitudinal strain (GLS) using speckle-tracking echocardiography. Compared with baseline, PBR_{5-25 μm} decreased only after apremilast (-12% at 4 months, p < 0.05) whereas no significant changes in PBR_{5-25 μm} were observed after etanercept or cyclosporine treatment. Compared with etanercept and cyclosporine, apremilast resulted in a greater increase of functional microvascular density (+14% versus +1% versus -1%) and in a higher reduction of PWV. Apremilast showed a greater increase of GLS (+13.5% versus +7% versus +2%) than etanercept and cyclosporine (p < 0.05). In conclusion, apremilast restores glycocalyx integrity and confers a greater improvement of vascular and myocardial function compared with etanercept or cyclosporine after 4 months.

Keywords: apremilast; endothelial glycocalyx; myocardial deformation; perfused boundary region; phosphodiesterase 4; psoriasis.

Figure 1

Perfused boundary region in sublingual microvessels with diameter 5–25 μm (PBR_{5–25 μm}) and functional microvascular density in the three study groups. (a) PBR_{5–25 μm} decreased in patients treated with apremilast, whereas there was no significant changes in patients treated with etanercept or cyclosporine. (b) Functional microvascular density increased in patients treated with apremilast, whereas no significant changes were observed in patients treated with etanercept or cyclosporine. Solid black dots indicate mean values.

Figure 2

Schematic representation of the molecular mechanism of action of apremilast and the possible effects on cardiovascular system. The inhibition of phosphodiesterase 4 (PDE4) by apremilast increases intracellular levels of cAMP leading to activation of protein kinase A (PKA). This enzyme induces cAMP responsive element binding protein (CREB) phosphorylation which subsequently induces release of anti-inflammatory cytokines. Moreover, PKA inhibits the nuclear factor kappa B (NF-κB) pathway, resulting in the suppression of major pro-inflammatory cytokines. Apremilast improves oxidized low-density lipoprotein (LDL)-induced endothelial dysfunction via the rescue of Krüppel like factor-6 expression and presents beneficial metabolic effects, suggesting a potential role for apremilast in the improvement of cardiovascular function.