Pathophysiological Mechanisms of Chronic Venous Disease and Implications for Venoactive Drug Therapy

Abstract

Chronic venous disease (CVD) is a common pathology, with significant physical and psychological impacts for patients and high economic costs for national healthcare systems. Throughout the last decades, several risk factors for this condition have been identified, but only recently, have the roles of inflammation and endothelial dysfunction been properly assessed. Although still incompletely understood, current knowledge of the pathophysiological mechanisms of CVD reveals several potential targets and strategies for therapeutic intervention, some of which are addressable by currently available venoactive drugs. The roles of these drugs in the clinical improvement of venous tone and contractility, reduction of edema and inflammation, as well as in improved microcirculation and venous ulcer healing have been studied extensively, with favorable results reported in the literature. Here, we aim to review these pathophysiological mechanisms and their implications regarding currently available venoactive drug therapies.

Keywords: MPFF; chronic venous disease; chronic venous insufficiency; endothelial dysfunction; flavonoid; inflammation; micronized purified flavonoid fraction; pathophysiology; venoactive drugs.

Figure 1

Schematic representation of the interplay of the pathophysiological mechanisms contributing to CVD development. Predisposing factors such as female sex, pregnancy, family history, obesity, sedentary lifestyles and occupations can lead to hemodynamic abnormalities in the veins of the lower legs, which may or may not be preceded by venal valve dysfunction. Elevated venous hydrostatic pressure and low shear stress lead to increased venous wall tension and distension, followed by activation of matrix metalloproteinases (MMP) through upregulation mediated by the hypoxia inducible factor (HIF) transcription factors. MMPs contribute to: degradation of the extracellular matrix (ECM); vascular smooth muscle cell (VSMC) relaxation through release of endothelium-derived hyperpolarizing factor (EDHF) and inhibition of calcium mobilization; and further venous wall dilatation. Inappropriate endothelial cell (EC) activation and injury to the glycocalyx (GCX) result in leukocyte infiltration and activation, setting up a proinflammatory environment within the vein wall, which in turn leads to further vein wall deterioration, leakage, tissue inflammation, and local prothrombotic abnormalities. Abbreviations: ELAM-1, endothelial-leukocyte adhesion molecule-1; ICAM-1, intercellular adhesion molecule-1; IL-, interleukin-; IFN-γ, interferon gamma; MCP-1, monocyte chemoattractant protein 1; MIP-1, macrophage inflammatory protein-1; NO, nitic oxide; PARs, protease-activated receptors; PGI2, prostaglandin I2/prostacyclin; ROS, reactive oxygen species; TNF-α, tumor necrosis factor alpha; VCAM-1, vascular cell adhesion molecule-1. (Reproduced from [34] with permission from the publisher).

Figure 2

MPFF 500 mg attenuates the postischemic increases in leukocyte adhesion (A) and emigration (B), flux of rolling leukocytes (C), and microvascular protein leakage (D) in rat cremaster muscles. I/R = ischemia/reperfusion. Statistically different from * control (nonischemic conditions) and ⁺ vehicle: p < 0.05. (Reproduced from [73] with permission from the publisher).

Figure 3

Changes in plasma levels if ICAM-1 and VCAM-1 in patients with CVD before (A) and after (B) 60 days of treatment with MPFF. A logarithmic scale has been used because of the differences in the absolute levels of the two molecules. p-levels are Wilcoxon ranked-sum test. The thick lines join the respective median levels. Vertical lines represent interquartile range. (Reproduced from [81] with permission from the publisher).