Understanding Chronic Venous Disease: A Critical Overview of Its Pathophysiology and Medical Management

Abstract

Chronic venous disease (CVD) is a multifactorial condition affecting an important percentage of the global population. It ranges from mild clinical signs, such as telangiectasias or reticular veins, to severe manifestations, such as venous ulcerations. However, varicose veins (VVs) are the most common manifestation of CVD. The explicit mechanisms of the disease are not well-understood. It seems that genetics and a plethora of environmental agents play an important role in the development and progression of CVD. The exposure to these factors leads to altered hemodynamics of the venous system, described as ambulatory venous hypertension, therefore promoting microcirculatory changes, inflammatory responses, hypoxia, venous wall remodeling, and epigenetic variations, even with important systemic implications. Thus, a proper clinical management of patients with CVD is essential to prevent potential harms of the disease, which also entails a significant loss of the quality of life in these individuals. Hence, the aim of the present review is to collect the current knowledge of CVD, including its epidemiology, etiology, and risk factors, but emphasizing the pathophysiology and medical care of these patients, including clinical manifestations, diagnosis, and treatments. Furthermore, future directions will also be covered in this work in order to provide potential fields to explore in the context of CVD.

Keywords: chronic venous disease (CVD); varicose veins; vascular therapies; venous hypertension; venous pathophysiology.

Figure 1

A general overview of the anatomy, physiology, and histology of venous system in the lower limbs. Superficial veins, mainly represented by the great and small saphenous veins, carry blood from the skin and subcutaneous tissues. Superficial veins might transport the blood through the saphenous junctions and the perforator veins to the deep venous system, the major contributors of the venous return. Deep veins are accompanied by an artery, nerves, and skeletal muscle at both sides, surrounded by a fascial compartment. Calf muscle pump is the most important source to assure an appropriated blood return from the lower limbs and it is frequently designed as the “peripheral heart”. Venous return is also permitted by the presence of venous valves, which are essential to prevent blood reflux. The cytoarchitecture of the vein comprises three main layers, intima, media, and adventitia, with unique properties.

Figure 2

A general view on the different etiological mechanisms of CVD. Primary CVD (left) is caused by different genetic and environmental factors and it is characterized by a persistent venous hypertension responsible for the onset and progression of the disease. Secondary CVD (middle) is preceded by a pathological event, which could be intravenous (DVT) or extravenous (e.g., calf muscle dysfunction, extrinsic tumoral mass or arterial compression). Congenital CVD (right) represent a small percentage of the problem, and it is caused by single gene mutations or chromosomic aberrations.

Figure 3

Biomechanical and biochemical alterations in CVD. As showed, ambulatory venous hypertension promotes a set of changes in the vascular wall, leading to a < n altered shear stress. The altered hemodynamic damage the endothelium, enhancing capillary permeability, leukocytes recruitment, lymphatic impairment, and edema formation. The microcirculatory dysfunction associated with these changes creates a hypoxic environment, and together with the inflammatory environment provide a extracellular matrix remodeling, eventually resulting in different venous wall compositions, reduced elasticity and extensibility, and venous fibrosis. This cycle is responsible for maintain and aggravate venous hypertension, getting worse with valve incompetence, reflux, and abnormal functioning of the calf muscle pump. Overall, these mechanisms are responsible for the progression of VVs to the most serious manifestations, such as skin changes and ulcerations.

Figure 4

Schematic representation of molecular changes induced in venous structure resulting in different biophysical properties. As previously described altered (mostly decreased) shear stress and venous hypertension are responsible for the venous wall remodeling in VVs, influencing a plethora of molecular pathways. An increased level of hydroxyproline, reduced protective endothelial glycocalyx, altered calcium signaling, imbalance in matrix metalloproteinases and their inhibitors, enhance ECM degradation and augmented nitric oxide are the most important effects described. Collectively, these alterations are responsible for modifications in collagen and elastic fibers, venous wall permeability, disrupted vessel morphology, and functioning and multiple defects associated to the progression of CVD. Legend: Up black arrow= Increased expression; Down black arrow: Decreased expression; ≠: Differential detection.

Figure 5

Future directions for CVD. The emergence of novel therapeutic or diagnostic methods are playing a key role in the clinical management of the patients with CVD. However, it is equally important to “deep” on the epigenetic and individual mechanisms, to allow for better comprehension of the disease, opening the possibilities of novel translational approaches. Perhaps one of the most disregarded and important factors are encompassed around prevention. In this sense, nutritional assessment and physical exercise could be powerful tools in the handle of patients affected by CVD, as they might favorably regulate clinical signs, pathophysiological mechanisms, such as inflammation or oxidative stress, and even psychological variables. Overall, these points will be crucial to improve the QOL of the patients, which might be particularly vulnerable by other variables (e.g., pregnant women or elder people).