Understanding the Mechanisms and Natural History of Chronic Venous Insufficiency in an Older Population

Proposed supervisory team:

Director of Studies: Dr Markos Klonizakis
Supervisor 1: Mr. Shah Nawaz - Consultant Vascular Surgeon - Sheffield Teaching Hospitals NHS Foundation Trust

Chronic Venous Insufficiency (CVI) is the commonest cause of leg ulcers. The prevalence and incidence of CVI (including varicose veins and ulcers) increases with age, and significantly affects older peoples’ quality of life. Varicose veins affect 36% of the general population with 1-2% developing venous ulceration. In the older groups, CVI affects 10-21% of the population, with the over 60-year group, representing almost 80% of those with venous ulceration. Direct health costs associated with CVI are estimated at £600 million annually.

The mechanism and natural history of CVI remains largely unknown. Until recently, CVI was attributed to valve dysfunction and incompetence. However, ultrasound and microscopic examination has challenged this theory, showing that varicose veins often precede valve incompetence or develop below competent valves. Additionally, recent work focusing on the structural and biochemical changes in the vein wall, suggests that disease in the small veins (micro-angiopathy) causing micro-vascular dysfunction is more likely to precede and cause CVI. This highlights the important role of the endothelium (or inner vein-lining) in this disease’s development.

In venous disease, venous stasis in the microcirculation reduces the stress on endothelial cells resulting in a reduction in NO cellular levels, where NO maintains endothelium integrity. This results in endothelial injury and micro-vascular dysfunction in small veins in the leg (Smith, 2006). Endothelial micro-vascular dysfunction is a strong candidate affecting susceptibility to ulceration. Our group has shown that micro-vascular dysfunction remains persistent following vein surgery which may explain the high recurrence rate for varicose veins (67% over 11 years) and venous ulcers (33% over one year).

We can monitor changes in skin micro-vascular structure and function with Laser Doppler (LD) techniques (e.g. Laser Doppler Fluximetry - LDF) which are non-invasive, easy-to-use and relatively inexpensive; iontophoresis is also used to study endothelial-dependent and -independent vasodilation. Clinical (macro-vascular) abnormalities in CVI including venous reflux, varicose veins and venous ulceration are assessed using Duplex scanning or Hand Held Doppler. These are classified under the Clinical-Etiology-Anatomy-Pathophysiology (CEAP) classification stages, ranging from C0 (No visible or palpable signs of venous disease) to C6 (Active venous ulcer).

Despite evidence presented in previous studies, it has not been shown conclusively that micro-angiopathy precedes macro-vascular clinical CVI changes. Furthermore, the exact relationship between macro-vascular disease and microvascular dysfunction, or indeed how, whether and to what extent these change with age in normal patients or those with disease affecting small vessels remains unknown.

The proposed PhD will attempt to respond to these questions and pave the way for research which will offer targeted therapies (e.g. surgery, lifestyle interventions etc) to those who are more prone to develop clinical complications.