Investigation of the Influence of Gender on Cardiovascular Function

Overview

Inflammation is a key initiating and damaging factor in many illnesses including infection, arthritis and cancer but also of particular relevance to this study in diseases of the heart and blood vessels (i.e. cardiovascular disease). Much evidence now exists demonstrating that male sex increases ones risk of cardiovascular disease. More recent evidence demonstrates that inflammatory responses in females appear to dampened in comparison to age matched males. Since inflammation is thought to be a key initiating phenomenon in many cardiovascular disease states the investigators will examine the differences in acute inflammatory responses between the sexes in healthy volunteers and the impact this has on the function of blood vessels.

We now know that one of the earliest events involved in precipitating disease of the heart and blood vessels is the phenomenon of inflammation and that this inflammation is a key process involved in dampening the protective nature of the inner lining (the endothelium) of the blood vessel wall, called endothelial dysfunction. In healthy arteries the endothelium releases a number of factors that maintain the health of the blood vessel. These factors act to keep the blood vessel in an open and dilated state and prevent the furring up of the vessel by actively inhibiting the cell components of the blood from collecting at the endothelium and blocking the flow of blood through the artery. Recent research in animals has demonstrated that one of the key components of inflammation i.e. the attraction of white cells, is reduced in females compared to males and that this is due to a reduced expression of key proteins called 'adhesion molecules', an in particular a molecule called P-selectin, on the endothelium. We now wish to determine whether similar differences in white cell attraction and adhesion molecules exist between the sexes in humans and whether these differences might underlie differences in endothelial function. To investigate this possibility we will conduct a study in two parts, using well validated models of acute inflammation in healthy volunteers. Part 1 To determine whether responses to inflammation differ between sexes in part 1 we will use a cantharidin-induced model of acute inflammation. Previous published studies have shown when cantharidin is applied to the skin it causes acantholysis and blister formation. It is a safe, reproducible technique with no permanent scarring or ill-effects. We will study the effects on inflammatory responses by measuring the levels of cells and inflammatory mediators in blister fluids, urine and plasma. Participants will given two blisters that will be harvested at 24 hours (acute phase) and 72 hours (resolution phase) after cantharidin application. The effects of inflammation on blood vessels will also be studied through non invasive blood pressure measurements. Part 2 To determine whether susceptibility to inflammation-induced endothelial dysfunction is distinct between the sexes in part 2 we will use typhoid vaccine to induce mild inflammation throughout the body including the blood vessels. Previous published studies have shown that vaccination induces an acute inflammation that results in a temporary (reversed within 48h) dysfunction of the endothelium that can be measured using a range of non-invasive techniques called ultrasound flow-mediated dilatation and pulse wave velocity. We will use these techniques together with biochemical measurements to determine possible associations of endothelial dysfunction with specific inflammatory factors. In particular we will investigate the possibility that differences in the expression of the adhesion molecule P-selectin might have a role to play in differences between the sexes.