Investigation of the Influence of Gender on Cardiovascular Function
Condition: Cardiovascular Function
Study type: Interventional
Phase: Early Phase 1

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Typhoid vaccine; Cantharidin
Intervention type(s): Biological; Drug
Intervention description(s): The typhoid vaccine is composed of purified polysaccharide from S. typhi capsule 25 micrograms contained in 0.5 ml solution; 0.1% cantharidin solution in acetone from 0.7% stock solution of cantharone is prepared and applied immediately. 10 μl of cantharidin per disc.
Other intervention name(s): Typhim Vi®; Cantharidin, cantharone 0.1%
Intervention MeSH terms: Cantharidin
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: vascular ultrasound; flow cytometry; platelet aggregation