Investigation of the Influence of Gender on Cardiovascular Function

Cardiovascular Function Clinical Trial

Official title:

Investigation of the Influence of Gender on Cardiovascular Function and Inflammation

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01582321
• Other study ID #: 11/LO/2038
• Status: Completed
• Phase: Early Phase 1
• First received: April 18, 2012
• Last updated: June 12, 2017
• Start date: March 2012
• Est. completion date: January 2017

Study information

• Verified date: June 2017
• Source: Queen Mary University of London
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 56
• Est. completion date: January 2017
• Est. primary completion date: December 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 45 Years

Eligibility

Inclusion Criteria:

Healthy subjects aged 18-45 who have volunteered themselves and are willing to sign the consent form.

Exclusion Criteria:

1. Healthy subjects unwilling to consent

2. History of hypertension, diabetes or hypertensive on BP measurement

3. Pregnant, or any possibility that a subject may be pregnant unless in the latter case a pregnancy test is performed with a negative result

4. History of any serious illnesses, including recent infections or trauma

5. Subjects taking systemic medication (other than the oral contraceptive pill)

6. Subjects with self-reported use of mouthwash or tongue scrapes

7. Subjects with recent or current antibiotic use

8. Subjects with a history, or recent treatment of (within last 3 months) of any oral condition (excluding caries), including gingivitis, periodontitis and halitosis.

9. Subjects that have recently participated (preceding 3 months) in any clinical studies involving administration of an inflammogen.

Related Conditions & MeSH terms

• Cardiovascular Function

Intervention

Biological:
• Typhoid vaccine
The typhoid vaccine is composed of purified polysaccharide from S. typhi capsule 25 micrograms contained in 0.5 ml solution

Drug:
• Cantharidin
0.1% cantharidin solution in acetone from 0.7% stock solution of cantharone is prepared and applied immediately. 10 µl of cantharidin per disc.

Locations

Country	Name	City	State
United Kingdom	William Harvey Heart Centre, Barts & The London Medical School	London

Sponsors (1)

Lead Sponsor	Collaborator
Queen Mary University of London

Country where clinical trial is conducted

United Kingdom, 

References & Publications (1)

Hingorani AD, Cross J, Kharbanda RK, Mullen MJ, Bhagat K, Taylor M, Donald AE, Palacios M, Griffin GE, Deanfield JE, MacAllister RJ, Vallance P. Acute systemic inflammation impairs endothelium-dependent dilatation in humans. Circulation. 2000 Aug 29;102(9):994-9. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Comparison change in blister fluid total and differential leukocyte numbers (Part 1)	plasma and fluid collected from the blisters at 24 hours (acute phase) and 72 hours (resolution phase) after the cantharidin application will be analysed using standard laboratory techniques including flow cytometry	24, 72 h
Primary	Flow-mediated dilatation (Part 2)	Flow mediated dilatation of the brachial artery will be assessed using ultrasound will be measured at time 0, 24 and 48h. At the 16h timepoint a single typhoid vaccination will be administered in the arm or buttock.	0, 24, 48 h
Secondary	Blood pressure (Part 1)	Blood pressure will be measured every 15 minutes for 1 hour	0, 48, 72 h
Secondary	Platelet reactivity (Part 2)	Blood will be collected and platelet reactivity assessed using impedance aggreometry	0, 24 and 48h
Secondary	Platelet activation (Part 2)	Blood will be collected and platelet p-selectin and platelet-monocyte expression determined using flow cytometry	0,24 and 48h
Secondary	Arterial stiffness (Part 2)	The speed of blood pressure waves will be measured to give a pulse wave velocity measure for the aorta.	0, 24 and 48h
Secondary	Inflammatory cell expression (Part 1 and 2)	Blood will be collected and inflammatory cell populations determined using flow cytometry	0, 48, 72h part 1, 0, 24 and 48h part 2
Secondary	Blood inflammatory molecule expression (Part 1 and 2)	Plasma will be collected for assessment of inflammatory markers	0, 48, 72 h part 1, 0, 24 and 48h part 2,