Testosterone and Myocardial Perfusion in Coronary Heart Disease (CHD)

Effects of Chronic Testosterone on Myocardial Ischaemia and Endothelial Function in Men With Documented Coronary Heart Disease

Testosterone has traditionally been regarded as a risk factor for heart disease due to the fact that males have a higher incidence of this disease than women, at least until the menopause. However recent studies have shown that men with low levels of testosterone may be at an increased risk of developing coronary heart disease (furring up of the blood vessels supplying blood to the heart). Our group has demonstrated a relaxing effect of testosterone in isolated animal coronary arteries (blood vessels supplying blood to the heart). We have shown that short-term testosterone administration can increase coronary artery and brachial artery (blood vessel in the arm) blood flow and can decrease the lack of blood supply to the heart muscle in men with coronary artery disease. These findings indicate a need for similar but longer-term studies to investigate the possible beneficial effects of longer-term testosterone therapy on the heart and blood vessels. Should this treatment be shown to be beneficial to men with coronary artery disease it may be a useful additional therapy for men with the furring up of arteries in the heart and the resulting angina. Aim To investigate our hypothesis that testosterone can beneficially affect myocardial perfusion, vascular reactivity, metabolic risk factors for coronary heart disease and improve quality of life in men with low plasma testosterone levels and coronary heart disease.

The main purpose of this project is to determine whether testosterone treatment over a number of weeks can beneficially affect myocardial perfusion, vascular reactivity, metabolic risk factors and quality of life in men with documented coronary heart disease. Men with documented significant coronary artery disease and a positive exercise test for myocardial ischaemia will be enrolled into the study. They will be randomised to active testosterone therapy (5 mg/day) or placebo for 2 months. After 2 months they will undergo MRI perfusion scanning, radial artery applanation tonometry to assess endothelial function, blood sampling for analysis of metabolic risk factors for coronary heart disease, complete quality of life questionnaires and will cross-over to the opposite treatment. After a further 2 month period these tests will be repeated. Angina diaries will be kept for the duration of the study.

oral testosterone undecanoate, 80mg twice daily (Andriol Testocaps, Organon, The Netherlands) for 8 weeks

Myocardial perfusion (blood flow in the heart muscle) in subendocardial myocardial segments (one of the inner layers of heart muscle), supplied by coronary arteries without significant obstruction. This was measured using Cardiovascular Magnetic Resonance (CMR) imaging and a dual-bolus gadnolinium infusion protocol. Myocardial perfusion index = the ratio between myocardial perfusion measurements following adenosine-induced stress and rest measurements.

The endothelium is a single layer of cells that line all blood vessels and regulates arterial function. Coronary artery disease causes dysfunction of the endothelium but some substances/drugs help to reverse this dysfunction. In this study, endothelial function was measured by radial applanation tonometry which measures the blood pressure waveform during each cardiac cycle (heart beat). Radial artery pulse recordings were acquired, with an averaged waveform generated from 20 sequential waveforms. Augmentation index (AIx) is derived from this averaged waveform, and is the ratio of the pulse pressure at the second systolic arterial pressure waveform peak to that of the first systolic peak. The change in AIx before and after salbutamol (400mcg) is a measure of endothelial function.

Inclusion Criteria: Men Aged 35 to 75 years Angiographically proven coronary artery disease (70 percent lesion in at least one major coronary artery, or major branch), including patients post-coronary artery bypass graft (CABG) and percutaneous coronary intervention (PCI) Plasma testosterone less than or equal to 12 nmol/l Normal prostate specific antigen (PSA; normal range 0 - 4 g/l) Willing to give written informed consent Exclusion Criteria: Significant arrhythmia, particularly those which would affect interpretation of the ST-segment of the ECG Treatment with digitalis Treatment with testosterone or similar hormonal therapy Thoracic or abdominal surgery within the previous 3 months Haemoglobin >16 g/dL Haematocrit >50 percent History of hormone-dependent cancer such as prostate or breast cancer Hypercalcaemia Nephrosis Pacemaker or automated implantable cardiac defibrillator Implanted ferromagnetic arterial clips Left ventricular hypertrophy New York Heart Association (NYHA) III or IV functional class Intolerance of confined spaces Previous allergic reaction to Gadolinium Participation in another research study within the previous 60 days Unwilling to give written informed consent

Webb CM, Elkington AG, Kraidly MM, Keenan N, Pennell DJ, Collins P. Effects of oral testosterone treatment on myocardial perfusion and vascular function in men with low plasma testosterone and coronary heart disease. Am J Cardiol. 2008 Mar 1;101(5):618-24. doi: 10.1016/j.amjcard.2007.09.114. Epub 2007 Dec 21.