Year

2012

Degree Name

Master of Science - Research

Department

Department of Biomedical Science

Abstract

Regular consumption of fish is associated with low morbidity and mortality from acute and chronic cardiovascular disease in humans. Fish are known to contain high concentrations of essential omega-3 (now referred to as n-3) polyunsaturated fatty acids (n-3 PUFA) eicosapentaenoic acid (EPA 20:5 n-3) and docosahexaenoic acid (DHA 22:6n-3). Experimental studies modelling cardiovascular disease in animals show that feeding fish oils provides many cardioprotective actions and those directly related to heart function (prevention of fatal cardiac arrhythmias; preconditioning, heart rate slowing, prevention of heart failure) are associated with the incorporation of the diet – derived n-3 PUFA into myocardial membranes. Human red blood cell (RBC) membrane EPA+DHA concentration has been found to correlate inversely with adverse cardiovascular outcomes and is proposed as a cardiovascular risk factor (termed the Omega-3 Index). The use of this readily obtained marker as a risk factor is based on the premise that it reflects the composition of the myocardium at risk. However this is by no means certain as, in animal tissues DHA is incorporated into myocardium well above circulating levels with little EPA detectable, whereas EPA and DHA are better matched within RBC membranes. There are large variations in relative concentrations of n-3 PUFA amongst other tissues in animals and in man. While there is a growing body of data on human atrial tissue obtained during surgical procedures, and blood samples are readily obtained, the limited data on the fatty acid composition of human ventricular myocardium is largely from cadaveric samples. It remains to be confirmed that the omega-3 index can be reliably used as a marker of the composition of the human ventricle and therefore an indicator of risk of cardiac morbidity and mortality. Objectives: To establish the fatty acid compositional profile of human ventricular myocardium and the relationships between EPA+DHA in human RBC, atria and ventricle.

Methods: This thesis combined two separate studies in which the fatty acid composition of both atria and ventricles were analysed from fresh, donor hearts and freshly explanted failing hearts, all made available through a heart transplant program, and right atrial biopsy and red blood cells were analysed from subjects undergoing cardiac surgery. Surgical subjects were additionally randomised to receive a daily supplement of 1g fish oil or placebo, commencing at the time of pre-admission check (baseline). Blood samples were taken at baseline and blood and atrial samples were taken perioperatively.

Results: DHA was identified as the major n-3 PUFA in all tissues, with concentrations significantly higher than EPA and the n-6 PUFA arachidonic acid (AA) and linoleic acid (LA) were the predominant PUFA (left ventricle: DHA 4.60±1.50; EPA 0.69±0.33; AA 22.95±2.97; LA 20.66±2.55 mean%±SD, N=38). Patterns of incorporation were different in different tissue types however no differences were seen between biopsy samples of right atria and donor right atria in the separate studies. Supplementation with fish oil significantly elevated RBC and atrial biopsy EPA+DHA. Despite variations in proportions of EPA and DHA from tissue to tissue and even greater variations between subjects, the concentration of EPA+DHA always provided the best tissue to tissue correlation within subjects. It was highly correlated between RBC and right atria biopsy (r2 = 0.4, P=0.0004) and between right atria donor and left ventricle donor (r2=0.7, P

Conclusions: This thesis has established that DHA is the main n-3 PUFA in human heart as it is in animal studies, with a range that overlaps with unsupplemented and lowdose supplemented laboratory rat. The DHA concentration is elevated as an apparently compensatory response to stressors and in response to dietary fish oil, as it is in animal studies. With DHA commonly the main n-3 PUFA of table fish, but EPA the principle n-3 PUFA provided as supplements in many clinical trials, establishing the pre-eminent position of DHA amongst n-3 PUFA in human myocardium increases confidence in the consistent human epidemiological studies associating usual fish consumption with cardiovascular outcomes and in translating outcomes of animal studies to interpret mechanisms of n-3 PUFA action in man. It also may provide some explanation for the more variable outcomes of clinical trials.

Despite the consistent predominance of DHA over EPA and variations in their relative concentrations in myocardium and RBC, this thesis has established that the omega-3 index provides the most robust correlations of red blood cells with human heart tissue and can be regarded as a good indicator of myocardial membrane n-3 PUFA composition, confirming its potential as a marker of cardiac-associated risk.

FoR codes (2008)

110104 Medical Biochemistry: Lipids, 110201 Cardiology (incl. Cardiovascular Diseases), 111603 Systems Physiology

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Unless otherwise indicated, the views expressed in this thesis are those of the author and do not necessarily represent the views of the University of Wollongong.