The effects of omega-3 fatty acids in an ovine model of anthracycline-induced non-ischaemic cardiomyopathy.

Abstract

Anthracycline drugs, such as Doxorubicin (Adriamycin) (DOX), have been widely used since the 1960s for treatment of various forms of cancer. Despite their excellent anti-tumour affects, their clinical use may be complicated by various forms of cardiotoxicity, most notably dose dependent, non-ischaemic dilated cardiomyopathy (NICM) leading to congestive heart failure (CHF). Increasingly, different strategies have been devised in recent years to mitigate the adverse cardiovascular effects of anthracycline administration. However these have had variable success and the burden of anthracycline induced NICM remains substantial. Marine derived omega-3 polyunsaturated fatty acids (PUFA) have been shown to have cardio-protective properties in a number of clinical settings. These include anti-arrhythmic, anti-inflammatory and anti-thrombotic properties and which are predominantly mediated by the longer chain omega-3 PUFA, eicosapentaenoic (EPA) and docosahexaenoic acid (DHA). Previously, a limited number of basic and small animal studies have evaluated the protective actions of omega-3 PUFA against anthracycline-induced cardiotoxicity, with mixed findings. There-fore the current study set out to expand on these results by investigating omega-3 PUFA supplementation in the translational setting of a large animal model of DOX-induced NICM. Initially, a pilot study was performed to assess fatty acid bio distribution in Merino wether sheep receiving marine fish oil (containing 300mg/mL EPA+DHA), administered by oral drenching of 23mL volumes three times weekly for up to 20 weeks. Plasma and erythrocyte fatty acids were monitored serially and myocardial membrane concentrations were determined at study end. Systemic and myocardial uptake of long-chain omega-3 PUFA was demonstrated, with plasma, erythrocyte and myocardial concentrations increasing by two to three-fold from baseline levels (p<0.05). For the main study, 17 age and weight-matched Merino wethers received fortnightly dosing with intracoronary DOX (1.2mg/kg for three doses) to induce cardiotoxicity. Animals were randomised to oral supplementation with fish oil (n=8) or olive oil placebo (n=9) commencing two to three weeks before DOX dosing and continued until 12 weeks after final DOX dose. Comparisons between the fish oil and placebo groups were made for left ventricular remodelling and function by cardiac magnetic resonance imaging (CMR), transthoracic echocardiography and histomorphometric analysis of myocardial fibrosis burden. Surprisingly, by comparison to placebo animals, sheep in the fish oil group showed greater decline in left ventricular ejection fraction (LVEF) (p<0.05), and greater end-diastolic and end-systolic dilatation after DOX (p<0.05). However, both groups demonstrated similar levels of left ventricular fibrosis, suggesting that the accentuation of systolic dysfunction observed in the omega-3 PUFA cohort was not mediated by excess myocardial collagen deposition. In summary, this is the first large animal study to evaluate omega-3 PUFA supplementation in the setting of anthracycline cardiotoxicity. Despite augmenting circulating and tissue long-chain fatty acid levels, oral intake of fishoil exacerbated cardiac remodelling induced by intracoronary DOX. Given these new observational findings, we recommend deferring clinical investigation until further basic mechanistic studies can better define the interactions between fatty acids and cardiac biology in the presence of anthracycline exposure.