P4503Copper chelation in hypertrophic cardiomyopathy; open-label pilot study assessing the effects of trientine on lv mass, myocardial fibrosis, performance and metabolism

Abstract

Background: HCM is the most inherited cardiomyopathy but as yet no pharmacological intervention has ever proven to alter the natural history or outcome of the disease, with a pressing need for a new impetus in this field. Furthermore, CMR appears ideally placed to characterise many of the key pathophysiological processes dominating the disease. Copper (Cu) is an essential cofactor for a variety of metabolic functions and whilst regulation of systemic Cu metabolism is critical to human health, free Cu ions are extremely redox-active and thus potentially toxic. We previously reported abnormal copper homeostasis in patients with HCM. In brief we found significantly elevated serum (free) copper and coeruloplasmin levels in HCM patients compared to controls. Given that disturbances of Cu homeostasis can lead to hypertrophic forms of heart disease (e.g. in Wilson disease) and given that we previously demonstrated that Cu chelation in absence of Cu deficiency is able to reverse LVH and organ fibrosis via Cu-dependent mechanism both in animal and human studies we hypothesised that Cu-selective chelation with trientine would slow disease progression in HCM. Methods: This open-label, pilot study explored the clinical efficacy and tolerability of trientine dihydrochloride in a group of 20 patients with HCM, over a 6-month period. Pre-defined endpoints included changes in LVM, markers of LV fibrosis, markers of LV performance and myocardial energetics. 10 further matched HCM patients were studied as controls. Patients underwent a complex assessment schedule during 6 visits including separate CMR and CMR 31P-spectroscopy at baseline and end of therapy. Results: Trientine induced no significant change in BP, HR or BMI. LV Mass decreased significantly in the treatment arm compared to the control group (-4.2g v 1.8g, p=0.03). A trend towards an absolute decrease in mass was observed in the treatment group (p=0.06). These changes were associated with a reduction in native T1 (1060±47ms vs 1049±42ms, p=0.06) and a reduction in ECV (30.0±4.5% v 29.5±4.0%, p=0.06). Furthermore, significant improvements were seen in global longitudinal strain using both Echo speckle tracking based and CMR feature tracking based technologies (-16.6±4.3 vs -18.9±4.4, p=0.01 and -18.3±3.4 vs -19.4±3.4, p=0.03 respectively). Equally, significant improvements were noted in atrial strain parameters, again with mirror changes between both imaging technologies. There was a trend towards increase in PCr/ATP ratio with trientine therapy (1.27±0.44 vs 1.4±0.39), however this did not reach statistical significance. No significant increase in exercise time, VO2max or AT was observed. Conclusion: Cu-selective chelation with trientine in a controlled environment is safe and appears to have beneficial effects on several disease imaging biomarkers. Indeed, it appears to at least slow disease progression. A larger Phase 2b double blind randomised trial is now warranted.