Abstract
Background: Disturbances of copper (CU) homeostasis can lead to hypertrophic cardiac phenotypes (e.g. Wilson’s disease). We previously identified abnormal Cu homeostasis in patients with hypertrophic cardiomyopathy (HCM) and therefore hypothesized that Cu2+–selective chelation with trientine dihydrochloride may slow or reverse disease progression in HCM. The aim of this study was therefore to explore the clinical efficacy, safety and tolerability of trientine in HCM.
Methods: In this MHPRA registered open-label pilot study we treated 20 HCM patients with trientine for 6-months. Patients underwent a comprehensive assessment schedule including separate CMR and CMR 31P-spectroscopy at baseline and end of therapy. Pre-defined endpoints included changes in left ventricular mass (LVM), markers of LV fibrosis, markers of LV performance and myocardial energetics. Ten matched HCM patients were studied as controls.
Results: Trientine treatment was safe and tolerated. Trientine caused a substantial increase in urinary copper excretion (0.42 ±0.2 vs 2.02±1.0, p=0.001) without affecting serum copper concentrations. Treatment was associated with significant improvements in total atrial strain and global longitudinal LV strain using both Echo and CMR. LVM decreased significantly in the treatment arm compared to the control group (-4.2g v 1.8g, p=0.03). A strong trend towards an absolute decrease in LVM was observed in the treatment group (p=0.06). These changes were associated with a significant change in total myocardial volume driven by a significant reduction in extracellular matrix (ECM) volume (43.83 ±18.42mls vs 41.49 ±16.89mls, p=0.04) as opposed to pure cellular mass reduction and occurred against a background of significant ECM volume increase in the control group (44.59 ±16.50mls vs 47.48 ±19.30mls, p=0.02). A non-significant 10% increase in PCr/ATP ratio with trientine therapy (1.27±0.44 vs 1.4±0.39) was noted.
Conclusions: Cu2+–selective chelation with trientine in a controlled environment is safe and a potential future therapeutic target. A phase 2b trial is now underway.
Methods: In this MHPRA registered open-label pilot study we treated 20 HCM patients with trientine for 6-months. Patients underwent a comprehensive assessment schedule including separate CMR and CMR 31P-spectroscopy at baseline and end of therapy. Pre-defined endpoints included changes in left ventricular mass (LVM), markers of LV fibrosis, markers of LV performance and myocardial energetics. Ten matched HCM patients were studied as controls.
Results: Trientine treatment was safe and tolerated. Trientine caused a substantial increase in urinary copper excretion (0.42 ±0.2 vs 2.02±1.0, p=0.001) without affecting serum copper concentrations. Treatment was associated with significant improvements in total atrial strain and global longitudinal LV strain using both Echo and CMR. LVM decreased significantly in the treatment arm compared to the control group (-4.2g v 1.8g, p=0.03). A strong trend towards an absolute decrease in LVM was observed in the treatment group (p=0.06). These changes were associated with a significant change in total myocardial volume driven by a significant reduction in extracellular matrix (ECM) volume (43.83 ±18.42mls vs 41.49 ±16.89mls, p=0.04) as opposed to pure cellular mass reduction and occurred against a background of significant ECM volume increase in the control group (44.59 ±16.50mls vs 47.48 ±19.30mls, p=0.02). A non-significant 10% increase in PCr/ATP ratio with trientine therapy (1.27±0.44 vs 1.4±0.39) was noted.
Conclusions: Cu2+–selective chelation with trientine in a controlled environment is safe and a potential future therapeutic target. A phase 2b trial is now underway.
| Original language | English |
|---|---|
| Journal | Open Heart |
| Publication status | Accepted/In press - 15 Nov 2021 |