Role of Trientine in Hypertrophic Cardiomyopathy: A Review of Mechanistic Aspects

Abstract

Abnormality in myocardial copper homeostasis is believed to contribute to the development of cardiomyopathy. Trientine, a copper-chelating drug used in the management of patients with Wilson's disease, demonstrates beneficial effects in patients with hypertrophic cardiomyopathy. This review aims to present the updated development of the roles of trientine in hypertrophic cardiomyopathy. The drug has been demonstrated in animal studies to restore myocardial intracellular copper content. However, its mechanisms for improving the medical condition remain unclear. Thus, comprehending its mechanistic aspects in cardiomyopathy is crucial and could help to expedite future research.

Keywords: TETA; cardiomyopathy; diabetes; hypertensive; triethylenetetramine.

Figure 1

Molecular structure of trientine.

Figure 2

Sites of action of trientine in cardiac remodeling. Extracellularly, trientine reduces interstitial fibrosis by inhibiting tissue inhibitor of metalloproteinase 1/2 (TIMP1/2), leading to an increase in matrix metalloproteinases (MMPs). This, in turn, augments collagen degradation. Inhibitory effects of trientine on transforming growth factor-β1 (TGF-β1), plasminogen activator inhibitor-1 (PAI-1), and small mothers against decapentaplegic (Smad4) lead to decreases in expression of matrix proteins (collagen and fibronectin). The complex of trientine-Cu(II) is brought into cells by an unknown transporter and partly by copper transporter-2 (CTR-2). The drug increases the expression of superoxide dismutase-1 (SOD1) and -3 (SOD3) as well as copper chaperone for superoxide dismutase-1 (CCS), leading to a decrease in reactive oxygen species (ROS) formation. Trientine also elevates the expression of cytosolic soluble cytochrome c oxidase (Cco) copper chaperones 11 (Cox11) and 17 (Cox17), cytochrome c oxidase assembly protein-1/2 (Sco1/2), and peroxisome proliferator-activated receptor coactivator-1α (pgc-1α), which improves mitochondrial biogenesis and function. It also augments the expression of ATPase copper-transporting α (ATP7A) but has no effect on ATPase copper-transporting β (ATP7B) or antioxidant 1 copper chaperone (ATOX1), which are responsible for shuttling copper into trans-Golgi network or secretory vesicles. CTR-1, copper transporter 1; MT, metallothionein; nrf2, nuclear factor erythroid 2-related factor 2; tfam, mitochondrial transcription factor A; ↑, significant increase; +, stimulates; −, inhibits. Blank arrows demonstrate subsequent events; brown arrow indicates degradation, dashed blue arrow displays translocation of copper, and pink arrows indicate the sites of action of trientine.