Endogenous cardiotonic steroids and cardiovascular disease, where to next?

Abstract

Ever since British Physician William Withering first described the use of foxglove extract for treatment of patients with congestive heart failure in 1785, cardiotonic steroids have been used clinically to treat heart failure and more recently atrial fibrillation. Due to their ability to bind and inhibit the ubiquitous transport enzyme sodium potassium pump, thus regulating intracellular Na⁺ concentration in every living cell, they are also an essential tool for research into the sodium potassium pump structure and function. Exogenous CTS have been clearly demonstrated to affect cardiovascular system through modulation of vagal tone, cardiac contraction (via ionic changes) and altered natriuresis. Reports of a number of endogenous CTS, since the 1980s, have intensified research into their physiologic and pathophysiologic roles and opened up novel therapeutic targets. Substantive evidence pointing to the role of endogenous ouabain and marinobufagenin, the two most prominent CTS, in development of cardiovascular disease has accumulated. Nevertheless, their presence, structure, biosynthesis pathways and even mechanism of action remain unclear or controversial. In this review the current state-of-the-art, the controversies and the remaining questions surrounding the role of endogenous cardiotonic steroids in health and disease are discussed.

Keywords: Atrial fibrillation; Cardiotonic steroids; Digoxin; Heart failure; Marinobufagenin; NKA; Ouabain; Sodium potassium pump.

Fig. 1

Structure of the NKA and the chemical structures of its commonly described ligands ouabain, marinobufagenin and digoxin. NKA is made up of the α and β subunits and the accessory FXYD protein. Conserved CTS binding site is found within the α subunit. Three commonly studied CTS are shown on the right. Ouabain and marinobufagenin have been detected in circulation in patients and healthy controls. Ouabain and digoxin have a five-membered lactone ring, whereas marinobufagenin contains a six-membered lactone ring.

Fig. 2

Schematic diagram of ionic versus signaling pathways for cardiotonic steroid effects. In the classic pathway (shown on the left), CTS binds and inhibits the NKA, which in turn is accompanied by changes in cytosolic [Na⁺]. The increase in cytosolic [Na⁺] then reduces NCX activity and induces an increase in cytosolic [Ca²⁺]. High cytosolic [Ca²⁺] mediates muscle contraction (inotropy) or activates a variety of signaling pathways. It is unclear whether the effects of CTS on heart rate (bradycardia) are also mediated via the ionic pathway. The signaling pathway (shown on the right hand side) occurs in the caveolar domain and involves the physical interaction with Src. When the CTS binds the NKA, SRC gets activated inducing further activation of mitogen-activated protein kinase (ERK) through activation of its mitogen-activated protein kinase kinase (MEK).

Fig. 3

Graphical representation of the proposed biosynthesis and function of endogenous cardiotonic steroids. Synthesis of endogenous cardiotonic steroids is thought to occur in the adrenal cortex from cholesterol. Acute effects of endogenous cardiotonic steroids are mediated via inhibition of the NKA. Isoform specific effect in each tissue is shown in red. Acute and chronic effects of elevated cardiotonic steroids levels on the specific organs are shown in black boxes. Adapted from Schoner and Scheiner-Bobis [107].