The Role of Cardiotonic Steroids in the Pathogenesis of Cardiomyopathy in Chronic Kidney Disease

Abstract

Cardiotonic steroids (CTS) are a new class of hormones that circulate in the blood and are divided into two distinct groups, cardenolides, such as ouabain and digoxin, and bufadienolides, such as marinobufagenin, telocinobufagin and bufalin. They have the ability to bind and inhibit the ubiquitous transport enzyme sodium potassium pump, thus regulating intracellular Na⁺ concentration in every living cell. Although digoxin has been prescribed to heart failure patients for at least 200 years, the realization that CTS are endogenously produced has intensified research into their physiological and pathophysiological roles. Over the last two decades, substantial evidence has accumulated demonstrating the effects of endogenously synthesised CTS on the kidneys, vasculature and the heart. In this review, the current state of art and the controversies surrounding the manner in which CTS mediate their pathophysiological effects are discussed. Several potential therapeutic strategies have emerged as a result of our increased understanding of the role CTS play in health and disease.

A New Animal Model to Study Endogenous Cardiotonic Steroids and the Progression of Cardiovascular Events in Salt-Sensitive Hypertension

“…Our preliminary results in the DS rats exposed to a high salt diet support the evidence suggesting that CTS may be of crucial importance in the high mortality rate associated with increased blood pressure response, salt sensitivity and renal salt handling [17,36]. Considering that high blood pressure is the number one cardiovascular risk factor for cardiac failure and stroke, [37,38] we propose the DSc rat as an experimental model to study these relationships and further define the role of endogenous cardiotonic steroids as potential early diagnostic biomarkers to identify those individuals who are at higher risk.…”

“…In conclusion, the DSc model may help to expand and strengthen our knowledge of the relationship of salt sensitivity of blood pressure as have been discussed in recent studies and reviews [17,18,36,40-43]. Moreover, the DSc model can help advance knowledge of the pathophysiology of ocular pathology in ageing [44].…”

Na+/Ca2+ exchange and Na+/K+‐ATPase in the heart

“…MBG, marinobufagenin. Adapted from Pavlovic (2014). vascular and skeletal muscle, and the role of the NKA in general in cardiovascular disease.…”

Endogenous Ouabain

“…EO, which may contribute to renal failure 96 and may be linked to cardiomyopathy in chronic kidney disease, 62, 97, 98 also appears to be a valuable biomarker of heart failure. In 845 patients undergoing elective cardiac surgery, plasma EO was correlated negatively with left ventricular ejection fraction, and positively with cardiac end-diastolic diameter and plasma NT-proBNP.…”