Marinobufagenin and its role in Uremic Cardiomyopathy

Cardiovascular disease is the main cause of death among ESRD patients. However, this excess cardiovascular mortality in ESRD patients should not be mainly attributed to coronary artery disease or myocardial infarction. The 4D study and other studies have shed some light on this issue and now we recognize that it is actually (non-coronary) sudden cardiac death, and not myocardial infarction, the most common cause of cardiovascular mortality among ESRD patients.

The pathological basis for sudden cardiac death in ESRD includes the development of left ventricular hypertrophy, myocardial fibrosis, and microvascular disease, the so called uremic cardiomyopathy.

Endogenous cardiotonic steroids (CTS), are molecules similar in structure to cardiac glycosides or digitalis, that are synthesized by the adrenal gland. Elevated levels of CTS have been identified in various pathological conditions such as essential hypertension. CTS bind to the extracellular domain of the α-subunit of Na⁺-K⁺-ATPase, which, in addition to its well-known function of maintaining cellular electrochemical balance through pumping sodium and potassium ions, can act as a typical membrane receptor with the production of intracellular 2nd messengers.

Marinobufagenin (MBG), a bufadienolide CTS (naturally produced by the toad Bufo rubescens) has been implicated in the pathophysiology of uremic cardiomyopathy. MBG is released from the adrenal gland in response to angiotensin II. There is evidence to support the role of MBG in the development of cardiac fibrosis in uremia. What is more, uremic rats who are administered a monoclonal antibody against MBG reverse cardiac fibrosis.

Interestingly enough, salt load triggers release of MBG … another reason why ESRD patients should be on a low sodium diet.