Endogenous Ouabain: An Old Cardiotonic Steroid as a New Biomarker of Heart Failure and a Predictor of Mortality after Cardiac Surgery.

Simonini M1, Pozzoli S1, Bignami E2, Casamassima N1, Messaggio E1, Lanzani C1, Frati E2, Botticelli IM1, Rotatori F3, Alfieri O4, Zangrillo A2, Manunta P1.
  • 1Genomics of Renal Diseases and Hypertension Department, “Vita-Salute” San Raffaele University, Chair of Nephrology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
  • 2Anesthesia and Intensive Care Department, “Vita-Salute” San Raffaele University, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
  • 3SUNY Downstate Medical Center, State University of New York, Brooklyn, NY 11203, USA.
  • 4Cardiac Surgery Department, “Vita-Salute” San Raffaele University, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.



Cardiovascular diseases remain the main cause of mortality and morbidity worldwide; primary prevention is a priority for physicians. Biomarkers are useful tools able to identify high-risk individuals, guide treatments, and determine prognosis. Our aim is to investigate Endogenous Ouabain (EO), an adrenal stress hormone with hemodynamic effects, as a valuable biomarker of heart failure. In a population of 845 patients undergoing elective cardiac surgery, we have investigated the relationships between EO and echocardiography parameters/plasmatic biomarker of cardiac function. EO was found to be correlated negatively with left ventricular EF (p = 0.001), positively with Cardiac End-Diastolic Diameter (p = 0.047), and positively with plasmatic NT-proBNP level (p = 0.02). Moreover, a different plasmatic EO level (both preoperative and postoperative) was found according to NYHA class (p = 0.013). All these results have been replicated on an independent cohort of patients (147 subjects from US). Finally, a higher EO level in the immediate postoperative time was indicative of a more severe cardiological condition and it was associated with increased perioperative mortality risk (p = 0.023 for 30-day morality). Our data suggest that preoperative and postoperative plasmatic EO level identifies patients with a more severe cardiovascular presentation at baseline. These patients have a higher risk of morbidity and mortality after cardiac surgery.

PMID: 26609532



Endogenous Ouabain (EO): a new biomarker of subclinical cardiovascular damage.

Endogenous Ouabain (EO) is a neuroendocrine hormone synthesized in the adrenal cortex1-3. EO may be considered as stress hormone secreted by the adrenal gland. It is possible to observe a significant increase of EO in plasma and adrenal both in human and animal models after intensive physical exercise4,5. EO modulates the activity of the Na,K-ATPase and induces signal transduction via sodium-calcium exchange and the Src-dependent pathway6. EO exerts a biphasic effect on Na,K-ATPase, either stimulating or inhibiting its activity at low (subnanomolar ) or high (micromolar) concentrations, respectively7. 

It was reported that increased circulating EO (in pM range) is related to cardiomyopathy8, and decreased renal function9,10. Endogenous cardiotonic steroids (CTS), and in particular Endogenous Ouabain, are implicated in regulation of natriuresis and vascular tone11. More recently, CTS have been shown to contribute to pro-hypertrophic and pro-fibrotic cell signaling12. In addition, different types of endogenous glycosides, are elevated in a large proportion of critically ill patients and correlate with increased morbidity and hospital mortality rates13.

Recently, we reported few significant associations between pre-operative Endogenous Ouabain levels and adverse renal outcomes and higher mortality rate in cardiac surgery patients and in critically ill ones14-16.

In this way EO could be considered a good marker of subclinical cardiovascular and kidney damage and this aspect of individual microvascular damage actually is not represented in any existing biomarker or risk score.
It is not yet known whether EO is simply a marker of the initial chronic GFR reduction17 or it is functionally responsible for podocyte integrity (see fig. 1). We support the second possibility; it means that when individuals, with elevated preoperative EO and with or without underlying kidney damage, are exposed to the acute stress of surgery the following elevation of circulating EO13,18 exacerbates the underlying damage and contributes directly to AKI.


These observations open up a totally new approach to the study and treatment of cardiovascular disease, based on the EO effects and on the genetic factors related to its production, functioning and metabolism. What we propose to study in the next future is precisely the relationship among plasma levels of EO, the individual genetic background and their relationship with the development of acute cardiovascular and renal disease in order to better clarify the patho-physiological mechanisms underlying the development of these.



Marco Simonini, MD

Università Vita Salute San Raffaele, Chair of Nephrology

Genomics of Renal Diseases and Hypertension Unit

IRCCS San Raffaele Scientific Institute, Milan, Italy 

e-mail: simonini.marco@hsr.it



  1. Dostanic-Larson, I., Van Huysse, J. W., Lorenz, J. N. & Lingrel, J. B. The highly conserved cardiac glycoside binding site of Na,K-ATPase plays a role in blood pressure regulation. Proc. Natl. Acad. Sci. U.S.A. 102, 15845–15850 (2005).
  2. Sophocleous, A., Elmatzoglou, I. & Souvatzoglou, A. Circulating endogenous digitalis-like factor(s) (EDLF) in man is derived from the adrenals and its secretion is ACTH-dependent. J. Endocrinol. Invest. 26, 668–674 (2003).
  3. Laredo, J., Hamilton, B. P. & Hamlyn, J. M. Secretion of endogenous ouabain from bovine adrenocortical cells: role of the zona glomerulosa and zona fasciculata. Biochem. Biophys. Res. Commun. 212, 487–493 (1995).
  4. Goto, A., Yamada, K., Nagoshi, H., Terano, Y. & Omata, M. Stress-induced elevation of ouabainlike compound in rat plasma and adrenal. Hypertension 26, 1173–1176 (1995).
  5. Bauer, N. et al. Ouabain-like compound changes rapidly on physical exercise in humans and dogs: effects of beta-blockade and angiotensin-converting enzyme inhibition. Hypertension 45, 1024–1028 (2005).
  6. Wang, H. et al. Ouabain assembles signaling cascades through the caveolar Na+/K+-ATPase. J. Biol. Chem. 279, 17250–17259 (2004).
  7. Ferrari, P. et al. PST2238: a new antihypertensive compound that antagonizes the long-term pressor effect of ouabain. J. Pharmacol. Exp. Ther. 285, 83–94 (1998).
  8. Pitzalis, M. V. et al. Independent and incremental prognostic value of endogenous ouabain in idiopathic dilated cardiomyopathy. Eur. J. Heart Fail. 8, 179–186 (2006).
  9. Manunta, P. et al. Endogenous ouabain and the renin-angiotensin-aldosterone system: distinct effects on Na handling and blood pressure in human hypertension. J. Hypertens. 29, 349–356 (2011).
  10. Kolmakova, E. V. et al. Endogenous cardiotonic steroids in chronic renal failure. Nephrol. Dial. Transplant. 26, 2912–2919 (2011).
  11. Bagrov, A. Y., Shapiro, J. I. & Fedorova, O. V. Endogenous cardiotonic steroids: physiology, pharmacology, and novel therapeutic targets. Pharmacol. Rev. 61, 9–38 (2009).
  12. Bagrov, A. Y. & Shapiro, J. I. Endogenous digitalis: pathophysiologic roles and therapeutic applications. Nat Clin Pract Nephrol 4, 378–392 (2008).
  13. Berendes, E. et al. Endogenous glycosides in critically ill patients. Crit. Care Med. 31, 1331–1337 (2003).
  14. Bignami, E. et al. Preoperative endogenous ouabain predicts acute kidney injury in cardiac surgery patients. Crit. Care Med. 41, 744–755 (2013).
  15. Simonini, M. et al. A new clinical multivariable model that predicts postoperative acute kidney injury: impact of endogenous ouabain. Nephrol. Dial. Transplant. 29, 1696–1701 (2014).
  16. Simonini, M. et al. Endogenous Ouabain: An Old Cardiotonic Steroid as a New Biomarker of Heart Failure and a Predictor of Mortality after Cardiac Surgery. Biomed Res Int 2015, 714793–10 (2015).
  17. Hamlyn, J. M. & Manunta, P. Endogenous Cardiotonic Steroids in Kidney Failure: A Review and an Hypothesis. Advances in Chronic Kidney Disease 22, 232–244 (2015).
  18. Bignami, E., Casamassima, N. & Frati, E. Endogenous Ouabain Changes Rapidly During Cardiac Pulmonary by Pass. J Steroids Hormon … (2011).