Elevated Plasma Marinobufagenin, An Endogenous Cardiotonic Steroid, Is Associated With Right Ventricular Dysfunction and Nitrative Stress in Heart Failure.
BACKGROUND
Plasma levels of cardiotonic steroids are elevated in volume-expanded states, such as chronic kidney disease, but the role of these natriuretic hormones in subjects with heart failure (HF) is unclear. We sought to determine the prognostic role of the cardiotonic steroids marinobufagenin (MBG) in HF, particularly in relation to long-term outcomes.


RESULTS
We first measured plasma MBG levels and performed comprehensive clinical, laboratory, and echocardiographic assessment in 245 patients with HF. All-cause mortality, cardiac transplantation, and HF hospitalization were tracked for 5 years. In our study cohort, median (interquartile range) MBG was 583 (383-812) pM. Higher MBG was associated with higher myeloperoxidase (r=0.42, P<0.0001), B-type natriuretic peptide (r=0.25, P=0.001), and asymmetrical dimethylarginine (r=0.32, P<0.001). Elevated levels of MBG were associated with measures of worse right ventricular function (RV s', r=-0.39, P<0.0001) and predicted increased risk of adverse clinical outcomes (MBG≥574 pmol/L: hazard ratio 1.58 [1.10-2.31], P=0.014) even after adjustment for age, sex, diabetes mellitus, and ischemic pathogenesis. In mice, a left anterior descending coronary artery ligation model of HF lead to increases in MBG, whereas infusion of MBG into mice for 4 weeks lead to significant increases in myeloperoxidase, asymmetrical dimethylarginine, and cardiac fibrosis.


CONCLUSIONS
In the setting of HF, elevated plasma levels of MBG are associated with right ventricular dysfunction and predict worse long-term clinical outcomes in multivariable models adjusting for established clinical and biochemical risk factors. Infusion of MBG seems to directly contribute to increased nitrative stress and cardiac fibrosis.
From the Department of Cellular and Molecular Medicine (D.J.K., K.S., B.S., X.S.L., A.G., Y.W., M.F., A.G., C.M.M., K.W., A.B., W.H.W.T.), Center for Cardiovascular Diagnostics and Prevention, Lerner Research Institute (W.H.W.T.), Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute (D.J.K.), and Department of Cardiovascular Medicine, Heart and Vascular Institute (W.H.W.T.), Cleveland Clinic, Cleveland, OH; and Laboratory of Cardiovascular Science, Hypertension Unit, National Institute on Aging, National Institutes of Health, Baltimore, MD (O.F., A.Y.B.).
David J
DJ
Kennedy
From the Department of Cellular and Molecular Medicine (D.J.K., K.S., B.S., X.S.L., A.G., Y.W., M.F., A.G., C.M.M., K.W., A.B., W.H.W.T.), Center for Cardiovascular Diagnostics and Prevention, Lerner Research Institute (W.H.W.T.), Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute (D.J.K.), and Department of Cardiovascular Medicine, Heart and Vascular Institute (W.H.W.T.), Cleveland Clinic, Cleveland, OH; and Laboratory of Cardiovascular Science, Hypertension Unit, National Institute on Aging, National Institutes of Health, Baltimore, MD (O.F., A.Y.B.).
Kevin
K
Shrestha
From the Department of Cellular and Molecular Medicine (D.J.K., K.S., B.S., X.S.L., A.G., Y.W., M.F., A.G., C.M.M., K.W., A.B., W.H.W.T.), Center for Cardiovascular Diagnostics and Prevention, Lerner Research Institute (W.H.W.T.), Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute (D.J.K.), and Department of Cardiovascular Medicine, Heart and Vascular Institute (W.H.W.T.), Cleveland Clinic, Cleveland, OH; and Laboratory of Cardiovascular Science, Hypertension Unit, National Institute on Aging, National Institutes of Health, Baltimore, MD (O.F., A.Y.B.).
Brendan
B
Sheehey
From the Department of Cellular and Molecular Medicine (D.J.K., K.S., B.S., X.S.L., A.G., Y.W., M.F., A.G., C.M.M., K.W., A.B., W.H.W.T.), Center for Cardiovascular Diagnostics and Prevention, Lerner Research Institute (W.H.W.T.), Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute (D.J.K.), and Department of Cardiovascular Medicine, Heart and Vascular Institute (W.H.W.T.), Cleveland Clinic, Cleveland, OH; and Laboratory of Cardiovascular Science, Hypertension Unit, National Institute on Aging, National Institutes of Health, Baltimore, MD (O.F., A.Y.B.).
Xinmin S
XS
Li
From the Department of Cellular and Molecular Medicine (D.J.K., K.S., B.S., X.S.L., A.G., Y.W., M.F., A.G., C.M.M., K.W., A.B., W.H.W.T.), Center for Cardiovascular Diagnostics and Prevention, Lerner Research Institute (W.H.W.T.), Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute (D.J.K.), and Department of Cardiovascular Medicine, Heart and Vascular Institute (W.H.W.T.), Cleveland Clinic, Cleveland, OH; and Laboratory of Cardiovascular Science, Hypertension Unit, National Institute on Aging, National Institutes of Health, Baltimore, MD (O.F., A.Y.B.).
Anuradha
A
Guggilam
From the Department of Cellular and Molecular Medicine (D.J.K., K.S., B.S., X.S.L., A.G., Y.W., M.F., A.G., C.M.M., K.W., A.B., W.H.W.T.), Center for Cardiovascular Diagnostics and Prevention, Lerner Research Institute (W.H.W.T.), Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute (D.J.K.), and Department of Cardiovascular Medicine, Heart and Vascular Institute (W.H.W.T.), Cleveland Clinic, Cleveland, OH; and Laboratory of Cardiovascular Science, Hypertension Unit, National Institute on Aging, National Institutes of Health, Baltimore, MD (O.F., A.Y.B.).
Yuping
Y
Wu
From the Department of Cellular and Molecular Medicine (D.J.K., K.S., B.S., X.S.L., A.G., Y.W., M.F., A.G., C.M.M., K.W., A.B., W.H.W.T.), Center for Cardiovascular Diagnostics and Prevention, Lerner Research Institute (W.H.W.T.), Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute (D.J.K.), and Department of Cardiovascular Medicine, Heart and Vascular Institute (W.H.W.T.), Cleveland Clinic, Cleveland, OH; and Laboratory of Cardiovascular Science, Hypertension Unit, National Institute on Aging, National Institutes of Health, Baltimore, MD (O.F., A.Y.B.).
Michael
M
Finucan
From the Department of Cellular and Molecular Medicine (D.J.K., K.S., B.S., X.S.L., A.G., Y.W., M.F., A.G., C.M.M., K.W., A.B., W.H.W.T.), Center for Cardiovascular Diagnostics and Prevention, Lerner Research Institute (W.H.W.T.), Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute (D.J.K.), and Department of Cardiovascular Medicine, Heart and Vascular Institute (W.H.W.T.), Cleveland Clinic, Cleveland, OH; and Laboratory of Cardiovascular Science, Hypertension Unit, National Institute on Aging, National Institutes of Health, Baltimore, MD (O.F., A.Y.B.).
Alaa
A
Gabi
From the Department of Cellular and Molecular Medicine (D.J.K., K.S., B.S., X.S.L., A.G., Y.W., M.F., A.G., C.M.M., K.W., A.B., W.H.W.T.), Center for Cardiovascular Diagnostics and Prevention, Lerner Research Institute (W.H.W.T.), Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute (D.J.K.), and Department of Cardiovascular Medicine, Heart and Vascular Institute (W.H.W.T.), Cleveland Clinic, Cleveland, OH; and Laboratory of Cardiovascular Science, Hypertension Unit, National Institute on Aging, National Institutes of Health, Baltimore, MD (O.F., A.Y.B.).
Charles M
CM
Medert
From the Department of Cellular and Molecular Medicine (D.J.K., K.S., B.S., X.S.L., A.G., Y.W., M.F., A.G., C.M.M., K.W., A.B., W.H.W.T.), Center for Cardiovascular Diagnostics and Prevention, Lerner Research Institute (W.H.W.T.), Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute (D.J.K.), and Department of Cardiovascular Medicine, Heart and Vascular Institute (W.H.W.T.), Cleveland Clinic, Cleveland, OH; and Laboratory of Cardiovascular Science, Hypertension Unit, National Institute on Aging, National Institutes of Health, Baltimore, MD (O.F., A.Y.B.).
Kristen
K
Westfall
From the Department of Cellular and Molecular Medicine (D.J.K., K.S., B.S., X.S.L., A.G., Y.W., M.F., A.G., C.M.M., K.W., A.B., W.H.W.T.), Center for Cardiovascular Diagnostics and Prevention, Lerner Research Institute (W.H.W.T.), Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute (D.J.K.), and Department of Cardiovascular Medicine, Heart and Vascular Institute (W.H.W.T.), Cleveland Clinic, Cleveland, OH; and Laboratory of Cardiovascular Science, Hypertension Unit, National Institute on Aging, National Institutes of Health, Baltimore, MD (O.F., A.Y.B.).
Allen
A
Borowski
From the Department of Cellular and Molecular Medicine (D.J.K., K.S., B.S., X.S.L., A.G., Y.W., M.F., A.G., C.M.M., K.W., A.B., W.H.W.T.), Center for Cardiovascular Diagnostics and Prevention, Lerner Research Institute (W.H.W.T.), Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute (D.J.K.), and Department of Cardiovascular Medicine, Heart and Vascular Institute (W.H.W.T.), Cleveland Clinic, Cleveland, OH; and Laboratory of Cardiovascular Science, Hypertension Unit, National Institute on Aging, National Institutes of Health, Baltimore, MD (O.F., A.Y.B.).
Olga
O
Fedorova
From the Department of Cellular and Molecular Medicine (D.J.K., K.S., B.S., X.S.L., A.G., Y.W., M.F., A.G., C.M.M., K.W., A.B., W.H.W.T.), Center for Cardiovascular Diagnostics and Prevention, Lerner Research Institute (W.H.W.T.), Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute (D.J.K.), and Department of Cardiovascular Medicine, Heart and Vascular Institute (W.H.W.T.), Cleveland Clinic, Cleveland, OH; and Laboratory of Cardiovascular Science, Hypertension Unit, National Institute on Aging, National Institutes of Health, Baltimore, MD (O.F., A.Y.B.).
Alexei Y
AY
Bagrov
From the Department of Cellular and Molecular Medicine (D.J.K., K.S., B.S., X.S.L., A.G., Y.W., M.F., A.G., C.M.M., K.W., A.B., W.H.W.T.), Center for Cardiovascular Diagnostics and Prevention, Lerner Research Institute (W.H.W.T.), Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute (D.J.K.), and Department of Cardiovascular Medicine, Heart and Vascular Institute (W.H.W.T.), Cleveland Clinic, Cleveland, OH; and Laboratory of Cardiovascular Science, Hypertension Unit, National Institute on Aging, National Institutes of Health, Baltimore, MD (O.F., A.Y.B.). tangw@ccf.org.
W H Wilson
WH
Tang
D000328:Adult; D000368:Aged; D000818:Animals; D015415:Biomarkers / Q000097:blood; D002018:Bufanolides / Q000097:blood*; D015331:Cohort Studies; D004195:Disease Models, Animal; D005260:Female; D006333:Heart Failure / Q000097:blood* / Q000150:complications / Q000503:physiopathology*; D016027:Heart Transplantation; D006760:Hospitalization; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D011237:Predictive Value of Tests; D013318:Stroke Volume / Q000502:physiology; D016019:Survival Analysis; D018497:Ventricular Dysfunction, Right / Q000097:blood* / Q000209:etiology / Q000401:mortality
D015415:Biomarkers; D002018:Bufanolides; C093896:marinobufagenin
cardiac fibrosis; cardiotonic steroids; heart failure; nitrative stress; outcome