Elevated Plasma Marinobufagenin, An Endogenous Cardiotonic Steroid, Is Associated With Right Ventricular Dysfunction and Nitrative Stress in Heart Failure

Abstract

Background Plasma levels of cardiotonic steroids (CTS) 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 CTS marinobufagenin (MBG) in HF, particularly in relation to long-term outcomes. Methods and Results We first measured plasma MBG levels and performed comprehensive clinical, laboratory, and echocardiographic assessment in 245 HF patients. 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 (MPO, r=0.42, p<0.0001), BNP (r=0.25, p=0.001), and asymmetric dimethylarginine (ADMA, 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 pM: HR 1.58 [1.10-2.31], p=0.014) even after adjustment for age, gender, diabetes mellitus, and ischemic etiology. In mice, a left anterior descending coronary artery ligation model of heart failure lead to increases in MBG, while infusion of MBG into mice for 4 weeks lead to significant increases in MPO, ADMA, and cardiac fibrosis. Conclusions In the setting of heart failure, 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 appears to directly contribute to increased nitrative stress and cardiac fibrosis.

Sodium fluoride induces hypertension and cardiac complications through generation of reactive oxygen species and activation of nuclear factor kappa beta

“…Furthermore, the MPO plays an essential role in inflammation and oxidative stress at the cellular level through its enzymatic action that leads to the generation of reactive molecules capable of oxidizing antioxidants, lipids and protein of LDL (Zang et al, ). The MPO has recently being recognized as a marker of heart failure and cardiac damage apart from its involvement in inflammation and oxidative stress (Kennedy et al, ). Hence, elevated serum XO and MPO activity could be suggestive of renal and cardiac damage.…”

Hemodialysis‐induced cardiovascular disease

“…In rats, partial nephrectomy increases plasma MBG, which stimulates fibroblast collagen production and causes fibrosis while immunization against MBG results in less cardiac hypertrophy, diastolic dysfunction, and cardiac fibrosis . In the setting of heart failure, MBG is associated with right ventricular dysfunction and cardiac fibrosis . MBG‐induced fibrosis may be mitigated by mineralocorticoid antagonists, which exhibit competitive inhibition of MBG's effect on Na/K‐ATPase; in a small prospective study of resistant hypertension patients, who exhibited elevated plasma MBG and reduced Na/K‐ATPase activity, spironolactone was associated with restoration of Na/K‐ATPase activity, decreased arterial pressure, and decreased pulse wave velocity .…”

“…38 In the setting of heart failure, MBG is associated with right ventricular dysfunction and cardiac fibrosis. 39 MBG-induced fibrosis may be mitigated by mineralocorticoid antagonists, which exhibit competitive inhibition of MBG's effect on Na/K-ATPase; in a small prospective study of resistant hypertension patients, who exhibited elevated plasma MBG and reduced Na/K-ATPase activity, spironolactone was associated with restoration of Na/K-ATPase activity, decreased arterial pressure, and decreased pulse wave velocity. 40 CTSs work in conjunction with renin-angiotensin-aldosterone system (RAAS) to regulate hemodynamic parameters 41 ; their accumulation and dose-dependent long term effects on gene expression in the context of ESRD has not been studied.…”

Potential Harmful Effects of PM2.5 on Occurrence and Progression of Acute Coronary Syndrome: Epidemiology, Mechanisms, and Prevention Measures

“…In the nitrative stress reaction, ROS products biochemically react with NO and NO-derived reactive nitrogen species, producing reactive nitrogen species (such as peroxynitrite) and leading to damage to DNA, proteins, and lipids [72]. Elevation of plasma 3-nitrotyrosine, the index reflecting nitrative stress level, was observed by Kumarathasan et al [73] after inhalation of concentrated particulate matter in animal experiments. Additionally, the decreased NO level via nitrative stress may also indirectly induce atherosclerosis [74].…”