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.

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Purpose: To report photokeratitis caused by the improper use of germicidal lamps purchased during the COVID-19 pandemic. Methods: Case series. Results: Seven patients presented with acute ocular surface pain after exposure to UV-emitting germicidal lamps. Visual acuity was 20/30 or better in 13 of 14 eyes (93%). Anterior segment examination revealed varying degrees of conjunctival injection and diffusely distributed punctate epithelial erosions (PEEs) in every patient. No intraocular inflammation was identified across the cohort and all fundus examinations were normal. Treatment varied by provider and included artificial tears alone or in combination with antibiotic ointments and/or topical steroids. Five patients were followed via telehealth, one patient returned for an in-office visit, and one patient was lost to follow-up. Five of six patients endorsed complete resolution of symptoms within 2-3 days. Conclusions: Patients should follow manufacturer recommendations when using UV-emitting germicidal lamps and avoid direct exposure to the ocular surface.

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Cardiotonic steroids (CTS) are Na+/K+-ATPase (NKA) ligands that are elevated in volume-expanded states and associated with cardiac and renal dysfunction in both clinical and experimental settings. We test the hypothesis that the CTS telocinobufagin (TCB) promotes renal dysfunction in a process involving signaling through the NKA α-1 in the following studies. First, we infuse TCB (4 weeks at 0.1 µg/g/day) or a vehicle into mice expressing wild-type (WT) NKA α-1, as well as mice with a genetic reduction (~40%) of NKA α-1 (NKA α-1+/−). Continuous TCB infusion results in increased proteinuria and cystatin C in WT mice which are significantly attenuated in NKA α-1+/− mice (all p < 0.05), despite similar increases in blood pressure. In a series of in vitro experiments, 24-h treatment of HK2 renal proximal tubular cells with TCB results in significant dose-dependent increases in both Collagens 1 and 3 mRNA (2-fold increases at 10 nM, 5-fold increases at 100 nM, p < 0.05). Similar effects are seen in primary human renal mesangial cells. TCB treatment (100 nM) of SYF fibroblasts reconstituted with cSrc results in a 1.5-fold increase in Collagens 1 and 3 mRNA (p < 0.05), as well as increases in both Transforming Growth factor beta (TGFb, 1.5 fold, p < 0.05) and Connective Tissue Growth Factor (CTGF, 2 fold, p < 0.05), while these effects are absent in SYF cells without Src kinase. In a patient study of subjects with chronic kidney disease, TCB is elevated compared to healthy volunteers. These studies suggest that the pro-fibrotic effects of TCB in the kidney are mediated though the NKA-Src kinase signaling pathway and may have relevance to volume-overloaded conditions, such as chronic kidney disease where TCB is elevated.

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