Abstract-We have observed recently that experimental renal failure in the rat is accompanied by increases in circulating concentrations of the cardiotonic steroid, marinobufagenin (MBG), and substantial cardiac fibrosis. We performed the following studies to examine whether MBG might directly stimulate cardiac fibroblast collagen production. In vivo studies were performed using the 5/6th nephrectomy model of experimental renal failure (PNx), MBG infusion (MBG), PNx after immunization against MBG, and concomitant PNx and adrenalectomy. Physiological measurements with a Millar catheter and immunohistochemistry were performed. In vitro studies were then pursued with cultured isolated cardiac fibroblasts. We observed that PNx and MBG increased MBG levels, blood pressure, heart size, impaired diastolic function, and caused cardiac fibrosis. PNx after immunization against MBG and concomitant PNx and adrenalectomy had similar blood pressure as PNx but less cardiac hypertrophy, diastolic dysfunction, and cardiac fibrosis. MBG induced increases in procollagen-1 expression by cultured cardiac fibroblasts at 1 nM concentration. These increases in procollagen expression were accompanied by increases in collagen translation and increases in procollagen-1 mRNA without any demonstrable increase in procollagen-1 protein stability. The stimulation of fibroblasts with MBG could be prevented by administration of inhibitors of tyrosine phosphorylation, Src activation, epidermal growth factor receptor transactivation, and N-acetyl cysteine. Based on these findings, we propose that MBG directly induces increases in collagen expression by fibroblasts, and we suggest that this may be important in the cardiac fibrosis seen with experimental renal failure. (Hypertension. 2007;49:215-224.)

The cardiotonic steroid marinobufagenin (MBG) has been implicated in the pathogenesis of experimental uremic cardiomyopathy, which is characterized by progressive cardiac fibrosis. We examined whether the transcription factor Friend leukemia integration-1 (Fli-1) might be involved in this process. Fli-1-knockdown mice demonstrated greater cardiac collagen-1 expression and fibrosis compared with wild-type mice; both developed increased cardiac collagen expression and fibrosis after 5/6 nephrectomy. There was a strong inverse relationship between the expressions of Fli-1 and procollagen in primary culture of rat cardiac and human dermal fibroblasts as well as a cell line derived from renal fibroblasts and MBG-induced decreases in nuclear Fli-1 as well as increases in procollagen-1 expression in these cells. Transfection of a Fli-1 expression vector prevented increased procollagen-1 expression from MBG. MBG exposure induced a rapid translocation of the δ-isoform of protein kinase C (PKCδ) to the nucleus. This translocation was prevented by pharmacological inhibition of phospholipase C, and MBG-induced increases in procollagen-1 expression were prevented with a PKCδ- but not a PKCα-specific inhibitor. Finally, immunoprecipitation studies strongly suggest that MBG induced phosphorylation of Fli-1. We feel these data support a causal relationship with MBG-induced translocation of PKCδ, which results in phosphorylation of as well as decreases in nuclear Fli-1 expression, which, in turn, leads to increases in collagen production. Should these findings be confirmed, we speculate that this pathway may represent a therapeutic target for uremic cardiomyopathy as well as other conditions associated with excessive fibrosis.

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Classically, phenytoin (PTN) infusion for the treatment of status epilepticus has been proven to be associated with cardiovascular toxicity, including dysrhythmias, hypotension, and cardiovascular collapse. Subsequently, fosphenytoin (FOS) was introduced on the market in 1997 with claims of having less cardiac toxicity. However, since then, many accounts of cardiac events have been reported undermining these claims. FOS gained popularity due to its water solubility, which allows 3 times faster infusion in comparison with PTN with less venous irritation and local toxicity. FOS is the phosphate ester prodrug of PTN and is rapidly converted to PTN independent of the dose and rate of administration. Intravenous FOS and PTN are bioequivalent. Adverse cardiac effects of both intravenous FOS and PTN have been correlated to the rate of infusion, concentration of the agent, known risk factors, or pre-existing hypersensitivity, and most cases have been identified after infusing a loading dose of these medications. This case report is unique, in that, the patient developed sinus arrest while concurrently receiving oral PTN and intravenous FOS. Clinicians should be more cognizant of the association of FOS and PTN with adverse cardiac events. Baseline electrocardiogram should be obtained on all patients prescribed FOS or PTN to identify underlying cardiac problems that may place the patient in a higher risk category. Telemetry should be performed on all patients receiving PTN in an inpatient setting.

BackgroundIn-training examination (ITE) has been used as a predictor of performance at the American Board of Internal Medicine (ABIM) certifying examination. ITE however may not be an ideal modality as it is held once a year and represents snapshots of performance as compared with a trend. We instituted monthly tests (MTs) to continually assess the performance of trainees throughout their residency.ObjectiveTo determine the predictors of ABIM performance and to assess whether the MTs can be used as a tool to predict passing the ABIM examination.MethodsThe MTs, core competencies, and ITE scores were analyzed for a cohort of graduates who appeared for the ABIM examination from 2010 to 2013. Logistic regression was performed to identify the predictors of a successful performance at the ABIM examination.ResultsFifty-one residents appeared for the ABIM examination between 2010 and 2013 with a pass rate of 84%. The MT score for the first year (odds ratio [OR] =1.302, CI =1.004–1.687, P=0.04) and second year (OR =1.125, CI =1.004–1.261, P=0.04) were independent predictors of ABIM performance along with the second-year ITE scores (OR =1.248, CI =1.096–1.420, P=0.001).ConclusionThe MT is a valuable tool to predict the performance at the ABIM examination. Not only it helps in the assessment of likelihood of passing the certification examination, it also helps to identify those residents who may require more assistance earlier during their residency. It may also highlight the areas of weakness in program curriculum and guide curriculum development.

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Background: Appropriate use criteria recommend against unwarranted cardiac catheterization (caths) in low risk patients. Reporting of risk stratification on non-invasive cardiac stress test reports was implemented at our institution to reduce low risk cardiac cath referrals. Methods: We performed a retrospective study to compare the effect of introduction of risk stratification in cardiac stress test reports. The percentages of low risk patients by nuclear stress, who underwent cardiac cath, before and after application of risk stratification were compared. Chi-square and Mann-Whitney-Wilcoxon tests were used for analysis. Results: There were significantly fewer low risk referrals after risk stratification, 43.2% of patients of low-risk patients were referred for catheterization before, compared to 28.3% of low-risk patients after risk stratification (p value 0.01). There was reduction in the percentage of normal cardiac caths in the low risk category after introduction of risk stratification (61.5% vs 33.3%, p value 0.05). Conclusion: Risk stratification led to a decrease in the percentage of low-risk patients referred for cath following a stress test.