Faculty Bibliography

Background: Obese adolescent with T2DM and /or pre diabetes demonstrate endothelial dysfunction (ED), a key early event in atherogenesis. Flow mediated dilatation (FMD) of the brachial artery is a well validated surrogate for ED. Traditional cardiovascular risk factors (BMI, LDL-cholesterol, systolic blood pressure and smoking) have a deleterious effect on the vasculature in adolescents. Objective and hypotheses: We proposed to delineate the relationship between glucose tolerance categories and ED in obese adolescents. Methods: 25 adolescents with a mean age of 15.7 +/- 1.5 years, BMI 35+/- 6 (60% female and Hispanic) underwent a 75 gram oral glucose tolerance test (OGTT). Duplex ultrasound (11MHz transducer) measured endothelium dependent vasodilatation. Reference range in our vascular lab for FMD is 5.89+/- 2.88% (95% CI: 4.53- 7.23). Results: Based on OGTT results: 16 subjects had normal glucose tolerance (NGT: fasting glucose <= 99 mg/dl and/ or 2 hour post challenge glucose <= 139 mg/dl) and 6 subjects were diagnosed with pre diabetes(fasting glucose>= 100 and/ or 2 hour post challenge glucose >= 140 mg/dl). Adolescents with T2DM (n= 3) had lower FMD (3.2+/- 2.8%) compared to adolescents with NGT (6.5+/- 5.08%) and of those with NGT; five had an impaired FMD (<= 5.8%). Adolescents with pre diabetes had FMD values (9.8+/- 3.08%) higher than NGT group, though differences between the glucose tolerance categories did not reach statistical significance (NGT vs. pre diabetes vs. T2DM, p= 0.26). FMD did not correlate with CVS risk factors in these adolescents. In adolescents with NGT, FMD was negatively correlated with 2 hour glucose (r= -0.6, p= 0.03). Conclusions: Adolescents with prediabetes compared to those with T2DM appear to have preserved endothelium dependent vasodilatation. In adolescents with NGT, lower FMD predicts impaired glucose tolerance and accelerated vascular dysfunction. CVS risk factors did not appear to affect FMD in these obese adolescents

BACKGROUND: The incidence and predictors of heart failure (HF) after myocardial infarction (MI) with modern post-MI treatment have not been well characterized. METHODS AND RESULTS: A total of 2,201 stable patients with persistent infarct-related artery occlusion >24 hours after MI with left ventricular ejection fraction <50% and/or proximal coronary artery occlusion were randomized to percutaneous intervention plus optimal medical therapy (PCI) or optimal medical therapy (MED) alone. Centrally adjudicated HF hospitalizations for New York Heart Association (NYHA) III/IV HF and mortality were determined in patients with and without baseline HF, defined as a history of HF, Killip Class >I at index MI, rales, S3 gallop, NYHA II at randomization, or NYHA >I before index MI. Long-term follow-up data were used to determine 7-year life-table estimated event rates and hazard ratios. There were 150 adjudicated HF hospitalizations during a mean follow-up of 6 years with no difference between the randomized groups (7.4% PCI vs. 7.5% MED, P = .97). Adjudicated HF hospitalization was associated with subsequent death (44.0% vs. 13.1%, HR 3.31, 99% CI 2.21-4.92, P < .001). Baseline HF (present in 32% of patients) increased the risk of adjudicated HF hospitalization (13.6% vs. 4.7%, HR 3.43, 99% CI 2.23-5.26, P < .001) and death (24.7% vs. 10.8%, HR 2.31, 99% CI 1.71-3.10, P < .001). CONCLUSIONS: In the overall Occluded Artery Trial (OAT) population, adjudicated HF hospitalizations occurred in 7.5% of subjects and were associated with increased risk of subsequent death. Baseline or prior HF was common in the OAT population and was associated with increased risk of hospitalization and death.

Interaction of estrogen with iron at the systemic level is long suspected, but direct evidence linking the two is limited. In the present study, we examined the effects of 17beta-estradiol (E2) on hepcidin, a key negative regulator of iron absorption from the liver. We found that transcription of hepcidin was suppressed by E2 treatment in human liver HuH7 and HepG2 cells, and this down-regulation was blocked by E2 antagonist ICI 182780. Chromatin immunoprecipitation, deletion, and EMSA detected a functional estrogen responsive element half-site that is located between -2474 and -2462 upstream from the start of transcription of the hepcidin gene. After cloning the human hepcidin promoter into the pGL3Luc-Reporter vector, luciferase activity was also down-regulated by E2 treatment in HepG2 cells. E2 reduced hepcidin mRNA in wild-type mice as well as in hemochromatosis Fe gene knockout mice. In summary, our data suggest that hepcidin inhibition by E2 is to increase iron uptake, a mechanism to compensate iron loss during menstruation. This mechanism may also contribute to increased iron stores in oral contraceptive users.

BACKGROUND: Heart failure is among the most common reasons for hospitalizations in the United States. Recent data from Medicare suggest that the number of hospitalizations with a primary diagnosis of heart failure has declined over the past decade. However, heart failure may increase hospitalization rates for related comorbidities and individuals with heart failure are commonly admitted for other reasons. Using a nationally representative sample of hospital admissions, we studied trends in hospitalizations with both a primary and a secondary diagnosis of heart failure. METHODS: We evaluated trends in heart failure hospitalizations from 2001 to 2009 using the Nationwide Inpatient Sample (NIS), the largest all-payer inpatient database in the United States. We included hospitalizations with an International Classification of Diseases, Ninth Revision discharge diagnosis codes of 402.X1, 404.X1, 404.X3, 428.XX in any position; these codes in the primary position are used by The Centers for Medicare & Medicaid Services for reporting heart failure quality measures. Admissions were categorized as either primary heart failure hospitalization, if heart failure was the primary discharge code, or heart failure associated hospitalization, if heart failure was listed as a secondary diagnosis. National estimates of heart failure hospitalizations were calculated using the sampling weights and stratified sample design of the NIS. Yearly hospitalization rateswere determined by dividing the number of hospitalizations by the United States population in a given year. Population estimates were obtained from the United States Census Bureau. RESULTS: The total number of heart failure hospitalizations in the United States increased from 3,900,305 in 2001 to 4,398,376 in 2006 and then decreased to 4,253,937 in 2009. The number of primary heart failure admissions decreased from 1,139,607 in 2001 to 1,087,913 in 2009, while the number of heart failure associated hospitalizations increased from 2,760,698 to 3,166,024 over !

Aldosterone antagonists (or mineralocorticoid receptor antagonists [MRAs]) are guideline-recommended therapy for patients with moderate to severe heart failure (HF) symptoms and reduced left ventricular ejection fraction (LVEF), and in postmyocardial infarction patients with HF. The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) trial evaluated the MRA eplerenone in patients with mild HF symptoms. Eplerenone reduced the risk of the primary endpoint of cardiovascular death or HF hospitalization (hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.54-0.74, P < .001) and all-cause mortality (adjusted HR 0.76, 95% CI 0.62-0.93, P < .008) after a median of 21 months. Based on EMPHASIS-HF, an MRA is recommended for patients with New York Heart Association (NYHA) Class II-IV symptoms and reduced LVEF (<35%) on standard therapy (Strength of Evidence A). Patients with NYHA Class II symptoms should have another high-risk feature to be consistent with the EMPHASIS-HF population (age >55 years, QRS duration >130 msec [if LVEF between 31% and 35%], HF hospitalization within 6 months or elevated B-type natriuretic peptide level). Renal function and serum potassium should be closely monitored. Dose selection should consider renal function, baseline potassium, and concomitant drug interactions. The efficacy of eplerenone in patients with mild HF symptoms translates into a unique opportunity to reduce morbidity and mortality earlier in the course of the disease.