Faculty Bibliography

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 !

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.

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.

Cardiac resynchronization therapy (CRT) improves survival, symptoms, quality of life, exercise capacity, and cardiac structure and function in patients with New York Heart Association (NYHA) functional class II or ambulatory class IV heart failure (HF) with wide QRS complex. The totality of evidence supports the use of CRT in patients with less severe HF symptoms. CRT is recommended for patients in sinus rhythm with a widened QRS interval (>/=150 ms) not due to right bundle branch block (RBBB) who have severe left ventricular (LV) systolic dysfunction and persistent NYHA functional class II-III symptoms despite optimal medical therapy (strength of evidence A). CRT may be considered for several other patient groups for whom evidence of benefit is clinically significant but less substantial, including patients with a QRS interval of >/=120 to <150 ms and severe LV systolic dysfunction who have persistent mild to severe HF despite optimal medical therapy (strength of evidence B), some patients with atrial fibrillation, and some with ambulatory class IV HF. Several evidence gaps remain that need to be addressed, including the ideal threshold for QRS duration, QRS morphology, lead placement, degree of myocardial scarring, and the modality for evaluating dyssynchrony. Recommendations will evolve over time as additional data emerge from completed and ongoing clinical trials.

OBJECTIVE:To characterize acute (postprandial) and chronic (after a 6-month period of weight loss) effects of a low-carbohydrate vs. a low-fat diet on subclinical markers of cardiovascular disease (CVD) in adults with type 2 diabetes. DESIGN/METHODS:At baseline and 6 months, measures of C-reactive protein (CRP), interleukin-6 (IL-6), soluble intercellular adhesion molecule (sICAM) and soluble E-selectin were obtained from archived samples (n = 51) of participants randomized in a clinical trial comparing a low-carbohydrate and a low-fat diet. In a subset of participants (n = 27), postprandial measures of these markers were obtained 3 h after a low-carbohydrate or low-fat liquid meal. Endothelial function was also measured by reactive hyperemic peripheral arterial tonometry during the meal test. Paired t tests and unpaired t tests compared within- and between-group changes. RESULTS:There were no significant differences observed in postprandial measures of inflammation or endothelial function. After 6 months, CRP (mean ± S.E.) decreased in the low-fat arm from 4.0 ± 0.77 to 3.0 ± 0.77 (P = .01). In the low-carbohydrate arm, sICAM decreased from 234 ± 22 to 199 ± 23 (P = .001), and soluble E-selectin decreased from 93 ± 10 to 82 ± 10 (P = .05.) A significant correlation between change in high-density lipoprotein and change in soluble E-selectin (r = -0.33, P = .04) and with the change in ICAM (r = -0.43, P = .01) was observed. CONCLUSIONS:Low-carbohydrate and low-fat diets both have beneficial effects on CVD markers. There may be different mechanisms through which weight loss with these diets potentially reduces CVD risk.