Effects of eplerenone on markers of myocardial fibrosis, 6-minute walk distance, and quality of life in adults with tetralogy of Fallot and complete transposition of the great arteries.

Ventricular dysfunction is common among patients with repaired cyanotic congenital heart disease. To date, no pharmacologic intervention has been demonstrated to be beneficial in this setting. To begin addressing this knowledge gap, we conducted a single-center prospective, randomized, open-label pilot study to investigate the effects of eplerenone on serologic markers of collagen turnover and inflammation, 6-minute walk distance, and quality of life in patients with tetralogy of Fallot (TOF) or transposition of the great arteries with a systemic right ventricle (transposition of the great arteries [TGA]). Patients were randomized to a 3-month drug-free period at the beginning of the treatment period or at the end. All patients received 12 months of eplerenone therapy during the treatment period. Twenty-six patients were enrolled in the trial; 17 completed the study protocol: 8 with TOF and 9 with TGV. Eplerenone had no effect on serum levels of procollagen 1 N-terminal peptide (PINP), procollagen 3 N-terminal peptide (PIIINP), or galectin-3 (G3). Similarly, eplerenone had no effect on 6-minute walk distance or quality of life. In conclusion, PINP and PIIINP levels are as high as or higher in patients with TOF and TGA than in patients with normal cardiac anatomy and heart failure, whereas G3 levels are lower. Eplerenone is well tolerated by adults born with congenital heart disease.

Health Care Costs After Cardiac Arrest in the United States.

BACKGROUND: This study was designed to estimate the costs of index hospitalizations after cardiac arrest in the United States. METHODS AND RESULTS: We used the US Nationwide Inpatient Sample (2003-2012) to identify patients with cardiac arrest. Log transformation of inflation-adjusted cost was determined for care to patient outcomes. Overall, an estimated 1 387 396 patients were hospitalized after cardiac arrest. The mean age of the cohort was 66 years, 45% were women, and the majority were white. Inpatient procedures included coronary angiography (15%), percutaneous coronary intervention (7%), intra-aortic balloon pump (4.4%), therapeutic hypothermia (1.1%), and mechanical circulatory support (0.1%). The rates of therapeutic hypothermia increased from zero in 2003 to 2.7% in 2012 (P<0.001). Both hospital charges and inflation-adjusted cost increased linearly over time. In a multivariate analysis, predictors of inflation-adjusted cost included large hospital size, urban teaching hospital, and length of stay. Among comorbidities, atrial fibrillation or fluid and electrolytes imbalance was most associated with cost. Among selected interventions, the cost was significantly increased with automatic implantable cardioverter defibrillators (odds ratio, 1.83; P<0.001), intra-aortic balloon pump (odds ratio, 1.50; P<0.001), hypothermia (odds ratio, 1.28; P<0.001), and extracorporeal membrane oxygenation (odds ratio, 2.38; P<0.001). CONCLUSIONS: In the period between 2003 and 2012, postcardiac arrest hospitalizations resulted in a steady rise in associated health care cost, likely related to increased length of stay, medical procedures, and systems of care. Although targeted cost containment for postarrest interventions may reduce the finance burden, there is an increasing need for funding research into prediction and prevention of cardiac arrest, which offers greater societal benefit.

Murine versus human apolipoprotein E4: differential facilitation of and co-localization in cerebral amyloid angiopathy and amyloid plaques in APP transgenic mouse models.

INTRODUCTION: Amyloid ß (Aß) accumulates in the extracellular space as diffuse and neuritic plaques in Alzheimer's disease (AD). Aß also deposits on the walls of arterioles as cerebral amyloid angiopathy (CAA) in most cases of AD and sometimes independently of AD. Apolipoprotein E (apoE) ɛ4 is associated with increases in both Aß plaques and CAA in humans. Studies in mouse models that develop Aß deposition have shown that murine apoE and human apoE4 have different abilities to facilitate plaque or CAA formation when studied independently. To better understand and compare the effects of murine apoE and human apoE4, we bred 5XFAD (line 7031) transgenic mice so that they expressed one copy of murine apoE and one copy of human apoE4 under the control of the normal murine apoE regulatory elements (5XFAD/apoE(m/4)). RESULTS: The 5XFAD/apoE(m/4) mice contained levels of parenchymal CAA that were intermediate between 5XFAD/apoE(m/m) and 5XFAD/apoE(4/4) mice. In 5XFAD/apoE(m/4) mice, we found that Aß parenchymal plaques co-localized with much more apoE than did parenchymal CAA, suggesting differential co-aggregation of apoE with Aß in plaques versus CAA. More importantly, within the brain parenchyma of the 5XFAD/apoE(m/4) mice, plaques contained more murine apoE, which on its own results in more pronounced and earlier plaque formation, while CAA contained more human apoE4 which on its own results in more pronounced CAA formation. We further confirmed the co-aggregation of mouse apoE with Aß in plaques by showing a strong correlation between insoluble mouse apoE and insoluble Aß in PS1APP-21/apoE(m/4) mice which develop plaques without CAA. CONCLUSIONS: These studies suggest that both murine apoE and human apoE4 facilitate differential opposing effects in influencing Aß plaques versus CAA via different co-aggregation with these two amyloid lesions and set the stage for understanding these effects at a molecular level.

Effects of growth hormone-releasing hormone on sleep and brain interstitial fluid amyloid-ß in an APP transgenic mouse model.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by impairment of cognitive function, extracellular amyloid plaques, intracellular neurofibrillary tangles, and synaptic and neuronal loss. There is substantial evidence that the aggregation of amyloid ß (Aß) in the brain plays a key role in the pathogenesis of AD and that Aß aggregation is a concentration dependent process. Recently, it was found that Aß levels in the brain interstitial fluid (ISF) are regulated by the sleep-wake cycle in both humans and mice; ISF Aß is higher during wakefulness and lower during sleep. Intracerebroventricular infusion of orexin increased wakefulness and ISF Aß levels, and chronic sleep deprivation significantly increased Aß plaque formation in amyloid precursor protein transgenic (APP) mice. Growth hormone-releasing hormone (GHRH) is a well-documented sleep regulatory substance which promotes non-rapid eye movement sleep. GHRHR(lit/lit) mice that lack functional GHRH receptor have shorter sleep duration and longer wakefulness during light periods. The current study was undertaken to determine whether manipulating sleep by interfering with GHRH signaling affects brain ISF Aß levels in APPswe/PS1ΔE9 (PS1APP) transgenic mice that overexpress mutant forms of APP and PSEN1 that cause autosomal dominant AD. We found that intraperitoneal injection of GHRH at dark onset increased sleep and decreased ISF Aß and that delivery of a GHRH antagonist via reverse-microdialysis suppressed sleep and increased ISF Aß. The diurnal fluctuation of ISF Aß in PS1APP/GHRHR(lit/lit) mice was significantly smaller than that in PS1APP/GHRHR(lit/+) mice. However despite decreased sleep in GHRHR deficient mice, this was not associated with an increase in Aß accumulation later in life. One of several possibilities for the finding is the fact that GHRHR deficient mice have GHRH-dependent but sleep-independent factors which protect against Aß deposition.

Anti-ApoE antibody given after plaque onset decreases Aß accumulation and improves brain function in a mouse model of Aß amyloidosis.

Apolipoprotein E (apoE) is the strongest known genetic risk factor for late onset Alzheimer's disease (AD). It influences amyloid-ß (Aß) clearance and aggregation, which likely contributes in large part to its role in AD pathogenesis. We recently found that HJ6.3, a monoclonal antibody against apoE, significantly reduced Aß plaque load when given to APPswe/PS1ΔE9 (APP/PS1) mice starting before the onset of plaque deposition. To determine whether the anti-apoE antibody HJ6.3 affects Aß plaques, neuronal network function, and behavior in APP/PS1 mice after plaque onset, we administered HJ6.3 (10 mg/kg/week) or PBS intraperitoneally to 7-month-old APP/PS1 mice for 21 weeks. HJ6.3 mildly improved spatial learning performance in the water maze, restored resting-state functional connectivity, and modestly reduced brain Aß plaque load. There was no effect of HJ6.3 on total plasma cholesterol or cerebral amyloid angiopathy. To investigate the underlying mechanisms of anti-apoE immunotherapy, HJ6.3 was applied to the brain cortical surface and amyloid deposition was followed over 2 weeks using in vivo imaging. Acute exposure to HJ6.3 affected the course of amyloid deposition in that it prevented the formation of new amyloid deposits, limited their growth, and was associated with occasional clearance of plaques, a process likely associated with direct binding to amyloid aggregates. Topical application of HJ6.3 for only 14 d also decreased the density of amyloid plaques assessed postmortem. Collectively, these studies suggest that anti-apoE antibodies have therapeutic potential when given before or after the onset of Aß pathology.