Effects of Perinatal Stroke on Executive Functioning and Mathematics Performance in Children.

The goal of this study was to examine executive functioning, math performance, and visuospatial processing skills of children with perinatal stroke, which have not been well explored in this population. Participants included 18 children with perinatal stroke (aged 6-16 years old) and their primary caregiver. Each child completed standardized tests of executive function and visuospatial processing skills, Intelligence Quotient (IQ), and math achievement. Performance on executive function, IQ, math, and visuospatial processing tests was significantly lower in children with perinatal stroke when compared to normative means. Poorer inhibitory control was associated with worse math performance. Increased age at testing was associated with better performance on visuospatial ability (using standardized scores), and females performed better than males on a test of inhibitory control. Children with perinatal stroke displayed a range of neuropsychological impairments, and difficulties with executive function (inhibition) may contribute to math difficulties in this population.

Learning and memory profiles in youth with perinatal stroke: a study of the Child and Adolescent Memory Profile (ChAMP).

There is limited understanding of the effect of perinatal stroke on child and adolescent learning and memory abilities. This study sought to evaluate the clinical utility of the Child and Adolescent Memory Profile (ChAMP) in quantifying memory performance in youth with perinatal stroke. Children and adolescents aged 6-16 years old with a history of perinatal stroke (PS; n = 41) completed two subtests from the ChAMP (Lists and Objects). Age, sex, and ethnicity-matched healthy control (HC) data were obtained from the test publisher's standardization data set. Participants with a history of PS performed significantly worse (p < .05) with medium effect size (ƞp2 ≥ .06) than HC on the ChAMP Screening Index and on all ChAMP Lists and Objects scaled scores. Classification accuracy for the ChAMP scores ranged from 57% to 68% with the area under the curve ranging from .62-.75. No significant group differences on ChAMP performance (p > .05) were found for stroke side (left versus right-sided) or for seizure history (present versus absent). This study supports the utility of the ChAMP in perinatal stroke patients by demonstrating significantly worse performance in verbal and visual memory than HC. Classification accuracy is limited, but supportive for the Screening Index and Objects Delayed scores. The ChAMP may be a useful tool for evaluating cognition in this population when taken alongside the context of other tests, background history, and clinical observations.

Executive behavior and functional abilities in children with perinatal stroke and the associated caregiver impact.

Perinatal stroke is the most common form of stroke in childhood and is followed by a variety of outcomes, with many children experiencing specific functional and neuropsychological deficits. The association of these outcomes with the psychosocial impact caregivers face is not well documented. The goal of our pilot study was to examine caregivers' perception of executive behavior and functional abilities among children with perinatal stroke, and how these outcomes impact the caregivers. We administered three questionnaires to primary caregivers of children with perinatal stroke to obtain caregiver-reported measures of (1) executive behavior of their child (Behavior Rating Inventory of Executive Function, Second Edition), (2) the functional abilities of their child (Pediatric Evaluation of Disability Inventory Computer Adaptive Test), and (3) the psychosocial impact experienced by the caregiver themselves (Parental Outcome Measure). Participants included 20 children (mean age = 9.3 years, range = 6-16 years) with perinatal stroke and their primary caregivers. Functional abilities in the children were rated as clinically impaired in the domains of daily activities and mobility. Half of the children exhibited clinically impaired ratings on at least one executive behavior domain, but the mean scores for these domains did not reach clinically impaired levels. Greater ratings of problems in daily activities for the child was associated with greater caregiver guilt (r = -0.55, p = 0.02). Caregivers of children with perinatal stroke who experience limitations in performing daily activities should be more closely monitored for adverse impact and be provided the necessary support and education to alleviate the associated guilt.

Maternal Metabolic Complications in Pregnancy and Offspring Behavior Problems at 2 Years of Age.

Objectives Prenatal maternal metabolic problems such as pre-pregnancy adiposity, excess gestational weight gain, and gestational diabetes mellitus (GDM) are associated with an increased risk of psychopathology in offspring. We examined whether these exposures were linked to symptoms of emotional and behavioral problems in offspring at 2 years of age, or if associations were due to confounding variables. Methods Data from 815 mother-child pairs enrolled at the Edmonton site of the Canadian Healthy Infant Longitudinal Development cohort were used to examine associations between gestational metabolic complications and scores on the externalizing and internalizing scales of the Child Behavior Checklist (CBCL-1½ to 5) at age two. Associations between maternal metabolic complications and offspring psychopathology were assessed before and after adjustment for gestational diet, socioeconomic status (SES), postpartum depression (PPD), prenatal smoking and breastfeeding. Results Pre-pregnancy body mass index and GDM, but not gestational weight gain, predicted more offspring externalizing and internalizing problems. However, after adjustment for confounding variables, these associations were no longer statistically significant. Post-hoc analyses revealed that gestational diet accounted for unique variance in both externalizing (semi-partial rdiet = - 0.20, p < 0.001) and internalizing (semi-partial rdiet = - 0.16, p = 0.01) problems. PPD and SES also accounted for a similar amount of variance for both externalizing (semi-partial rPPD = 0.17, p < 0.001; rses = - 0.11, p = 0.03) and internalizing problems (semi-partial rPPD = 0.21, p < 0.001; rses = - 0.14, p = 0.004). Conclusions for Practice Since the confounding effect of gestational diet persisted after adjustment for, and was similar in magnitude to, SES and PPD, future research should consider the impact of unhealthy prenatal diets on offspring neurodevelopment.

Shorter sleep duration is associated with reduced cognitive development at two years of age.

BACKGROUND: Both short sleep duration and sleep-disordered breathing (SDB) are associated with poor neurocognitive development. However, the co-contributions of short sleep duration and SDB on neurodevelopment in pre-school children are relatively unknown. METHODS: We assessed both sleep duration and SDB by quarterly questionnaire from three months to two years of age among Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort participants. Group-based modeling determined trajectories of total, daytime, and nighttime sleep duration and SDB. Linear regression was used to assess the impact of sleep duration and SDB trajectories on cognitive (primary outcome) and language (secondary) development at two years of age as assessed by the Bayley Scale of Infant Development (BSID-III) (mean 100; standard deviation of 15). RESULTS: Of the 822 CHILD Edmonton participants, 703 (86%) were still enrolled at two years of age with 593 having BSID-III data at two years of age. Trajectory analysis identified four total sleep durations phenotypes [short sleepers (17.9%), decline to short sleepers (21.1%), intermediate sleepers (36.9%) and long sleepers (24.1%)]. Compared to children with intermediate sleep durations, short sleepers had a 5.2-point lower cognitive development score at two years of age [standard error (SE) 1.7; p = 0.002]. Nocturnal sleep duration, compared to daytime sleep duration had the greatest effect on cognitive development. We also identified three SDB symptom trajectories [early-onset SDB (15.7%), late-onset SDB (14.2%), and persistent SDB (5.3%)] and 79.5% of children had no SDB symptoms. Children with persistent SDB also had a 5.3-point lower language score (SE 2.7; p = 0.05) compared to children with no SDB. SDB trajectories were not associated with cognitive development. CONCLUSION: In a population-representative birth cohort study, both short sleep duration and SDB were associated with adverse neurodevelopment at two years of age. Children with short nighttime sleep duration had lowered cognitive and language scores and children with persistent SDB also had lower language scores.

Phenotypes of sleep-disordered breathing symptoms to two years of age based on age of onset and duration of symptoms.

OBJECTIVE: Childhood sleep-disordered breathing (SDB) symptoms may comprise multiple phenotypes depending on craniofacial anatomy, tonsil and adenoid growth, body habitus, and rhinitis symptoms. The primary objective of this study is to identify and characterize the different SDB phenotypes to two years of age. METHODS: Data from 770 infants in the Edmonton sub-cohort of the Canadian Healthy Infant Longitudinal Study (CHILD) were analyzed to identify SDB phenotypes based on age of onset and duration of symptoms. Parents completed the 22-item sleep-related breathing disorder (SRBD) scale. Children with a SRBD ratio greater than 0.33 were considered positive for SDB at each quarterly assessment between three months and two years. The STATA Proc trajectory extension identified SDB phenotypes based on their age of onset and duration of symptoms and attributed the percentage chance of a participant being assigned to each phenotype. Multivariate linear regression identified factors associated with increased risk of being assigned to each SDB phenotype. RESULTS: Trajectory analysis identified four phenotypes: no SDB (65.7%), early-onset SDB (15.7%) with peak symptoms at nine months, late-onset SDB (14.2%) with peak symptoms at 18 months, and persistent SDB (5.3%) with symptoms from 3 to 24 months. Rhinitis was associated with all three SDB symptom trajectories (p < 0.05). Children with gastroesophageal reflux disease presented with early (p = 0.03) and late SDB (p < 0.001). Maternal obstructive sleep apnea syndrome (OSAS) was associated with persistent (p = 0.01) and late SDB (p < 0.001). Atopy (positive skin prick test at one year) was associated with persistent SDB (p = 0.04). Infants born prior to 36.5 weeks gestational age were more likely to present with late SDB (p = 0.03). CONCLUSION: Childhood SDB symptoms, rather than being a homogenous disorder, may comprise multiple overlapping phenotypes each with unique risk factors.

Parent-Reported Symptoms of Sleep-Disordered Breathing Are Associated With Increased Behavioral Problems at 2 Years of Age: The Canadian Healthy Infant Longitudinal Development Birth Cohort Study.

Study Objectives: To examine the association between the age of onset and duration of parent-reported symptoms of sleep-disordered breathing (SDB) and behavioral problems at age 2. Methods: Parent-reported SDB symptoms were assessed quarterly between 3 months and 2 years among 583 Canadian Healthy Infant Longitudinal Development Edmonton-site participants. Parent-reported SDB symptoms were clustered into phenotypes using group-based trajectory analysis based on age of onset and duration of symptoms. Home-based polysomnography (PSG) was completed at 1 year. The Child Behavior Checklist preschool-version (Mean T-score 50, standard deviation 10 points) assessed total, externalizing (attention), and internalizing (anxiety, depression) behaviors at 2 years. Results: Four phenotypes were identified: no SDB (64.7%), early-onset SDB (15.7%, peak symptoms at 9 months), late-onset (14.2%, peak symptoms at 18 months), and persistent SDB symptoms (5.3%, peak symptoms from 3 through 24 months). Persistent SDB (9.5 points, 95% CI 1.7, 17.2; p = .02) predicted the greatest magnitude of effect of total behavior problems, compared with children without SDB. Children with early-onset SDB (3.5 points, 95% CI 1.6, 5.4; p ≤ .001) and late-onset SDB (6.1 points 95% CI 4.0, 8.3; p ≤ .001) had increased total behavioral problems than children without SDB to 2 years. Additional analyses showed that the SDB phenotypes' trajectories were important for internalizing but not for externalizing behavior problems. There were no significant associations between home-PSG and parent-reported behavior problems. Conclusions: Findings suggest that the age of onset and duration of parent-reported SDB symptoms prior to age 2 have adverse consequences for overall behavior problems.

A KCNC3 mutation causes a neurodevelopmental, non-progressive SCA13 subtype associated with dominant negative effects and aberrant EGFR trafficking.

The autosomal dominant spinocerebellar ataxias (SCAs) are a diverse group of neurological disorders anchored by the phenotypes of motor incoordination and cerebellar atrophy. Disease heterogeneity is appreciated through varying comorbidities: dysarthria, dysphagia, oculomotor and/or retinal abnormalities, motor neuron pathology, epilepsy, cognitive impairment, autonomic dysfunction, and psychiatric manifestations. Our study focuses on SCA13, which is caused by several allelic variants in the voltage-gated potassium channel KCNC3 (Kv3.3). We detail the clinical phenotype of four SCA13 kindreds that confirm causation of the KCNC3R423H allele. The heralding features demonstrate congenital onset with non-progressive, neurodevelopmental cerebellar hypoplasia and lifetime improvement in motor and cognitive function that implicate compensatory neural mechanisms. Targeted expression of human KCNC3R423H in Drosophila triggers aberrant wing veins, maldeveloped eyes, and fused ommatidia consistent with the neurodevelopmental presentation of patients. Furthermore, human KCNC3R423H expression in mammalian cells results in altered glycosylation and aberrant retention of the channel in anterograde and/or endosomal vesicles. Confirmation of the absence of plasma membrane targeting was based on the loss of current conductance in cells expressing the mutant channel. Mechanistically, genetic studies in Drosophila, along with cellular and biophysical studies in mammalian systems, demonstrate the dominant negative effect exerted by the mutant on the wild-type (WT) protein, which explains dominant inheritance. We demonstrate that ocular co-expression of KCNC3R423H with Drosophila epidermal growth factor receptor (dEgfr) results in striking rescue of the eye phenotype, whereas KCNC3R423H expression in mammalian cells results in aberrant intracellular retention of human epidermal growth factor receptor (EGFR). Together, these results indicate that the neurodevelopmental consequences of KCNC3R423H may be mediated through indirect effects on EGFR signaling in the developing cerebellum. Our results therefore confirm the KCNC3R423H allele as causative for SCA13, through a dominant negative effect on KCNC3WT and links with EGFR that account for dominant inheritance, congenital onset, and disease pathology.

Cognitive Enhancement in Infants Associated with Increased Maternal Fruit Intake During Pregnancy: Results from a Birth Cohort Study with Validation in an Animal Model.

In-utero nutrition is an under-studied aspect of cognitive development. Fruit has been an important dietary constituent for early hominins and humans. Among 808 eligible CHILD-Edmonton sub-cohort subjects, 688 (85%) had 1-year cognitive outcome data. We found that each maternal daily serving of fruit (sum of fruit plus 100% fruit juice) consumed during pregnancy was associated with a 2.38 point increase in 1-year cognitive development (95% CI 0.39, 4.37; p<0.05). Consistent with this, we found 30% higher learning Performance index (PI) scores in Drosophila offspring from parents who consumed 30% fruit juice supplementation prenatally (PI: 85.7; SE 1.8; p<0.05) compared to the offspring of standard diet parents (PI: 65.0 SE 3.4). Using the Drosophila model, we also show that the cyclic adenylate monophosphate (cAMP) pathway may be a major regulator of this effect, as prenatal fruit associated cognitive enhancement was blocked in Drosophila rutabaga mutants with reduced Ca(2+)-Calmodulin-dependent adenylyl cyclase. Moreover, gestation is a critical time for this effect as postnatal fruit intake did not enhance cognitive performance in either humans or Drosophila. Our study supports increased fruit consumption during pregnancy with significant increases in infant cognitive performance. Validation in Drosophila helps control for potential participant bias or unmeasured confounders.

Visuospatial Working Memory Capacity Predicts Physiological Arousal in a Narrative Task.

Physiological arousal that occurs during narrative production is thought to reflect emotional processing and cognitive effort (Bar-Haim et al. in Dev Psychobiol 44:238-249, 2004). The purpose of this study was to determine whether individual differences in visuospatial working memory and/or verbal working memory capacity predict physiological arousal in a narrative task. Visuospatial working memory was a significant predictor of skin conductance level (SCL); verbal working memory was not. When visuospatial working memory interference was imposed, visuospatial working memory was no longer a significant predictor of SCL. Visuospatial interference also resulted in a significant reduction in SCL. Furthermore, listener ratings of narrative quality were contingent upon the visuospatial working memory resources of the narrator. Potential implications for educators and clinical practitioners are discussed.

Cholestenoic acid, an endogenous cholesterol metabolite, is a potent γ-secretase modulator.

BACKGROUND: Amyloid-ß (Aß) 42 has been implicated as the initiating molecule in the pathogenesis of Alzheimer's disease (AD); thus, therapeutic strategies that target Aß42 are of great interest. γ-Secretase modulators (GSMs) are small molecules that selectively decrease Aß42. We have previously reported that many acidic steroids are GSMs with potencies ranging in the low to mid micromolar concentration with 5ß-cholanic acid being the most potent steroid identified GSM with half maximal effective concentration (EC50) of 5.7 µM. RESULTS: We find that the endogenous cholesterol metabolite, 3ß-hydroxy-5-cholestenoic acid (CA), is a steroid GSM with enhanced potency (EC50 of 250 nM) relative to 5ß-cholanic acid. CA i) is found in human plasma at ~100-300 nM concentrations ii) has the typical acidic GSM signature of decreasing Aß42 and increasing Aß38 levels iii) is active in in vitro γ-secretase assay iv) is made in the brain. To test if CA acts as an endogenous GSM, we used Cyp27a1 knockout (Cyp27a1-/-) and Cyp7b1 knockout (Cyp7b1-/-) mice to investigate if manipulation of cholesterol metabolism pathways relevant to CA formation would affect brain Aß42 levels. Our data show that Cyp27a1-/- had increased brain Aß42, whereas Cyp7b1-/- mice had decreased brain Aß42 levels; however, peripheral dosing of up to 100 mg/kg CA did not affect brain Aß levels. Structure-activity relationship (SAR) studies with multiple known and novel CA analogs studies failed to reveal CA analogs with increased potency. CONCLUSION: These data suggest that CA may act as an endogenous GSM within the brain. Although it is conceptually attractive to try and increase the levels of CA in the brain for prevention of AD, our data suggest that this will not be easily accomplished.

The stress response neuropeptide CRF increases amyloid-ß production by regulating γ-secretase activity.

The biological underpinnings linking stress to Alzheimer's disease (AD) risk are poorly understood. We investigated how corticotrophin releasing factor (CRF), a critical stress response mediator, influences amyloid-ß (Aß) production. In cells, CRF treatment increases Aß production and triggers CRF receptor 1 (CRFR1) and γ-secretase internalization. Co-immunoprecipitation studies establish that γ-secretase associates with CRFR1; this is mediated by ß-arrestin binding motifs. Additionally, CRFR1 and γ-secretase co-localize in lipid raft fractions, with increased γ-secretase accumulation upon CRF treatment. CRF treatment also increases γ-secretase activity in vitro, revealing a second, receptor-independent mechanism of action. CRF is the first endogenous neuropeptide that can be shown to directly modulate γ-secretase activity. Unexpectedly, CRFR1 antagonists also increased Aß. These data collectively link CRF to increased Aß through γ-secretase and provide mechanistic insight into how stress may increase AD risk. They also suggest that direct targeting of CRF might be necessary to effectively modulate this pathway for therapeutic benefit in AD, as CRFR1 antagonists increase Aß and in some cases preferentially increase Aß42 via complex effects on γ-secretase.

Comment on "ApoE-directed therapeutics rapidly clear ß-amyloid and reverse deficits in AD mouse models".

Cramer et al. (Reports, 23 March 2012, p. 1503; published online 9 February 2012) demonstrates short-term bexarotene treatment clearing preexisting ß-amyloid deposits from the brains of APP/PS1ΔE9 mice with low amyloid burden, providing a rationale for repurposing this anticancer agent as an Alzheimer's disease (AD) therapeutic. Using a nearly identical treatment regimen, we were unable to detect any evidence of drug efficacy despite demonstration of target engagement.

Now you see it, now you don't: on emotion, context, and the algorithmic prediction of human imageability judgments.

Many studies have shown that behavioral measures are affected by manipulating the imageability of words. Though imageability is usually measured by human judgment, little is known about what factors underlie those judgments. We demonstrate that imageability judgments can be largely or entirely accounted for by two computable measures that have previously been associated with imageability, the size and density of a word's context and the emotional associations of the word. We outline an algorithmic method for predicting imageability judgments using co-occurrence distances in a large corpus. Our computed judgments account for 58% of the variance in a set of nearly two thousand imageability judgments, for words that span the entire range of imageability. The two factors account for 43% of the variance in lexical decision reaction times (LDRTs) that is attributable to imageability in a large database of 3697 LDRTs spanning the range of imageability. We document variances in the distribution of our measures across the range of imageability that suggest that they will account for more variance at the extremes, from which most imageability-manipulating stimulus sets are drawn. The two predictors account for 100% of the variance that is attributable to imageability in newly-collected LDRTs using a previously-published stimulus set of 100 items. We argue that our model of imageability is neurobiologically plausible by showing it is consistent with brain imaging data. The evidence we present suggests that behavioral effects in the lexical decision task that are usually attributed to the abstract/concrete distinction between words can be wholly explained by objective characteristics of the word that are not directly related to the semantic distinction. We provide computed imageability estimates for over 29,000 words.

Pharmacologic inhibition of phosphoinositide 3-kinase gamma (PI3Kγ) promotes infarct resorption and prevents adverse cardiac remodeling after myocardial infarction in mice.

BACKGROUND: Phosphoinositide 3-kinase gamma is upregulated in the heart during acute myocardial infarction (AMI) potentially contributing to the development and maintenance of heart failure. METHODS: CD-1 male mice were randomly assigned to pharmacologic inhibition of phosphoinositide 3-kinase gamma using AS-605240 (10 mg/kg/day intraperitoneally) or vehicle (NaCl 0.9% + DMSO 25% solution) for 14 days after experimental AMI induced by surgical coronary artery ligation. Echocardiography was performed at baseline and 1, 7, 14, and 28 days after surgery to measure left ventricular dimensions and function. Infarct size was also measured at weekly intervals to evaluate for infarct resorption. RESULTS: When compared with vehicle-treated mice over the 4-week period, animals treated with AS-605240 showed a smaller increase in left ventricular cavitary dimensions, a smaller decrease in left ventricular systolic function (P < 0.05), and a significant increase in posterior wall diastolic and systolic thickness reflective of compensatory hypertrophy (P < 0.05). Initial infarct size (measured at 24 hours) was not different comparing AS-605240 (29% ± 4%) and vehicle-treated mice (31% ± 1%, P = nonsignificant). At 4 weeks after AMI, infarct size was significantly smaller in the AS-605240-treated mice (14% ± 2%) compared with vehicle-treated mice (28% ± 3%, P < 0.001), reflecting greater infarct resorption. CONCLUSIONS: Phosphoinositide 3-kinase gamma inhibition with AS-605240 after AMI leads to enhanced infarct resorption, greater compensatory hypertrophy of the nonischemic myocardium, and more favorable cardiac remodeling and function.

Pharmacologic inhibition of myeloid differentiation factor 88 (MyD88) prevents left ventricular dilation and hypertrophy after experimental acute myocardial infarction in the mouse.

BACKGROUND: Myeloid differentiation factor 88 (MyD88) is an endogenous adaptor protein that coordinates the inflammatory response to agonists of the Toll-like receptor and interleukin-1 receptor families. This particular response is activated following myocardial ischemia and infarction and may represent a viable target for pharmacologic inhibition. The current study tested MyD88 inhibitors in a murine model of nonreperfused acute myocardial infarction (AMI). METHODS: AMI was induced by permanent ligation of the left coronary artery. Adult, male, Imprinting Control Region mice were randomized to daily injections with 1 of 2 MyD88 pharmacologic inhibitors (ST2825 25 mg/kg or IMG2005 1 mg/kg), saline, or pretreatment with MyD88-targeted silencing small interfering RNA (siRNA) or scrambled nontargeted siRNA (n = 6 for each group). Echocardiography was performed at baseline and 7 days after surgery to evaluate pathologic cardiac enlargement. RESULTS: Pharmacologic inhibition of MyD88 with ST2825 or IMG2005) and MyD88-targeted siRNA protected against left ventricular (LV) dilatation (reduced LV end-systolic and LV end-diastolic diameter) and hypertrophy. This protection occurred despite no measurable reduction in infarct size. CONCLUSIONS: Pharmacologic MyD88 inhibition protects against pathologic LV remodeling without altering infarct scar formation. MyD88 may be a viable target for pharmacologic inhibition in AMI.

Interleukin-1 trap attenuates cardiac remodeling after experimental acute myocardial infarction in mice.

BACKGROUND: Interleukin-1 (IL-1) is an inflammatory cytokine that responds as an acute phase reactant during acute myocardial infarction. Conflicting data describe the role of anti-IL-1 interventions to reduce cardiac remodeling after AMI. IL-1 Trap is a modified recombinant fusion protein that binds circulating IL-1. Our study evaluated the effects of murine IL-1 Trap on cardiac remodeling after AMI resulting from permanent surgical coronary artery ligation. METHODS: Mice received treatment with intraperitoneal injection of murine IL-1 Trap (1 mg/kg [n = 5], 5 mg/kg [n = 5], or 30 mg/kg [n = 5]) or NaCl 0.9% (saline; n = 10) every 48 hours after surgery. Transthoracic echocardiography was performed at baseline and 7 days after surgery. Inhibition of IL-1 signaling was determined by measurement of IL-6 plasma levels (enzyme-linked immunosorbent assay) after IL-1b injection. Apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling) was measured in murine heart samples and in a primary culture of murine cardiomyocytes. RESULTS: Mice treated with 5 mg/kg or 30 mg/kg IL-1 Trap had more favorable cardiac remodeling and echocardiographic assessment of infarct size at 7 days compared with saline (P < 0.05 for each comparison). Treatment with IL-1 Trap also reduced apoptosis and IL-6 levels compared with saline treatment. CONCLUSIONS: IL-1 Trap ameliorates cardiac remodeling and reduces cardiomyocyte apoptosis after experimental acute myocardial infarction in the mouse.

Chronic pulmonary artery pressure elevation is insufficient to explain right heart failure.

BACKGROUND: The most important determinant of longevity in pulmonary arterial hypertension is right ventricular (RV) function, but in contrast to experimental work elucidating the pathobiology of left ventricular failure, there is a paucity of data on the cellular and molecular mechanisms of RV failure. METHODS AND RESULTS: A mechanical animal model of chronic progressive RV pressure overload (pulmonary artery banding, not associated with structural alterations of the lung circulation) was compared with an established model of angioproliferative pulmonary hypertension associated with fatal RV failure. Isolated RV pressure overload induced RV hypertrophy without failure, whereas in the context of angioproliferative pulmonary hypertension, RV failure developed that was associated with myocardial apoptosis, fibrosis, a decreased RV capillary density, and a decreased vascular endothelial growth factor mRNA and protein expression despite increased nuclear stabilization of hypoxia-induced factor-1alpha. Induction of myocardial nuclear factor E2-related factor 2 and heme-oxygenase 1 with a dietary supplement (Protandim) prevented fibrosis and capillary loss and preserved RV function despite continuing pressure overload. CONCLUSIONS: These data brought into question the commonly held concept that RV failure associated with pulmonary hypertension is due strictly to the increased RV afterload.

Prolyl hydroxylase inhibition attenuates post-ischemic cardiac injury via induction of endoplasmic reticulum stress genes.

Ischemia/reperfusion (I/R) unleashes cellular events that threaten organ survival. I/R affects endoplasmic reticulum (ER) integrity and initiates the unfolded protein response (UPR). The adaptive arm of the UPR attenuates ER stress by increasing expression of chaperones promoting proper protein folding. However, failure to resolve ER stress leads to apoptotis. We recently showed that prolyl hydroxylase inhibition (PHI) attenuated post-ischemic cardiac injury. We hypothesized that PHI attenuated myocardial I/R injury through modulation of the UPR. We show for the first time that PHI activates all three regulatory arms of the UPR in murine microvascular endothelial cells and in mouse hearts. Cardiac I/R activated expression of pro-apoptotic CHOP (2.8 fold, n=3, p<0.01). PHI significantly decreased CHOP expression (50%, n=3, p<0.05) in post-ischemic hearts. PHI also induced activating transcription factor 4 (3.5 fold, n=3, p<0.001), glucose-regulated protein 78 (6 fold, n=3, p<0.001) and ER degradation-enhancing alpha-mannosidase-like protein (2.8 fold, n=3, p<0.001) expression in reperfusing hearts. Thus PHI resulted in significant reduction of apoptosis in post-ischemic myocardium. Our studies suggest that PHI induces protective ER stress proteins and attenuates post-ischemic myocardial damage by decreasing the pro-apoptotic components of the UPR.