FFAR4 regulates cardiac oxylipin balance to promote inflammation resolution in HFpEF secondary to metabolic syndrome.

Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome, but a predominant subset of HFpEF patients has metabolic syndrome (MetS). Mechanistically, systemic, nonresolving inflammation associated with MetS might drive HFpEF remodeling. Free fatty acid receptor 4 (Ffar4) is a GPCR for long-chain fatty acids that attenuates metabolic dysfunction and resolves inflammation. Therefore, we hypothesized that Ffar4 would attenuate remodeling in HFpEF secondary to MetS (HFpEF-MetS). To test this hypothesis, mice with systemic deletion of Ffar4 (Ffar4KO) were fed a high-fat/high-sucrose diet with L-NAME in their water to induce HFpEF-MetS. In male Ffar4KO mice, this HFpEF-MetS diet induced similar metabolic deficits but worsened diastolic function and microvascular rarefaction relative to WT mice. Conversely, in female Ffar4KO mice, the diet produced greater obesity but no worsened ventricular remodeling relative to WT mice. In Ffar4KO males, MetS altered the balance of inflammatory oxylipins systemically in HDL and in the heart, decreasing the eicosapentaenoic acid-derived, proresolving oxylipin 18-hydroxyeicosapentaenoic acid (18-HEPE), while increasing the arachidonic acid-derived, proinflammatory oxylipin 12-hydroxyeicosatetraenoic acid (12-HETE). This increased 12-HETE/18-HEPE ratio reflected a more proinflammatory state both systemically and in the heart in male Ffar4KO mice and was associated with increased macrophage numbers in the heart, which in turn correlated with worsened ventricular remodeling. In summary, our data suggest that Ffar4 controls the proinflammatory/proresolving oxylipin balance systemically and in the heart to resolve inflammation and attenuate HFpEF remodeling.

Parental psychopathology and expectations for the futures of children with autism spectrum disorder.

BACKGROUND: The influence of parental psychopathology and parental expectations on child well-being is well documented among typically developing populations. However, to date little research has examined the relationship among these factors in families of children with autism spectrum disorder (ASD). This study examines an observed relationship between parental psychopathology and expectations in families with children with ASD in the light of research in other populations. METHOD: Twenty-four parents of children diagnosed with ASD were assessed for symptoms of psychopathology. Parents completed measures of child ASD severity as well as their expectations for possible outcomes of their child. RESULTS: Two main effects were found: higher parental psychopathology and ASD severity were both related to lower expectations. Interaction of ASD severity and parental psychopathology in relation to parent expectations was not observed. CONCLUSION: These results emphasize the necessity of providing services not only to individuals diagnosed with ASD, but to caregivers as well.

Multi-omic and multispecies analysis of right ventricular dysfunction.

BACKGROUND: Right ventricular failure (RVF) is a leading cause of morbidity and mortality in multiple cardiovascular diseases, but there are no treatments for RVF as therapeutic targets are not clearly defined. Contemporary transcriptomic/proteomic evaluations of RVF are predominately conducted in small animal studies, and data from large animal models are sparse. Moreover, a comparison of the molecular mediators of RVF across species is lacking. METHODS: Transcriptomics and proteomics analyses defined the pathways associated with cardiac magnetic resonance imaging (MRI)-derived values of RV hypertrophy, dilation, and dysfunction in control and pulmonary artery banded (PAB) pigs. Publicly available data from rat monocrotaline-induced RVF and pulmonary arterial hypertension patients with preserved or impaired RV function were used to compare molecular responses across species. RESULTS: PAB pigs displayed significant right ventricle/ventricular (RV) hypertrophy, dilation, and dysfunction as quantified by cardiac magnetic resonance imaging. Transcriptomic and proteomic analyses identified pathways associated with RV dysfunction and remodeling in PAB pigs. Surprisingly, disruptions in fatty acid oxidation (FAO) and electron transport chain (ETC) proteins were different across the 3 species. FAO and ETC proteins and transcripts were mostly downregulated in rats but were predominately upregulated in PAB pigs, which more closely matched the human response. All species exhibited similar dysregulation of the dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy pathways. CONCLUSIONS: The porcine metabolic molecular signature was more similar to human RVF than rodents. These data suggest there may be divergent molecular responses of RVF across species, and pigs may more accurately recapitulate metabolic aspects of human RVF.

Junctophilin-2 Regulates Mitochondrial Metabolism.

Right ventricular dysfunction (RVD) is a risk factor for mortality in multiple cardiovascular diseases, but approaches to combat RVD are lacking. Therapies used for left heart failure are largely ineffective in RVD, and thus the identification of molecules that augment RV function could improve outcomes in a wide-array of cardiac limitations. Junctophilin-2 (JPH2) is an essential protein that plays important roles in cardiomyocytes, including calcium handling/maintenance of t-tubule structure and gene transcription. Additionally, JPH2 may regulate mitochondrial function as Jph2 knockout mice exhibit cardiomyocyte mitochondrial swelling and cristae derangements. Moreover, JPH2 knockdown in embryonic stem cell-derived cardiomyocytes induces downregulation of the mitochondrial protein mitofusin-2 (MFN2), which disrupts mitochondrial cristae structure and transmembrane potential. Impaired mitochondrial metabolism drives RVD, and here we evaluated the mitochondrial role of JPH2. We showed JPH2 directly interacts with MFN2, ablation of JPH2 suppresses mitochondrial biogenesis, oxidative capacity, and impairs lipid handling in iPSC-CM. Gene therapy with AAV9-JPH2 corrects RV mitochondrial morphological defects, mitochondrial fatty acid metabolism enzyme regulation, and restores the RV lipidomic signature in the monocrotaline rat model of RVD. Finally, AAV-JPH2 improves RV function without altering PAH severity, showing JPH2 provides an inotropic effect to the dysfunction RV.

Intermittent Fasting Activates AMP-Kinase to Restructure Right Ventricular Lipid Metabolism and Microtubules.

Intermittent fasting (IF) extends life span via pleotropic mechanisms, but one important molecular mediator is adenosine monophosphate-activated protein kinase (AMPK). AMPK enhances lipid metabolism and modulates microtubule dynamics. Dysregulation of these molecular pathways causes right ventricular (RV) failure in patients with pulmonary arterial hypertension. In rodent pulmonary arterial hypertension, IF activates RV AMPK, which restores mitochondrial and peroxisomal morphology and restructures mitochondrial and peroxisomal lipid metabolism protein regulation. In addition, IF increases electron transport chain protein abundance and activity in the right ventricle. Echocardiographic and hemodynamic measures of RV function are positively associated with fatty acid oxidation and electron transport chain protein levels. IF also combats heightened microtubule density, which normalizes transverse tubule structure.

A Multi-omic and Multi-Species Analysis of Right Ventricular Failure.

Right ventricular failure (RVF) is a leading cause of morbidity and mortality in multiple cardiovascular diseases, but there are no approved treatments for RVF as therapeutic targets are not clearly defined. Contemporary transcriptomic/proteomic evaluations of RVF are predominately conducted in small animal studies, and data from large animal models are sparse. Moreover, a comparison of the molecular mediators of RVF across species is lacking. Here, we used transcriptomics and proteomics analyses to define the molecular pathways associated with cardiac MRI-derived values of RV hypertrophy, dilation, and dysfunction in pulmonary artery banded (PAB) piglets. Publicly available data from rat monocrotaline-induced RVF and pulmonary arterial hypertension patients with preserved or impaired RV function were used to compare the three species. Transcriptomic and proteomic analyses identified multiple pathways that were associated with RV dysfunction and remodeling in PAB pigs. Surprisingly, disruptions in fatty acid oxidation (FAO) and electron transport chain (ETC) proteins were different across the three species. FAO and ETC proteins and transcripts were mostly downregulated in rats, but were predominately upregulated in PAB pigs, which more closely matched the human data. Thus, the pig PAB metabolic molecular signature was more similar to human RVF than rodents. These data suggest there may be divergent molecular responses of RVF across species, and that pigs more accurately recapitulate the metabolic aspects of human RVF.

Targeted Delivery of Electrical Shocks and Epinephrine, Guided by Ventricular Fibrillation Amplitude Spectral Area, Reduces Electrical and Adrenergic Myocardial Burden, Improving Survival in Swine.

Background We previously reported that resuscitation delivering electrical shocks guided by real-time ventricular fibrillation amplitude spectral area (AMSA) enabled return of spontaneous circulation (ROSC) with fewer shocks, resulting in less myocardial dysfunction. We now hypothesized that AMSA could also guide delivery of epinephrine, expecting further outcome improvement consequent to less electrical and adrenergic burdens. Methods and Results A swine model of ventricular fibrillation was used to compare after 10 minutes of untreated ventricular fibrillation a guidelines-driven (n=8) resuscitation protocol, delivering shocks every 2 minutes and epinephrine every 4 minutes, with an AMSA-driven shocks (n=8) protocol, delivering epinephrine every 4 minutes, and with an AMSA-driven shocks and epinephrine (ADSE; n=8) protocol. For guidelines-driven, AMSA-driven shocks, and ADSE protocols, the time to ROSC (mean±SD) was 569±164, 410±111, and 400±80 seconds (P=0.045); the number of shocks (mean±SD) was 5±2, 3±1, and 3±2 (P=0.024) with ADSE fewer than guidelines-driven (P=0.03); and the doses of epinephrine (median [interquartile range]) were 2.0 (1.3-3.0), 1.0 (1.0-2.8), and 1.0 (0.3-3.0) (P=0.419). The ROSC rate was similar, yet survival after ROSC favored AMSA-driven protocols (guidelines-driven, 3/6; AMSA-driven shocks, 6/6; and ADSE, 7/7; P=0.019 by log-rank test). Left ventricular function and survival after ROSC correlated inversely with electrical burden (ie, cumulative unsuccessful shocks, J/kg; P=0.020 and P=0.046) and adrenergic burden (ie, total epinephrine doses, mg/kg; P=0.042 and P=0.002). Conclusions Despite similar ROSC rates achieved with all 3 protocols, AMSA-driven shocks and ADSE resulted in less postresuscitation myocardial dysfunction and better survival, attributed to attaining ROSC with less electrical and adrenergic myocardial burdens.

Friendship in school-age boys with autism spectrum disorders: A meta-analytic summary and developmental, process-based model.

Friendship-making is considered a well-established domain of deficit for children with autism spectrum disorders (ASD; American Psychiatric Association, 2013), with this population sometimes described as incapable of making friends. However, the majority of children with ASD indicate a desire for friends, and many report having friends. To what degree, then, do youth with ASD succeed in achieving friendships with peers? If and when they do succeed, by what means do these friendships emerge relative to models of typically developing (TD) youths' friendships? To address these questions, we first meta-analyzed the descriptive friendship literature (peer-reported sociometrics, self-report, parent-report) among school-age boys with ASD. Using random effects models, we found that youth with ASD do make friends according to peers and parents (Hedges's g > 2.84). However, self-reported friendship quality (Hedges's g = -1.09) and parent- and peer-reported quantity (Hedges's g < -0.63) were poorer than TD peers. We consider these findings in light of 2 conceptual frameworks for understanding social deficits in ASD (social cognition and social motivation theory) and in view of a leading model of friendship in TD youth (Hartup & Stevens, 1997). We then present a model that synthesizes these domains through the construct of social information processing speed, and thereby present the first developmental, process-based model of friendship development among youth with ASD. (PsycINFO Database Record

A Preliminary Investigation of a Specialized Music Therapy Model for Children with Disabilities Delivered in a Classroom Setting.

Music therapy is gaining popularity as an intervention strategy for children with developmental disabilities, including autism spectrum disorder (ASD). This study was a pilot investigation of a classroom-based music-based intervention, Voices Together®, for improving communication skills in children with ASD and children with intellectual disabilities. Four local public elementary school special education classrooms, serving 5 children with a classification of autistic disorder and 32 children with intellectual disability without autism, were randomly selected to receive one of two levels of exposure to Voices Together music therapy: "long-term" (15 weeks beginning in January 2015 (Time 1), n = 14) or "short-term" (7 weeks beginning 7 weeks later in February (Time 2), n = 17). Using observational ratings, investigators reliably scored participants live in terms of their level of verbal responsiveness to prompts during three songs featured each week of the program. Both groups demonstrated increases in verbal responses over time; however, only the long-term group demonstrated significant within-group increases. Preliminary findings suggest that music therapy delivered in a classroom in 45-minute weekly sessions for 15 weeks can promote improvements in verbal responsiveness among individuals with autism and other developmental disabilities. Findings warrant further investigation into the efficacy of classroom-based music therapy programs.