Impact of 2016 UNOS pediatric heart allocation policy changes on VAD utilization, waitlist, and post-transplant survival outcomes in children with CHD versus Non-CHD.

AIMS: We analyzed the impact of the revised pediatric heart allocation policy on types of ventricular assist device (VAD) utilization, and waitlist (WL) and post-heart transplant (HT) survival outcomes in congenital heart disease (CHD) versus non-CHD patients before (Era-1) and after (Era-2) pediatric heart allocation policy implementation. METHODS: We retrospectively reviewed the UNOS database from December 16, 2011, through March 31, 2021, for patients < 18 years old and listed for primary HT. We compared the differences observed between Era-1 and Era-2. RESULTS: 5551 patients were listed for HT, of whom 2447(44%) were in Era-1 and 3104(56%) were in Era-2. CHD patients were listed as status 1A unchanged, but the number of patients listed as status 1B decreased in Era-2, whereas the number of non-CHD patients listed as status 1A decreased, but status 1B increased. In Era-2 compared to Era-1, both temporary (1% to 4%, p < .001) and durable VAD (13.6% to 17.8%, p < .001) utilization increased, and the transplantation rate per 100-patient years increased in both groups. The median WL period for CHD patients increased marginally from 70 to 71 days (p = .06), whereas for non-CHD patients it decreased from 61 to 54 days (p < .001). Adjusted 90-day WL survival increased from 84% to 88%, p = .016 in CHD, but there was no significant change in non-CHD patients (p = .57). There was no significant difference in 1-year post-HT survival in CHD and non-CHD patients between Era-1 and Era-2. CONCLUSIONS: In summary, after the revised heart allocation policy implementation, temporary and durable VAD support increased, HT rate increased, waitlist duration marginally increased in the CHD cohort and decreased in the non-CHD cohort, and 90-day WL survival probability improved in children with CHD without significant change in 1-year post-HT outcomes. Future studies are needed to identify changes to the policy that may further improve the listing criteria to improve WL duration and post-HT survival.

Enhanced recovery after surgery multimodality pain regimen performs similar to PRN narcotics on outcomes and pain control after cardiac surgery: A quality improvement project.

BACKGROUND: While enhanced recovery after surgery (ERAS) pathways have been successfully applied for cardiac surgery, there has been limited research directly comparing ERAS protocols to ad hoc narcotic use after surgery. We hypothesized that a standardized ERAS protocol would provide similar pain management and psychoemotional outcomes while decreasing the use of opioids in the hospital and after discharge. METHODS: As part of a 7-month quality improvement project, cardiac surgery patients on a fast-tracked to extubate pathway were assigned pro re nata (PRN) narcotic pain management for 3 months (n = 49). After a 1-month ERAS protocol optimization period, a separate group of patients were given the ERAS protocol (n = 34). Clinical outcomes were gathered, and participants completed a quality of recovery survey that allowed for the assessment of pain and symptom control at four-time points after surgery. RESULTS: Among 83 participants, 66% were male and the mean age was 53 years. There were no differences in patient characteristics between PRN and ERAS groups (all p > .244). There were no differences between ERAS and PRN groups for surgery characteristics (all p > .060), inpatient outcomes (all p > .658), or after-discharge outcomes (all p > .397). Furthermore, across all time-point comparisons, there were no supported differences in patient-reported outcome and pain control between the ERAS and PRN narcotic groups (all p > .075). CONCLUSIONS: An ERAS protocol demonstrated similar patient outcomes and pain control to traditional opioid use for postoperative cardiac surgery patients. Further research is recommended to further confirm the results of this study.

Abnormal brain cholesterol homeostasis in Alzheimer's disease-a targeted metabolomic and transcriptomic study.

The role of brain cholesterol metabolism in Alzheimer's disease (AD) remains unclear. Peripheral and brain cholesterol levels are largely independent due to the impermeability of the blood brain barrier (BBB), highlighting the importance of studying the role of brain cholesterol homeostasis in AD. We first tested whether metabolite markers of brain cholesterol biosynthesis and catabolism were altered in AD and associated with AD pathology using linear mixed-effects models in two brain autopsy samples from the Baltimore Longitudinal Study of Aging (BLSA) and the Religious Orders Study (ROS). We next tested whether genetic regulators of brain cholesterol biosynthesis and catabolism were altered in AD using the ANOVA test in publicly available brain tissue transcriptomic datasets. Finally, using regional brain transcriptomic data, we performed genome-scale metabolic network modeling to assess alterations in cholesterol biosynthesis and catabolism reactions in AD. We show that AD is associated with pervasive abnormalities in cholesterol biosynthesis and catabolism. Using transcriptomic data from Parkinson's disease (PD) brain tissue samples, we found that gene expression alterations identified in AD were not observed in PD, suggesting that these changes may be specific to AD. Our results suggest that reduced de novo cholesterol biosynthesis may occur in response to impaired enzymatic cholesterol catabolism and efflux to maintain brain cholesterol levels in AD. This is accompanied by the accumulation of nonenzymatically generated cytotoxic oxysterols. Our results set the stage for experimental studies to address whether abnormalities in cholesterol metabolism are plausible therapeutic targets in AD.

Correction: Dysregulation of multiple metabolic networks related to brain transmethylation and polyamine pathways in Alzheimer disease: A targeted metabolomic and transcriptomic study.

[This corrects the article DOI: 10.1371/journal.pmed.1003012.].

Dysregulation of multiple metabolic networks related to brain transmethylation and polyamine pathways in Alzheimer disease: A targeted metabolomic and transcriptomic study.

BACKGROUND: There is growing evidence that Alzheimer disease (AD) is a pervasive metabolic disorder with dysregulation in multiple biochemical pathways underlying its pathogenesis. Understanding how perturbations in metabolism are related to AD is critical to identifying novel targets for disease-modifying therapies. In this study, we test whether AD pathogenesis is associated with dysregulation in brain transmethylation and polyamine pathways. METHODS AND FINDINGS: We first performed targeted and quantitative metabolomics assays using capillary electrophoresis-mass spectrometry (CE-MS) on brain samples from three groups in the Baltimore Longitudinal Study of Aging (BLSA) (AD: n = 17; Asymptomatic AD [ASY]: n = 13; Control [CN]: n = 13) (overall 37.2% female; mean age at death 86.118 ± 9.842 years) in regions both vulnerable and resistant to AD pathology. Using linear mixed-effects models within two primary brain regions (inferior temporal gyrus [ITG] and middle frontal gyrus [MFG]), we tested associations between brain tissue concentrations of 26 metabolites and the following primary outcomes: group differences, Consortium to Establish a Registry for Alzheimer's Disease (CERAD) (neuritic plaque burden), and Braak (neurofibrillary pathology) scores. We found significant alterations in concentrations of metabolites in AD relative to CN samples, as well as associations with severity of both CERAD and Braak, mainly in the ITG. These metabolites represented biochemical reactions in the (1) methionine cycle (choline: lower in AD, p = 0.003; S-adenosyl methionine: higher in AD, p = 0.005); (2) transsulfuration and glutathione synthesis (cysteine: higher in AD, p < 0.001; reduced glutathione [GSH]: higher in AD, p < 0.001); (3) polyamine synthesis/catabolism (spermidine: higher in AD, p = 0.004); (4) urea cycle (N-acetyl glutamate: lower in AD, p < 0.001); (5) glutamate-aspartate metabolism (N-acetyl aspartate: lower in AD, p = 0.002); and (6) neurotransmitter metabolism (gamma-amino-butyric acid: lower in AD, p < 0.001). Utilizing three Gene Expression Omnibus (GEO) datasets, we then examined mRNA expression levels of 71 genes encoding enzymes regulating key reactions within these pathways in the entorhinal cortex (ERC; AD: n = 25; CN: n = 52) and hippocampus (AD: n = 29; CN: n = 56). Complementing our metabolomics results, our transcriptomics analyses also revealed significant alterations in gene expression levels of key enzymatic regulators of biochemical reactions linked to transmethylation and polyamine metabolism. Our study has limitations: our metabolomics assays measured only a small proportion of all metabolites participating in the pathways we examined. Our study is also cross-sectional, limiting our ability to directly test how AD progression may impact changes in metabolite concentrations or differential-gene expression. Additionally, the relatively small number of brain tissue samples may have limited our power to detect alterations in all pathway-specific metabolites and their genetic regulators. CONCLUSIONS: In this study, we observed broad dysregulation of transmethylation and polyamine synthesis/catabolism, including abnormalities in neurotransmitter signaling, urea cycle, aspartate-glutamate metabolism, and glutathione synthesis. Our results implicate alterations in cellular methylation potential and increased flux in the transmethylation pathways, increased demand on antioxidant defense mechanisms, perturbations in intermediate metabolism in the urea cycle and aspartate-glutamate pathways disrupting mitochondrial bioenergetics, increased polyamine biosynthesis and breakdown, as well as abnormalities in neurotransmitter metabolism that are related to AD.

Neck circumference and cardiovascular outcomes: Insights from the Jackson Heart Study.

BACKGROUND: Emerging data suggest that neck circumference (NC) is associated with cardiometabolic risk factors. Limited research is available regarding the association between NC and cardiovascular outcomes in African Americans. METHODS: Using data from the Jackson Heart Study, we included participants with recorded NC measurements at baseline (2000-2004). Baseline characteristics for the included population were summarized by tertiles of NC. We then calculated age- and sex-adjusted cumulative incidence of clinical cardiovascular outcomes and performed Cox proportional-hazards with stepwise models. RESULTS: Overall, 5,290 participants were categorized into tertiles of baseline NC defined as ≤37 cm (n = 2179), 38-40 cm (n = 1552), and >40 cm (n = 1559). After adjusting for age and sex, increasing NC was associated with increased risk of heart failure (HF) hospitalization (cumulative incidence = 13.4% [99% CI, 10.7-16.7] in the largest NC tertile vs 6.5% [99% CI, 4.7-8.8] in the smallest NC tertile), but not mortality, stroke, myocardial infarction, or coronary heart disease (all P ≥ .1). Following full risk adjustment, there was a nominal increase in the risk of HF hospitalization with increasing NC, but this was not statistically significant (hazard ratio per 1-cm increase, 1.04 [99% CI, 0.99-1.10], P = .06). CONCLUSIONS: In this large cohort of African American individuals, a larger NC was associated with increased risk for HF hospitalization following adjustment for age and sex, but this risk was not statistically significant after adjusting for other clinical variables. Although NC is not independently associated with increased risk for cardiovascular events, it may offer prognostic information particularly related to HF hospitalization.

Financial Stress and Risk of Coronary Heart Disease in the Jackson Heart Study.

INTRODUCTION: Financial hardship is associated with coronary heart disease risk factors, and may disproportionately affect some African American groups. This study examines whether stress because of financial hardship is associated with incident coronary heart disease in African Americans. METHODS: The Jackson Heart Study is a longitudinal cohort study of cardiovascular disease risks in African Americans in the Jackson, Mississippi metropolitan statistical area. Participant enrollment began in 2000. Analyses were performed in 2017 and included adjudicated endpoints through December 2012. Financial stress was assessed from the Jackson Heart Study Weekly Stress Inventory and categorized into four levels: (1) did not experience financial stress, (2) no stress, (3) mild stress, and (4) moderate to high stress. Incident coronary heart disease was defined as the first event of definite or probable myocardial infarction, definite fatal myocardial infarction, definite fatal coronary heart disease, or cardiac procedure. There were 2,256 individuals in this analysis. RESULTS: Participants with moderate to high (versus no) financial stress were more likely to have incident coronary heart disease events after controlling for demographics, SES, access to care, and traditional clinical risk factors (hazard ratio=2.42, 95% CI=1.13, 5.17). The association between financial stress and coronary heart disease was no longer statistically significant in a model adjusting for three specific risk factors: depression, smoking status, and diabetes (hazard ratio=1.99, 95% CI=0.91, 4.39). CONCLUSIONS: Financial stress may be an unrecognized risk factor for coronary heart disease for African Americans. Additional research should examine these associations in intervention studies that address perceived stress, in addition to other coronary heart disease risk factors, in patients experiencing financial stress.

Ideal Cardiovascular Health and Incident Cardiovascular Events: The Jackson Heart Study.

INTRODUCTION: The epidemiology of American Heart Association ideal cardiovascular health (CVH) metrics has not been fully examined in African Americans. This study examines the associations of CVH metrics with incident cardiovascular disease (CVD) in the Jackson Heart Study, a longitudinal cohort study of CVD in African Americans. METHODS: Jackson Heart Study participants without CVD (n=4,702) were followed prospectively between 2000 and 2011. Incidence rates and Cox proportional hazard ratios estimated risks for incident CVD (myocardial infarction, stroke, cardiac procedures, and CVD mortality) associated with seven CVH metrics by sex. Analyses were performed in 2015. RESULTS: Participants were followed for a median of 8.3 years; none had ideal health on all seven CVH metrics. The prevalence of ideal health was low for nutrition, physical activity, BMI, and blood pressure metrics. The age-adjusted CVD incidence rate (IR) per 1,000 person years was highest for individuals with the least ideal health metrics: zero to one (IR=12.5, 95% CI=9.7, 16.1), two (IR=8.2, 95% CI=6.5, 10.4), three (IR=5.7, 95% CI=4.2, 7.6), and four or more (IR=3.4, 95% CI=2.0, 5.9). Adjusting for covariates, individuals with four or more ideal CVH metrics had lower risks of incident CVD compared with those with zero or one ideal CVH metric (hazard ratio, 0.29; 95% CI=0.17, 0.52; p<0.001). CONCLUSIONS: African Americans with more ideal CVH metrics have lower risks of incident CVD. Comprehensive preventive behavioral and clinical supports should be intensified to improve CVD risk for African Americans with few ideal CVH metrics.

Pterostilbene on metabolic parameters: a randomized, double-blind, and placebo-controlled trial.

Introduction. The purpose of this trial was to evaluate the effect of pterostilbene on metabolic parameters. Methods. A prospective, randomized, double-blind, and placebo-controlled study that enrolled 80 patients with a total cholesterol ≥200 mg/dL and/or LDL ≥ 100 mg/dL. Subjects were divided into four groups: (1) pterostilbene 125 mg twice daily; (2) pterostilbene 50 mg twice daily; (3) pterostilbene 50 mg + grape extract (GE) 100 mg twice daily; (4) matching placebo twice daily for 6-8 weeks. Endpoints included lipids, blood pressure, and weight. Linear mixed models were used to examine and compare changes in parameters over time. Models were adjusted for age, gender, and race. Results. LDL increased with pterostilbene monotherapy (17.1 mg/dL; P = 0.001) which was not seen with GE combination (P = 0.47). Presence of a baseline cholesterol medication appeared to attenuate LDL effects. Both systolic (-7.8 mmHg; P < 0.01) and diastolic blood pressure (-7.3 mmHg; P < 0.001) were reduced with high dose pterostilbene. Patients not on cholesterol medication (n = 51) exhibited minor weight loss with pterostilbene (-0.62 kg/m(2); P = 0.012). Conclusion. Pterostilbene increases LDL and reduces blood pressure in adults. This trial is registered with Clinicaltrials.gov NCT01267227.