The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.
If you have any questions or comments, please contact us.
Background Heart failure with preserved ejection fraction (HFpEF) constitutes half of hospitalized heart failure cases and is commonly associated with obesity. The role of natriuretic peptide levels in hospitalized obese patients with HFpEF, however, is not well defined. We sought to evaluate change in NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels by obesity category and related clinical outcomes in patients with HFpEF hospitalized for acute heart failure. Methods and Results A total of 89 patients with HFpEF hospitalized with acute decompensated heart failure were stratified into 3 obesity categories: nonobese (body mass index [BMI] <30.0 kg/m, 19%), obese (BMI 30.0-39.9 kg/m, 29%), and severely obese (BMI ≥40.0 kg/m, 52%), and compared for percent change in NT-proBNP during hospitalization and clinical outcomes. Clinical characteristics were compared between patients with normal NT-proBNP (≤125 pg/mL) and elevated NT-proBNP. Admission NT-proBNP was inversely related to BMI category (nonobese, 2607 pg/mL [interquartile range, IQR: 2112-5703]; obese, 1725 pg/mL [IQR: 889-3900]; and severely obese, 770.5 pg/mL [IQR: 128-1268]; <0.01). Severely obese patients had the largest percent change in NT-proBNP with diuresis (-64.8% [95% CI, -85.4 to -38.9] versus obese -40.4% [95% CI, -74.3 to -12.0] versus nonobese -46.9% [95% CI, -57.8 to -37.4]; =0.03). Nonobese and obese patients had significantly worse 1-year survival compared with severely obese patients (63% versus 76% versus 95%, respectively; <0.01). Patients with normal NT-proBNP (13%) were younger, with higher BMI, less atrial fibrillation, and less structural heart disease than those with elevated NT-proBNP. Conclusions In hospitalized patients with HFpEF, NT-proBNP was inversely related to BMI with the largest decrease in NT-proBNP seen in the highest obesity category. These findings have implications for the role of NT-proBNP in the diagnosis and assessment of treatment response in obese patients with HFpEF.
Background α Carboxyl terminus 1 (αCT1) is a 25-amino acid therapeutic peptide incorporating the zonula occludens-1 (ZO-1)-binding domain of connexin 43 (Cx43) that is currently in phase 3 clinical testing on chronic wounds. In mice, we reported that αCT1 reduced arrhythmias after cardiac injury, accompanied by increases in protein kinase Cε phosphorylation of Cx43 at serine 368. Herein, we characterize detailed molecular mode of action of αCT1 in mitigating cardiac ischemia-reperfusion injury. Methods and Results To study αCT1-mediated increases in phosphorylation of Cx43 at serine 368, we undertook mass spectrometry of protein kinase Cε phosphorylation assay reactants. This indicated potential interaction between negatively charged residues in the αCT1 Asp-Asp-Leu-Glu-Iso sequence and lysines (Lys345, Lys346) in an α-helical sequence (helix 2) within the Cx43-CT. In silico modeling provided further support for this interaction, indicating that αCT1 may interact with both Cx43 and ZO-1. Using surface plasmon resonance, thermal shift, and phosphorylation assays, we characterized a series of αCT1 variants, identifying peptides that interacted with either ZO-1-postsynaptic density-95/disks large/zonula occludens-1 2 or Cx43-CT, but with limited or no ability to bind both molecules. Only peptides competent to interact with Cx43-CT, but not ZO-1-postsynaptic density-95/disks large/zonula occludens-1 2 alone, prompted increased pS368 phosphorylation. Moreover, in an ex vivo mouse model of ischemia-reperfusion injury, preischemic infusion only with those peptides competent to bind Cx43 preserved ventricular function after ischemia-reperfusion. Interestingly, a short 9-amino acid variant of αCT1 (αCT11) demonstrated potent cardioprotective effects when infused either before or after ischemic injury. Conclusions Interaction of αCT1 with the Cx43, but not ZO-1, is correlated with cardioprotection. Pharmacophores targeting Cx43-CT could provide a translational approach to preserving heart function after ischemic injury.
OBJECTIVE - Natriuretic peptides (NPs) are hormones with cardioprotective effects. NP levels vary by race; however, the pathophysiological consequences of lower NP levels are not well understood. We aimed to quantify the association between NPs and endothelial function as measured by flow-mediated dilation (FMD) and the contribution of NP levels to racial differences in endothelial function.
METHODS - In this cross-sectional study of 2938 Multi-Ethnic Study of Atherosclerosis participants (34% Caucasian, 20% African-American, 20% Asian-American and 26% Hispanic) without cardiovascular disease at baseline, multivariable linear regression models were used to examine the association between serum N-terminal pro-B-type NP (NT-proBNP) and natural log-transformed FMD. We also tested whether NT-proBNP mediated the relationship between race and FMD using the product of coefficients method.
RESULTS - Among African-American and Chinese-American individuals, lower NT-proBNP levels were associated with lower FMD, β=0.06 (95% CI: 0.03 to 0.09; p<0.001) and β=0.06 (95% CI: 0.02 to 0.09; p=0.002), respectively. Non-significant associations between NT-proBNP and FMD were found in Hispanic and Caucasian individuals. In multivariable models, endothelial function differed by race, with African-American individuals having the lowest FMD compared with Caucasians, p<0.001. Racial differences in FMD among African-Americans and Chinese-Americans were mediated in part by NT-proBNP levels (African-Americans, mediation effect: -0.03(95% CI: -0.05 to -0.01); Chinese-Americans, mediation effect: -0.03(95% CI: -0.05 to -0.01)).
CONCLUSIONS - Lower NP levels are associated with worse endothelial function among African-Americans and Chinese-Americans. A relative NP deficiency in some racial/ethnic groups may contribute to differences in vascular function.
© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.
Alzheimer's disease currently lacks treatment options that effectively reverse the biological/anatomical pathology and cognitive deficits associated with the disease. Loss of function of the nuclear receptor REV-ERB is associated with reduced cognitive function in mouse models. The effect of enhanced REV-ERB activity on cognitive function has not been examined. In this study, we tested the hypothesis that enhanced REV-ERB function may enhance cognitive function in a model of Alzheimer's disease. We utilized the REV-ERB agonist SR9009 to pharmacologically activate the activity of REV-ERB in the SAMP8 mouse model of Alzheimer's disease. SR9009 reversed cognitive dysfunction of an aged SAMP8 mouse in several behavioral assays including novel object recognition, T-maze foot shock avoidance, and lever press operant conditioning task assessments. SR9009 treatment reduced amyloid-β 1-40 and 1-42 levels in the cortex, which is consistent with improved cognitive function. Furthermore, SR9009 treatment led to increased hippocampal PSD-95, cortical synaptophysin expression and the number of synapses suggesting improvement in synaptic function. We conclude that REV-ERB is a potential target for treatment of Alzheimer's disease.
Na-K-2Cl cotransporter-1 (NKCC1) mediates the electroneutral transport of Na, K, and Cl and is normally localized to the basolateral membrane of polarized epithelial cells. We recently reported the first known solute carrier family 12 member 2 ( SLC12A2) mutation (we call NKCC1-DFX) that causes epithelial dysfunction in an undiagnosed disease program case. The heterozygous mutation leads to truncation of the COOH-terminal tail of the cotransporter, resulting in both mutant and wild-type cotransporters being mistrafficked to the apical membrane of polarized epithelial cells. Here we demonstrate by using consecutive truncations and site-directed mutagenesis of the COOH-terminal domain of NKCC1 that truncation of NKCC1 COOH domain uncouples the cotransporter from the lateral membrane. We identify a dileucine motif that, when mutated, leads to cotransporter accumulation in the cytoplasm and mistrafficking to the apical/subapical region of epithelial cells, thereby recapitulating the phenotype observed with the patient mutation. We show that truncation deletion and LL substitution mutants are trafficked out of the endoplasmic reticulum and trans-Golgi network but accumulate in early and late endosomes where they are degraded.
Cerebrospinal fluid (CSF) neurofilament light (NFL) is a protein biomarker of axonal injury. To study whether NFL is associated with diffusion tensor imaging (DTI) measurements of white matter (WM) microstructure, Vanderbilt Memory & Aging Project participants with normal cognition (n = 77), early mild cognitive impairment (n = 15), and MCI (n = 55) underwent lumbar puncture to obtain CSF and 3T brain MRI. Voxel-wise analyses cross-sectionally related NFL to DTI metrics, adjusting for demographic and vascular risk factors. Increased NFL correlated with multiple DTI metrics (p-values < 0.05). An NFL × diagnosis interaction (excluding early mild cognitive impairment) on WM microstructure (p-values < 0.05) was detected, with associations strongest among MCI. Multiple NFL × CSF biomarker interactions were detected. Associations between NFL and worse WM metrics were strongest among amyloid-β-negative, tau-positive, and suspected nonamyloid pathology participants. Findings suggest increased NFL, a biomarker of axonal injury, is correlated with compromised WM microstructure. Results highlight the role of elevated NFL in predicting WM damage in cognitively impaired older adults who are amyloid-negative, tau-positive, or meet suspected nonamyloid pathology criteria.
Copyright © 2018 Elsevier Inc. All rights reserved.
Cerebrospinal fluid (CSF) levels of amyloid-β 42 (Aβ42) and tau have been evaluated as endophenotypes in Alzheimer's disease (AD) genetic studies. Although there are sex differences in AD risk, sex differences have not been evaluated in genetic studies of AD endophenotypes. We performed sex-stratified and sex interaction genetic analyses of CSF biomarkers to identify sex-specific associations. Data came from a previous genome-wide association study (GWAS) of CSF Aβ42 and tau (1527 males, 1509 females). We evaluated sex interactions at previous loci, performed sex-stratified GWAS to identify sex-specific associations, and evaluated sex interactions at sex-specific GWAS loci. We then evaluated sex-specific associations between prefrontal cortex (PFC) gene expression at relevant loci and autopsy measures of plaques and tangles using data from the Religious Orders Study and Rush Memory and Aging Project. In Aβ42, we observed sex interactions at one previous and one novel locus: rs316341 within SERPINB1 (p = 0.04) and rs13115400 near LINC00290 (p = 0.002). These loci showed stronger associations among females (β = - 0.03, p = 4.25 × 10; β = 0.03, p = 3.97 × 10) than males (β = - 0.02, p = 0.009; β = 0.01, p = 0.20). Higher levels of expression of SERPINB1, SERPINB6, and SERPINB9 in PFC was associated with higher levels of amyloidosis among females (corrected p values < 0.02) but not males (p > 0.38). In total tau, we observed a sex interaction at a previous locus, rs1393060 proximal to GMNC (p = 0.004), driven by a stronger association among females (β = 0.05, p = 4.57 × 10) compared to males (β = 0.02, p = 0.03). There was also a sex-specific association between rs1393060 and tangle density at autopsy (p = 0.047; p = 0.96), and higher levels of expression of two genes within this locus were associated with lower tangle density among females (OSTN p = 0.006; CLDN16 p = 0.002) but not males (p ≥ 0.32). Results suggest a female-specific role for SERPINB1 in amyloidosis and for OSTN and CLDN16 in tau pathology. Sex-specific genetic analyses may improve understanding of AD's genetic architecture.
Importance - The strongest genetic risk factor for Alzheimer disease (AD), the apolipoprotein E (APOE) gene, has a stronger association among women compared with men. Yet limited work has evaluated the association between APOE alleles and markers of AD neuropathology in a sex-specific manner.
Objective - To evaluate sex differences in the association between APOE and markers of AD neuropathology measured in cerebrospinal fluid (CSF) during life or in brain tissue at autopsy.
Design, Setting, and Participants - This multicohort study selected data from 10 longitudinal cohort studies of normal aging and AD. Cohorts had variable recruitment criteria and follow-up intervals and included population-based and clinic-based samples. Inclusion in our analysis required APOE genotype data and either CSF data available for analysis. Analyses began on November 6, 2017, and were completed on December 20, 2017.
Main Outcomes and Measures - Biomarker analyses included levels of β-amyloid 42, total tau, and phosphorylated tau measured in CSF. Autopsy analyses included Consortium to Establish a Registry for Alzheimer's Disease staging for neuritic plaques and Braak staging for neurofibrillary tangles.
Results - Of the 1798 patients in the CSF biomarker cohort, 862 were women, 226 had AD, 1690 were white, and the mean (SD) age was 70  years. Of the 5109 patients in the autopsy cohort, 2813 were women, 4953 were white, and the mean (SD) age was 84 (9) years. After correcting for multiple comparisons using the Bonferroni procedure, we observed a statistically significant interaction between APOE-ε4 and sex on CSF total tau (β = 0.41; 95% CI, 0.27-0.55; P < .001) and phosphorylated tau (β = 0.24; 95% CI, 0.09-0.38; P = .001), whereby APOE showed a stronger association among women compared with men. Post hoc analyses suggested this sex difference was present in amyloid-positive individuals (β = 0.41; 95% CI, 0.20-0.62; P < .001) but not among amyloid-negative individuals (β = 0.06; 95% CI, -0.18 to 0.31; P = .62). We did not observe sex differences in the association between APOE and β-amyloid 42, neuritic plaque burden, or neurofibrillary tangle burden.
Conclusions and Relevance - We provide robust evidence of a stronger association between APOE-ε4 and CSF tau levels among women compared with men across multiple independent data sets. Interestingly, APOE-ε4 is not differentially associated with autopsy measures of neurofibrillary tangles. Together, the sex difference in the association between APOE and CSF measures of tau and the lack of a sex difference in the association with neurofibrillary tangles at autopsy suggest that APOE may modulate risk for neurodegeneration in a sex-specific manner, particularly in the presence of amyloidosis.