Sex-Specific Disparities in Clinical Outcomes After Transcatheter Aortic Valve Replacement Among Different Racial Populations.

Background: Sex-related disparities in clinical outcomes following transcatheter aortic valve replacement (TAVR) and the impact of sex on clinical outcomes after TAVR among different racial groups are undetermined. Objectives: This study assessed whether sex-specific differences in baseline clinical and anatomical characteristics affect clinical outcomes after TAVR and investigated the impact of sex on clinical outcomes among different racial groups. Methods: The TP-TAVR (Trans-Pacific TAVR) registry is a multinational cohort study of patients with severe aortic stenosis who underwent TAVR at 2 major centers in the United States and 1 major center in South Korea. The primary outcome was a composite of death from any cause, stroke, or rehospitalization after 1 year. Results: The incidence of the primary composite outcome was not significantly different between sexes (27.9% in men vs 28% in women; adjusted HR: 0.97; 95% CI: 0.79-1.20). This pattern was consistent in Asian (23.5% vs 23.3%; adjusted HR: 0.99; 95% CI: 0.69-1.41) and non-Asian (30.8% vs 31.6%; adjusted HR: 0.95; 95% CI: 0.72-1.24) cohorts, without a significant interaction between sex and racial group (P for interaction = 0.74). The adjusted risk for all-cause mortality was similar between sexes, regardless of racial group. However, the adjusted risk of stroke was significantly lower in male patients than in female patients, which was more prominent in the non-Asian cohort. Conclusions: Despite significantly different baseline and procedural characteristics, there were no sex-specific differences in the adjusted 1-year rates of primary composite outcomes and all-cause mortality, regardless of different racial groups. (Transpacific TAVR registry [TP-TAVR]; NCT03826264).

Introduction to subpressure-driven soft deformation method for removing inherent voids in green components manufactured by material extrusion.

This study introduces a post-treatment process, the subpressure-driven soft deformation method, to reduce inherent voids in Material Extrusion (MEX) components. By subjecting printed green components to heat treatment under subpressure, the process enhances viscosity, effectively filling voids formed between deposited tracks. The average porosities of the samples sintered from the green components without and with soft deformation are calculated to be 3.55% and 2.36%, respectively. A comparison of the tensile strengths and fracture surfaces of the sintered samples with and without soft deformation treatment indicated that the sintered samples with soft deformation treatment exhibited narrower standard deviation for the various mechanical properties. Capillary rheometer calculations indicate feedstock viscosity to be between 450.34 and 1018.31 Pa s under subpressure, diminishing inter-track voids without sizeable dimensional changes. Molecular dynamics simulation demonstrates a 3.7-fold increase in bond strength, indicating intertrack voids effectively eliminated. Reduced inter-particle distances facilitate necking, grain growth, and improved sintered density.

Associations of Sarcopenia and Body Composition Measures With Mortality After Transcatheter Aortic Valve Replacement.

BACKGROUND: Frailty associates with worse outcomes after transcatheter aortic valve replacement (TAVR). Sarcopenia underlies frailty, but the association between a comprehensive assessment of sarcopenia-muscle mass, strength, and performance-and outcomes after TAVR has not been examined. METHODS: From a multicenter prospective registry of patients with symptomatic severe aortic stenosis undergoing TAVR, 445 who had a preprocedure computed tomography and clinical assessment of frailty were included. Cross-sectional muscle (psoas and paraspinal) areas were measured on computed tomography and indexed to height. Gait speed and handgrip strength were obtained, and patients were dichotomized into fast versus slow; strong versus weak; and normal versus low muscle mass. As measures of body composition, cross-sectional fat (subcutaneous and visceral) was measured and indexed to height. RESULTS: The frequency of patients who were slow, weak, and had low muscle mass was 56%, 59%, and 42%, respectively. Among the 3 components of sarcopenia, only slower gait speed (muscle performance) was independently associated with increased post-TAVR mortality (adjusted hazard ratio, 1.12 per 0.1 m/s decrease [95% CI, 1.04-1.21]; P=0.004; adjusted hazard ratio, 1.38 per 1 SD decrease [95% CI, 1.11-1.72]; P=0.004). Meeting multiple sarcopenia criteria was not associated with higher mortality risk than fewer. Lower indexed visceral fat area (adjusted hazard ratio, 1.48 per 1 SD decrease [95% CI, 1.15-1.89]; P=0.002) was associated with mortality but indexed subcutaneous fat was not. Death occurred in 169 (38%) patients. CONCLUSIONS: Among patients with symptomatic severe aortic stenosis and comprehensive sarcopenia and body composition phenotyping, gait speed was the only sarcopenia measure associated with post-TAVR mortality. Lower visceral fat was also associated with increased risk pointing to an obesity paradox also observed in other patient populations. These findings reinforce the clinical utility of gait speed as a measure of risk and a potential target for adjunctive interventions alongside TAVR to optimize clinical outcomes.

Association of Depression and Cognitive Dysfunction With Patient-Centered Outcomes After Transcatheter Aortic Valve Replacement.

BACKGROUND: Depression and cognitive dysfunction (CD) are not routinely screened for in patients before transcatheter aortic valve replacement (TAVR) and their association with postprocedural outcomes is poorly understood. The objectives of this study are to determine the prevalence of depression and CD in patients with aortic stenosis undergoing TAVR and evaluate their association with mortality and quality of life. METHODS: We analyzed a prospective, multicenter TAVR registry that systematically screened patients for preexisting depression and CD with the Patient Health Questionnaire-2 and Mini-Cog, respectively. The associations with mortality were assessed with Cox proportional hazard models and quality of life (Kansas City Cardiomyopathy Questionnaire and EuroQol visual analogue scale) were evaluated using multivariable ordinal regression models. RESULTS: A total of 884 patients were included; median follow-up was 2.88 years (interquartile range=1.2-3.7). At baseline, depression was observed in 19.6% and CD in 31.8%. In separate models, after adjustment, depression (HR, 1.45 [95% CI, 1.13-1.86]; P<0.01) and CD (HR, 1.27 [95% CI, 1.02-1.59]; P=0.04) were each associated with increased mortality. Combining depression and CD into a single model, mortality was greatest among those with both depression and CD (n=62; HR, 2.06 [CI, 1.44-2.96]; P<0.01). After adjustment, depression was associated with 6.6 (0.3-13.6) points lower on the Kansas City Cardiomyopathy Questionnaire 1-year post-TAVR and 6.7 (0.5-12.7) points lower on the EuroQol visual analogue scale. CD was only associated with lower EuroQol visual analogue scale. CONCLUSIONS: Depression and CD are common in patients that undergo TAVR and are associated with increased mortality and worse quality of life. Depression may be a modifiable therapeutic target to improve outcomes after TAVR.

Race-Specific Impact of Conventional Surgical Risk Score on 1-Year Mortality After Transcatheter Aortic Valve Replacement.

Background: Interracial differences in the distribution and prognostic value of conventional Society of Thoracic Surgeons (STS) score on long-term mortality after transcatheter aortic valve replacement (TAVR) are uncertain. Objectives: This study aims to compare the impact of STS scores on clinical outcomes at 1-year after TAVR between Asian and non-Asian populations. Methods: We used the Trans-Pacific TAVR (TP-TAVR) registry, a multinational multicenter, observational registry involving patients undergoing TAVR at 2 major centers in the United States and 1 major center in Korea. Patients were classified into 3 groups (low, intermediate, and high-risk) according to the STS score and compared between STS risk groups and race. The primary outcome was all-cause mortality at 1-year. Results: Among 1,412 patients, 581 were Asian and 831 were non-Asian. The distribution of the STS risk score group was different between Asian and non-Asian groups (62.5% low-, 29.8% intermediate-, and 7.7% high-risk in Asian vs 40.6% low-, 39.1% intermediate-, and 20.3% high-risk in non-Asian). In the Asian population, the all-cause mortality at 1-year was substantially higher in the high-risk STS group than in the low- and intermediate-risk groups (3.6% low-risk, 8.7% intermediate-risk, and 24.4% high-risk; log-rank P < 0.001), which was primarily driven by noncardiac mortality. In the non-Asian group, there was a proportional increase in all-cause mortality at 1-year according to the STS risk category (5.3% low-risk, 12.6% intermediate-risk, and 17.8% high-risk; log-rank P < 0.001). Conclusions: In this multiracial registry of patients with severe aortic stenosis who underwent TAVR, we identified a differential proportion and prognostic impact of STS score on 1-year mortality between Asian and non-Asian patients (TP-TAVR [Transpacific TAVR Registry]; NCT03826264).

Metabolic Signatures of Cardiac Dysfunction, Multimorbidity, and Post-Transcatheter Aortic Valve Implantation Death.

Background Studies in mice and small patient subsets implicate metabolic dysfunction in cardiac remodeling in aortic stenosis, but no large comprehensive studies of human metabolism in aortic stenosis with long-term follow-up and characterization currently exist. Methods and Results Within a multicenter prospective cohort study, we used principal components analysis to summarize 12 echocardiographic measures of left ventricular structure and function pre-transcatheter aortic valve implantation in 519 subjects (derivation). We used least absolute shrinkage and selection operator regression across 221 metabolites to define metabolic signatures for each structural pattern and measured their relation to death and multimorbidity in the original cohort and up to 2 validation cohorts (N=543 for overall validation). In the derivation cohort (519 individuals; median age, 84 years, 45% women, 95% White individuals), we identified 3 axes of left ventricular remodeling, broadly specifying systolic function, diastolic function, and chamber volumes. Metabolite signatures of each axis specified both known and novel pathways in hypertrophy and cardiac dysfunction. Over a median of 3.1 years (205 deaths), a metabolite score for diastolic function was independently associated with post-transcatheter aortic valve implantation death (adjusted hazard ratio per 1 SD increase in score, 1.54 [95% CI, 1.25-1.90]; P<0.001), with similar effects in each validation cohort. This metabolite score of diastolic function was simultaneously associated with measures of multimorbidity, suggesting a metabolic link between cardiac and noncardiac state in aortic stenosis. Conclusions Metabolite profiles of cardiac structure identify individuals at high risk for death following transcatheter aortic valve implantation and concurrent multimorbidity. These results call for efforts to address potentially reversible metabolic biology associated with risk to optimize post-transcatheter aortic valve implantation recovery, rehabilitation, and survival.

Air Pollution, Built Environment, and Early Cardiovascular Disease.

As the world's population becomes increasingly urbanized, there is growing concern about the impact of urban environments on cardiovascular health. Urban residents are exposed to a variety of adverse environmental exposures throughout their lives, including air pollution, built environment, and lack of green space, which may contribute to the development of early cardiovascular disease and related risk factors. While epidemiological studies have examined the role of a few environmental factors with early cardiovascular disease, the relationship with the broader environment remains poorly defined. In this article, we provide a brief overview of studies that have examined the impact of the environment including the built physical environment, discuss current challenges in the field, and suggest potential directions for future research. Additionally, we highlight the clinical implications of these findings and propose multilevel interventions to promote cardiovascular health among children and young adults.

Reduced Pulmonary Artery Distensibility Predicts Persistent Pulmonary Hypertension and 2-Year Mortality in Patients with Severe Aortic Stenosis Undergoing TAVR.

RATIONALE AND OBJECTIVES: Post-TAVR persistent pulmonary hypertension (PH) is a better predictor of poor outcome than pre-TAVR PH. In this longitudinal study we sought to evaluate whether pulmonary artery (distensibility (DPA) measured on preprocedural ECG-gated CTA is associated with persistent-PH and 2-year mortality after TAVR. MATERIALS AND METHODS: Three hundred and thirty-six patients undergoing TAVR between July 2012 and March 2016 were retrospectively included and followed for all-cause mortality until November 2017. All patients underwent retrospectively ECG-gated CTA prior to TAVR. Main pulmonary artery (MPA) area was measured in systole and in diastole. DPA was calculated as: [(area-MPAmax-area-MPAmin)/area-MPAmax]%. ROC analysis was performed to assess the AUC for persistent-PH. Youden Index was used to determine the optimal threshold of DPA for persistent-PH. Two groups were compared based on a DPA threshold of 8% (specificity of 70% for persistent-PH). Kaplan-Meier, Cox proportional-hazard, and logistic regression analyses were performed. The primary clinical endpoint was defined as persistent-PH post-TAVR. The secondary endpoint was defined as all-cause mortality 2 years after TAVR. RESULTS: Median follow-up time was 413 (interquartiles 339-757) days. A total of 183 (54%) had persistent-PH and 68 (20%) patients died within 2-years after TAVR. Patients with DPA<8% had significantly more persistent-PH (67% vs 47%, p<0.001) and 2-year deaths (28% vs 15%, p=0.006), compared to patients with DPA>8%. Adjusted multivariable regression analyses showed that DPA<8% was independently associated with persistent-PH (OR 2.10 [95%-CI 1.3-4.5], p=0.007) and 2-year mortality (HR 2.91 [95%-CI 1.5-5.8], p=0.002). Kaplan-Meier analysis showed that 2-year mortality of patients with DPA<8% was significantly higher compared to patients with DPA≥8% (mortality 28% vs 15%; log-rank p=0.003). CONCLUSION: DPA on preprocedural CTA is independently associated with persistent-PH and two-year mortality in patients who undergo TAVR.

The Cannabinoids, CBDA and THCA, Rescue Memory Deficits and Reduce Amyloid-Beta and Tau Pathology in an Alzheimer's Disease-like Mouse Model.

Most studies related to hemp are focused on Cannabidiol (CBD) and Tetrahydrocannabinol (THC); however, up to 120 types of phytocannabinoids are present in hemp. Hemp leaves contain large amounts of Cannabidiolic acid (CBDA) and Tetrahydrocannabinolic acid (THCA), which are acidic variants of CBD and THC and account for the largest proportion of CBDA. In recent studies, CBDA exhibited anti-hyperalgesia and anti-inflammatory effects. THCA also showed anti-inflammatory and neuroprotective effects that may be beneficial for treating neurodegenerative diseases. CBDA and THCA can penetrate the blood-brain barrier (BBB) and affect the central nervous system. The purpose of this study was to determine whether CBDA and THCA ameliorate Alzheimer's disease (AD)-like features in vitro and in vivo. The effect of CBDA and THCA was evaluated in the Aß1-42-treated mouse model. We observed that Aß1-42-treated mice had more hippocampal Aß and p-tau levels, pathological markers of AD, and loss of cognitive function compared with PBS-treated mice. However, CBDA- and THCA-treated mice showed decreased hippocampal Aß and p-tau and superior cognitive function compared with Aß1-42-treated mice. In addition, CBDA and THCA lowered Aß and p-tau levels, alleviated calcium dyshomeostasis, and exhibited neuroprotective effects in primary neurons. Our results suggest that CBDA and THCA have anti-AD effects and mitigate memory loss and resilience to increased hippocampal Ca2+, Aß, and p-tau levels. Together, CBDA and THCA may be useful therapeutic agents for treating AD.

Ca2+-Permeable TRPV1 Receptor Mediates Neuroprotective Effects in a Mouse Model of Alzheimer's Disease via BDNF/CREB Signaling Pathway.

Transient receptor potential vanilloid 1 (TRPV1) protein is a Ca2+-permeable non-selective cation channel known for its pain modulation pathway. In a previous study, it was discovered that a triple-transgenic Alzheimer's disease (AD) mouse model (3xTg-AD+/+) has anti-AD effects. The expression of proteins in the brain-derived neurotrophic factor (BDNF)/cAMP response element binding protein (CREB) pathway in a 3xTg-AD/TRPV1 transgenic mice model was investigated to better understand the AD regulatory effect of TRPV1 deficiency. The results show that TRPV1 deficiency leads to CREB activation by increasing BDNF levels and promoting phosphorylation of tyrosine receptor kinase B (TrkB), extracellular signal-regulated kinase (ERK), protein kinase B (Akt), and CREB in the hippocampus. Additionally, TRPV1 deficiency-induced CREB activation increases the antiapoptotic factor B-cell lymphoma 2 (Bcl-2) gene, which consequently downregulates Bcl-2-associated X (Bax) expression and decreases cleaved caspase-3 and cleaved poly (ADP-ribose) polymerase (PARP), which leads to the prevention of hippocampal apoptosis. In conclusion, TRPV1 deficiency exhibits neuroprotective effects by preventing apoptosis through the BDNF/CREB signal transduction pathway in the hippocampus of 3xTg-AD mice.

Discovery of Transacting Long Noncoding RNAs That Regulate Smooth Muscle Cell Phenotype.

BACKGROUND: Smooth muscle cells (SMC), the major cell type in atherosclerotic plaques, are vital in coronary artery diseases (CADs). SMC phenotypic transition, which leads to the formation of various cell types in atherosclerotic plaques, is regulated by a network of genetic and epigenetic mechanisms and governs the risk of disease. The involvement of long noncoding RNAs (lncRNAs) has been increasingly identified in cardiovascular disease. However, SMC lncRNAs have not been comprehensively characterized, and their regulatory role in SMC state transition remains unknown. METHODS: A discovery pipeline was constructed and applied to deeply strand-specific RNA sequencing from perturbed human coronary artery SMC with different disease-related stimuli, to allow for the detection of novel lncRNAs. The functional relevance of a select few novel lncRNAs were verified in vitro. RESULTS: We identified 4579 known and 13 655 de novo lncRNAs in human coronary artery SMC. Consistent with previous long noncoding RNA studies, these lncRNAs overall have fewer exons, are shorter in length than protein-coding genes (pcGenes), and have relatively low expression level. Genomic location of these long noncoding RNA is disproportionately enriched near CAD-related TFs (transcription factors), genetic loci, and gene regulators of SMC identity, suggesting the importance of their function in disease. Two de novo lncRNAs, ZIPPOR (ZEB-interacting suppressor) and TNS1-AS2 (TNS1-antisense 2), were identified by our screen. Combining transcriptional data and in silico modeling along with in vitro validation, we identified CAD gene ZEB2 as a target through which these lncRNAs exert their function in SMC phenotypic transition. CONCLUSIONS: Expression of a large and diverse set of lncRNAs in human coronary artery SMC are highly dynamic in response to CAD-related stimuli. The dynamic changes in expression of these lncRNAs correspond to alterations in transcriptional programs that are relevant to CAD, suggesting a critical role for lncRNAs in SMC phenotypic transition and human atherosclerotic disease.

Case report: Recovery of hallucinations and cognitive impairment after administration of donepezil in a patient with schizophrenia and carbon monoxide poisoning.

Objectives: This report aims to introduce a rare case of a dramatic recovery by donepezil with a patient with schizophrenia who suffered from remaining psychotic symptoms despite proper treatment and had a cognitive impairment by carbon monoxide (CO) poisoning sequelae. Case report: A 38-year-old male who developed schizophrenia 2 years ago had attempted suicide via CO inhalation due to his uncontrolled symptoms. He was hospitalized with delayed neurological sequelae (DNS). Though hyperbaric oxygen therapy (HBOT) was applied 10 times, his cognitive impairment did not recover. Surprisingly, with 5-10 mg donepezil, both cognitive function and the psychotic symptoms of the patient remarkably improved. Conclusion: This case showed a good response of donepezil for a patient with schizophrenia and CO-induced DNS after ineffective HBOT. Although the mechanism of the phenomenon is unclear, it can be possible reasons that the neuroprotective effect of donepezil and white matter insult by CO poisoning.

Modulation of mouse laryngeal inflammatory and immune cell responses by low and high doses of mainstream cigarette smoke.

Cigarette smoking is a major risk factor for laryngeal diseases. Despite well-documented cigarette smoke (CS) induced laryngeal histopathological changes, the underlying immunopathological mechanisms remain largely unexplored. The goal of this study was to evaluate inflammatory and immune cell responses in a CS-exposed larynx. Specifically, we used a 4-week subacute whole-body CS inhalation mouse model to assess these responses in the laryngeal mucosa upon exposure to low (LD; 1 h/day) and high dose (HD; 4 h/day) CS. Laryngeal tissues were harvested and evaluated using a 254-plex NanoString inflammation panel and neutrophil/macrophage/T-cell immunohistochemistry (IHC). NanoString global and differential gene expression analysis revealed a unique expression profile only in the HD group, with 26 significant differentially expressed genes (DEGs). StringDB KEGG pathway enrichment analysis revealed the involvement of these DEGs with pro-inflammatory pathways including TNF/TNFα and IL-17. Furthermore, inflammatory responses remained inhibited in conjunction with predicted activated states of anti-inflammatory regulators like PPARγ and NFE2L2 upon Ingenuity Pathway Analysis (IPA). Subglottic T-cell levels remained significantly inhibited as corroborated by IPA predictions. Overall, our key findings are consistent with HD exposures being anti-inflammatory and immunosuppressive. Furthermore, the identification of important regulatory genes and enriched pathways may help improve clinical interventions for CS-induced laryngeal diseases.

Smad3 regulates smooth muscle cell fate and mediates adverse remodeling and calcification of the atherosclerotic plaque.

Atherosclerotic plaques consist mostly of smooth muscle cells (SMC), and genes that influence SMC phenotype can modulate coronary artery disease (CAD) risk. Allelic variation at 15q22.33 has been identified by genome-wide association studies to modify the risk of CAD and is associated with the expression of SMAD3 in SMC. However, the mechanism by which this gene modifies CAD risk remains poorly understood. Here we show that SMC-specific deletion of Smad3 in a murine atherosclerosis model resulted in greater plaque burden, more outward remodelling and increased vascular calcification. Single-cell transcriptomic analyses revealed that loss of Smad3 altered SMC transition cell state toward two fates: a SMC phenotype that governs both vascular remodelling and recruitment of inflammatory cells, as well as a chondromyocyte fate. Together, the findings reveal that Smad3 expression in SMC inhibits the emergence of specific SMC phenotypic transition cells that mediate adverse plaque features, including outward remodelling, monocyte recruitment, and vascular calcification.

Global Longitudinal Strain and Biomarkers of Cardiac Damage and Stress as Predictors of Outcomes After Transcatheter Aortic Valve Implantation.

Background Global longitudinal strain (GLS) is a sensitive measure of left ventricular function and a risk marker in severe aortic stenosis. We sought to determine whether biomarkers of cardiac damage (cardiac troponin) and stress (NT-proBNP [N-terminal pro-B-type natriuretic peptide]) could complement GLS to identify patients with severe aortic stenosis at highest risk. Methods and Results From a multicenter prospective cohort of patients with symptomatic severe aortic stenosis who underwent transcatheter aortic valve implantation, we measured absolute GLS (aGLS), cardiac troponin, and NT-proBNP at baseline in 499 patients. Left ventricular ejection fraction <50% was observed in 19% and impaired GLS (aGLS <15%) in 38%. Elevations in cardiac troponin and NT-proBNP were present in 79% and 89% of those with impaired GLS, respectively, as compared with 63% and 60% of those with normal GLS, respectively (P<0.001 for each). aGLS <15% was associated with increased mortality in univariable analysis (P=0.009), but, in a model with both biomarkers, aGLS, and clinical covariates included, aGLS was not associated with mortality; elevation in each biomarker was associated with an increased hazard of mortality (adjusted hazard ratio, >2; P≤0.002 for each) when the other biomarker was elevated, but not when the other biomarker was normal (interaction P=0.015). Conclusions Among patients with symptomatic severe aortic stenosis undergoing transcatheter aortic valve implantation, elevations in circulating cardiac troponin and NT-proBNP are more common as GLS worsens. Biomarkers of cardiac damage and stress are independently associated with mortality after transcatheter aortic valve implantation, whereas GLS is not. These findings may have implications for risk stratification of asymptomatic patients to determine optimal timing of valve replacement.

Chiroptical Characteristics of Nanosegregated Phases in Binary Mixture Consisting of Achiral Bent-Core Molecule and Bent-Core Base Main-Chain Polymer.

In this paper, a binary mixture system consisting of an achiral bent-core molecule and a bent-core base main-chain polymer is described. The mixture exhibits an intriguing nanosegregated phase generated by the phase separation of the helical nanofilament B4 phase (originating from the bent-core molecule) and the dark conglomerate phase (originating from the bent-core base main-chain polymer). This nanosegregated phase was identified using polarized optical microscopy, differential scanning calorimetry, and X-ray diffraction analysis. In this nanosegregated phase, the enantiomeric domains grew to a few millimeters and a giant circular dichroism was observed. The structural chirality of the helical nanofilament B4 phase affected the conformation of the bent-core base main-chain polymer embedded within the helical nanofilament networks of bent-core molecules.

GPCR19 Regulates P2X7R-Mediated NLRP3 Inflammasomal Activation of Microglia by Amyloid ß in a Mouse Model of Alzheimer's Disease.

Amyloid ß (Aß) and/or ATP activate the NLRP3 inflammasome (N3I) via P2X7R in microglia, which is crucial in neuroinflammation in Alzheimer's disease (AD). Due to polymorphisms, subtypes, and ubiquitous expression of P2X7R, inhibition of P2X7R has not been effective for AD. We first report that taurodeoxycholate (TDCA), a GPCR19 ligand, inhibited the priming phase of N3I activation, suppressed P2X7R expression and P2X7R-mediated Ca++ mobilization and N3I oligomerization, which is essential for production of IL-1ß/IL-18 by microglia. Furthermore, TDCA enhanced phagocytosis of Aß and decreased the number of Aß plaques in the brains of 5x Familial Alzheimer's disease (5xFAD) mice. TDCA also reduced microgliosis, prevented neuronal loss, and improved memory function in 5xFAD mice. The pleiotropic roles of GPCR19 in P2X7R-mediated N3I activation suggest that targeting GPCR19 might resolve neuroinflammation in AD patients.

Left Ventricular Hypertrophy and Biomarkers of Cardiac Damage and Stress in Aortic Stenosis.

Background Left ventricular hypertrophy (LVH) is associated with increased mortality risk and rehospitalization after transcatheter aortic valve replacement among those with severe aortic stenosis. Whether cardiac troponin (cTnT) and NT-proBNP (N-terminal pro-B-type natriuretic peptide) risk stratify patients with aortic stenosis and without LVH is unknown. Methods and Results In a multicenter prospective registry of 923 patients with severe aortic stenosis undergoing transcatheter aortic valve replacement, we included 674 with core-laboratory-measured LV mass index, cTnT, and NT-proBNP. LVH was defined by sex-specific guideline cut-offs and elevated biomarker levels were based on age and sex cut-offs. Adjusted Cox proportional hazards models evaluated associations between LVH and biomarkers and all-cause death out to 5 years. Elevated cTnT and NT-proBNP were present in 82% and 86% of patients with moderate/severe LVH, respectively, as compared with 66% and 69% of patients with no/mild LVH, respectively (P<0.001 for each). After adjustment, compared with no/mild LVH, moderate/severe LVH was associated with an increased hazard of mortality (adjusted hazard ratio [aHR], 1.34; 95% CI 1.01-1.77, P=0.043). cTnT and NT-proBNP each risk stratified patients with moderate/severe LVH (P<0.05). In a model with both biomarkers and LVH included, elevated cTnT (aHR, 2.08; 95% CI 1.45-3.00, P<0.001) and elevated NT-proBNP (aHR, 1.46; 95% CI 1.00-2.11, P=0.049) were each associated with increased mortality risk, whereas moderate/severe LVH was not (P=0.15). Conclusions Elevations in circulating cTnT and NT-proBNP are more common as LVH becomes more pronounced but are also observed in those with no/minimal LVH. As measures of maladaptive remodeling and cardiac injury, cTnT and NT-proBNP predict post-transcatheter aortic valve replacement mortality better than LV mass index. These findings may have important implications for risk stratification and treatment of patients with aortic stenosis.