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| 3. |
- Panyard, D. J., et al.
(author)
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Large-scale proteome and metabolome analysis of CSF implicates altered glucose and carbon metabolism and succinylcarnitine in Alzheimer's disease
- 2023
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In: Alzheimers & Dementia. - 1552-5260.
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Journal article (peer-reviewed)abstract
- INTRODUCTIONA hallmark of Alzheimer's disease (AD) is the aggregation of proteins (amyloid beta [A] and hyperphosphorylated tau [T]) in the brain, making cerebrospinal fluid (CSF) proteins of particular interest. METHODSWe conducted a CSF proteome-wide analysis among participants of varying AT pathology (n = 137 participants; 915 proteins) with nine CSF biomarkers of neurodegeneration and neuroinflammation. RESULTSWe identified 61 proteins significantly associated with the AT category (P < 5.46 x 10(-5)) and 636 significant protein-biomarker associations (P < 6.07 x 10(-6)). Proteins from glucose and carbon metabolism pathways were enriched among amyloid- and tau-associated proteins, including malate dehydrogenase and aldolase A, whose associations with tau were replicated in an independent cohort (n = 717). CSF metabolomics identified and replicated an association of succinylcarnitine with phosphorylated tau and other biomarkers. DISCUSSIONThese results implicate glucose and carbon metabolic dysregulation and increased CSF succinylcarnitine levels with amyloid and tau pathology in AD. HIGHLIGHTSCerebrospinal fluid (CSF) proteome enriched for extracellular, neuronal, immune, and protein processing.Glucose/carbon metabolic pathways enriched among amyloid/tau-associated proteins.Key glucose/carbon metabolism protein associations independently replicated.CSF proteome outperformed other omics data in predicting amyloid/tau positivity.CSF metabolomics identified and replicated a succinylcarnitine-phosphorylated tau association.
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| 6. |
- Di Feo, Maria Francesca, et al.
(author)
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Inferring disease course from differential exon usage in the wide titinopathy spectrum
- 2024
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In: Annals of Clinical and Translational Neurology. - : John Wiley and Sons Inc. - 2328-9503.
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Journal article (peer-reviewed)abstract
- Objective: Biallelic titin truncating variants (TTNtv) have been associated with a wide phenotypic spectrum, ranging from complex prenatal muscle diseases with dysmorphic features to adult-onset limb-girdle muscular dystrophy, with or without cardiac involvement. Given the size and complexity of TTN, reaching an unequivocal molecular diagnosis and precise disease prognosis remains challenging. Methods: In this case series, 12 unpublished cases and one already published case with biallelic TTNtv were collected from multiple international medical centers between November 2022 and September 2023. TTN mutations were detected through exome or genome sequencing. Information about familial and personal clinical history was collected in a standardized form. RNA-sequencing and analysis of TTN exon usage were performed on an internal sample cohort including postnatal skeletal muscles, fetal skeletal muscles, postnatal heart muscles, and fetal heart muscles. In addition, publicly available RNA-sequencing data was retrieved from ENCODE. Results: We generated new RNA-seq data on TTN exons and identified genotype–phenotype correlations with prognostic implications for each titinopathy patient (whether worsening or improving in prenatal and postnatal life) using percentage spliced in (PSI) data for the involved exons. Interestingly, thanks to exon usage, we were also able to rule out a titinopathy diagnosis in one prenatal case. Interpretation: This study demonstrates that exon usage provides valuable insights for a more exhaustive clinical interpretation of TTNtv; additionally, it may serve as a model for implementing personalized medicine in many other genetic diseases, since most genes undergo alternative splicing.
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| 8. |
- Morrow, A., et al.
(author)
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Cerebrospinal Fluid Sphingomyelins in Alzheimer's Disease, Neurodegeneration, and Neuroinflammation
- 2022
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In: Journal of Alzheimers Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 90:2, s. 667-680
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Journal article (peer-reviewed)abstract
- Background: Sphingomyelin (SM) levels have been associated with Alzheimer's disease (AD), but the association direction has been inconsistent and research on cerebrospinal fluid (CSF) SMs has been limited by sample size, breadth of SMs examined, and diversity of biomarkers available. Objective: Here, we seek to build on our understanding of the role of SM metabolites in AD by studying a broad range of CSF SMs and biomarkers of AD, neurodegeneration, and neuroinflammation. Methods: Leveraging two longitudinal AD cohorts with metabolome-wide CSF metabolomics data (n = 502), we analyzed the relationship between the levels of 12 CSF SMs, and AD diagnosis and biomarkers of pathology, neurodegeneration, and neuroinflammation using logistic, linear, and linear mixed effects models. Results: No SMs were significantly associated with AD diagnosis, mild cognitive impairment, or amyloid biomarkers. Phosphorylated tau, neurofilament light, alpha-synuclein, neurogranin, soluble triggering receptor expressed on myeloid cells 2, and chitinase-3-like-protein 1 were each significantly, positively associated with at least 5 of the SMs. Conclusion: The associations between SMs and biomarkers of neurodegeneration and neuroinflammation, but not biomarkers of amyloid or diagnosis of AD, point to SMs as potential biomarkers for neurodegeneration and neuroinflammation that may not be AD-specific.
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| 9. |
- Adamson, Carly, et al.
(author)
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IGFBP-7 and Outcomes in Heart Failure With Reduced Ejection Fraction : Findings From DAPA-HF.
- 2023
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In: JACC. Heart failure. - : Elsevier BV. - 2213-1779 .- 2213-1787. ; 11:3, s. 291-304
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Journal article (peer-reviewed)abstract
- BACKGROUND: Insulin-like growth factor-binding protein-7 (IGFBP-7) has been proposed as a potential prognostic biomarker in heart failure (HF), but the association between elevation in IGFBP-7 and HF outcomes in ambulant patients with heart failure with reduced ejection fraction (HFrEF) is unknown. OBJECTIVES: The authors addressed this question in a post hoc analysis of the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial. METHODS: The primary outcome was a composite of cardiovascular death or a worsening HF event. The risk of adverse outcome was compared across tertiles of IGFBP-7 concentration by means of Cox proportional hazard models adjusted for N-terminal pro-B- type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hsTnT). The efficacy of randomized treatment across IGFBP-7 tertiles was assessed. Change in IGFBP-7 at 12 months was compared with the use of geometric means. RESULTS: A total of 3,158 patients had IGFBP-7 measured at baseline, and 2,493 had a repeated measure at 12 months. Patients in the highest tertile of IGFBP-7 had evidence of more advanced HFrEF. The adjusted HR for the primary endpoint in tertile 3, compared with tertile 1, was 1.48 (95% CI: 1.17-1.88). There was no modification of the benefit of dapagliflozin by baseline IGFBP-7 (P interaction = 0.34). Dapagliflozin did not change IGFBP-7 levels over 1 year (P = 0.34). CONCLUSIONS: Higher IGFBP-7 in patients with HFrEF was associated with worse clinical profile and an increased risk of adverse clinical outcomes. IGFBP-7 provided prognostic information incremental to clinical variables, NT-proBNP, and hsTnT. The benefit of dapagliflozin was not modulated by IGFBP-7 level. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124).
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| 10. |
- Barrenäs, Fredrik, et al.
(author)
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Interleukin-15 response signature predicts RhCMV/SIV vaccine efficacy
- 2021
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In: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 17:7
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Journal article (peer-reviewed)abstract
- Simian immunodeficiency virus (SIV) challenge of rhesus macaques (RMs) vaccinated with strain 68-1 Rhesus Cytomegalovirus (RhCMV) vectors expressing SIV proteins (RhCMV/SIV) results in a binary outcome: stringent control and subsequent clearance of highly pathogenic SIV in similar to 55% of vaccinated RMs with no protection in the remaining 45%. Although previous work indicates that unconventionally restricted, SIV-specific, effector-memory (EM)-biased CD8(+) T cell responses are necessary for efficacy, the magnitude of these responses does not predict efficacy, and the basis of protection vs. non-protection in 68-1 RhCMV/SIV vector-vaccinated RMs has not been elucidated. Here, we report that 68-1 RhCMV/SIV vector administration strikingly alters the whole blood transcriptome of vaccinated RMs, with the sustained induction of specific immune-related pathways, including immune cell, toll-like receptor (TLR), inflammasome/cell death, and interleukin-15 (IL-15) signaling, significantly correlating with subsequent vaccine efficacy. Treatment of a separate RM cohort with IL-15 confirmed the central involvement of this cytokine in the protection signature, linking the major innate and adaptive immune gene expression networks that correlate with RhCMV/SIV vaccine efficacy. This change-from-baseline IL-15 response signature was also demonstrated to significantly correlate with vaccine efficacy in an independent validation cohort of vaccinated and challenged RMs. The differential IL-15 gene set response to vaccination strongly correlated with the pre-vaccination activity of this pathway, with reduced baseline expression of IL-15 response genes significantly correlating with higher vaccine-induced induction of IL-15 signaling and subsequent vaccine protection, suggesting that a robust de novo vaccine-induced IL-15 signaling response is needed to program vaccine efficacy. Thus, the RhCMV/SIV vaccine imparts a coordinated and persistent induction of innate and adaptive immune pathways featuring IL-15, a known regulator of CD8(+) T cell function, that support the ability of vaccine-elicited unconventionally restricted CD8(+) T cells to mediate protection against SIV challenge.
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| 11. |
- Cristea, A. Ioana, et al.
(author)
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Approaches to Interdisciplinary Care for Infants with Severe Bronchopulmonary Dysplasia: A Survey of the Bronchopulmonary Dysplasia Collaborative
- 2022
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In: American Journal of Perinatology. - : Georg Thieme Verlag KG. - 0735-1631 .- 1098-8785.
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Journal article (peer-reviewed)abstract
- Objective: Bronchopulmonary dysplasia (BPD) remains the most common late morbidity for extremely premature infants. Care of infants with BPD requires a longitudinal approach from the neonatal intensive care unit to ambulatory care though interdisciplinary programs. Current approaches for the development of optimal programs vary among centers.Study design: We conducted a survey of 18 academic centers that are members of the BPD Collaborative, a consortium of institutions with an established interdisciplinary BPD program. We aimed to characterize the approach, composition, and current practices of the interdisciplinary teams in inpatient and outpatient domains.Results: Variations exist among centers, including composition of the interdisciplinary team, whether the team is the primary or consult service, timing of the first team assessment of the patient, frequency and nature of rounds during the hospitalization, and the timing of ambulatory visits postdischarge.Conclusion: Further studies to assess long-term outcomes are needed to optimize interdisciplinary care of infants with severe BPD.Key points: · Care of infants with BPD requires a longitudinal approach from the NICU to ambulatory care.. · Benefits of interdisciplinary care for children have been observed in other chronic conditions.. · Current approaches for the development of optimal interdisciplinary BPD programs vary among centers..
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| 12. |
- Docherty, Kieran F., et al.
(author)
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Iron Deficiency in Heart Failure and Effect of Dapagliflozin : Findings From DAPA-HF.
- 2022
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In: Circulation. ; 146:13, s. 980-994
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Journal article (peer-reviewed)abstract
- BACKGROUND: Iron deficiency is common in heart failure and associated with worse outcomes. We examined the prevalence and consequences of iron deficiency in the DAPA-HF trial (Dapagliflozin and Prevention of Adverse- Outcomes in Heart Failure) and the effect of dapagliflozin on markers of iron metabolism. We also analyzed the effect of dapagliflozin on outcomes, according to iron status at baseline. METHODS: Iron deficiency was defined as a ferritin level $<$100 ng/mL or a transferrin saturation $<$20% and a ferritin level 100 to 299 ng/mL. Additional biomarkers of iron metabolism, including soluble transferrin receptor, erythropoietin, and hepcidin were measured at baseline and 12 months after randomization. The primary outcome was a composite of worsening heart failure (hospitalization or urgent visit requiring intravenous therapy) or cardiovascular death. RESULTS: Of the 4744 patients randomized in DAPA- HF, 3009 had ferritin and transferrin saturation measurements available at baseline, and 1314 of these participants (43.7%) were iron deficient. The rate of the primary outcome was higher in patients with iron deficiency (16.6 per 100 person-years) compared with those without (10.4 per 100 person-years; P$<$0.0001). The effect of dapagliflozin on the primary outcome was consistent in iron-deficient compared with iron- replete patients (hazard ratio, 0.74 [95% CI, 0.58-0.92] versus 0.81 [95% CI, 0.63-1.03]; P-interaction=0.59). Similar findings were observed for cardiovascular death, heart failure hospitalization, and all-cause mortality. Transferrin saturation, ferritin, and hepcidin were reduced and total iron-binding capacity and soluble transferrin receptor increased with dapagliflozin compared with placebo. CONCLUSIONS: Iron deficiency was common in DAPA-HF and associated with worse outcomes. Dapagliflozin appeared to increase iron use but improved outcomes, irrespective of iron status at baseline. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03036124.
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| 13. |
- Berg, David D., et al.
(author)
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Serial Assessment of High-Sensitivity Cardiac Troponin and the Effect of Dapagliflozin in Patients With Heart Failure With Reduced Ejection Fraction : An Analysis of the DAPA-HF Trial.
- 2022
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In: Circulation. ; 145:3, s. 158-169
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Journal article (peer-reviewed)abstract
- BACKGROUND: Circulating high-sensitivity cardiac troponin T (hsTnT) predominantly reflects myocardial injury, and higher levels are associated with a higher risk of worsening heart failure and death in patients with heart failure with reduced ejection fraction. Less is known about the prognostic significance of changes in hsTnT over time, the effects of dapagliflozin on clinical outcomes in relation to baseline hsTnT levels, and the effect of dapagliflozin on hsTnT levels. METHODS: DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) was a randomized, double-blind, placebo-controlled trial of dapagliflozin (10 mg daily) in patients with New York Heart Association class II to IV symptoms and left ventricular ejection fraction $<$/=40% (median follow-up, 18.2 months). hsTnT (Roche Diagnostics) was measured at baseline in 3112 patients and at 1 year in 2506 patients. The primary end point was adjudicated worsening heart failure or cardiovascular death. Clinical end points were analyzed according to baseline hsTnT and change in hsTnT from baseline to 1 year. Comparative treatment effects on clinical end points with dapagliflozin versus placebo were assessed by baseline hsTnT. The effect of dapagliflozin on hsTnT was explored. RESULTS: Median baseline hsTnT concentration was 20.0 (25th-75th percentile, 13.7-30.2) ng/L. Over 1 year, 67.9% of patients had a $>$/=10% relative increase or decrease in hsTnT concentrations, and 43.5% had a $>$/=20% relative change. A stepwise gradient of higher risk for the primary end point was observed across increasing quartiles of baseline hsTnT concentration (adjusted hazard ratio Q4 versus Q1, 3.44 [95% CI, 2.46-4.82]). Relative and absolute increases in hsTnT over 1 year were associated with higher subsequent risk of the primary end point. The relative reduction in the primary end point with dapagliflozin was consistent across quartiles of baseline hsTnT (P-interaction=0.55), but patients in the top quartile tended to have the greatest absolute risk reduction (absolute risk difference, 7.5% [95% CI, 1.0%-14.0%]). Dapagliflozin tended to attenuate the increase in hsTnT over time compared with placebo (relative least squares mean reduction, -3% [-6% to 0%]; P=0.076). CONCLUSIONS: Higher baseline hsTnT and greater increase in hsTnT over 1 year are associated with worse clinical outcomes. Dapagliflozin consistently reduced the risk of the primary end point, irrespective of baseline hsTnT levels. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036124.
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| 14. |
- Carnicelli, Anthony P., et al.
(author)
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Direct Oral Anticoagulants Versus Warfarin in Patients With Atrial Fibrillation : Patient-Level Network Meta-Analyses of Randomized Clinical Trials With Interaction Testing by Age and Sex
- 2022
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In: Circulation. - : Ovid Technologies (Wolters Kluwer Health). - 0009-7322 .- 1524-4539. ; 145:4, s. 242-255
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Journal article (peer-reviewed)abstract
- Background: Direct oral anticoagulants (DOACs) are preferred over warfarin for stroke prevention in atrial fibrillation. Meta-analyses using individual patient data offer substantial advantages over study-level data.Methods: We used individual patient data from the COMBINE AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation) database, which includes all patients randomized in the 4 pivotal trials of DOACs versus warfarin in atrial fibrillation (RE-LY [Randomized Evaluation of Long-Term Anticoagulation Therapy], ROCKET AF [Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation], ARISTOTLE [Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation], and ENGAGE AF-TIMI 48 [Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48]), to perform network meta-analyses using a stratified Cox model with random effects comparing standard-dose DOAC, lower-dose DOAC, and warfarin. Hazard ratios (HRs [95% CIs]) were calculated for efficacy and safety outcomes. Covariate-by-treatment interaction was estimated for categorical covariates and for age as a continuous covariate, stratified by sex.Results: A total of 71 683 patients were included (29 362 on standard-dose DOAC, 13 049 on lower-dose DOAC, and 29 272 on warfarin). Compared with warfarin, standard-dose DOACs were associated with a significantly lower hazard of stroke or systemic embolism (883/29 312 [3.01%] versus 1080/29 229 [3.69%]; HR, 0.81 [95% CI, 0.74-0.89]), death (2276/29 312 [7.76%] versus 2460/29 229 [8.42%]; HR, 0.92 [95% CI, 0.87-0.97]), and intracranial bleeding (184/29 270 [0.63%] versus 409/29 187 [1.40%]; HR, 0.45 [95% CI, 0.37-0.56]), but no statistically different hazard of major bleeding (1479/29 270 [5.05%] versus 1733/29 187 [5.94%]; HR, 0.86 [95% CI, 0.74-1.01]), whereas lower-dose DOACs were associated with no statistically different hazard of stroke or systemic embolism (531/13 049 [3.96%] versus 1080/29 229 [3.69%]; HR, 1.06 [95% CI, 0.95-1.19]) but a lower hazard of intracranial bleeding (55/12 985 [0.42%] versus 409/29 187 [1.40%]; HR, 0.28 [95% CI, 0.21-0.37]), death (1082/13 049 [8.29%] versus 2460/29 229 [8.42%]; HR, 0.90 [95% CI, 0.83-0.97]), and major bleeding (564/12 985 [4.34%] versus 1733/29 187 [5.94%]; HR, 0.63 [95% CI, 0.45-0.88]). Treatment effects for standard- and lower-dose DOACs versus warfarin were consistent across age and sex for stroke or systemic embolism and death, whereas standard-dose DOACs were favored in patients with no history of vitamin K antagonist use (P=0.01) and lower creatinine clearance (P=0.09). For major bleeding, standard-dose DOACs were favored in patients with lower body weight (P=0.02). In the continuous covariate analysis, younger patients derived greater benefits from standard-dose (interaction P=0.02) and lower-dose DOACs (interaction P=0.01) versus warfarin.Conclusions: Compared with warfarin, DOACs have more favorable efficacy and safety profiles among patients with atrial fibrillation.
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| 15. |
- Carnicelli, Anthony P, et al.
(author)
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Individual Patient Data from the Pivotal Randomized Controlled Trials of Non-Vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation (COMBINE AF) : Design and Rationale
- 2021
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In: American Heart Journal. - : Elsevier. - 0002-8703 .- 1097-6744. ; Mar:233, s. 48-58
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Journal article (peer-reviewed)abstract
- BACKGROUND: Non-vitamin K antagonist oral anticoagulants (NOACs) are the preferred class of medications for prevention of stroke and systemic embolism in patients with atrial fibrillation unless contraindications exist. Five large, international, randomized, controlled trials of NOACs versus either warfarin or aspirin have been completed to date.DESIGN: COMBINE AF incorporates de-identified individual patient data from 77,282 patients with atrial fibrillation at risk for stroke randomized to NOAC, warfarin, or aspirin from 5 pivotal randomized controlled trials. All patients randomized in the constituent trials are included. Variables common to ≥3 of the constituent trials are included in the master database. Individual trial data sets from the 4 coordinating centers were combined at the Duke Clinical Research Institute. The final database will be securely shared with the 4 academic coordinating centers. The combined master database will be used to perform statistical analyses aimed at better understanding underlying risk factors and outcomes in patients with atrial fibrillation treated with oral anticoagulants, with a special focus on patient subgroups and uncommon outcomes. The initial analysis from COMBINE AF will be a network meta-analysis investigating the relative efficacy and safety of pooled higher-dose NOACs versus pooled lower-dose NOACs versus warfarin with respect to multiple time-to-event efficacy and safety outcomes. COMBINE AF is registered with PROSPERO (CRD42020178771).CONCLUSIONS: In conclusion, COMBINE AF provides a rich and robust database consisting of individual patient data and will offer opportunities to investigate oral anticoagulants across many patient subgroups. Data sharing and collaboration across academic institutions and investigators will serve as overarching themes.
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| 16. |
- Deming, Y., et al.
(author)
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Neuropathology-based APOE genetic risk score better quantifies Alzheimer's risk
- 2023
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In: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:8, s. 3406-3416
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Journal article (peer-reviewed)abstract
- IntroductionApolipoprotein E (APOE) epsilon 4-carrier status or epsilon 4 allele count are included in analyses to account for the APOE genetic effect on Alzheimer's disease (AD); however, this does not account for protective effects of APOE epsilon 2 or heterogeneous effect of epsilon 2, epsilon 3, and epsilon 4 haplotypes. MethodsWe leveraged results from an autopsy-confirmed AD study to generate a weighted risk score for APOE (APOE-npscore). We regressed cerebrospinal fluid (CSF) amyloid and tau biomarkers on APOE variables from the Wisconsin Registry for Alzheimer's Prevention (WRAP), Wisconsin Alzheimer's Disease Research Center (WADRC), and Alzheimer's Disease Neuroimaging Initiative (ADNI). ResultsThe APOE-npscore explained more variance and provided a better model fit for all three CSF measures than APOE epsilon 4-carrier status and epsilon 4 allele count. These findings were replicated in ADNI and observed in subsets of cognitively unimpaired (CU) participants. DiscussionThe APOE-npscore reflects the genetic effect on neuropathology and provides an improved method to account for APOE in AD-related analyses.
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| 17. |
- McDowell, Kirsty, et al.
(author)
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Dapagliflozin Reduces Uric Acid Concentration, an Independent Predictor of Adverse Outcomes in DAPA-HF.
- 2022
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In: European journal of heart failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 24:6, s. 1066-1076
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Journal article (peer-reviewed)abstract
- AIMS: Blood uric acid (UA) levels are frequently elevated in patients with heart failure and reduced ejection fraction (HFrEF), may lead to gout and are associated with worse outcomes. Reduction in UA is desirable in HFrEF and sodium-glucose cotransporter 2 inhibitors may have this effect. We aimed to examine the association between UA and outcomes, the effect of dapagliflozin according to baseline UA level, and the effect of dapagliflozin on UA in patients with HFrEF in the DAPA-HF trial. METHODS AND RESULTS: The association between UA and the primary composite outcome of cardiovascular death or worsening heart failure, its components, and all-cause mortality was examined using Cox regression analyses among 3119 patients using tertiles of UA, after adjustment for other prognostic variables. Change in UA from baseline over 12 months was also evaluated. Patients in tertile 3 (UA $>$/=6.8 mg/dl) versus tertile 1 ($<$5.4 mg/dl) were younger (66.3 +/- 10.8 vs. 68 +/- 10.2 years), more often male (83.1% vs. 71.5%), had lower estimated glomerular filtration rate (58.2 +/- 17.4 vs. 70.6 +/- 18.7 ml/min/1.73 m(2) ), and more often treated with diuretics. Higher UA was associated with a greater risk of the primary outcome (adjusted hazard ratio tertile 3 vs. tertile 1: 1.32, 95% confidence interval [CI] 1.06-1.66; p = 0.01). The risk of heart failure hospitalization and cardiovascular death increased by 7% and 6%, respectively per 1 mg/dl unit increase of UA (p = 0.04 and p = 0.07). Spline analysis revealed a linear increase in risk above a cut-off UA value of 7.09 mg/dl. Compared with placebo, dapagliflozin reduced UA by 0.84 mg/dl (95% CI -0.93 to -0.74) over 12 months (p $<$ 0.001). Dapagliflozin improved outcomes, irrespective of baseline UA concentration. CONCLUSION: Uric acid remains an independent predictor of worse outcomes in a well-treated contemporary HFrEF population. Compared with placebo, dapagliflozin reduced UA and improved outcomes irrespective of UA concentration.
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