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Article ; Online: CYP2D6 genotype and reduced codeine analgesic effect in real-world clinical practice.

Carranza-Leon, Daniel / Dickson, Alyson L / Gaedigk, Andrea / Stein, C Michael / Chung, Cecilia P

2021 Volume 21, Issue 4, Page(s) 484–490

Abstract: Cytochrome P450 2D6 (CYP2D6) O-demethylates codeine to the active drug, morphine. However, the utility of testing for CYP2D6 metabolizer status in patients receiving codeine in real-world clinical practice is poorly defined. Using data from a DNA bank ... ...

Abstract	Cytochrome P450 2D6 (CYP2D6) O-demethylates codeine to the active drug, morphine. However, the utility of testing for CYP2D6 metabolizer status in patients receiving codeine in real-world clinical practice is poorly defined. Using data from a DNA bank linked to de-identified electronic health records, we studied 157 patients with a baseline pain score higher than 4 (0-10 scale) who received codeine. Based on CYP2D6 genotyping, 69 were classified as poor/intermediate and 88 as normal/ultrarapid CYP2D6 metabolizers. Pain response was defined as a score of 4 or lower while receiving codeine. In a propensity-score adjusted model, poor/intermediate metabolizers had lower odds (OR = 0.35, p = 0.02) of achieving a pain response than normal/ultrarapid metabolizers. To discriminate between codeine responders and nonresponders, a score including CYP2D6 phenotype and clinical variables was built. The response rate was 38.5% among patients in the high, 17.3% in the intermediate, and 9.4% in the low-score groups, respectively (p = 0.001).
MeSH term(s)	Aged ; Analgesics, Opioid/therapeutic use ; Codeine/therapeutic use ; Cytochrome P-450 CYP2D6/genetics ; Female ; Genotype ; Humans ; Male ; Middle Aged ; Morphine/therapeutic use ; Phenotype ; Polymorphism, Genetic/genetics
Chemical Substances	Analgesics, Opioid ; Morphine (76I7G6D29C) ; Cytochrome P-450 CYP2D6 (EC 1.14.14.1) ; Codeine (UX6OWY2V7J)
Language	English
Publishing date	2021-03-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2106831-8
ISSN	1473-1150 ; 1470-269X
ISSN (online)	1473-1150
ISSN	1470-269X
DOI	10.1038/s41397-021-00226-8
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Article ; Online: Intensive Care and Organ Support Related Mortality in Patients With COVID-19: A Systematic Review and Meta-Analysis.

Chandel, Abhimanyu / Leazer, Sahar / Alcover, Karl C / Farley, Josiah / Berk, Joshua / Jayne, Christopher / Mcnutt, Ryan / Olsen, Meredith / Allard, Rhonda / Yang, Jiahong / Johnson, Caitlyn / Tripathi, Ananya / Rechtin, Maria / Leon, Mathew / Williams, Mathias / Sheth, Phorum / Messer, Kyle / Chung, Kevin K / Collen, Jacob

Critical care explorations

2023 Volume 5, Issue 3, Page(s) e0876

Abstract: To perform a systematic review and meta-analysis to generate estimates of mortality in patients with COVID-19 that required hospitalization, ICU admission, and organ support.: Data sources: A systematic search of PubMed, Embase, and the Cochrane ... ...

Abstract	To perform a systematic review and meta-analysis to generate estimates of mortality in patients with COVID-19 that required hospitalization, ICU admission, and organ support. Data sources: A systematic search of PubMed, Embase, and the Cochrane databases was conducted up to December 31, 2021. Study selection: Previously peer-reviewed observational studies that reported ICU, mechanical ventilation (MV), renal replacement therapy (RRT) or extracorporeal membrane oxygenation (ECMO)-related mortality among greater than or equal to 100 individual patients. Data extraction: Random-effects meta-analysis was used to generate pooled estimates of case fatality rates (CFRs) for in-hospital, ICU, MV, RRT, and ECMO-related mortality. ICU-related mortality was additionally analyzed by the study country of origin. Sensitivity analyses of CFR were assessed based on completeness of follow-up data, by year, and when only studies judged to be of high quality were included. Data synthesis: One hundred fifty-seven studies evaluating 948,309 patients were included. The CFR for in-hospital mortality, ICU mortality, MV, RRT, and ECMO were 25.9% (95% CI: 24.0-27.8%), 37.3% (95% CI: 34.6-40.1%), 51.6% (95% CI: 46.1-57.0%), 66.1% (95% CI: 59.7-72.2%), and 58.0% (95% CI: 46.9-68.9%), respectively. MV (52.7%, 95% CI: 47.5-58.0% vs 31.3%, 95% CI: 16.1-48.9%; Conclusions: We present updated estimates of CFR for patients hospitalized and requiring intensive care for the management of COVID-19. Although mortality remain high and varies considerably worldwide, we found the CFR in patients supported with MV significantly improved since 2020.
Language	English
Publishing date	2023-03-03
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2639-8028
ISSN (online)	2639-8028
DOI	10.1097/CCE.0000000000000876
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Article ; Online: Ambulatory blood pressure in patients with systemic lupus erythematosus: Association with markers of immune activation.

Carranza-Leon, Daniel A / Oeser, Annette / Wu, Qiong / Stein, C Michael / Ormseth, Michelle J / Chung, Cecilia P

Lupus

2020 Volume 29, Issue 13, Page(s) 1683–1690

Abstract: Objectives: ...

Abstract	Objectives:
MeSH term(s)	Adult ; Biomarkers/blood ; Blood Pressure ; Blood Pressure Monitoring, Ambulatory ; Case-Control Studies ; Circadian Rhythm ; Female ; Humans ; Hypertension/blood ; Hypertension/diagnosis ; Immune System/physiopathology ; Lupus Erythematosus, Systemic/blood ; Lupus Erythematosus, Systemic/complications ; Lupus Erythematosus, Systemic/immunology ; Male ; Middle Aged
Chemical Substances	Biomarkers
Language	English
Publishing date	2020-08-25
Publishing country	England
Document type	Journal Article
ZDB-ID	1154407-7
ISSN	1477-0962 ; 0961-2033
ISSN (online)	1477-0962
ISSN	0961-2033
DOI	10.1177/0961203320951274
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Article ; Online: Genome-wide association analyses of common infections in a large practice-based biobank.

Jiang, Lan / Kerchberger, V Eric / Shaffer, Christian / Dickson, Alyson L / Ormseth, Michelle J / Daniel, Laura L / Leon, Barbara G Carranza / Cox, Nancy J / Chung, Cecilia P / Wei, Wei-Qi / Stein, C Michael / Feng, QiPing

BMC genomics

2022 Volume 23, Issue 1, Page(s) 672

Abstract: ... herpes labialis, hepatitis B, infectious mononucleosis, tuberculosis (TB) or a positive TB test, and hepatitis C ...

Abstract	Introduction: Infectious diseases are common causes of morbidity and mortality worldwide. Susceptibility to infection is highly heritable; however, little has been done to identify the genetic determinants underlying common infectious diseases. One GWAS was performed using 23andMe information about self-reported infections; we set out to confirm previous loci and identify new ones using medically diagnosed infections. Methods: We used the electronic health record (EHR)-based biobank at Vanderbilt and diagnosis codes to identify cases of 12 infectious diseases in white patients: urinary tract infection, pneumonia, chronic sinus infections, otitis media, candidiasis, streptococcal pharyngitis, herpes zoster, herpes labialis, hepatitis B, infectious mononucleosis, tuberculosis (TB) or a positive TB test, and hepatitis C. We selected controls from patients with no diagnosis code for the candidate disease and matched by year of birth, sex, and calendar year at first and last EHR visits. We conducted GWAS using SAIGE and transcriptome-wide analysis (TWAS) using S-PrediXcan. We also conducted phenome-wide association study to understand associations between identified genetic variants and clinical phenotypes. Results: We replicated three 23andMe loci (p ≤ 0.05): herpes zoster and rs7047299-A (p = 2.6 × 10 Conclusion: We conducted GWAS and TWAS for 12 infectious diseases and identified novel genetic contributors to the susceptibility of infectious diseases.
MeSH term(s)	Biological Specimen Banks ; Candidiasis ; Communicable Diseases ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Hepatitis B ; Herpes Zoster ; Humans ; Otitis Media/genetics ; Polymorphism, Single Nucleotide
Language	English
Publishing date	2022-09-27
Publishing country	England
Document type	Journal Article
ZDB-ID	2041499-7
ISSN	1471-2164 ; 1471-2164
ISSN (online)	1471-2164
ISSN	1471-2164
DOI	10.1186/s12864-022-08888-9
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Article ; Online: Tissue sodium content in patients with systemic lupus erythematosus: association with disease activity and markers of inflammation.

Carranza-León, D A / Oeser, A / Marton, A / Wang, P / Gore, J C / Titze, J / Stein, C M / Chung, C P / Ormseth, M J

Lupus

2020 Volume 29, Issue 5, Page(s) 455–462

Abstract: Objectives: Sodium (Na: Methods: Lower-leg skin and muscle Na: Results: Muscle Na: Conclusion: Patients with SLE had higher muscle ... ...

Abstract	Objectives: Sodium (Na Methods: Lower-leg skin and muscle Na Results: Muscle Na Conclusion: Patients with SLE had higher muscle Na
MeSH term(s)	Adult ; Biomarkers/metabolism ; Blood Pressure ; Case-Control Studies ; Cross-Sectional Studies ; Female ; Humans ; Inflammation/metabolism ; Interleukin-10/metabolism ; Linear Models ; Lupus Erythematosus, Systemic/metabolism ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Muscles/metabolism ; Skin/metabolism ; Sodium/metabolism ; Sodium Isotopes
Chemical Substances	Biomarkers ; Sodium Isotopes ; Interleukin-10 (130068-27-8) ; Sodium (9NEZ333N27)
Language	English
Publishing date	2020-02-18
Publishing country	England
Document type	Journal Article
ZDB-ID	1154407-7
ISSN	1477-0962 ; 0961-2033
ISSN (online)	1477-0962
ISSN	0961-2033
DOI	10.1177/0961203320908934
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Article ; Online: Association Between Low-Density Lipoprotein Cholesterol Levels and Risk for Sepsis Among Patients Admitted to the Hospital With Infection.

Feng, QiPing / Wei, Wei-Qi / Chaugai, Sandip / Leon, Barbara G Carranza / Mosley, Jonathan D / Leon, Daniel A Carranza / Jiang, Lan / Ihegword, Andrea / Shaffer, Christian M / Linton, MacRae F / Chung, Cecilia P / Stein, C Michael

JAMA network open

2019 Volume 2, Issue 1, Page(s) e187223

Abstract: Importance: Whether low levels of low-density lipoprotein cholesterol (LDL-C) are associated ... LDL-C levels and risk of sepsis among patients admitted to the hospital with infection.: Design ... from January 24 through October 31, 2018.: Interventions: Clinically measured LDL-C levels (excluding ...

Abstract	Importance: Whether low levels of low-density lipoprotein cholesterol (LDL-C) are associated with increased risk of sepsis and poorer outcomes is unknown. Objective: To examine the association between LDL-C levels and risk of sepsis among patients admitted to the hospital with infection. Design, setting, and participants: Cohort study in which deidentified electronic health records were used to define a cohort of patients admitted to Vanderbilt University Medical Center, Nashville, Tennessee, with infection. Patients were white adults, had a code indicating infection from the International Classification of Diseases, Ninth Revision, Clinical Modification, and received an antibiotic within 1 day of hospital admission (N = 61 502). Data were collected from January 1, 1993, through December 31, 2017, and analyzed from January 24 through October 31, 2018. Interventions: Clinically measured LDL-C levels (excluding measurements <1 year before hospital admission and those associated with acute illness) and a genetic risk score (GRS). Main outcomes and measures: The primary outcome was sepsis; secondary outcomes included admission to an intensive care unit (ICU) and in-hospital death. Results: Among the 3961 patients with clinically measured LDL-C levels (57.8% women; mean [SD] age, 64.1 [15.9] years) and the 7804 with a GRS for LDL-C (54.0% men; mean [SD] age, 59.8 [15.2] years), lower measured LDL-C levels were significantly associated with increased risk of sepsis (odds ratio [OR], 0.86; 95% CI, 0.79-0.94; P = .001) and ICU admission (OR, 0.85; 95% CI, 0.76-0.96; P = .008), but not in-hospital mortality (OR, 0.80; 95% CI, 0.63-1.00; P = .06); however, none of these associations were statistically significant after adjustment for age, sex, and comorbidity variables (OR for risk of sepsis, 0.96 [95% CI, 0.88-1.06]; OR for ICU admission, 0.94 [95% CI, 0.83-1.06]; OR for in-hospital death, 0.97 [95% CI, 0.76-1.22]; P > .05 for all). The LDL-C GRS correlated with measured LDL-C levels (r = 0.24; P < 2.2 × 10-16) but was not significantly associated with any of the outcomes. Conclusions and relevance: Results of this study suggest that lower measured LDL-C levels were significantly associated with increased risk of sepsis and admission to ICU in patients admitted to the hospital with infection; however, this association was due to comorbidities because both clinical models adjusted for confounders, and the genetic model showed no increased risk. Levels of LDL-C do not appear to directly alter the risk of sepsis or poor outcomes in patients hospitalized with infection.
MeSH term(s)	Aged ; Cholesterol, LDL/metabolism ; Female ; Hospital Mortality ; Hospitalization ; Humans ; Infections/blood ; Infections/diagnosis ; Intensive Care Units ; Male ; Middle Aged ; Risk Factors ; Sepsis/blood
Chemical Substances	Cholesterol, LDL
Language	English
Publishing date	2019-01-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2574-3805
ISSN (online)	2574-3805
DOI	10.1001/jamanetworkopen.2018.7223
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Article ; Online: Improved Cardiac Function in Postischemic Rats Using an Optimized Cardiac Reprogramming Cocktail Delivered in a Single Novel Adeno-Associated Virus.

Zhou, Huanyu / Yang, Jin / Srinath, Chetan / Zeng, Aliya / Wu, Iris / Leon, Elena C / Qureshi, Tawny Neal / Reid, Christopher A / Nettesheim, Emily R / Xu, Emma / Duclos, Zoe / Mohamed, Tamer M A / Farshidfar, Farshad / Fejes, Anthony / Liu, Jun / Jones, Samantha / Feathers, Charles / Chung, Tae Won / Jing, Frank /

Prince, William S / Lin, JianMin / Yu, Pengzhi / Srivastava, Deepak / Hoey, Timothy / Ivey, Kathryn N / Lombardi, Laura M

Circulation

2023 Volume 148, Issue 14, Page(s) 1099–1112

Abstract: Background: Cardiac reprogramming is a technique to directly convert nonmyocytes into myocardial cells using genes or small molecules. This intervention provides functional benefit to the rodent heart when delivered at the time of myocardial infarction ... ...

Abstract	Background: Cardiac reprogramming is a technique to directly convert nonmyocytes into myocardial cells using genes or small molecules. This intervention provides functional benefit to the rodent heart when delivered at the time of myocardial infarction or activated transgenically up to 4 weeks after myocardial infarction. Yet, several hurdles have prevented the advancement of cardiac reprogramming for clinical use. Methods: Through a combination of screening and rational design, we identified a cardiac reprogramming cocktail that can be encoded in a single adeno-associated virus. We also created a novel adeno-associated virus capsid that can transduce cardiac fibroblasts more efficiently than available parental serotypes by mutating posttranslationally modified capsid residues. Because a constitutive promoter was needed to drive high expression of these cell fate-altering reprogramming factors, we included binding sites to a cardiomyocyte-restricted microRNA within the 3' untranslated region of the expression cassette that limits expression to nonmyocytes. After optimizing this expression cassette to reprogram human cardiac fibroblasts into induced cardiomyocyte-like cells in vitro, we also tested the ability of this capsid/cassette combination to confer functional benefit in acute mouse myocardial infarction and chronic rat myocardial infarction models. Results: We demonstrated sustained, dose-dependent improvement in cardiac function when treating a rat model 2 weeks after myocardial infarction, showing that cardiac reprogramming, when delivered in a single, clinically relevant adeno-associated virus vector, can support functional improvement in the postremodeled heart. This benefit was not observed with GFP (green fluorescent protein) or a hepatocyte reprogramming cocktail and was achieved even in the presence of immunosuppression, supporting myocyte formation as the underlying mechanism. Conclusions: Collectively, these results advance the application of cardiac reprogramming gene therapy as a viable therapeutic approach to treat chronic heart failure resulting from ischemic injury.
MeSH term(s)	Rats ; Mice ; Humans ; Animals ; Dependovirus/genetics ; Myocytes, Cardiac/metabolism ; Myocardial Infarction/therapy ; Myocardial Infarction/drug therapy ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Genetic Therapy/methods ; Green Fluorescent Proteins/genetics ; Cellular Reprogramming ; Fibroblasts/metabolism
Chemical Substances	MicroRNAs ; Green Fluorescent Proteins (147336-22-9)
Language	English
Publishing date	2023-08-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80099-5
ISSN	1524-4539 ; 0009-7322 ; 0069-4193 ; 0065-8499
ISSN (online)	1524-4539
ISSN	0009-7322 ; 0069-4193 ; 0065-8499
DOI	10.1161/CIRCULATIONAHA.122.061542
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Article ; Online: Indoor-air purification by photoelectrochemical oxidation mitigates allergic airway responses to aerosolized cat dander in a murine model.

Devadoss, Dinesh / Surbaugh, Kerri / Manevski, Marko / Wickramaratne, Chatura / Chaput, Dale / Chung, Arianne / de Leon, Francisco / Chand, Hitendra S / Dhau, Jaspreet S

Scientific reports

2023 Volume 13, Issue 1, Page(s) 10980

Abstract: Portable air purifiers help improve indoor air quality by neutralizing allergens, including animal dander proteins. However, there are limited in-vivo models to assess the efficacy of these devices. Here, we developed a novel animal model of experimental ...

Abstract	Portable air purifiers help improve indoor air quality by neutralizing allergens, including animal dander proteins. However, there are limited in-vivo models to assess the efficacy of these devices. Here, we developed a novel animal model of experimental asthma using aerosolized cat dander extract (CDE) exposure and compared the efficacy of select air purification technologies. Mice were exposed to CDE aerosols for 6 weeks in separate custom-built whole-body exposure chambers equipped with either a photoelectrochemical oxidative (PECO) Molekule filtration device (PFD) or a HEPA-assisted air filtration device (HFD) along with positive (a device with no filtration capability) and negative controls. Compared to the positive control group, the CDE-induced airway resistance, and plasma IgE and IL-13 levels were significantly reduced in both air purifier groups. However, PFD mice showed a better attenuation of lung tissue mucous hyperplasia and eosinophilia than HFD and positive control mice, indicating a better efficacy in managing CDE-induced allergic responses. Cat dander protein destruction was evaluated by LCMS proteomic analysis, which revealed the degradation of 2731 unique peptides on PECO media in 1 h. Thus, allergen protein destruction on filtration media enhances air purifier efficacy that could provide relief from allergy responses compared to traditional HEPA-based filtration alone.
MeSH term(s)	Mice ; Animals ; Disease Models, Animal ; Dander/metabolism ; Proteomics ; Hypersensitivity/metabolism ; Asthma ; Allergens ; Air Pollution, Indoor
Chemical Substances	Allergens
Language	English
Publishing date	2023-07-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-38155-0
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Article ; Online: A Genetic Approach to the Association Between PCSK9 and Sepsis.

Feng, QiPing / Wei, Wei-Qi / Chaugai, Sandip / Carranza Leon, Barbara G / Kawai, Vivian / Carranza Leon, Daniel A / Jiang, Lan / Zhong, Xue / Liu, Ge / Ihegword, Andrea / Shaffer, Christian M / Linton, MacRae F / Chung, Cecilia P / Stein, C Michael

JAMA network open

2019 Volume 2, Issue 9, Page(s) e1911130

Abstract: Importance: Whether the PCSK9 gene is associated with the progress from infection to sepsis is unknown to date.: Objective: To test the associations between PCSK9 genetic variants, a PCSK9 genetic risk score (GRS), or genetically estimated PCSK9 ... ...

Abstract	Importance: Whether the PCSK9 gene is associated with the progress from infection to sepsis is unknown to date. Objective: To test the associations between PCSK9 genetic variants, a PCSK9 genetic risk score (GRS), or genetically estimated PCSK9 expression levels and the risk of sepsis among patients admitted to a hospital with infection. Design, setting, and participants: This retrospective cohort study used deidentified electronic health records to identify patients admitted to Vanderbilt University Medical Center, Nashville, Tennessee, with infection. Patients were white adults, had a code indicating infection from the International Classification of Diseases, Ninth Revision, Clinical Modification, or the International Statistical Classification of Diseases, Tenth Revision, Clinical Modification, and received an antibiotic within 1 day of hospital admission (N = 61 502). Data were collected from January 1, 1993, through December 31, 2017, and analyzed from April 1, 2018, to March 16, 2019. Exposures: Four known PCSK9 functional variants, a GRS for PCSK9, and genetically estimated PCSK9 expression. Main outcomes and measures: The primary outcome was sepsis; secondary outcomes included cardiovascular failure and in-hospital death. Results: Of patients with infection, genotype information was available in 10 922 white patients for PCSK9 functional variants (5628 men [51.5%]; mean [SD] age, 60.1 [15.7] years), including 7624 patients with PCSK9 GRS and 6033 patients with estimated PCSK9 expression. Of these, 3391 developed sepsis, 835 developed cardiovascular failure, and 366 died during hospitalization. None of the 4 functional PCSK9 variants were significantly associated with sepsis, cardiovascular failure, or in-hospital death, with or without adjustment for (1) age and sex or (2) age, sex, and Charlson-Deyo comorbidities (in model adjusted for age, sex, and comorbidities, odds ratios for any loss-of function variant were 0.96 [95% CI, 0.88-1.04] for sepsis, 1.05 [95% CI, 0.90-1.22] for cardiovascular failure, and 0.89 [95% CI, 0.72-1.11] for death). Similarly, neither the PCSK9 GRS nor genetically estimated PCSK9 expression were significantly associated with sepsis, cardiovascular failure, or in-hospital death in any of the analysis models. For GRS, in the full model adjusted for age, sex, and comorbidities, the odds ratios were 1.01 for sepsis (95% CI, 0.96-1.06; P = .70), 1.03 for cardiovascular failure (95% CI, 0.95-1.12; P = .48), and 1.05 for in-hospital death (95% CI, 0.92-1.19; P = .50). For genetically estimated PCSK9 expression, in the full model adjusted for age, sex, and comorbidities, the odds ratios were 1.01 for sepsis (95% CI, 0.95-1.06; P = .86), 0.96 for cardiovascular failure (95% CI, 0.88-1.05; P = .41), and 0.99 for in-hospital death (95% CI, 0.87-1.14; P = .94). Conclusions and relevance: In this study, PCSK9 genetic variants were not significantly associated with risk of sepsis or the outcomes of sepsis in patients hospitalized with infection.
MeSH term(s)	Adult ; Aged ; Cohort Studies ; Female ; Genetic Predisposition to Disease ; Genetic Variation ; Hospital Mortality ; Hospitalization ; Humans ; Infections/epidemiology ; Infections/therapy ; Male ; Middle Aged ; Odds Ratio ; Proprotein Convertase 9/genetics ; Renal Insufficiency/epidemiology ; Respiration, Artificial ; Respiratory Insufficiency/epidemiology ; Respiratory Insufficiency/therapy ; Retrospective Studies ; Sepsis/epidemiology ; Sepsis/genetics ; Shock/epidemiology ; Shock/genetics ; Shock/therapy ; Vasoconstrictor Agents/therapeutic use
Chemical Substances	Vasoconstrictor Agents ; PCSK9 protein, human (EC 3.4.21.-) ; Proprotein Convertase 9 (EC 3.4.21.-)
Language	English
Publishing date	2019-09-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2574-3805
ISSN (online)	2574-3805
DOI	10.1001/jamanetworkopen.2019.11130
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Article ; Online: Atrial shunt device for heart failure with preserved and mildly reduced ejection fraction (REDUCE LAP-HF II): a randomised, multicentre, blinded, sham-controlled trial.

Lancet (London, England)

2022 Volume 399, Issue 10330, Page(s) 1130–1140

Abstract: Background: Placement of an interatrial shunt device reduces pulmonary capillary wedge pressure during exercise in patients with heart failure and preserved or mildly reduced ejection fraction. We aimed to investigate whether an interatrial shunt can ... ...

Abstract	Background: Placement of an interatrial shunt device reduces pulmonary capillary wedge pressure during exercise in patients with heart failure and preserved or mildly reduced ejection fraction. We aimed to investigate whether an interatrial shunt can reduce heart failure events or improve health status in these patients. Methods: In this randomised, international, blinded, sham-controlled trial performed at 89 health-care centres, we included patients (aged ≥40 years) with symptomatic heart failure, an ejection fraction of at least 40%, and pulmonary capillary wedge pressure during exercise of at least 25 mm Hg while exceeding right atrial pressure by at least 5 mm Hg. Patients were randomly assigned (1:1) to receive either a shunt device or sham procedure. Patients and outcome assessors were masked to randomisation. The primary endpoint was a hierarchical composite of cardiovascular death or non-fatal ischemic stroke at 12 months, rate of total heart failure events up to 24 months, and change in Kansas City Cardiomyopathy Questionnaire overall summary score at 12 months. Pre-specified subgroup analyses were conducted for the heart failure event endpoint. Analysis of the primary endpoint, all other efficacy endpoints, and safety endpoints was conducted in the modified intention-to-treat population, defined as all patients randomly allocated to receive treatment, excluding those found to be ineligible after randomisation and therefore not treated. This study is registered with ClinicalTrials.gov, NCT03088033. Findings: Between May 25, 2017, and July 24, 2020, 1072 participants were enrolled, of whom 626 were randomly assigned to either the atrial shunt device (n=314) or sham procedure (n=312). There were no differences between groups in the primary composite endpoint (win ratio 1·0 [95% CI 0·8-1·2]; p=0·85) or in the individual components of the primary endpoint. The prespecified subgroups demonstrating a differential effect of atrial shunt device treatment on heart failure events were pulmonary artery systolic pressure at 20W of exercise (p Interpretation: Placement of an atrial shunt device did not reduce the total rate of heart failure events or improve health status in the overall population of patients with heart failure and ejection fraction of greater than or equal to 40%. Funding: Corvia Medical.
MeSH term(s)	Adult ; Cardiac Catheterization/instrumentation ; Flavins ; Heart Atria/surgery ; Heart Failure/physiopathology ; Humans ; Luciferases ; Male ; Stroke Volume
Chemical Substances	Flavins ; high fluorescent intermediate II ; Luciferases (EC 1.13.12.-)
Language	English
Publishing date	2022-02-01
Publishing country	England
Document type	Journal Article
ZDB-ID	3306-6
ISSN	1474-547X ; 0023-7507 ; 0140-6736
ISSN (online)	1474-547X
ISSN	0023-7507 ; 0140-6736
DOI	10.1016/S0140-6736(22)00016-2
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Ua VI Zs.5: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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