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Article ; Online: Influence of Weight and Body Size on the Pharmacokinetics of Heart Failure Pharmacotherapy: A Systematic Review.

Hindi, Jessica / Fréchette-Le Bel, Myriam / Rouleau, Jean Lucien / de Denus, Simon

2023 Volume 58, Issue 3, Page(s) 255–272

Abstract: Objective: To conduct a review of studies evaluating the influence of body size and weight (WT) on the pharmacokinetics (PK) of drugs recommended for heart failure (HF) treatment.: Data sources: A systematic search of the MEDLINE (1946 to April 2023) ...

Abstract	Objective: To conduct a review of studies evaluating the influence of body size and weight (WT) on the pharmacokinetics (PK) of drugs recommended for heart failure (HF) treatment. Data sources: A systematic search of the MEDLINE (1946 to April 2023) and EMBASE (1974 to April 2023) databases was conducted for articles that focused on the impact of WT or body size on the PK of drugs of interest used in HF patients. Study selection and data extraction: Articles written in English or French related to the aim of our study were retained for analysis. Data synthesis: Of 6493 articles, 20 were retained for analysis. Weight was associated with the clearance of digoxin, carvedilol, enalapril, and candesartan as well as the volume of distribution of eplerenone and bisoprolol. There was no documented direct impact of WT on the PK of furosemide, valsartan, and metoprolol, although these studies were limited or confounded by the small sample size, adjustment of PK factors by WT, or the use of the Cockroff-Gault equation for the evaluation of creatinine clearance, which includes WT. Relevance to patient care and clinical practice: This review highlights and summarizes the available data on the importance of WT on the PK of HF treatment. Conclusion: Considering the significant impact of WT on most HF drugs in this review, it may be important to further investigate it in the context of personalized therapy, particularly in patients presenting extreme WTs.
MeSH term(s)	Humans ; Heart Failure/drug therapy ; Valsartan/therapeutic use ; Metoprolol/therapeutic use ; Carvedilol/therapeutic use ; Body Size ; Adrenergic beta-Antagonists/therapeutic use
Chemical Substances	Valsartan (80M03YXJ7I) ; Metoprolol (GEB06NHM23) ; Carvedilol (0K47UL67F2) ; Adrenergic beta-Antagonists
Language	English
Publishing date	2023-06-20
Publishing country	United States
Document type	Systematic Review ; Journal Article ; Review
ZDB-ID	1101370-9
ISSN	1542-6270 ; 1060-0280
ISSN (online)	1542-6270
ISSN	1060-0280
DOI	10.1177/10600280231179484
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Article ; Online: High-sensitivity C-reactive protein in heart failure with preserved ejection fraction: Findings from TOPCAT.

Ferreira, João Pedro / Claggett, Brian L / Liu, Jiankang / Sharma, Abhinav / Desai, Akshay S / Anand, Inder S / O'Meara, Eileen / Rouleau, Jean L / De Denus, Simon / Pitt, Bertram / Pfeffer, Marc A / Zannad, Faiez / Solomon, Scott D

International journal of cardiology

2024 Volume 402, Page(s) 131818

Abstract: Background: Inflammation plays a central role in the genesis and progression of heart failure with preserved ejection fraction (HFpEF). C-reactive protein (CRP) is widely used as means to assess systemic inflammation, and elevated levels of CRP have ... ...

Abstract	Background: Inflammation plays a central role in the genesis and progression of heart failure with preserved ejection fraction (HFpEF). C-reactive protein (CRP) is widely used as means to assess systemic inflammation, and elevated levels of CRP have been associated with poor HF prognosis. Identification of chronic low-grade inflammation in outpatients can be performed measuring high-sensitivity CRP (hsCRP). The clinical characteristics and outcome associations of a pro-inflammatory state among outpatients with HFpEF requires further study. Aims: Using a biomarker subset of TOPCAT-Americas (NCT00094302), we aim to characterize HFpEF patients according to hsCRP levels and study the prognostic associations of hsCRP. Methods: hsCRP was available in a subset of 232 participants. Comparisons were performed between patients with hsCRP <2 mg/L and ≥ 2 mg/L. Cox regression models were used to study the association between hsCRP and the study outcomes. Results: Compared to patients with hsCRP <2 mg/L (n = 89, 38%), those with hsCRP ≥2 mg/L (n = 143, 62%) had more frequent HF hospitalizations prior to randomization, chronic obstructive pulmonary disease, orthopnea, higher body mass index, and worse health-related quality-of-life. A hsCRP level ≥ 2 mg/L was associated with an increased risk of cardiovascular death and HF hospitalizations: hsCRP ≥2 mg/L vs <2 mg/L adjusted HR 2.36, 95%CI 1.27-4.38, P = 0.006. Spironolactone did not influence hsCRP levels from baseline to month 12: gMean ratio = 1.11, 95%CI 0.87-1.42, P = 0.39. Conclusions: A hsCRP ≥2 mg/L identified HFpEF patients with a high risk of HF events and cardiovascular mortality. Spironolactone did not influence hsCRP levels at 12 months.
MeSH term(s)	Humans ; Heart Failure/diagnosis ; Heart Failure/drug therapy ; Spironolactone ; C-Reactive Protein ; Mineralocorticoid Receptor Antagonists ; Stroke Volume ; Prognosis ; Inflammation/diagnosis ; Hospitalization
Chemical Substances	Spironolactone (27O7W4T232) ; C-Reactive Protein (9007-41-4) ; Mineralocorticoid Receptor Antagonists
Language	English
Publishing date	2024-02-01
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	779519-1
ISSN	1874-1754 ; 0167-5273
ISSN (online)	1874-1754
ISSN	0167-5273
DOI	10.1016/j.ijcard.2024.131818
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Article ; Online: Pharmacogenomic markers of metoprolol and α-OH-metoprolol concentrations: a genome-wide association study.

Laverdière, Jean / Meloche, Maxime / Provost, Sylvie / Leclair, Grégoire / Oussaïd, Essaïd / Jutras, Martin / Perreault, Louis-Philippe Lemieux / Valois, Diane / Mongrain, Ian / Busseuil, David / Rouleau, Jean Lucien / Tardif, Jean-Claude / Dubé, Marie-Pierre / Denus, Simon de

Pharmacogenomics

2023 Volume 24, Issue 8, Page(s) 441–448

Abstract: Aim: ...

Abstract	Aim:
MeSH term(s)	Humans ; Metoprolol/therapeutic use ; Metoprolol/pharmacokinetics ; Genome-Wide Association Study ; Cytochrome P-450 CYP2D6/genetics ; Pharmacogenetics ; Cross-Sectional Studies
Chemical Substances	Metoprolol (GEB06NHM23) ; Cytochrome P-450 CYP2D6 (EC 1.14.14.1)
Language	English
Publishing date	2023-06-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2019513-8
ISSN	1744-8042 ; 1462-2416
ISSN (online)	1744-8042
ISSN	1462-2416
DOI	10.2217/pgs-2023-0067
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Article ; Online: CKing Precision in the Interpretation of Diagnostic Biomarkers.

de Denus, Simon / Tardif, Jean-Claude / Dubé, Marie-Pierre

Circulation. Cardiovascular genetics

2017 Volume 10, Issue 4

MeSH term(s)	Biomarkers ; Creatine Kinase ; Humans ; Myalgia ; Pharmacogenetics ; Precision Medicine
Chemical Substances	Biomarkers ; Creatine Kinase (EC 2.7.3.2)
Language	English
Publishing date	2017-05-12
Publishing country	United States
Document type	Editorial ; Comment
ZDB-ID	2477394-3
ISSN	1942-3268 ; 1942-325X
ISSN (online)	1942-3268
ISSN	1942-325X
DOI	10.1161/CIRCGENETICS.117.001874
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Article: Comparative Effectiveness and Safety of Low-Dose Oral Anticoagulants in Patients With Atrial Fibrillation.

Perreault, Sylvie / Dragomir, Alice / Côté, Robert / Lenglet, Aurélie / de Denus, Simon / Dorais, Marc / White-Guay, Brian / Brophy, James / Schnitzer, Mireille E / Dubé, Marie-Pierre / Tardif, Jean-Claude

Frontiers in pharmacology

2022 Volume 12, Page(s) 812018

Abstract: Aims: ...

Abstract	Aims:
Language	English
Publishing date	2022-01-14
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2021.812018
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Article ; Online: Construction of a femininity score in the UK Biobank and its association with angina diagnosis prior to myocardial infarction.

Levinsson, Anna / de Denus, Simon / Sandoval, Johanna / Lemieux Perreault, Louis-Philippe / Rouleau, Joëlle / Tardif, Jean-Claude / Hussin, Julie / Dubé, Marie-Pierre

Scientific reports

2022 Volume 12, Issue 1, Page(s) 1780

Abstract: Gender captures social components beyond biological sex and can add valuable insight to health studies in populations. However, assessment of gender typically relies on questionnaires which may not be available. The aim of this study is to construct a ... ...

Abstract	Gender captures social components beyond biological sex and can add valuable insight to health studies in populations. However, assessment of gender typically relies on questionnaires which may not be available. The aim of this study is to construct a gender metric using available variables in the UK Biobank and to apply it to the study of angina diagnosis. Proxy variables for femininity characteristics were identified in the UK Biobank and regressed on sex to construct a composite femininity score (FS) validated using tenfold cross-validation. The FS was assessed as a predictor of angina diagnosis before incident myocardial infarction (MI) events. The FS was derived for 315,937 UK Biobank participants. In 3059 individuals with no history of MI at study entry who had an incident MI event, the FS was a significant predictor of angina diagnosis prior to MI (OR 1.24, 95% CI 1.10-1.39, P < 0.001) with a significant sex-by-FS interaction effect (P = 0.003). The FS was positively associated with angina diagnosis prior to MI in men (OR 1.37, 95% CI 1.19-1.57, P < 0.001), but not in women. We have provided a new tool to conduct gender-sensitive analyses in observational studies, and applied it to study of angina diagnosis prior to MI.
MeSH term(s)	Angina Pectoris/diagnosis ; Angina Pectoris/epidemiology ; Biological Specimen Banks/statistics & numerical data ; Female ; Femininity ; Humans ; Male ; Middle Aged ; Myocardial Infarction/physiopathology ; Risk Assessment/methods ; Risk Factors ; Sex Factors ; United Kingdom/epidemiology
Language	English
Publishing date	2022-02-02
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/s41598-022-05713-x
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Article ; Online: Isocyanate derivatization coupled with phospholipid removal microelution-solid phase extraction for the simultaneous quantification of (S)-metoprolol and (S)-α-hydroxymetoprolol in human plasma with LC-MS/MS.

Meloche, Maxime / Jutras, Martin / St-Jean, Isabelle / de Denus, Simon / Leclair, Grégoire

Journal of pharmaceutical and biomedical analysis

2021 Volume 204, Page(s) 114263

Abstract: A sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was developed and validated for the quantification of (S)-metoprolol (MET) and its main metabolite, (S)-α-hydroxymetoprolol (OH-MET). Human plasma samples (50 μL) were spiked ... ...

Abstract	A sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was developed and validated for the quantification of (S)-metoprolol (MET) and its main metabolite, (S)-α-hydroxymetoprolol (OH-MET). Human plasma samples (50 μL) were spiked with both analytes and their deuterated internal standards (IS) (S)-MET-(d7) and α-OH-MET-(d5). Phospholipid removal microelution-solid phase extraction (PRM-SPE) was performed using a 4-step protocol with Oasis PRiME MCX μElution 96-well cartridges. The eluates were reconstituted in 100 μL of acetonitrile with 50 μg/mL (S)-α-methylbenzyl isocyanate (MBIC) for chiral derivatization. After 60 min at room temperature, the reaction was quenched using 100 μL of water 2 % formic acid. Chromatographic separation of the derivatized analytes was performed on a Kinetex phenyl-hexyl core-shell stationary phase with an elution gradient. Mobile phases were composed of a mixture of water and methanol, with ammonium formate and formic acid as buffers. Total runtime was 15 min. Analyte detection was performed by an AB/SCIEX 4000 QTRAP mass spectrometer with multiple reaction monitoring. Chromatograms showed MBIC successfully reacted with racemic MET, α-OH-MET, and their respective IS. Detection by positive electrospray ionization did not reveal derivatized by-products. Quantification ranges were validated for (S)-MET and (S)-α-OH-MET between 0.5-500 and 1.25-500 ng/mL, respectively, with correlation coefficients (r
MeSH term(s)	Chromatography, High Pressure Liquid ; Chromatography, Liquid ; Humans ; Isocyanates ; Metoprolol/analogs & derivatives ; Phospholipids ; Reproducibility of Results ; Solid Phase Extraction ; Tandem Mass Spectrometry
Chemical Substances	Isocyanates ; Phospholipids ; alpha-hydroxymetoprolol (56392-16-6) ; Metoprolol (GEB06NHM23)
Language	English
Publishing date	2021-07-13
Publishing country	England
Document type	Journal Article
ZDB-ID	604917-5
ISSN	1873-264X ; 0731-7085
ISSN (online)	1873-264X
ISSN	0731-7085
DOI	10.1016/j.jpba.2021.114263
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Article ; Online: Impact of amiodarone use on metoprolol concentrations, α-OH-metoprolol concentrations, metoprolol dosing and heart rate: A cross-sectional study.

Robert, Sabrina / Pilon, Marc-Olivier / Oussaïd, Essaïd / Meloche, Maxime / Leclair, Grégoire / Jutras, Martin / Gaulin, Marie-Josée / Mongrain, Ian / Busseuil, David / Tardif, Jean-Claude / Dubé, Marie-Pierre / de Denus, Simon

Pharmacology research & perspectives

2023 Volume 11, Issue 5, Page(s) e01137

Abstract: Small studies suggest that amiodarone is a weak inhibitor of cytochrome P450 (CYP) 2D6. Inhibition of CYP2D6 leads to increases in concentrations of drugs metabolized by the enzyme, such as metoprolol. Considering that both metoprolol and amiodarone have ...

Abstract	Small studies suggest that amiodarone is a weak inhibitor of cytochrome P450 (CYP) 2D6. Inhibition of CYP2D6 leads to increases in concentrations of drugs metabolized by the enzyme, such as metoprolol. Considering that both metoprolol and amiodarone have β-adrenergic blocking properties and that the modest interaction between the two drugs would result in increased metoprolol concentrations, this could lead to a higher risk of bradycardia and atrioventricular block. The primary objective of this study was to evaluate whether metoprolol plasma concentrations collected at random timepoints from patients enrolled in the Montreal Heart Institute Hospital Cohort could be useful in identifying the modest pharmacokinetic interaction between amiodarone and metoprolol. We performed an analysis of a cross-sectional study, conducted as part of the Montreal Heart Institute Hospital Cohort. All participants were self-described "White" adults with metoprolol being a part of their daily pharmacotherapy regimen. Of the 999 patients being treated with metoprolol, 36 were also taking amiodarone. Amiodarone use was associated with higher metoprolol concentrations following adjustment for different covariates (p = .0132). Consistently, the association between amiodarone use and lower heart rate was apparent and significant after adjustment for all covariates under study (p = .0001). Our results highlight that single randomly collected blood samples can be leveraged to detect modest pharmacokinetic interactions.
MeSH term(s)	Adult ; Humans ; Amiodarone ; Heart Rate ; Cross-Sectional Studies ; Metoprolol ; Bradycardia ; Cytochrome P-450 CYP2D6
Chemical Substances	Amiodarone (N3RQ532IUT) ; Metoprolol (GEB06NHM23) ; Cytochrome P-450 CYP2D6 (EC 1.14.14.1)
Language	English
Publishing date	2023-09-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2740389-0
ISSN	2052-1707 ; 2052-1707
ISSN (online)	2052-1707
ISSN	2052-1707
DOI	10.1002/prp2.1137
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Article ; Online: Heart Failure, Iron Deficiency, and Supplementation: Where Do We Stand?

O'Meara, Eileen / de Denus, Simon / Lepage, Serge

The Canadian journal of cardiology

2016 Volume 32, Issue 2, Page(s) 148–150

MeSH term(s)	Anemia, Iron-Deficiency/drug therapy ; Heart Failure/complications ; Humans ; Iron Compounds/administration & dosage ; Nutritional Support/methods
Chemical Substances	Iron Compounds
Language	English
Publishing date	2016-02
Publishing country	England
Document type	Comment ; Editorial ; Research Support, Non-U.S. Gov't
ZDB-ID	632813-1
ISSN	1916-7075 ; 0828-282X
ISSN (online)	1916-7075
ISSN	0828-282X
DOI	10.1016/j.cjca.2015.07.725
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Article ; Online: CYP2D6 polymorphism and its impact on the clinical response to metoprolol: A systematic review and meta-analysis.

Meloche, Maxime / Khazaka, Michael / Kassem, Imad / Barhdadi, Amina / Dubé, Marie-Pierre / de Denus, Simon

British journal of clinical pharmacology

2020 Volume 86, Issue 6, Page(s) 1015–1033

Abstract: Aims: CYP2D6 genetic polymorphisms are associated with metoprolol pharmacokinetics. Whether the clinical response to metoprolol is also affected remains uncertain.: Methods: We conducted a systematic review on the effects of CYP2D6 polymorphism on ... ...

Abstract	Aims: CYP2D6 genetic polymorphisms are associated with metoprolol pharmacokinetics. Whether the clinical response to metoprolol is also affected remains uncertain. Methods: We conducted a systematic review on the effects of CYP2D6 polymorphism on the clinical response to metoprolol. Searches were conducted using MEDLINE. Meta-analyses were performed on the impact of CYP2D6-inferred phenotypes on heart rate (HR) reduction, diastolic (DBP) and systolic (SBP) blood pressure reduction, average daily doses, all-type adverse events and bradycardia. Results: Our qualitative assessment indicated inconsistent results in individual studies and endpoints, but CYP2D6 poor metabolizers (PM) generally presented a greater reduction in HR. The meta-analysis of 15 studies, including a total of 1146 individuals, found a reduction in HR of 3 beats/min (P = .017), and of SBP and DBP by 3 mmHg (P = .0048) for PM compared to non-PM individuals using similar metoprolol doses. Bradycardia appeared more frequent by 4-fold for PM, although significant heterogeneity was observed regarding bradycardia, which limits the scope of this finding. Conclusion: Patients without any CYP2D6 metabolic capacities appear to have increased reduction in DBP, HR and SBP during metoprolol treatment and may be at a higher risk of bradycardia compared to patients with active CYP2D6 phenotypes. Further prospective data are required to determine whether CYP2D6 is associated with clinical events in patients treated with metoprolol, as well as to demonstrate the clinical utility of an individualized approach of prescribing metoprolol using CYP2D6-inferred phenotypes.
MeSH term(s)	Cytochrome P-450 CYP2D6/genetics ; Genotype ; Humans ; Metoprolol/adverse effects ; Phenotype ; Polymorphism, Genetic
Chemical Substances	Cytochrome P-450 CYP2D6 (EC 1.14.14.1) ; Metoprolol (GEB06NHM23)
Language	English
Publishing date	2020-04-05
Publishing country	England
Document type	Journal Article ; Meta-Analysis ; Research Support, Non-U.S. Gov't ; Review ; Systematic Review
ZDB-ID	188974-6
ISSN	1365-2125 ; 0306-5251 ; 0264-3774
ISSN (online)	1365-2125
ISSN	0306-5251 ; 0264-3774
DOI	10.1111/bcp.14247
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