A Study Of the effect of Sex on drug dosing, concentrations, and pharmacogenomics in the Montreal Heart Institute Hospital Cohort (SOS-PGx): methodology and research progress.

Background: Women are underrepresented in drug development trials and there is no sex-tailored drug regimen for most medications. It has been repeatedly shown that women have more adverse drug reactions than men for several medications. These differences could be explained by higher dose-adjusted drug concentrations in women.

High-sensitivity C-reactive protein in heart failure with preserved ejection fraction: Findings from TOPCAT.

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).

Impact of amiodarone use on metoprolol concentrations, α-OH-metoprolol concentrations, metoprolol dosing and heart rate: A cross-sectional study.

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.

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

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.

Pharmacogenomic markers of metoprolol and α-OH-metoprolol concentrations: a genome-wide association study.

Few genome-wide association studies (GWASs) have been conducted to identify predictors of drug concentrations. The authors therefore sought to discover the pharmacogenomic markers involved in metoprolol pharmacokinetics. The authors performed a GWAS of a cross-sectional study of 993 patients from the Montreal Heart Institute Biobank taking metoprolol.

Females present higher dose-adjusted drug concentrations of metoprolol and allopurinol/oxypurinol than males.

Females present a higher risk of adverse drug reactions. Sex-related differences in drug concentrations may contribute to these observations but they remain understudied given the underrepresentation of females in clinical trials. The aim of this study was to investigate whether anthropometric and socioeconomic factors and comorbidities could explain sex-related differences in concentrations and dosing for metoprolol and oxypurinol, the active metabolite of allopurinol.

Optimization of pharmacotherapies for ambulatory patients with heart failure and reduced ejection fraction is associated with improved outcomes.

Background: In heart failure, specific target doses for each drug are recommended, but some patients receive suboptimal dosing, others are undertreated or remain chronically in a titration phase, despite having no apparent contraindication or intolerance. We assessed the association of different levels of adherence to guidelines with outcomes in patients with heart failure and reduced ejection fraction (HFrEF).

Methods: Medical records of patients with HFrEF followed at our heart failure (HF) clinic for at least 6 months (n = 511) were reviewed and patients categorized as: 1) optimized (25.

Pharmacogenomic study of heart failure and candesartan response from the CHARM programme.

Aims: The Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) programme consisted of three parallel, randomized, double-blind clinical trials comparing candesartan with placebo in patients with heart failure (HF) categorized according to left ventricular ejection fraction and tolerability to an angiotensin-converting enzyme inhibitor. We conducted a pharmacogenomic study of the CHARM trials with the objective of identifying genetic predictors of HF progression and of the efficacy and safety of treatment with candesartan.

Methods: We performed genome-wide association studies in 2727 patients of European ancestry from CHARM-Overall and stratified by CHARM study according to preserved and reduced ejection fraction and according to assignment to the interventional treatment with candesartan.

Leveraging large observational studies to discover genetic determinants of drug concentrations: A proof-of-concept study.

Large, observational genetic studies are commonly used to identify genetic factors associated with diseases and disease-related traits. Such cohorts have not been commonly used to identify genetic predictors of drug dosing or concentrations, perhaps because of the heterogeneity in drug dosing and formulation, and the random timing of blood sampling. We hypothesized that large sample sizes relative to traditional pharmacokinetic studies would compensate for this variability and enable the identification of pharmacogenetic predictors of drug concentrations.

Construction of a femininity score in the UK Biobank and its association with angina diagnosis prior to myocardial infarction.

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.

Comparative Effectiveness and Safety of Low-Dose Oral Anticoagulants in Patients With Atrial Fibrillation.

Observational studies of various dose levels of direct oral anticoagulants (DOACs) for patients with atrial fibrillation (AF) found that a high proportion of patients received a dose lower than the target dose tested in randomized controlled trials. There is a need to compare low-dose DOACs with warfarin or other DOACs on effectiveness and safety. Using administrative data from Quebec province, Canada, we built a cohort of new warfarin or DOAC users discharged from hospital between 2011 and 2017.

A Meta-Analysis of the Effect of Paper Versus Digital Reading on Reading Comprehension in Health Professional Education.

Despite a rise in the use of digital education in health professional education (HPE), little is known about the comparative effectiveness of paper-based reading and its digital alternative on reading comprehension. The objectives of this study were to identify, appraise, and synthesize the evidence regarding the effect of how media is read on reading comprehension in the context of HPE. Observational, quasi-experimental, and experimental studies published before April 16, 2021, were included if they compared the effectiveness of paper-based vs digital-based reading on reading comprehension among HPE students, trainees, and residents.

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.

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.

Genetics of symptom remission in outpatients with COVID-19.

We conducted a genome-wide association study of time to remission of COVID-19 symptoms in 1723 outpatients with at least one risk factor for disease severity from the COLCORONA clinical trial. We found a significant association at 5p13.3 (rs1173773; P = 4.

Pharmacogenomics of the Efficacy and Safety of Colchicine in COLCOT.

Background: The randomized, placebo-controlled COLCOT (Colchicine Cardiovascular Outcomes Trial) has shown the benefits of colchicine 0.5 mg daily to lower the rate of ischemic cardiovascular events in patients with a recent myocardial infarction. Here, we conducted a post hoc pharmacogenomic study of COLCOT with the aim to identify genetic predictors of the efficacy and safety of treatment with colchicine.

Comparative effectiveness and safety of high-dose rivaroxaban and apixaban for atrial fibrillation: A propensity score-matched cohort study.

Study Objective: Observational studies assessing direct oral anticoagulant (DOACs) dosage in atrial fibrillation (AF) reported that a lower proportion of patients received high-dose DOACs compared to those in randomized controlled trials (RCTs). Effectiveness and safety of high-dose DOACs relative to apixaban in a real-world AF population need to be addressed. The aim is to assess comparative effectiveness and safety of high-dose rivaroxaban relative to apixaban.

Impact of diabetes on serum biomarkers in heart failure with preserved ejection fraction: insights from the TOPCAT trial.

Aims: Diabetes mellitus (DM) is common in heart failure with preserved ejection fraction (HFpEF). Patients with DM and heart failure with reduced ejection fraction have higher levels of cardiac, profibrotic, and proinflammatory biomarkers relative to non-diabetics. Limited data are available regarding the biomarker profiles of HFpEF patients with diabetes (DM) vs.

A genetic association study of heart failure: more evidence for the role of BAG3 in idiopathic dilated cardiomyopathy.

Aims: Few investigations have been conducted to identify genetic determinants of common, polygenetic forms of heart failure (HF), and only a limited number of these genetic associations have been validated by multiple groups.

Methods And Results: We performed a case-control study to further investigate the potential impact of 14 previously reported candidate genes on the risk of HF and specific HF sub-types. We also performed an exploratory genome-wide study.

Effects of reading media on reading comprehension in health professional education: a systematic review protocol.

Objective: To evaluate the effect of digital-based reading versus paper-based reading on reading comprehension among students, trainees, and residents participating in health professional education.

Introduction: Several reviews have examined the effects of reading media on reading comprehension; however, none have considered health professional education specifically. The growing use of electronic media in health professional education, as well as recent data on the consequences of digital-based reading on learning, justify the necessity to review the current literature to provide research and educational recommendations.

Obese-Inflammatory Phenotypes in Heart Failure With Preserved Ejection Fraction.

Background: Comorbidity-driven microvascular inflammation is posited as a unifying pathophysiologic mechanism for heart failure with preserved ejection fraction (HFpEF). Obesity is proinflammatory and common in HFpEF. We hypothesized that unique obesity-inflammation HFpEF phenotypes exist and are associated with differences in clinical features, fibrosis biomarkers, and functional performance.

Population Pharmacokinetics of Candesartan in Patients with Chronic Heart Failure.

Heart failure (HF) causes pathological changes in multiple organs, thus affecting the pharmacokinetics (PK) of drugs. The aim of this study was to investigate the PK of candesartan in patients with HF while examining significant covariates and their related impact on estimated clearance using a population PK (Pop-PK) modeling approach. Data from a prospective, multicenter study were used.