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.

Canadian colorectal cancer screening programs: How do they measure up using the International Agency for Research on Cancer criteria for organized screening?

Background: Canada has one of the highest incidences of colorectal cancer (CRC) worldwide. CRC screening improves CRC outcomes and is cost-effective. This study compares Canadian CRC screening programs using essential elements of an organized screening program outlined by the International Agency for Research on Cancer (IARC).

The Influence of Illness Perception and Coping on Anxiety in Adults With Congenital Heart Disease.

Background: Up to one-half of adults with congenital heart disease (CHD) experience psychological distress, including anxiety.

Objectives: This paper sought to: 1) assess the contribution of illness perception in explaining anxiety symptoms beyond sociodemographic and medical variables in adults with CHD; and 2) investigate the potential mediating effect of coping style.

Methods: CHD adult patients were recruited at Montreal Heart Institute between June 2019 and April 2021 for this cross-sectional study.

A dataset of proteomic changes during human heat stress and heat acclimation.

Hotter climates have important impacts on human health and performance. Yet, the cellular and molecular responses involved in human heat stress and acclimation remain understudied. This dataset includes physiological measurements and the plasma concentration of 2,938 proteins collected from 10 healthy adults, before and during passive heat stress that was performed both prior to and after a 7-day heat acclimation protocol.

Post COVID sequelae among COVID-19 survivors: insights from the Indian National Clinical Registry for COVID-19.

Introduction: The effects of COVID-19 infection persist beyond the active phase. Comprehensive description and analysis of the post COVID sequelae in various population groups are critical to minimise the long-term morbidity and mortality associated with COVID-19. This analysis was conducted with an objective to estimate the frequency of post COVID sequelae and subsequently, design a framework for holistic management of post COVID morbidities.

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.

FHL5 Controls Vascular Disease-Associated Gene Programs in Smooth Muscle Cells.

Background: Genome-wide association studies have identified hundreds of loci associated with common vascular diseases, such as coronary artery disease, myocardial infarction, and hypertension. However, the lack of mechanistic insights for many GWAS loci limits their translation into the clinic. Among these loci with unknown functions is -four-and-a-half LIM (LIN-11, Isl-1, MEC-3) domain 5 (; chr6q16.

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.

Pharmacogenetics-guided dalcetrapib therapy after an acute coronary syndrome: the dal-GenE trial.

Aims: In a retrospective analysis of dal-Outcomes, the effect of dalcetrapib on cardiovascular events was influenced by an adenylate cyclase type 9 (ADCY9) gene polymorphism. The dal-GenE study was conducted to test this pharmacogenetic hypothesis.

Methods And Results: dal-GenE was a double-blind trial in patients with an acute coronary syndrome within 1-3 months and the AA genotype at variant rs1967309 in the ADCY9 gene.

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.

A sex-specific evolutionary interaction between and .

Pharmacogenomic studies have revealed associations between rs1967309 in the adenylyl cyclase type 9 () gene and clinical responses to the cholesteryl ester transfer protein (CETP) modulator dalcetrapib, however, the mechanism behind this interaction is still unknown. Here, we characterized selective signals at the locus associated with the pharmacogenomic response in human populations and we show that rs1967309 region exhibits signatures of positive selection in several human populations. Furthermore, we identified a variant in , rs158477, which is in long-range linkage disequilibrium with rs1967309 in the Peruvian population.

Role of Adenylate Cyclase 9 in the Pharmacogenomic Response to Dalcetrapib: Clinical Paradigm and Molecular Mechanisms in Precision Cardiovascular Medicine.

Following the neutral results of the dal-OUTCOMES trial, a genome-wide study identified the rs1967309 variant in the adenylate cyclase type 9 () gene on chromosome 16 as being associated with the risk of future cardiovascular events only in subjects taking dalcetrapib, a CETP (cholesterol ester transfer protein) modulator. Homozygotes for the minor A allele (AA) were protected from recurrent cardiovascular events when treated with dalcetrapib, while homozygotes for the major G allele (GG) had increased risk. Here, we present the current state of knowledge regarding the impact of rs1967309 in on clinical observations and biomarkers in dalcetrapib trials and the effects of mouse gene inactivation on cardiovascular physiology.

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.

Influenza Causes MLKL-Driven Cardiac Proteome Remodeling During Convalescence.

Rationale: Patients with and without cardiovascular diseases have been shown to be at risk of influenza-mediated cardiac complications. Recent clinical reports support the notion of a direct link between laboratory-confirmed influenza virus infections and adverse cardiac events.

Objective: Define the molecular mechanisms underlying influenza virus-induced cardiac pathogenesis after resolution of pulmonary infection and the role of necroptosis in this process.

Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect.

The heart muscle diseases hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure in young, otherwise healthy, individuals. We conducted genome-wide association studies and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases) and nine left ventricular (LV) traits (19,260 UK Biobank participants with structurally normal hearts). We identified 16 loci associated with HCM, 13 with DCM and 23 with LV traits.

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.