Characterizing apparent treatment resistant hypertension in the United States: insights from the All of Us Research Program.

Background: Hypertension (HTN) remains a significant public health concern and the primary modifiable risk factor for cardiovascular disease, which is the leading cause of death in the United States. We applied our validated HTN computable phenotypes within the All of Us Research Program to uncover prevalence and characteristics of HTN and apparent treatment-resistant hypertension (aTRH) in United States.

Methods: Within the All of Us Researcher Workbench, we built a retrospective cohort (January 1, 2008-July 1, 2023), identifying all adults with available age data, at least one blood pressure (BP) measurement, prescribed at least one antihypertensive medication, and with at least one SNOMED "Essential hypertension" diagnosis code.

Precision Antiplatelet Therapy after Percutaneous Coronary Intervention (Precision PCI) Registry - Informing optimal antiplatelet strategies.

Dual antiplatelet therapy (DAPT) with aspirin and a P2Y receptor inhibitor (clopidogrel, prasugrel, or ticagrelor) is indicated after percutaneous coronary intervention (PCI) to reduce the risk of atherothrombotic events. Approximately 30% of the US population has a CYP2C19 no-function allele that reduces the effectiveness of clopidogrel, but not prasugrel or ticagrelor, after PCI. We have shown improved outcomes with the integration of CYP2C19 genotyping into clinical care to guide the selection of prasugrel or ticagrelor in CYP2C19 no-function allele carriers.

Using electronic health records for clinical pharmacology research: Challenges and considerations.

Electronic health records (EHRs) contain a vast array of phenotypic data on large numbers of individuals, often collected over decades. Due to the wealth of information, EHR data have emerged as a powerful resource to make first discoveries and identify disparities in our healthcare system. While the number of EHR-based studies has exploded in recent years, most of these studies are directed at associations with disease rather than pharmacotherapeutic outcomes, such as drug response or adverse drug reactions.

Assessing the Performance of In silico Tools and Molecular Dynamics Simulations for Predicting Pharmacogenetic Variant Impact.

The ability of freely available in silico tools to predict the effect of non-synonymous single nucleotide polymorphisms (nsSNPs) in pharmacogenes on protein function is not well defined. We assessed the performance of seven sequence-based (SIFT, PolyPhen2, mutation accessor, FATHMM, PhD-SNP, MutPred2, and SNPs & Go) and five structure-based (mCSM, SDM, DDGun, CupSat, and MAESTROweb) tools in predicting the impact of 118 nsSNPs in the CYP2C19, CYP2C9, CYP2B6, CYP2D6, and DPYD genes with known function (24 normal, one increased, 42 decreased, and 51 no-function). Sequence-based tools had a higher median (IQR) positive predictive value (89% [89-94%] vs.

Genotype Is Associated With Adverse Cardiovascular Outcomes in Black Patients Treated With Clopidogrel Undergoing Percutaneous Coronary Intervention.

Background: Cytochrome P450 2C19 (CYP2C19) intermediate and poor metabolizer patients exhibit diminished clopidogrel clinical effectiveness after percutaneous coronary intervention (PCI). However, outcome studies to date have lacked racial diversity. Thus, the impact of genotype on cardiovascular outcomes in patients treated with clopidogrel who identify as Black or African American remains unclear.

Use of CYP2D6 Inhibitors with CYP2D6 Opioids: Association with Emergency Department Visits for Pain.

Hydrocodone, tramadol, codeine, and oxycodone are commonly prescribed opioids that rely on activation by cytochrome P450 2D6 (CYP2D6). CYP2D6 inhibitors can significantly decrease CYP2D6 activity, leading to reduced generation of active metabolites, and impairing pain control. To understand this impact, we assessed emergency department (ED) visits in patients initiating these CYP2D6-dependent opioids while on CYP2D6-inhibitor antidepressants vs.

Integrated metabolomics analysis reveals mechanistic insights into variability in blood pressure response to thiazide diuretics and beta blockers.

Hypertensive patients with a higher proportion of genetic West African ancestry (%GWAA) have better blood pressure (BP) response to thiazide diuretics (TDs) and worse response to β-blockers (BBs) than those with lower %GWAA, associated with their lower plasma renin activity (PRA). TDs and BBs are suggested to reduce BP in the long term through vasodilation via incompletely understood mechanisms. This study aimed at identifying pathways underlying ancestral differences in PRA, which might reflect pathways underlying BP-lowering mechanisms of TDs and BBs.

Effectiveness of Clopidogrel vs Alternative P2Y Inhibitors Based on the ABCD-GENE Score.

Background: An ABCD-GENE (age, body mass index, chronic kidney disease, diabetes, and CYP2C19 genetic variants) score ≥10 predicts reduced clopidogrel effectiveness, but its association with response to alternative therapy remains unclear.

Objectives: The aim of this study was to evaluate the association between ABCD-GENE score and the effectiveness of clopidogrel vs alternative P2Y inhibitor (prasugrel or ticagrelor) therapy after percutaneous coronary intervention (PCI).

Methods: A total of 4,335 patients who underwent PCI, CYP2C19 genotyping, and P2Y inhibitor treatment were included.

Characteristics and Predictors of Apparent Treatment-Resistant Hypertension in Real-World Populations Using Electronic Health Record-Based Data.

Background: Apparent treatment-resistant hypertension (aTRH) is defined as uncontrolled blood pressure (BP) despite using ≥3 antihypertensive classes or controlled BP while using ≥4 antihypertensive classes. Patients with aTRH have a higher risk for adverse cardiovascular outcomes compared with patients with controlled hypertension (HTN). Although there have been prior reports on the prevalence, characteristics, and predictors of aTRH, these have been broadly derived from smaller datasets, randomized controlled trials, or closed healthcare systems.

Characteristics and Predictors of Apparent Treatment Resistant Hypertension in Real-World Populations Using Electronic Health Record-Based Data.

Background: Apparent treatment-resistant hypertension (aTRH) is defined as uncontrolled blood pressure (BP) despite using ≥3 antihypertensive classes or controlled BP while using ≥4 antihypertensive classes. Patients with aTRH have a higher risk for adverse cardiovascular outcomes compared to patients with controlled hypertension. Although there have been prior reports on the prevalence, characteristics, and predictors of aTRH, these have been broadly derived from smaller datasets, randomized controlled trials, or closed healthcare systems.

Exploring perceptions, knowledge, and attitudes regarding pharmacogenetic testing in the medically underserved.

Pharmacogenetic testing may hold promise in addressing health disparities, as medically underserved patients appear to be prescribed medications with pharmacogenetic guidelines at higher rates. While routine clinical implementation of testing in medically underserved populations has not yet been achieved, using patient perspectives to inform implementation should increase the likelihood of success. The aim of this study was to assess the perceptions, knowledge, and attitudes regarding pharmacogenetic testing in medically underserved patients.

The relevance of rich club regions for functional outcome post-stroke is enhanced in women.

This study aimed to investigate the influence of stroke lesions in predefined highly interconnected (rich-club) brain regions on functional outcome post-stroke, determine their spatial specificity and explore the effects of biological sex on their relevance. We analyzed MRI data recorded at index stroke and ~3-months modified Rankin Scale (mRS) data from patients with acute ischemic stroke enrolled in the multisite MRI-GENIE study. Spatially normalized structural stroke lesions were parcellated into 108 atlas-defined bilateral (sub)cortical brain regions.

Evaluation of Potential Racial Disparities in CYP2C19-Guided P2Y Inhibitor Prescribing After Percutaneous Coronary Intervention.

Black patients suffer worse outcomes after percutaneous coronary intervention (PCI) than White patients. Inequities in antiplatelet prescribing may contribute to this health disparity. We compared P2Y inhibitor prescribing by race following CYP2C19 genotyping to guide antiplatelet therapy selection after PCI.

Influence of Genetic West African Ancestry on Metabolomics among Hypertensive Patients.

Patients with higher genetic West African ancestry (GWAA) have hypertension (HTN) that is more difficult to treat and have higher rates of cardiovascular diseases (CVD) and differential responses to antihypertensive drugs than those with lower GWAA. The mechanisms underlying these disparities are poorly understood. Using data from 84 ancestry-informative markers in US participants from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) and PEAR-2 trials, the GWAA proportion was estimated.

Deep profiling of multiple ischemic lesions in a large, multi-center cohort: Frequency, spatial distribution, and associations to clinical characteristics.

Background Purpose: A substantial number of patients with acute ischemic stroke (AIS) experience multiple acute lesions (MAL). We here aimed to scrutinize MAL in a large radiologically deep-phenotyped cohort.

Materials And Methods: Analyses relied upon imaging and clinical data from the international MRI-GENIE study.

Genetic Contributors of Efficacy and Adverse Metabolic Effects of Chlorthalidone in African Americans from the Genetics of Hypertension Associated Treatments (GenHAT) Study.

Hypertension is a leading risk factor for cardiovascular disease mortality. African Americans (AAs) have the highest prevalence of hypertension in the United States, and to alleviate the burden of hypertension in this population, better control of blood pressure (BP) is needed. Previous studies have shown considerable interpersonal differences in BP response to antihypertensive treatment, suggesting a genetic component.

Impact of the ABCD-GENE Score on Clopidogrel Clinical Effectiveness after PCI: A Multi-Site, Real-World Investigation.

The Age, Body mass index, Chronic kidney disease, Diabetes mellitus, and CYP2C19 GENEtic variants (ABCD-GENE) score was developed to identify patients at risk for diminished antiplatelet effects with clopidogrel after percutaneous coronary intervention (PCI). The objective of this study was to validate the ability of the ABCD-GENE score to predict the risk for atherothrombotic events in a diverse, real-world population of clopidogrel-treated patients who underwent PCI and received clinical CYP2C19 genotyping to guide antiplatelet therapy. A total of 2,341 adult patients who underwent PCI, were genotyped for CYP2C19, and received treatment with clopidogrel across four institutions were included (mean age 64 ± 12 years, 35% women, and 20% Black).

Sex-specific lesion pattern of functional outcomes after stroke.

Stroke represents a considerable burden of disease for both men and women. However, a growing body of literature suggests clinically relevant sex differences in the underlying causes, presentations and outcomes of acute ischaemic stroke. In a recent study, we reported sex divergences in lesion topographies: specific to women, acute stroke severity was linked to lesions in the left-hemispheric posterior circulation.

Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention in Diverse Clinical Settings.

Background Studies have demonstrated increased risk of major atherothrombotic events in loss-of-function (LOF) variant carriers versus non-carriers treated with clopidogrel after percutaneous coronary intervention (PCI). We sought to evaluate real-world outcomes with the clinical implementation of -guided antiplatelet therapy after PCI. Methods and Results Data from 9 medical centers where genotyping was performed in the setting of PCI were included.

Genetic polymorphisms in ADRB2 and ADRB1 are associated with differential survival in heart failure patients taking β-blockers.

Single nucleotide polymorphisms (SNPs) have been associated with differential beta-blocker (BB) effects on heart rate, blood pressure, and left ventricular ejection fraction in various patient populations. This study aimed to determine if SNPs previously associated with BB response are also associated with differential survival in heart failure (HF) patients receiving BBs. HF patient data were derived from electronic health records and the Social Security Death Index.