Predicting responsiveness to GLP-1 pathway drugs using real-world data.

Background: Medications targeting the glucagon-like peptide-1 (GLP-1) pathway are an important therapeutic class currently used for the treatment of Type 2 diabetes (T2D). However, there is not enough known about which subgroups of patients would receive the most benefit from these medications.

Objective: The goal of this study was to develop a predictive model for patient responsiveness to medications, here collectively called GLP-1 M, that include GLP-1 receptor agonists and dipeptidyl peptidase-4 (DPP4) inhibitors (that normally degrade endogenously-produced GLP-1).

A prognostic molecular signature of hepatic steatosis is spatially heterogeneous and dynamic in human liver.

Hepatic steatosis is a central phenotype in multi-system metabolic dysfunction and is increasing in parallel with the obesity pandemic. We use a translational approach integrating clinical phenotyping and outcomes, circulating proteomics, and tissue transcriptomics to identify dynamic, functional biomarkers of hepatic steatosis. Using multi-modality imaging and broad proteomic profiling, we identify proteins implicated in the progression of hepatic steatosis that are largely encoded by genes enriched at the transcriptional level in the human liver.

No Increased Risk of Major Adverse Cardiovascular Events following Nicotinamide Exposure.

Importance: Nicotinamide metabolites have recently been implicated in increased risk of major cardiovascular events (MACE). Supportive data about clinical risk of MACE for nicotinamide users is lacking.

Objective: To determine whether nicotinamide use results in an increase of MACE.

A Multivariable Mendelian Randomization Study of Systolic and Diastolic Blood Pressure, Lipid Profile, and Heart Failure Subtypes.

Heart failure (HF) is a significant health burden, with two major clinical subtypes: HF with reduced (HFrEF) and preserved ejection fraction (HFpEF). Blood pressure and lipid profile are established risk factors of HF. We performed univariable and multivariable Mendelian randomization (MR) analyses to assess potential causal effects of blood pressures and lipids on HF subtypes.

Left Ventricular Wall Stress and Incident Heart Failure in Elderly Community-Dwelling Individuals.

Background: Greater left ventricular (LV) wall stress is associated with adverse outcomes among patients with prevalent heart failure (HF). Less is known about the association between LV wall stress and incident HF.

Objectives: The purpose of the study was to identify clinical factors associated with wall stress and test the association between wall stress and incident HF.

Impact of metabolic and weight components on incident asthma using a real-world cohort.

Background: Obesity and metabolic dysregulation (MetD) have increasing prevalence and adversely affect asthma morbidity and therapeutic response.

Objective: To determine the role of weight and MetD on incident asthma in adulthood.

Methods: In a retrospective, longitudinal cohort of patients, we performed a time-to-asthma diagnosis analysis after a 3-year landmark period (t-t) during which weight and MetD components were evaluated.

SOX6 expression and aneurysms of the thoracic and abdominal aorta.

Abdominal and thoracic aortic aneurysms (AAAs, TAAs) remain a major cause of deaths worldwide, in part due to the lack of reliable prognostic markers or early warning signs. Sox6 has been found to regulate renin controlling blood pressure. We hypothesized that Sox6 may serve as an important regulator of the mechanisms contributing to hypertension-induced aortic aneurysms.

Proteomic analysis of cardiorespiratory fitness for prediction of mortality and multisystem disease risks.

Despite the wide effects of cardiorespiratory fitness (CRF) on metabolic, cardiovascular, pulmonary and neurological health, challenges in the feasibility and reproducibility of CRF measurements have impeded its use for clinical decision-making. Here we link proteomic profiles to CRF in 14,145 individuals across four international cohorts with diverse CRF ascertainment methods to establish, validate and characterize a proteomic CRF score. In a cohort of around 22,000 individuals in the UK Biobank, a proteomic CRF score was associated with a reduced risk of all-cause mortality (unadjusted hazard ratio 0.

Impact of Insurance Status and Region on Angiotensin Receptor-Neprilysin Inhibitor Prescription During Heart Failure Hospitalizations.

Background: An angiotensin receptor-neprilysin inhibitor (ARNI) is the preferred renin-angiotensin system (RAS) inhibitor for heart failure with reduced ejection fraction (HFrEF). Among eligible patients, insurance status and prescriber concern regarding out-of-pocket costs may constrain early initiation of ARNI and other new therapies.

Objectives: In this study, the authors sought to evaluate the association of insurance and other social determinants of health with ARNI initiation at discharge from HFrEF hospitalization.

Interoperability of phenome-wide multimorbidity patterns: a comparative study of two large-scale EHR systems.

Background: Electronic health records (EHR) are increasingly used for studying multimorbidities. However, concerns about accuracy, completeness, and EHRs being primarily designed for billing and administrative purposes raise questions about the consistency and reproducibility of EHR-based multimorbidity research.

Methods: Utilizing phecodes to represent the disease phenome, we analyzed pairwise comorbidity strengths using a dual logistic regression approach and constructed multimorbidity as an undirected weighted graph.

Recurrence After Atrial Fibrillation Ablation and Investigational Biomarkers of Cardiac Remodeling.

Background: Recurrence after atrial fibrillation (AF) ablation remains common. We evaluated the association between recurrence and levels of biomarkers of cardiac remodeling, and their ability to improve recurrence prediction when added to a clinical prediction model.

Methods And Results: Blood samples collected before de novo catheter ablation were analyzed.

Volumetric brain MRI signatures of heart failure with preserved ejection fraction in the setting of dementia.

Heart failure with preserved ejection fraction (HFpEF) is an important, emerging risk factor for dementia, but it is not clear whether HFpEF contributes to a specific pattern of neuroanatomical changes in dementia. A major challenge to studying this is the relative paucity of datasets of patients with dementia, with/without HFpEF, and relevant neuroimaging. We sought to demonstrate the feasibility of using modern data mining tools to create and analyze clinical imaging datasets and identify the neuroanatomical signature of HFpEF-associated dementia.

Unbiased characterization of atrial fibrillation phenotypic architecture provides insight to genetic liability and clinically relevant outcomes.

Background: Atrial Fibrillation (AF) is a common and clinically heterogeneous arrythmia. Machine learning (ML) algorithms can define data-driven disease subtypes in an unbiased fashion, but whether the AF subgroups defined in this way align with underlying mechanisms, such as high polygenic liability to AF or inflammation, and associate with clinical outcomes is unclear.

Methods: We identified individuals with AF in a large biobank linked to electronic health records (EHR) and genome-wide genotyping.

LNK/SH2B3 loss of function increases susceptibility to murine and human atrial fibrillation.

Aims: The lymphocyte adaptor protein (LNK) is a negative regulator of cytokine and growth factor signalling. The rs3184504 variant in SH2B3 reduces LNK function and is linked to cardiovascular, inflammatory, and haematologic disorders, including stroke. In mice, deletion of Lnk causes inflammation and oxidative stress.

Identification of Clinical Drivers of Left Atrial Enlargement Through Genomics of Left Atrial Size.

Background: Greater left atrial size is associated with a higher incidence of cardiovascular disease and mortality, but the full spectrum of diagnoses associated with left atrial enlargement in sex-stratified clinical populations is not well known. Our study sought to identify genetic risk mechanisms affecting left atrial diameter (LAD) in a clinical cohort.

Methods: Using Vanderbilt deidentified electronic health record, we studied 6163 females and 5993 males of European ancestry who had at least 1 LAD measure and available genotyping.