Ascending Aortic Dimensions and Body Size: Allometric Scaling, Normative Values, and Prognostic Performance.

Background: Ascending aortic (AscAo) dimensions partially depend on body size. Ratiometric (linear) indexing of AscAo dimensions to height and body surface area (BSA) are currently recommended, but it is unclear whether these allometric relationships are indeed linear.

Objectives: This study aimed to evaluate allometric relations, normative values, and the prognostic performance of AscAo dimension indices.

Proteome-Wide Mendelian Randomization Identifies Natriuretic Peptide-B and Novel Proteins as Potential Regulators of Pulse Pressure in Humans.

Background: Large-artery stiffness (LAS) significantly contributes to cardiovascular morbidity and death and is characterized by increased pulse pressure (PP). The biology underlying large-artery stiffness in humans remains incompletely understood.

Methods And Results: We investigated associations between PP and circulating levels of 2941 proteins among 53 016 UK Biobank participants.

Genetic determinants of blood-cell traits and the risk of cardiometabolic Diseases: Triangulating evidence from Mendelian randomization and observational analyses.

Background And Aims: Blood cell traits (BCTs) are linked to cardiometabolic diseases (CMDs) through mechanisms such as inflammation, thrombosis, endothelial dysfunction, and lipid metabolism. BCTs could serve as readily available, cost-effective biomarkers to enhance CVD risk prediction and, if proven causal, may also emerge as novel therapeutic targets. This study examined the genetic architecture and tested potential causal relations between 29 BCTs and 20 CMDs.

Thoracic Aortic Three-Dimensional Geometry.

Introduction: Aortic structure impacts cardiovascular health through multiple mechanisms. Aortic structural degeneration occurs with aging, increasing left ventricular afterload and promoting increased arterial pulsatility and target organ damage. Despite the impact of aortic structure on cardiovascular health, three-dimensional (3D) aortic geometry has not been comprehensively characterized in large populations.

Evaluating the Cardiometabolic Efficacy and Safety of Lipoprotein Lipase Pathway Targets in Combination With Approved Lipid-Lowering Targets: A Drug Target Mendelian Randomization Study.

Background: Therapies targeting the LPL (lipoprotein lipase) pathway are under development for cardiometabolic disease. Insights into their efficacy-both alone and in combination with existing lipid-lowering therapies-modes of action, and safety of these agents are essential to inform clinical development. Using Mendelian randomization, we aimed to (1) evaluate efficacy, (2) explore shared mechanisms, (3) assess additive effects with approved lipid-lowering drugs, and (4) identify secondary indications and potential adverse effects.

Unravelling the Relationship Between Height, Lean Mass, Alzheimer's Disease and Cognition Through Mendelian Randomization.

Background: Genetic evidence from Mendelian randomization (MR) analyses suggests that higher lean mass causally protects against Alzheimer's disease (AD) and enhances cognitive function. However, the potential confounding role of height, which shares genetic etiology with lean mass, has not been fully examined.

Methods: Genetic predictors of whole-body lean mass were obtained from a genome-wide association study (GWAS) performed in the UK Biobank cohort (UKB; = 448,322).

Transferrin Saturation, Serum Iron, and Ferritin in Heart Failure: Prognostic Significance and Proteomic Associations.

Background: Iron deficiency (ID) is currently defined as a serum ferritin level <100 or 100 to 299 ng/mL with transferrin saturation (TSAT) <20%. Serum ferritin and TSAT are currently used to define absolute and functional ID. However, individual markers of iron metabolism may be more informative than current arbitrary definitions of ID.

Proteome-Wide Genetic Investigation of Large Artery Stiffness.

The molecular mechanisms contributing to large artery stiffness (LAS) are not fully understood. The aim of this study was to investigate the association between circulating plasma proteins and LAS using complementary proteomic and genomic analyses. A total of 106 proteins associated with carotid-femoral pulse-wave velocity, a noninvasive measure of LAS, were identified in 1,178 individuals from the Asklepios study cohort.

Proteomic Correlates and Prognostic Significance of Kidney Injury in Heart Failure With Preserved Ejection Fraction.

Background: Kidney disease is common in heart failure with preserved ejection fraction (HFpEF). However, the biologic correlates and prognostic significance of kidney injury (KI), in HFpEF, beyond the estimated glomerular filtration rate (eGFR), are unclear.

Methods And Results: Using baseline plasma samples from the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial, we measured the following KI biomarkers: cystatin-C, fatty acid-binding protein-3, Beta-2 microglobulin, neutrophil gelatinase-associated lipocalin, and kidney-injury molecule-1.

Prognostic Significance and Biologic Associations of Senescence-Associated Secretory Phenotype Biomarkers in Heart Failure.

Background: The role of cellular senescence in human heart failure (HF) remains unclear. The senescence-associated secretory phenotype (SASP) is composed of proteins released by senescent cells. We assessed the prognostic significance and biologic pathways associated with the SASP in human HF using a plasma proteomics approach.

Effects of ACLY Inhibition on Body Weight Distribution: A Drug Target Mendelian Randomization Study.

Adenosine triphosphate-citrate lyase (ACLY) inhibition has proven clinically efficacious for low-density lipoprotein cholesterol (LDL-c) lowering and cardiovascular disease (CVD) risk reduction. Clinical and genetic evidence suggests that some LDL-c lowering strategies, such as 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibition with statin therapy increase body weight and the risk of developing type 2 diabetes mellitus (T2DM). However, whether ACLY inhibition affects metabolic risk factors is currently unknown.

Associations of genetically predicted vitamin D status and deficiency with the risk of carotid artery plaque: a Mendelian randomization study.

Low concentrations of circulating 25-hydroxy-vitamin D are observationally associated with an increased risk of subclinical atherosclerosis and cardiovascular disease. However, randomized controlled trials have not reported the beneficial effects of vitamin D supplementation on atherosclerotic cardiovascular disease (ASCVD) outcomes. Whether genetically predicted vitamin D status confers protection against the development of carotid artery plaque, a powerful predictor of subclinical atherosclerosis, remains unknown.

Thoracic Aortic Three-Dimensional Geometry.

Background: Aortic structure impacts cardiovascular health through multiple mechanisms. Aortic structural degeneration occurs with aging, increasing left ventricular afterload and promoting increased arterial pulsatility and target organ damage. Despite the impact of aortic structure on cardiovascular health, three-dimensional (3D) aortic geometry has not been comprehensively characterized in large populations.

LDL-c Lowering, Ischemic Stroke, and Small Vessel Disease Brain Imaging Biomarkers: A Mendelian Randomization Study.

Background: The effects of lipid-lowering drug targets on different ischemic stroke subtypes are not fully understood. We aimed to explore the mechanisms by which lipid-lowering drug targets differentially affect the risk of ischemic stroke subtypes and their underlying pathophysiology.

Methods: Using a 2-sample Mendelian randomization approach, we assessed the effects of genetically proxied low-density lipoprotein cholesterol (LDL-c) and 3 clinically approved LDL-lowering drugs (HMGCR [3-hydroxy-3-methylglutaryl-CoA reductase], PCSK9 [proprotein convertase subtilisin/kexin type 9], and NPC1L1 [Niemann-Pick C1-Like 1]) on stroke subtypes and brain imaging biomarkers associated with small vessel stroke (SVS), including white matter hyperintensity volume and perivascular spaces.

Proteomic Associations of Adverse Outcomes in Human Heart Failure.

Background: Identifying novel molecular drivers of disease progression in heart failure (HF) is a high-priority goal that may provide new therapeutic targets to improve patient outcomes. The authors investigated the relationship between plasma proteins and adverse outcomes in HF and their putative causal role using Mendelian randomization.

Methods And Results: The authors measured 4776 plasma proteins among 1964 participants with HF with a reduced left ventricular ejection fraction enrolled in PHFS (Penn Heart Failure Study).

Proteomic Associations of NT-proBNP (N-Terminal Pro-B-Type Natriuretic Peptide) in Heart Failure With Preserved Ejection Fraction.

Background: NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels are variably elevated in heart failure with preserved ejection fraction (HFpEF), even in the presence of increased left ventricular filling pressures. NT-proBNP levels are prognostic in HFpEF and have been used as an inclusion criterion for several recent randomized clinical trials. However, the underlying biologic differences between HFpEF participants with high and low NT-proBNP levels remain to be fully understood.

Cerebrospinal Fluid C1-Esterase Inhibitor and Tie-1 Levels Affect Cognitive Performance: Evidence from Proteome-Wide Mendelian Randomization.

Objective: The association of cerebrospinal fluid (CSF) protein levels with cognitive function in the general population remains largely unexplored. We performed Mendelian randomization (MR) analyses to query which CSF proteins may have potential causal effects on cognitive performance.

Methods And Analysis: Genetic associations with CSF proteins were obtained from a genome-wide association study conducted in up to 835 European-ancestry individuals and for cognitive performance from a meta-analysis of GWAS including 257,841 European-ancestry individuals.

Proteomic Correlates of the Urinary Protein/Creatinine Ratio in Heart Failure With Preserved Ejection Fraction.

Proteinuria is common in heart failure with preserved ejection fraction (HFpEF), but its biologic correlates are poorly understood. We assessed the relation between 49 plasma proteins and the urinary protein/creatinine ratio (UPCR) in 365 participants in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial. Linear regression and network analysis were used to represent relations between protein biomarkers and UPCR.

Associations of genetically predicted fatty acid levels across the phenome: A mendelian randomisation study.

Background: Fatty acids are important dietary factors that have been extensively studied for their implication in health and disease. Evidence from epidemiological studies and randomised controlled trials on their role in cardiovascular, inflammatory, and other diseases remains inconsistent. The objective of this study was to assess whether genetically predicted fatty acid concentrations affect the risk of disease across a wide variety of clinical health outcomes.