Kerri L. Wiggins

Key Points: Ultraprocessed foods are associated with incident CKD. Whether sources of ultraprocessed foods (plant or animal) are related to incident CKD remains unknown. In 2661 older adults, total, plant-, and animal-sourced ultraprocessed foods were associated with incident CKD, but associations were weaker for plant-sourced ultraprocessed foods. It is important to consider future studies to investigate whether altering processing levels in plant foods can prevent CKD. Background: Ultraprocessed foods (UPFs) are associated with adverse health. Plant foods can be highly processed. It is not clear whether plant- and animal-sourced UPFs are associated CKD risk. Methods: Data came from the Cardiovascular Health Study, a prospective cohort of 2661 adults aged 65 years and older. The exposure was UPF intake, classified as plant or animal sourced in servings/d using the Nova framework from food frequency questionnaires (1989–1990 and 1995–1996). The outcome was incident CKD (eGFR 2 ) and absolute eGFR change (up to 18 years). Time-dependent Cox and linear models were used to examine the associations between total, plant-, and animal-sourced UPF and minimally processed food (MPF) intake with incident CKD and eGFR change. Results: After a median 6.8 years of follow-up and adjusting for demographics and health behaviors, those in the highest tertiles of total and animal-sourced UPF intake had 26% and 37% higher risk of incident CKD compared with the lowest tertile (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.08 to 1.47; P trend = 0.003 and HR, 1.37; 95% CI, 1.17 to 1.60; P trend < 0.001, respectively). Per SD higher plant-sourced UPF was associated with higher CKD risk (HR, 1.07; 95% CI, 1.01 to 1.13) but not in categorical analyses ( P trend = 0.12). Higher total MPF was associated with 20% lower risk of incident CKD (HR, 0.80 for tertile 3 versus 1; 95% CI, 0.69 to 0.95; P trend = 0.008). Replacing 3 servings of total MPF with total UPF (HR, 1.02; 95% CI, 1.001 to 1.03, P = 0.04) and plant-sourced MPF with plant-sourced UPF (HR, 1.02; 95% CI, 1.002 to 1.05, P = 0.03) was weakly associated with elevated risks of CKD. No associations were observed for eGFR change. Competing-risk analyses for mortality attenuated estimates. Conclusions: Total and animal-sourced UPFs were associated with incident CKD, and plant-sourced UPF was modestly associated with incident CKD. Health benefits of plant foods may be dampened by ultraprocessing, but additional work is needed in younger populations.

Abnormal cardiac atrial structure and function, termed atrial cardiopathy, typically precedes atrial fibrillation and downstream cardiovascular complications, yet detection is limited by the cost and accessibility of high-quality cardiac imaging. Here we show that a deep learning model trained on 12-lead electrocardiograms paired with 21,749 cardiac magnetic resonance scans from the UK Biobank predicts left atrial structure and function. Model-derived measures of atrial cardiopathy are strongly associated with new-onset atrial fibrillation, heart failure, and ischemic stroke after adjustment for clinical risk factors and biomarkers in two external cohorts, with magnitudes comparable to or greater than those for direct imaging measures and clinical risk factors. The risk of cardioembolic stroke, the hallmark complication of atrial fibrillation, increases 66% per standard deviation of left atrial volume. In exploratory analyses, model measures predict cardiac monitor-detected atrial fibrillation more accurately than a clinical risk prediction tool and NT-proBNP levels. This model is an inexpensive, accessible tool that identifies individuals at high-risk for atrial fibrillation and related complications.

Background and Aims: Residual pulmonary vascular obstruction (RPVO) defined as the persistence of thrombotic material within the pulmonary arteries several months after an acute pulmonary embolism (PE) is associated with an increased risk of severe complications, including recurrent events and chronic pulmonary hypertension. However, the genomic architecture underlying RPVO in unprovoked PE remains poorly understood, and this study aims to address this gap. Method: By leveraging genetic and imaging RPVO data from three independent cohorts totaling 586 unprovoked PE patients, we conducted a meta-analysis of genome wide association study (GWAS) of RPVO using a dedicated statistical method to handle the semi-continuous distribution of RPVO. The meta-GWAS was complemented by haplotype association analyses and transcriptome wide association studies as well as Mendelian Randomization (MR) approaches based on plasma metabolites and proteins. Results: Through meta-GWAS, we identified one locus, OSTN, associated with RPVO (lead variant rs59109356 associated with a ~2-fold increase of RPVO, p=3.92x10-8). A second locus, CCN4, previously reported to associate with pulmonary fibrosis, was also identified, with evidence of association approaching genome-wide significance (p=6.7x10-8). We also identified a common haplotype spanning over AHSG/HRG/KNG1 associated with a ~3-fold increase of RPVO (p=2.96x10-8). Using plasma protein-based MR, we demonstrated that one unit increase in genetically determined plasma levels of IL-1 R AcP encoding IL1RAP was associated with a 28% (p=1.32x10-6) reduction in RPVO. We also observed statistical evidence that the CCN4 (p=0.06) and IL1RAP (p=0.02) loci associate with the risk of PE recurrence in a sample of 1,617 unprovoked PE patients. Conclusions: By identifying novel molecular determinants of RPVO that map to loci involved in inflammatory pathways and vascular remodeling, our study provides evidence that inflammation is the predominant, and likely the key mechanism underlying RPVO, whereas impaired fibrinolysis appears to play a more limited role.

BACKGROUND: Atrial cardiopathy often precedes atrial fibrillation (AF) and has emerged as an independent risk factor for cardiovascular outcomes. However, previous studies have been limited in size and have overlooked the right atrium. METHODS: In 51 693 UK Biobank participants without prevalent AF, we assessed biatrial volumes and emptying fraction from cardiac magnetic resonance imaging using deep learning segmentation. We evaluated associations with new-onset AF, ischemic stroke, heart failure, and dementia, conducted a genome-wide association study, and evaluated causal associations using Mendelian randomization. RESULTS: Among 51 693 adults, the mean (SD) age was 65 (7.7) years, and 24 584 (48%) were male. During the 4-year follow-up, 964 (1.9%) developed AF, 266 (0.5%) developed ischemic stroke, 365 (0.7%) developed heart failure, and 72 (0.1%) developed dementia. After adjustment for clinical risk factors, both left and right atrial measures were associated with new-onset AF (left atrial minimal volume; hazard ratio, 1.55 [95% CI, 1.48–1.62]), ischemic stroke, and heart failure, with stronger associations in women. Left atrial minimal volume was also associated with dementia. Our genome-wide association study identified 51 (27 novel) genetic associations with atrial measures, many of which do not overlap with established AF loci. Genetic correlations revealed that each atrium had varying correlations with cardiometabolic risk factors, and Mendelian randomization demonstrated that left atrial measures had direct causal effects on AF and stroke risk. However, the stroke associations were attenuated after accounting for AF variants. CONCLUSIONS: In this largest assessment of biatrial structure and function to date, both left and right atrial cardiopathies were independently associated with increased risk of adverse cardiovascular events. We identified several novel genetic loci for atrial traits and observed unique genetic correlations between left and right atrial traits and cardiovascular phenotypes, providing insight into chamber-specific remodeling. Several of these measures are likely to be causal determinants of cardiovascular complications previously attributed to AF.

Venous thromboembolism (VTE) is a frequent (annual incidence of 1-2 per 1000 individuals) and potentially life-threatening (case-fatality rate up to 10%) disease. VTE is associated with serious short-term and long-term complications, including a recurrence rate approaching 20% within 5 years. Anticoagulant therapy, the mainstay of VTE treatment, drastically reduces the risk of early VTE recurrence, but it exposes patients to a substantial risk of bleeding. We analyzed the genomic architecture of VTE recurrence using data from 6355 patients across 8 cohorts (including 1775 recurrences), enriched by subgroup analyses, according to sex and clinical manifestation of first VTE, which led to the identification of 28 molecular markers. Through genome-wide association studies, we identified 1 locus associated with VTE recurrence, GPR149/MME. Among all variants known to be associated with first VTE, KNG1, and FGG were associated with recurrence. Additionally, Mendelian randomization analyses identified 7 proteins as risk factors for recurrence: elevated plasma levels of coagulation factor XI, coagulation factor VIII, von Willebrand factor, histo-blood group ABO system transferase, and Golgi membrane protein 2; and decreased levels of proprotein convertase subtilisin/kexin 9 and pro–interleukin-16. Subgroup analyses revealed 18 molecular determinants associated with VTE recurrence, with notable differences between subgroups. For example, the exonic variant SLC4A1 p.Glu40Lys was significantly associated in patients who experienced pulmonary embolism but showed no effect in those with deep vein thrombosis. These findings emphasize the role of specific genetic loci and protein pathways in influencing VTE recurrence and provide valuable insights into potential therapeutic targets. Further research is needed to clarify the biological mechanisms driving these associations.

Background: Atrial cardiomyopathy, defined as adverse changes to the cardiac atria, is an emerging risk factor for atrial fibrillation (AF). Despite the disproportionate burden of AF‐related complications in Black adults, the relationship between electrocardiographic (ECG) measures of atrial cardiomyopathy, referred to as P‐wave indices (PWIs), and outcomes remains largely unknown in this population. Methods: In 4900 participants without AF at baseline from the JHS (Jackson Heart Study), a prospective cohort study of Black adults, we assessed atrial cardiomyopathy using PWIs from resting 12‐lead ECGs: PR interval, P‐wave duration, P‐wave axis, and P‐wave terminal force in V1 (PTFV1). Cox proportional hazards models evaluated associations of PWIs with incident AF and ischemic stroke, adjusting for established risk factors. Results: Over 13.7 years of follow‐up, 396 (9.3%) participants developed incident AF, and 135 (3.8%) experienced ischemic stroke. Each SD‐unit increase in PR interval, P‐wave duration, and PTFV1 was associated with increased AF risk, with the strongest association for PTFV1 (hazard ratio [HR], 1.27 [95% CI, 1.16–1.38]). These PWIs were also associated with AF risk using clinically accepted thresholds, including HR of 1.76 for PTFV1 ≥4000 ms×μV (95%CI, 1.38–2.25). Each SD increase in PTFV1 was associated with a 22% increased risk of ischemic stroke (HR, 1.22 [95% CI, 1.07–1.40]). Conclusions: In this large cohort study of Black adults, PWIs, particularly PTFV1, were independently associated with an increased risk of incident AF and ischemic stroke. These findings underscore the significance of PTFV1 as an underlying marker of atrial cardiomyopathy in Black adults.

Suppression of plasminogen activation and/or plasmin activity (PA) reduces blood loss and decreases hemorrhage-related death. However, whether the endogenous PA system is a biological mechanism to prevent intravascular thrombus formation is debated, and the potential that reduced PA may increase venous thrombosis/thromboembolism (VTE) risk cautions against the use of antifibrinolytic agents. We aimed to determine the contribution of PA to VTE. Type 1 plasminogen-deficient humans enrolled in the Hypoplasminogenemia International Retrospective and Prospective Cohort Study registry reported pathologic pseudomembrane formation, but not unprovoked VTE. When subjected to an experimental model of venous thrombosis, compared with Plg+/+ mice, neither partial (Plg+/−) nor complete (Plg–/–) deletion of plasminogen altered thrombus mass or thrombus nucleated cell, platelet, or fibrin(ogen) content at 24 or 6 hours after thrombus induction. Administration of tranexamic acid (TXA) to mouse plasma in vitro or healthy mice in vivo dose-dependently delayed and suppressed plasma plasmin generation for up to 3 hours. However, mice administered TXA did not have significantly altered thrombus mass or thrombus composition at 24 or 6 hours after thrombus induction, despite unexpectedly persistent TXA in plasma. In a genome-wide association study, variants in gene regions encoding PA pathway proteins were not significantly associated with VTE risk. In the UK Biobank repository, plasminogen protein levels were not significantly associated with VTE risk. These data from genetic, pharmacologic, and proteomic analyses of mice and humans indicate that perturbations in PA do not increase VTE risk. Collectively, these results suggest PA is not a molecular regulatory mechanism to protect against VTE. This trial was registered at www.clinicaltrials.gov as #NCT03797495).

Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51% were of non-European population groups. We discovered 18 BMI-associated signals (P < 5 × 10^{− 9}), including two secondary signals. Notably, we identified and replicated a novel low-frequency single nucleotide polymorphism (SNP) in MTMR3 that was common in individuals of African descent. Using a diverse study population, we further identified two novel secondary signals in known BMI loci and pinpointed two likely causal variants in the POC5 and DMD loci. Our work demonstrates the benefits of combining WGS and diverse cohorts in expanding current catalog of variants and genes confer risk for obesity, bringing us one step closer to personalized medicine.

Heart failure (HF) is a major contributor to global morbidity and mortality. While distinct clinical subtypes, defined by etiology and left ventricular ejection fraction, are well recognized, their genetic determinants remain inadequately understood. In this study, we report a genome-wide association study of HF and its subtypes in a sample of 1.9 million individuals. A total of 153,174 individuals had HF, of whom 44,012 had a nonischemic etiology (ni-HF). A subset of patients with ni-HF were stratified based on left ventricular systolic function, where data were available, identifying 5,406 individuals with reduced ejection fraction and 3,841 with preserved ejection fraction. We identify 66 genetic loci associated with HF and its subtypes, 37 of which have not previously been reported. Using functionally informed gene prioritization methods, we predict effector genes for each identified locus, and map these to etiologic disease clusters through phenome-wide association analysis, network analysis and colocalization. Through heritability enrichment analysis, we highlight the role of extracardiac tissues in disease etiology. We then examine the differential associations of upstream risk factors with HF subtypes using Mendelian randomization. These findings extend our understanding of the mechanisms underlying HF etiology and may inform future approaches to prevention and treatment.

Venous thromboembolism (VT) is a frequent (annual incidence of 1 to 2 per 1,000) and potentially life-threatening (case-fatality rate up to 10%) disease. VT is associated with serious short-term and long-term complications including a recurrence rate of approximately 20% within five years. Anticoagulant therapy, the mainstay of VT treatment, drastically reduces the risk of early VT recurrence, but it exposes patients to a substantial risk of bleeding. We analysed the genomic architecture of VT recurrence using data from 6,571 patients across eight cohorts, 1,816 of whom experienced recurrence, with a particular focus on the clinical manifestation of the type of first VT event. Through genome-wide association studies (GWAS), we identified three loci significantly associated (P-8 ) with VT recurrence in the general VT population: GPR149/MME , L3MBTL4 , and THSD7B . Protein Quantitative Trait Locus and Mendelian Randomization analyses further identified elevated plasma levels of coagulation factor XI and GOLM2 as risk factors for recurrence, while decreased levels of PCSK9 and pro-IL16 were linked to reduced VT recurrence risk. Subgroup analyses revealed 18 loci associated with VT recurrence, with notable differences between pulmonary embolism (PE) and deep vein thrombosis (DVT). For example, the exonic variant SLC4A1 p.Glu40Lys was significantly associated with recurrence in PE patients (Hazard Ratio (HR)=3.23, P=9.7×10 ^-12 ) but showed no effect in DVT (HR=1.00, P=0.98). These findings emphasize the role of specific genetic loci and protein pathways in influencing VT recurrence and provide valuable insights into potential therapeutic targets. Further research is needed to clarify the biological mechanisms driving these associations. Key points: 29 loci/proteins associated with VT recurrence risk. The genomic architecture of VT recurrence risk varies based on the initial clinical presentation.