VGLL3-centered network connects placental, vascular, and immune defects in preeclampsia.

Preeclampsia affects approximately 1 in 10 pregnancies, leading to severe complications and long-term health risks for both mother and offspring. While the etiology remains unclear, preeclampsia has been linked to both autoimmunity and the timing of menarche. Through human single-cell and spatial analyses, coupled with in vitro, in vivo, and ex vivo models, we demonstrate that VGLL3, a transcription co-regulator in the Hippo pathway, is upregulated in preeclamptic placentas.

Cross-Ancestry Associations of Spontaneous Coronary Artery Dissection Genetic Risk With Coronary Atherosclerosis and Migraine Headache.

Background: Research studies of spontaneous coronary artery dissection (SCAD) have been primarily focused on European-ancestry individuals, with limited recognition and investigation in non-European-ancestry individuals. While SCAD has not been well ascertained in non-European-ancestry groups, pleiotropic associated traits identified in those of European ancestry have been assessed in individuals of other ancestries. Whether these traits are associated with the complex genetic architecture of SCAD in those of non-European ancestry has not been previously investigated.

Peripartum dapagliflozin improves late-life maternal cardiovascular outcomes in a murine model of superimposed preeclampsia.

Background: Hypertensive disorders of pregnancy are important risk factors for later-life cardiovascular diseases. SGLT2 (sodium-glucose cotransporter-2) inhibition improves outcomes in heart failure, a later-life risk that disproportionately affects those with preeclampsia superimposed on chronic hypertension. SGLT2 inhibition during pregnancy and the postpartum period has not been effectively modeled or tested in superimposed preeclampsia as a potential cardiovascular risk-reducing intervention.

Meta-analysis of genome-wide associations and polygenic risk prediction for atrial fibrillation in more than 180,000 cases.

Atrial fibrillation (AF) is the most common heart rhythm abnormality and is a leading cause of heart failure and stroke. This large-scale meta-analysis of genome-wide association studies increased the power to detect single-nucleotide variant associations and found more than 350 AF-associated genetic loci. We identified candidate genes related to muscle contractility, cardiac muscle development and cell-cell communication at 139 loci.

Oxidative Stress in Kidney Injury and Hypertension.

Hypertension (HTN) is a major contributor to kidney damage, leading to conditions such as nephrosclerosis and hypertensive nephropathy, significant causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD). HTN is also a risk factor for stroke and coronary heart disease. Oxidative stress, inflammation, and activation of the renin-angiotensin-aldosterone system (RAAS) play critical roles in causing kidney injury in HTN.

Coordination among cytoskeletal organization, cell contraction, and extracellular matrix development is dependent on LOX for aneurysm prevention.

Distinct and seemingly independent cellular pathways affecting intracellular machinery or extracellular matrix (ECM) deposition and organization have been implicated in aneurysm formation. One of the key genes associated with this pathology in both humans and mice is lysyl oxidase (LOX), a secreted ECM-modifying enzyme, highly expressed in medial vascular smooth muscle cells. To dissect the mechanisms leading to aneurysm development, we conditionally deleted Lox in smooth muscle cells.

Can Peripheral Arterial Tonometry and Biomarkers Help Identify Women Who Will Have Progressively Worsening Hypertensive Disorders of Pregnancy?

Objective:  This study aimed to (1) evaluate whether endothelial dysfunction, as measured by peripheral arterial tonometry (PAT) indices and biomarker (soluble fms-like tyrosine kinase-1 [sFLT], brain natriuretic peptide [BNP]) levels at 34 weeks gestation, can predict progression from nonsevere to severe hypertensive disorders of pregnancy (HDPs); and (2) develop a clinical risk model for prediction of progression from nonsevere to severe HDP.

Study Design:  We prospectively enrolled patients with a singleton gestation carrying a nonsevere HDP diagnosis. Forty-five participants were enrolled for PAT evaluation and serum collection between 34 and 36 weeks.

From Atherosclerosis to Spontaneous Coronary Artery Dissection: Defining a Clinical and Genetic Risk Spectrum for Myocardial Infarction.

Purpose Of Review: Spontaneous coronary artery dissection (SCAD) has been increasingly recognized as a significant cause of acute myocardial infarction (AMI) in young and middle-aged women and arises through mechanisms independent of atherosclerosis. SCAD has a multifactorial etiology that includes environmental, individual, and genetic factors distinct from those typically associated with coronary artery disease. Here, we summarize the current understanding of the genetic factors contributing to the development of SCAD and highlight those factors which differentiate SCAD from atherosclerotic coronary artery disease.

Identification of the Molecular Components of Enhancer-Mediated Gene Expression Variation in Multiple Tissues Regulating Blood Pressure.

Background: Inter-individual variation in blood pressure (BP) arises in part from sequence variants within enhancers modulating the expression of causal genes. We propose that these genes, active in tissues relevant to BP physiology, can be identified from tissue-level epigenomic data and genotypes of BP-phenotyped individuals.

Methods: We used chromatin accessibility data from the heart, adrenal, kidney, and artery to identify cis-regulatory elements (CREs) in these tissues and estimate the impact of common human single-nucleotide variants within these CREs on gene expression, using machine learning methods.

Coordination between cytoskeletal organization, cell contraction and extracellular matrix development, is depended on LOX for aneurysm prevention.

Distinct, seemingly independent, cellular pathways affecting intracellular machineries or extracellular matrix (ECM) deposition and organization, have been implicated in aneurysm formation. One of the key genes associated with the pathology in both humans and mice is Lysyl oxidase (LOX), a secreted ECM-modifying enzyme, highly expressed in medial vascular smooth muscle cells. To dissect the mechanisms leading to aneurysm development, we conditionally deleted in smooth muscle cells.

Sex-specific genetic architecture of blood pressure.

The genetic and genomic basis of sex differences in blood pressure (BP) traits remain unstudied at scale. Here, we conducted sex-stratified and combined-sex genome-wide association studies of BP traits using the UK Biobank resource, identifying 1,346 previously reported and 29 new BP trait-associated loci. Among associated loci, 412 were female-specific (P ≤ 5 × 10; P > 5 × 10) and 142 were male-specific (P ≤ 5 × 10; P > 5 × 10); these sex-specific loci were enriched for hormone-related transcription factors, in particular, estrogen receptor 1.

Advancements in the Genetics of Spontaneous Coronary Artery Dissection.

Purpose Of Review: Spontaneous coronary artery dissection (SCAD) is a significant cause of acute myocardial infarction that is increasingly recognized in young and middle-aged women. The etiology of SCAD is likely multifactorial and may include the interaction of environmental and individual factors. Here, we summarize the current understanding of the genetic factors contributing to the development of SCAD.

Tissue-specific and tissue-agnostic effects of genome sequence variation modulating blood pressure.

Genome-wide association studies (GWASs) have identified numerous variants associated with polygenic traits and diseases. However, with few exceptions, a mechanistic understanding of which variants affect which genes in which tissues to modulate trait variation is lacking. Here, we present genomic analyses to explain trait heritability of blood pressure (BP) through the genetics of transcriptional regulation using GWASs, multiomics data from different tissues, and machine learning approaches.

mtPGS: Leverage multiple correlated traits for accurate polygenic score construction.

Accurate polygenic scores (PGSs) facilitate the genetic prediction of complex traits and aid in the development of personalized medicine. Here, we develop a statistical method called multi-trait assisted PGS (mtPGS), which can construct accurate PGSs for a target trait of interest by leveraging multiple traits relevant to the target trait. Specifically, mtPGS borrows SNP effect size similarity information between the target trait and its relevant traits to improve the effect size estimation on the target trait, thus achieving accurate PGSs.

Placental transcriptome analysis of hypertensive pregnancies identifies distinct gene expression profiles of preeclampsia superimposed on chronic hypertension.

Background: The pathogenesis of preeclampsia superimposed on chronic hypertension (SI) is poorly understood relative to preeclampsia (PreE) occurring in pregnant people without chronic hypertension. Placental transcriptomes in pregnancies complicated by PreE and SI have not been previously compared.

Methods: We identified pregnant people in the University of Michigan Biorepository for Understanding Maternal and Pediatric Health with hypertensive disorders affecting singleton, euploid gestations (N = 36) along with non-hypertensive control subjects (N = 12).

Genetic Risk Score for Intracranial Aneurysms: Prediction of Subarachnoid Hemorrhage and Role in Clinical Heterogeneity.

Background: Recently, common genetic risk factors for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (ASAH) were found to explain a large amount of disease heritability and therefore have potential to be used for genetic risk prediction. We constructed a genetic risk score to (1) predict ASAH incidence and IA presence (combined set of unruptured IA and ASAH) and (2) assess its association with patient characteristics.

Methods: A genetic risk score incorporating genetic association data for IA and 17 traits related to IA (so-called metaGRS) was created using 1161 IA cases and 407 392 controls from the UK Biobank population study.

Fibromuscular Dysplasia and Abdominal Aortic Aneurysms Are Dimorphic Sex-Specific Diseases With Shared Complex Genetic Architecture.

Background: The risk of arterial diseases may be elevated among family members of individuals having multifocal fibromuscular dysplasia (FMD). We sought to investigate the risk of arterial diseases in families of individuals with FMD.

Methods: Family histories for 73 probands with FMD were obtained, which included an analysis of 463 total first-degree relatives focusing on FMD and related arterial disorders.

Phospholipase Cε insufficiency causes ascending aortic aneurysm and dissection.

Phospholipase Cε (PLCε) is a phospholipase C isoform with a wide range of physiological functions. It has been implicated in aortic valve disorders, but its role in frequently associated aortic disease remains unclear. To determine the role of PLCε in thoracic aortic aneurysm and dissection (TAAD) we used PLCε-deficient mice, which develop aortic valve insufficiency and exhibit aortic dilation of the ascending thoracic aorta and arch without histopathological evidence of injury.

Canadian Spontaneous Coronary Artery Dissection Cohort Study: 3-Year Outcomes.

Background: Spontaneous coronary artery dissection (SCAD) is an important cause of myocardial infarction (MI) in young to middle-aged women.

Objectives: We aim to define the long-term natural history of SCAD.

Methods: We performed a multicenter, prospective, observational study of patients with nonatherosclerotic SCAD presenting acutely from 22 North American centers.

Differences in Demographics and Outcomes Between Men and Women With Spontaneous Coronary Artery Dissection.

Background: Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of myocardial infarction (MI) that most frequently affects women. The characteristics of men with SCAD are less well described.

Objectives: The aim of this study was to describe the characteristics of men with SCAD.

Burden of Rare Genetic Variants in Spontaneous Coronary Artery Dissection With High-risk Features.

Importance: The emerging genetic basis of spontaneous coronary artery dissection (SCAD) has been defined as both partially complex and monogenic in some patients, involving variants predominantly in genes known to underlie vascular connective tissue diseases (CTDs). The effect of these genetic influences has not been defined in high-risk SCAD phenotypes, and the identification of a high-risk subgroup of individuals may help to guide clinical genetic evaluations of SCAD.

Objective: To identify and quantify the burden of rare genetic variation in individuals with SCAD with high-risk clinical features.