Spontaneous coronary artery dissection (SCAD) has emerged as an important cause of acute coronary syndrome, myocardial infarction, and sudden death, particularly among young women and individuals with few conventional atherosclerotic risk factors. Patient-initiated research has spurred increased awareness of SCAD, and improved diagnostic capabilities and findings from large case series have led to changes in approaches to initial and long-term management and increasing evidence that SCAD not only is more common than previously believed but also must be evaluated and treated differently from atherosclerotic myocardial infarction. High rates of recurrent SCAD; its association with female sex, pregnancy, and physical and emotional stress triggers; and concurrent systemic arteriopathies, particularly fibromuscular dysplasia, highlight the differences in clinical characteristics of SCAD compared with atherosclerotic disease. Recent insights into the causes of, clinical course of, treatment options for, outcomes of, and associated conditions of SCAD and the many persistent knowledge gaps are presented.

Blood pressure (BP) is a major cardiovascular disease risk factor. To date, few variants associated with inter-individual BP variation have been identified. A genome-wide association study of systolic (SBP), diastolic BP (DBP), and hypertension in the CHARGE Consortium (n=29,136) identified 13 SNPs for SBP, 20 for DBP, and 10 for hypertension at p <4×10 -7 . The top 10 loci for SBP and DBP were incorporated into a risk score; mean BP and prevalence of hypertension increased in relation to number of risk alleles carried. When 10 CHARGE SNPs for each trait were meta-analyzed jointly with the Global BPgen Consortium (n=34,433), four CHARGE loci attained genome-wide significance (p<5×10 -8 ) for SBP (ATP2B1, CYP17A1, PLEKHA7, SH2B3), six for DBP (ATP2B1, CACNB2, CSK/ULK3, SH2B3, TBX3/TBX5, ULK4), and one for hypertension (ATP2B1). Identifying novel BP genes advances our understanding of BP regulation and highlights potential drug targets for the prevention or treatment of hypertension.High blood pressure affects about one third of adults and contributes to 13.5 million deaths worldwide each year and about half the global risk for stroke and ischemic heart disease. 1,2 Clinical trials, dating back more than forty years, have proven that drug treatment to lower blood pressure dramatically reduces the risk of cardiovascular events in people with hypertension. 3,4 The substantial (30-60 percent) 5 heritability of blood pressure has prompted extensive efforts to identify its genetic underpinnings. The search for genes associated with interindividual variation in blood pressure in the general population has used a variety of complementary approaches, which have yielded relatively few clues. Linkage and candidate gene studies, despite considerable knowledge about pathways that are critical to blood pressure homeostasis, have provided limited consistent evidence of blood pressure quantitative trait loci. 6,7,8 The study of families with rare Mendelian high or low blood pressure syndromes has identified mutations with gain or loss of function in about a dozen renal sodium regulatory genes. 9 Common variants in two renal sodium regulatory genes have been found to be associated with blood pressure in the general population. 10 The vast majority of the genetic contribution to variation in blood pressure, however, remains unexplained.Large-scale genome-wide association studies (GWAS), in which hundreds of thousands of common genetic variants are genotyped and analyzed for disease association, have shown great success in identifying genes associated with common diseases and traits. 11,12 The fact that six GWAS published to date, however, have not identified loci associated with blood pressure or hypertension at p<5×10 -8 , has raised concerns about the utility of this approach for these traits. 13,14,15,16,17,18 If blood pressure variation in the general population is due to multiple variants with small effects, very large study samples are needed to identify them. We established the Cohorts for Heart and Aging Research i...

Birth weight (BW) is influenced by both foetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease1. These lifecourse associations have often been attributed to the impact of an adverse early life environment. We performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where foetal genotype was associated with BW (P <5x10-8). Overall, ˜15% of variance in BW could be captured by assays of foetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (rg=-0.22, P =5.5x10-13), T2D (rg=-0.27, P =1.1x10-6) and coronary artery disease (rg=-0.30, P =6.5x10-9) and, in large cohort data sets, demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions (P =1.9x10-4). We have demonstrated that lifecourse associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and have highlighted some of the pathways through which these causal genetic effects are mediated.

We screened DNA sequence variants on an exome-focused genotyping array in >300,000 participants with replication in >280,000 participants and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice revealed lipid changes consistent with the human data. We utilized mapped variants to address four clinically relevant questions and found the following: (1) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease; (2) outside of the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (3) only some mechanisms of lowering LDL-C seemed to increase risk for type 2 diabetes; and (4) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (e.g., TM6SF2, PNPLA3) tracked with higher liver fat, higher risk for type 2 diabetes, and lower risk for coronary artery disease whereas TG-lowering alleles involved in peripheral lipolysis (e.g., LPL, ANGPTL4) had no effect on liver fat but lowered risks for both type 2 diabetes and coronary artery disease.