Spontaneous coronary artery dissection (SCAD) is an understudied cause of myocardial infarction primarily affecting women. It is not known to what extent SCAD is genetically distinct from other cardiovascular diseases, including atherosclerotic coronary artery disease (CAD). Here we present a genome-wide association meta-analysis (1,917 cases and 9,292 controls) identifying 16 risk loci for SCAD. Integrative functional annotations prioritized genes that are likely to be regulated in vascular smooth muscle cells and artery fibroblasts and implicated in extracellular matrix biology. One locus containing the tissue factor gene F3, which is involved in blood coagulation cascade initiation, appears to be specific for SCAD risk. Several associated variants have diametrically opposite associations with CAD, suggesting that shared biological processes contribute to both diseases, but through different mechanisms. We also infer a causal role for high blood pressure in SCAD. Our findings provide novel pathophysiological insights involving arterial integrity and tissue-mediated coagulation in SCAD and set the stage for future specific therapeutics and preventions.

Spontaneous coronary artery dissection (SCAD) is a pathophysiologically distinct cause of acute coronary syndromes (ACS). It is increasingly recognized that optimal management is different from that for atherosclerotic ACS and that a SCAD diagnosis has specific long-term prognostic and therapeutic implications. Accurate diagnosis is therefore essential to ensure the best treatment of patients. At present this relies on the recognition of typical features of SCAD identified on invasive coronary angiography. Although most SCAD can be readily distinguished angiographically from alternative causes of ACS, false positive and false negative diagnoses remain common. In particular, sometimes non-SCAD presentations, including atherothrombosis, takotsubo cardiomyopathy, coronary embolism, coronary vasospasm, contrast streaming, and myocardial infarction with nonobstructive coronary arteries, can mimic angiographic features usually associated with SCAD. The authors present the combined experience from European and US SCAD referral centers reviewing the classical angiographic appearances of SCAD, presenting potential diagnostic pitfalls and exemplars of SCAD mimickers. The authors further review the benefits and limitations of intracoronary imaging in the context of SCAD. Finally, the authors discuss the investigation of ambiguous cases and an approach to minimize misdiagnosis in difficult cases.

Background: Spontaneous coronary artery dissection (SCAD) occurs when an epicardial coronary artery is narrowed or occluded by an intramural hematoma. SCAD mainly affects women and is associated with pregnancy and systemic arteriopathies, particularly fibromuscular dysplasia. Variants in several genes, such as those causing connective tissue disorders, have been implicated; however, the genetic architecture is poorly understood. Here, we aim to better understand the diagnostic yield of rare variant genetic testing among a cohort of SCAD survivors and to identify genes or gene sets that have a significant enrichment of rare variants.Methods: We sequenced a cohort of 384 SCAD survivors from the United Kingdom, alongside 13 722 UK Biobank controls and a validation cohort of 92 SCAD survivors. We performed a research diagnostic screen for pathogenic variants and exome-wide and gene-set rare variant collapsing analyses.Results: The majority of patients within both cohorts are female, 29% of the study cohort and 14% validation cohort have a remote arteriopathy. Four cases across the 2 cohorts had a diagnosed connective tissue disorder. We identified pathogenic or likely pathogenic variants in 7 genes (PKD1,COL3A1,SMAD3,TGFB2,LOX,MYLK, andYY1AP1) in 14/384 cases in the study cohort and in 1/92 cases in the validation cohort. In our rare variant collapsing analysis,PKD1was the highest-ranked gene, and several functionally plausible genes were enriched for rare variants, although no gene achieved study-wide statistical significance. Gene-set enrichment analysis suggested a role for additional genes involved in renal function.Conclusions: By studying the largest sequenced cohort of SCAD survivors, we demonstrate that, based on current knowledge, only a small proportion have a pathogenic variant that could explain their disease. Our findings strengthen the overlap between SCAD and renal and connective tissue disorders, and we highlight several new genes for future validation.

Although a common challenge for patients and clinicians, there is little population-level evidence on the prevalence of cardiovascular disease (CVD) in individuals diagnosed with potentially curable cancer. We investigated CVD rates in patients with common potentially curable malignancies and evaluated the associations between patient and disease characteristics and CVD prevalence. The study included cancer registry patients diagnosed in England with stage I to III breast cancer, stage I to III colon or rectal cancer, stage I to III prostate cancer, stage I to IIIA non-small-cell lung cancer, stage I to IV diffuse large B-cell lymphoma, and stage I to IV Hodgkin lymphoma from 2013 to 2018. Linked hospital records and national CVD databases were used to identify CVD. The rates of CVD were investigated according to tumor type, and associations between patient and disease characteristics and CVD prevalence were determined. Among the 634,240 patients included, 102,834 (16.2%) had prior CVD. Men, older patients, and those living in deprived areas had higher CVD rates. Prevalence was highest for non-small-cell lung cancer (36.1%) and lowest for breast cancer (7.7%). After adjustment for age, sex, the income domain of the Index of Multiple Deprivation, and Charlson comorbidity index, CVD remained higher in other tumor types compared to breast cancer patients. There is a significant overlap between cancer and CVD burden. It is essential to consider CVD when evaluating national and international treatment patterns and cancer outcomes.