Spontaneous Coronary Artery Dissection – Advanced Phenotyping and Risk Stratification in Key Subpopulations

BackgroundSpontaneous coronary artery dissection (SCAD) is an uncommon cause of myocardial infarction predominantly affecting women. It is caused by the development of a false lumen in the arterial wall leading to compression of the true lumen and myocardial infarction.MethodsThe thesis is comprised of three studies. Study one is a phenotyping study of women with a history of two or more SCAD events compared with matched healthy controls. Participants underwent clinical assessment and detailed phenotyping with brachial artery flow mediated dilatation, cardiopulmonary exercise testing, quantitative adenosine and psychological stress MRI perfusion and ambulatory ECG monitoring. Study two is a phenotyping study of men with SCAD compared with matched healthy controls, who underwent the same tests as the women. Study three is an observational study of a larger group of men from the SCAD registry; these men were compared to a previously studied female group in terms of demographic data, clinical history, risk factors and recurrent events.ResultsCardiopulmonary exercise testing demonstrated both male and female SCAD patients to have a significantly greater increase in blood pressure per unit workload than healthy controls (P=0.002 for male, 0.02 for female). Female recurrent SCAD participants had lower myocardial perfusion reserve with psychological stress than healthy controls (P=0.022).Men were found to have recurrent SCAD sooner than women, at 2.66 versus 4.43 years after their first SCAD.Female SCAD patients showed greater flow mediated dilatation than healthy controls (P = 0.0145) whilst male SCAD patients had greater nitrate mediated dilatation (P=0.041).Many of the other test results did not differ between SCAD patients and healthy controls.ConclusionsSCAD survivors did not differ significantly from healthy controls in terms of measures of autonomic dysfunction or myocardial perfusion at rest and with adenosine stress.Female SCAD patients had greater flow mediated dilatation than controls, whereas male SCAD patients had greater nitrate mediated dilatation.Both female recurrent and male SCAD survivors showed an enhanced blood pressure response to exercise, and female recurrent patients showed a reduced level of perfusion with psychological stress.Male SCAD patients experience recurrence earlier than female SCAD participants.</p

Editorial on "Characteristics of extension and de novo recurrent spontaneous coronary artery dissection".

Editorial on "Characteristics of extension and de novo recurrent spontaneous coronary artery dissection"

Spontaneous Coronary Artery Dissection: Insights on Rare Genetic Variation from Genome Sequencing

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 UK, 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 two cohorts had a diagnosed connective tissue disorder. We identified pathogenic or likely pathogenic variants in seven genes (PKD1, COL3A1, SMAD3, TGFB2, LOX, MYLK, and YY1AP1) in 14/384 cases in the study cohort and in 1/92 cases in the validation cohort. In our rare variant collapsing analysis, PKD1 was 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.</div