Lucy McGrath-Cadell’s research while affiliated with Victor Chang Cardiac Research Institute and other places

Background Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndrome or sudden cardiac death, primarily affecting relatively young women (median age, 51 years) without typical cardiovascular risk factors. SCAD has a genetic component, with genome‐wide association studies identifying multiple risk loci. Thoracic aortic dissection (type A) shares some genetic overlap with SCAD, suggesting potential common predispositions. Methods We performed genetic screening or whole‐genome sequencing of 17 patients with SCAD (94% women) with a first‐ or second‐degree relative (89% men) affected by aortic dissection (AD). We assessed rare variants in candidate genes and genome‐wide using the American College of Medical Genetics and Genomics criteria. Polygenic risk scores were calculated to assess genetic risk for SCAD, fibromuscular dysplasia, AD, and abdominal aortic aneurysm in patients with SCAD, relatives with AD, and controls. Results Whole‐genome sequencing identified pathogenic or likely pathogenic variants in SMAD3 , CBS , and COL3A1 in 3 SCAD cases. Additionally, 4 variants of uncertain significance were found in candidate genes. Polygenic risk scores for SCAD were significantly associated with increased odds of SCAD in probands versus controls (odds ratio, 1.79 [95% CI, 1.08–2.99]; P =0.024). Conclusions Our study supports a complex genetic landscape underlying SCAD, implicating rare monogenic pathogenic variants and polygenic risk. We identified pathogenic variants in patients with SCAD with a family history of AD, highlighting potential genetic links between these vascular disorders. The findings underscore the importance of genetic screening in patients with SCAD with a history of AD to identify individuals at risk and guide preventive strategies.

Spontaneous coronary artery dissection (SCAD) is an increasingly recognised cause of acute coronary syndrome predominantly affecting women (>90% of cases) that is frequently associated with other arteriopathies, such as fibromuscular dysplasia (FMD) and migraine. We present a case of multi-vessel SCAD in a woman in her 40s presenting with myocardial infarction in whom incidental widespread FMD was found, including a massive right renal artery aneurysm requiring ex vivo resection, repair and autotransplantation. The case underscores the need for routine angiographic screening for FMD, which has a shared genetic risk with SCAD, and is associated with aneurysms, stenoses and hypertension.

Objective: Studies have shown marked sex disparities in Coronary Artery Diseases (CAD) epidemiology, yet the underlying mechanisms remain unclear. We explored the coronary anatomy and the resulting haemodynamics in patients with suspected but no significant CAD. Left Main (LM) bifurcations were 3D-reconstructed from 127 Computed Tomography Angiography images (42 males and 85 females, aged 38-81). Methods: Shape parameters including bifurcation angles, curvature, and diameters were measured, before solving the clinically relevant haemodynamic metrics. The severity and location of the vascular area exposed to adverse haemodynamics were compared between sexes. Results: Females were more likely than males to exhibit adversely low Time Averaged Endothelial Shear Stress (TAESS) along the inner wall of a bifurcation (16.8% vs. 10.7%). Males had a higher percentage of areas exposed to both adversely high Relative Residence Time (6.1% vs 4.2%, p = 0.001) and high Oscillatory Shear Index OSI (4.6% vs 2.3%, p<0.001). However, the OSI values were generally small and should be interpreted cautiously. Males had larger arteries (M vs F, LM: 4.0±0.5mm vs 3.3±0.6mm, LAD: 3.6±0.5mm vs 3.0±0.5mm, LCX:3.5±0.5mm vs 2.9±0.6mm), and females exhibited higher curvatures in all three branches (M vs F, LM: 0.40 vs 0.46, LAD: 0.45 vs 0.51, LCx: 0.47 vs 0.55,p<0.001). There was no difference in bifurcation angles. Conclusion: These differences may in part contribute to differences in CAD risk between sexes. Significance: This work facilitates a better understanding of sex differences in factors contributing to CAD, ultimately improving screening and therapeutic strategies particularly for women who currently have worse predictive outcomes.

Importance Spontaneous coronary artery dissection (SCAD) is a poorly understood cause of acute coronary syndrome that predominantly affects women. Evidence to date suggests a complex genetic architecture, while a family history is reported for a minority of cases. Objective To determine the contribution of rare and common genetic variants to SCAD risk in familial cases, the latter via the comparison of a polygenic risk score (PRS) with those with sporadic SCAD and healthy controls. Design, Setting, and Participants This genetic association study analyzed families with SCAD, individuals with sporadic SCAD, and healthy controls. Genotyping was undertaken for all participants. Participants were recruited between 2017 and 2021. A PRS for SCAD was calculated for all participants. The presence of rare variants in genes associated with connective tissue disorders (CTD) was also assessed. Individuals with SCAD were recruited via social media or from a single medical center. A previously published control database of older healthy individuals was used. Data were analyzed from January 2022 to October 2023. Exposures PRS for SCAD comprised of 7 single-nucleotide variants. Main Outcomes and Measures Disease status (familial SCAD, sporadic SCAD, or healthy control) associated with PRS. Results A total of 13 families with SCAD (27 affected and 12 unaffected individuals), 173 individuals with sporadic SCAD, and 1127 healthy controls were included. A total of 188 individuals with SCAD (94.0%) were female, including 25 of 27 with familial SCAD and 163 of 173 with sporadic SCAD; of 12 unaffected individuals from families with SCAD, 6 (50%) were female; and of 1127 healthy controls, 672 (59.6%) were female. Compared with healthy controls, the odds of being an affected family member or having sporadic SCAD was significantly associated with a SCAD PRS (where the odds ratio [OR] represents an increase in odds per 1-SD increase in PRS) (affected family member: OR, 2.14; 95% CI, 1.78-2.50; adjusted P = 1.96 × 10 ⁻⁴ ; sporadic SCAD: OR, 1.63; 95% CI, 1.37-1.89; adjusted P = 5.69 × 10 ⁻⁴ ). This association was not seen for unaffected family members (OR, 1.03; 95% CI, 0.46-1.61; adjusted P = .91) compared with controls. Further, those with familial SCAD were overrepresented in the top quintile of the control PRS distribution (OR, 3.70; 95% CI, 2.93-4.47; adjusted P = .001); those with sporadic SCAD showed a similar pattern (OR, 2.51; 95% CI, 1.98-3.04; adjusted P = .001). Affected individuals within a family did not share any rare deleterious variants in CTD-associated genes. Conclusions and Relevance Extreme aggregation of common genetic risk appears to play a significant role in familial clustering of SCAD as well as in sporadic case predisposition, although further study is required.

Background Spontaneous coronary artery dissection (SCAD) affects mainly women with a mean age of 51 years.(1) Predicted damaging variants in connective tissue disease (CTD) genes have been found in a subset of patients with SCAD, however in some cases the typical phenotype associated with these conditions is lacking. Variants in the COL3A1 gene, on chromosome 2 encoding type III collagen, appear to be one of the most frequently reported in SCAD. Mutations in COL3A1 alter the production and structure of type III procollagen and weaken connective tissues, including blood vessel walls and cause vascular Ehlers-Danlos Syndrome (vEDS).(2) Purpose Systematically determine the known cases of SCAD with COL3A1 likely pathogenic/pathogenic (LP/P) variants to highlight COL3A1 as a SCAD-causative gene, in a subset of SCAD cases. Methods We searched PubMed using search terms "spontaneous coronary artery dissection" AND COL3A1, "spontaneous coronary artery dissection" AND "vascular Ehlers-Danlos syndrome", "spontaneous coronary artery dissection" AND genetics. We also searched the ClinVar database using COL3A1 [gene] and the following stipulations: clinical significance limited to pathogenic or likely Pathogenic; molecular consequence limited to frameshift, missense or nonsense, and review status limited to multiple submitters or at least one star. The COL3A1 variants identified were reclassified using American College of Medical Genetics (ACMG) criteria. Fisher's exact test was used for statistical comparisons. Results There were 42 published cases of SCAD with a LP/P mutation in COL3A1. Of the 42 published cases, there were two cases published twice. Using updated ACMG criteria, three cases were reclassified to variant of uncertain significance (VUS), from LP/P. This resulted in 37 unique cases of SCAD with LP/P variants using ACMG criteria. Of the cases with LP/P mutations where sex was known, 11/33 cases (35%) were male, higher than that reported in a large, published cohort where 86/750 SCAD cases (11.5%) were male (1) (p = 0.001129, 95% CI 0.115876 0.614725). Most SCAD cases with a COL3A1 LP/P mutation in whom age was reported, were under age 40 years (23/31, 74%), proportionally more cases when compared to a cohort of SCAD cases where 82/460 SCAD cases were under age 40 years (18%) (p value = 8.782e-11, 95% CI 0.02837315 0.18361793). Of the variant types reported (16/37), the majority were single nucleotide variants with one copy number variation (duplication). Conclusion While no one gene carries damaging variants in a large proportion of SCAD cases, COL3A1 variants have been found in a number of people with SCAD. Patients presenting with SCAD under 40 years and particularly males should be screened for pathogenic variants in aortopathy and connective tissue genes, such as COL3A1.Table:SCAD with COL3A1 LP/P variants 1TableSCAD with COL3A1 LP/P variants 2