Aims Spontaneous coronary artery dissection (SCAD) is a cause of acute coronary syndromes and in rare cases sudden cardiac death (SCD). Connective tissue abnormalities, coronary inflammation, increased coronary vasa vasorum density and coronary fibromuscular dysplasia have all been implicated in the pathophysiology of SCAD but have not previously been systematically assessed. We designed a study to investigate the coronary histological and dermal collagen ultrastructural findings in SCAD. Methods and Results 36 autopsy SCAD cases were compared with 359 SCAD survivors. Coronary and myocardial histology and immunohistochemistry were undertaken. Transmission electron microscopy (TEM) of dermal extracellular matrix components (ECM) of n = 31 SCAD survivors and n = 16 healthy volunteers were compared. Autopsy cases were more likely male (19% versus 5%; p = 0.0004) with greater proximal left coronary involvement (56% versus 18%; p < 0.0001) compared to SCAD survivors. N = 24 (66%) of cases showed no myocardial infarction on macro- or microscopic examination consistent with arrhythmogenic death. There was significantly (p < 0.001) higher inflammation in cases with delayed-onset death vs sudden death and significantly more inflammation surrounding the dissected vs. non-dissected vessel segments. N = 17 (47%) cases showed limited intimal fibro-elastic thickening but no features of fibromuscular dysplasia and no endothelial or internal elastic lamina abnormalities. There were no differences in vasa vasorum density between SCAD and control cases. TEM revealed no general ultrastructural differences in ECM components or markers of fibroblast metabolic activity. Conclusions Assessment of SCD requires careful exclusion of SCAD, particularly in cases without myocardial necrosis. Peri-coronary inflammation in SCAD is distinct from vasculitides and likely a reaction to, rather than a cause for SCAD. Coronary fibromuscular dysplasia or increased vasa vasorum density do not appear pathophysiologically important. Dermal connective tissue changes are not common in SCAD survivors. Translational Perspective SCAD, especially of distal coronary territories should be carefully assessed at post mortem in SCD cases, even where there are no signs of myocardial infarction. The immediate cause of SCAD is likely to be the development of a spontaneous intramural haematoma rather than an intimal disruption or ‘tear’. This does not seem to be directly related to increased vasa vasorum density, coronary fibromuscular dysplasia or local inflammation (except as a response to injury). Although SCAD is rarely associated with hereditary connective tissue disorders, there does not seem to be a more generalizable global connective tissue ultrastructural abnormality in most cases.

Pancreatic ductal adenocarcinoma (PDAC) is characterised by desmoplasia, thought to support progression and chemotherapeutic resistance. The Hedgehog pathway is known to play an important role in this cancer. While the upregulation of Sonic hedgehog (Shh) in the epithelium of PDAC is known, we investigated its expression in the tumour microenvironment in order to find new targets for new chemotherapeutical approaches. Immunohistochemistry was used for the investigation of Shh and Vimentin in primary human pancreatic tissues. Gene (qRT-PCR) and protein (immunofluorescence) expression of Shh, αSMA (a marker of the mesenchymal phenotype) and periostin (a marker of mesenchymal cells within a mixed population) were investigated in in vitro cell models. Shh expression was significantly upregulated in the stromal and epithelial compartments of poorly-differentiated PDAC samples, with a strong correlation with the amount of stroma present. Characterisation of stromal cells showed that there was expression of Shh ligand in a mixed population comprising αSMA+ myofibroblasts and αSMA− mesenchymal stem cells. Moreover, we demonstrated the interaction between these cell lines by showing a higher rate of mesenchymal cell proliferation and the upregulation of periostin. Therefore, targeting stromal Shh could affect the equilibrium of the tumour microenvironment and its contribution to tumour growth.

Introduction Spontaneous coronary artery dissection (SCAD) is a cause of acute coronary syndromes and rarely sudden cardiac death (SCD). SCAD is characterised by medial false lumen haematoma formation and periadventitial inflammatory cell infiltrate. Although SCAD has been linked to connective tissue disorders, its pathophysiology remains poorly understood and the role of inflammation unknown. Purpose We sought to establish the definitive histopathological features of SCAD and explore pathophysiological mechanisms through assessment of dermal connective tissue ultrastructure. Methods N=36 SCD cases diagnosed as SCAD on autopsy were identified in pathology archives at four international centres. Their demographic and clinical characteristics were compared with n=359 survivors recruited in a SCAD survivors cohort. Haematoxylin & eosin sections were examined under light microscope. Immunohistochemistry (IHC) was employed for quantification of inflammatory cell infiltrate (CD68, CD3) and vasa vasorum density (CD31) of SCAD cases (n=20) compared to age- and sex-matched controls (n=10). Dermal extracellular matrix components (EMC) of n=32 SCAD survivors and n=16 healthy volunteers (HV) were compared using electron microscopy (EM). Results The autopsy series cases were more likely to be male (p=0.0256) and had higher incidence of left main stem (p=0.0475) and proximal left anterior descending (p<0.001) disease compared to SCAD survivors. N=24 (66%) of SCAD autopsy case showed no evidence of myocardial necrosis. N=17 (47%) showed mild-moderate atherosclerotic changes but no features of fibromuscular dysplasia. There were no differences in vasa vasorum density between SCAD and control cases (A). The degree of inflammatory cell infiltrate varied greatly but significantly higher than controls (B), comprising CD68+ macrophages, eosinophils and CD3+ positive T-cells. There was a statistically significant association (p=0.006) between the degree of inflammatory cell infiltrate and the length of time from onset of symptoms to death (Panel C), as well as significantly (p<0.001) denser inflammatory cell infiltrate adjacent to the dissection plane (D, exemplary sections E&F). EM revealed no differences between SCAD and HV in dermal fibroblast size & activity or elastin size & damage indicators, but possible changes in subgroups with more extreme clinical phenotype or pregnancy-related SCAD (G). Conclusions To our knowledge this is the largest SCAD pathology case series so far. We show for the first time that periadvential inflammation in SCAD appears to be time-dependent and localising to the dissected coronary segment, suggesting healing response to injury rather than causal contribution. We found no evidence to suggest increased vasa vasorum density is pathophysiologically important. Connective tissue changes were only linked to a small proportion of cases. These novel findings may have important implications for the management of SCAD patients. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): British Heart Foundation, Leicester NIHR Biomedical Research Centre

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