Tricuspid aortic valve regurgitation associate with ascending aortic aneurysm through endothelial activation and lipoprotein infiltration.

AIMS: An abnormal accumulation of immune cells and inflammation has been described in ascending aortic aneurysm but the factor driving disease initiation remains elusive. Interestingly, ascending aortic dilatation often occurs alongside aortic regurgitation but rarely with aortic stenosis. We sought to investigate ascending aortic aneurysm initiation by assessing the relation between aortic regurgitation and vascular activation and inflammation.
MATERIAL AND RESULTS: In this prospective cohort study, patients with tricuspid aortic valves undergoing elective open-heart surgery were included. Aortic specimens from organ donors were obtained through the University of Miami Tissue Bank. Spatial transcriptomics measured gene expression in non-dilated aortic endothelium, intima and subintima. Immunohistochemistry determined protein expression. Aortic dimensions were recorded pre-operatively and ten years after surgery using echocardiography. Aortic gene expression affected by physiological blood flow was previously measured in Wistar rats.
We show a mesenchymal activation of endothelial cells, possibly mediated by bidirectional flow, in the non-dilated ascending aorta of patients with aortic valve regurgitation, accompanied by intimal infiltration, retention and oxidation of apolipoprotein B-containing lipoproteins. We further observed intimal upregulation of genes coding for core proteins of lipoprotein-binding proteoglycans and the Oxidized Low Density Lipoprotein Receptor 1 (OLR1), the latter by infiltrating macrophages and in association with progressive inflammation and dilatation. None of the above was observed in patients with aortic stenosis. Notably, surgical replacement of regurgitant valves, but not stenotic valves, mitigated 10-year aortic growth.
CONCLUSIONS: Our results highlight a distinct pathological role of aortic valve regurgitation in ascending aortic aneurysm formation by promoting mesenchymal activation of endothelial cells and lipoprotein-related immune cell infiltration and inflammation, in patients with tricuspid aortic valves. We also provide novel insights into the long-term impact of surgical aortic valve replacement on ascending aortic growth and suggest a diagnostic or therapeutic target in oxidized Low-Density Lipoprotein Cholesterol.