Lipoprotein retention and inflammation due to regurgitant blood flow as part of the natural history of degenerative ascending aortic aneurysms

Abstract

BACKGROUND: An abnormal accumulation of immune cells and a disrupted lipoprotein metabolism has previously been described as part of the pathogenesis of ascending aortic aneurysm in patients with tricuspid aortic valves. The factor driving the accumulation of immune cells remains unclear; however, it may be considered in light of the observation that proximal aortic dilatation often occurs alongside aortic regurgitation but rarely with aortic stenosis. In the present study we aim to investigate the natural history of ascending aortic aneurysm in patients with tricuspid aortic valves by assessing the association between aortic regurgitation and vascular deterioration. MATERIAL AND METHODS: Patients tricuspid aortic valves undergoing elective open-heart surgery for ascending aortic- and/or aortic valve replacement were included. Aortic specimens from organ donors were obtained through the University of Miami Tissue Bank, USA. Protein expression/localization and differences in aortic intima-media gene expression were assessed using immunohistochemistry and transcriptomics, respectively. Ten-year aortic growth was measured using echocardiography. In total 142 patients were included across experiments (mRNA expression n=44, immunohistochemistry n=49, 10-year follow-up n=49). RESULTS: Aortic regurgitation was associated with the presence of oxidized apolipoprotein B-containing lipoproteins and infiltrating CD68+ cells in the non-dilated ascending aortic media, which was not observed in aortas of patients with aortic stenosis. Assessing factors influencing lipoprotein retention showed increased levels of genes encoding core proteins of proteoglycans (HSPG2, CSPG4, ACAN, and BGN) in patients with regurgitant valves, compared with aortas from patients with stenotic valves. Moreover, dilated aortas of patients with aortic regurgitation exhibited higher levels of the receptor for oxidized low-density lipoprotein, OLR1, which correlated positively with inflammatory markers in both dilated and non-dilated aortas. Surgical replacement of regurgitant aortic valves mitigated long-term aortic growth, in contrast to replacement of stenotic valves, which was associated with continuous aortic dilation. CONCLUSIONS: The natural history of ascending aortic aneurysm in patients with tricuspid aortic valves involves medial lipoprotein retention and oxidation with subsequent OLR1-driven pathological inflammation, and can be mitigated by replacement of the regurgitant aortic valve.