From maturation to degeneration: Distinct biological trajectories in bicuspid and tricuspid aortopathy.

Abstract

Ascending thoracic aortic aneurysm formation differs fundamentally between patients with bicuspid (BAV) and tricuspid (TAV) aortic valve phenotypes, yet current clinical management largely relies on shared diameter thresholds, although clinical and scientific data fail to correlate with diameter and risk of rupture. Over the past two decades, histological, biochemical and biomechanical studies have revealed unique differences between dilated tissue properties from patients with BAV- and TAV-associated idiopathic degenerative ascending aortic aneurysms even at similar aortic diameters. This review focuses on histological, biochemical and biomechanical differences between BAV and TAV aortopathy with a focus on ageing. Idiopathic degenerative TAV aortopathy is characterised by medial degeneration with elastic lamellar fragmentation and loss, smooth muscle cell depletion, medial fibrosis, mucoid extracellular matrix accumulation and inflammatory features. These degenerative changes correlate with ageing and, in region-specific mechanical testing, with reduced delamination resistance and age-dependent biomechanical weakening. In contrast, BAV aortopathy frequently demonstrates relative preservation of medial architecture despite similar dilatation, alongside altered collagen maturation, and distinct osteogenic/microcalcification signatures. Lifespan analyses indicate that TAV follows a maturation-stabilisation-degeneration trajectory, whereas BAV exhibits aberrant vascular maturation without a true stabilisation phase. Importantly, aortic diameter correlates poorly with histological severity or biomechanical vulnerability, particularly in BAV. Collectively, these data support the concept that ascending thoracic aortic aneurysms in BAV and idiopathic degenerative TAV patients represent biologically divergent aortopathies requiring phenotype-informed risk stratification beyond diameter alone.