Structural dysregulation of the pulmonary autograft was associated with a greater density of p16INK4A-vascular smooth muscle cells

The Ross procedure involves replacement of a diseased aortic valve by the patient's own pulmonary valve (autograft) [1,2]. The majority of patients undergoing the Ross procedure have congenital aortic valve disease characterized by a bicuspid or unicuspid aortic valve leading to aortic stenosis or aortic insufficiency [3,4]. An important advantage of the Ross procedure is the ability of the pulmonary autograft to undergo physiological remodeling translating to superior hemodynamic function as compared to conventional aortic valve replacement [3], [4], [5]. Furthermore, patients undergoing the Ross procedure avoid lifelong anticoagulation thereby reducing valve-related complications (e.g. endocarditis and thrombosis).[3], [4], [5] However, in a modest number of cases, progressive dilation of the pulmonary autograft was reported in patients that underwent the Ross procedure translating to aneurysm formation and/or autograft valve regurgitation, both of which require re-operation [5], [6], [7], [8]. Morphological characteristics of an aneurysmal vessel include elastin fragmentation and collagen degradation translating to a loss of structural integrity [9], [10], [11], [12], [13]. At the cellular level, an aneurysmal phenotype was highlighted in part by the increased expression of cell cycle inhibitors, including p21cip1, p27kip1, p53 and p16INK4a [14], [15], [16], [17], [18], [19], [20]. The increased expression of a panel of cell cycle inhibitors induced a senescent phenotype and p21cip1 and p16INK4a protein levels were upregulated in vascular smooth muscle cells of the aneurysmal aorta of BAV patients.21 Moreover, senescent vascular smooth muscle cells that acquired a senescence-associated secretory phenotype were characterized by the increased synthesis and release of matrix metalloproteinases facilitating elastin fragmentation and collagen degradation [14,15,[20], [21], [22]]. Thus, despite the established role of the aforementioned events in both human and experimental models of aortic aneurysm, the rarity of pulmonary autograft dilatation after the Ross procedure has prevented the elucidation of cellular events that may contribute to vessel expansion in this specific pathological disease state. In the present study, the pulmonary autograft of three male patients excised between 16 and 21 years after the initial Ross procedure was obtained to test the hypothesis that maladaptive vessel remodeling was attributed in part to the appearance of a senescent phenotype characterized by the increased density of medial vascular smooth muscle cells expressing the cell cycle inhibitor p16INK4a.

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