Daniela Galli1, Roberta Manuguerra2, Rodolfo Monaco2, Laura Manotti2, Matteo Goldoni3, Gabriella Becchi2, Cecilia Carubbi1, Giulia Vignali4, Nicola Cucurachi4, Tiziano Gherli5, Francesco Nicolini5, Roberto Lorusso6, Marco Vitale7, Domenico Corradi8. 1. Department of Biomedical, Biotechnological, and Translational Sciences (S. Bi. Bi. T.), Anatomy and Histology Unit, University of Parma, Parma, Italy. 2. Department of Biomedical, Biotechnological, and Translational Sciences (S. Bi. Bi. T.), Unit of Pathology, University of Parma, Italy. 3. Department of Clinical and Experimental Medicine, Unit of Occupational and Environmental Medicine, University of Parma, Italy. 4. Department of Biomedical, Biotechnological, and Translational Sciences (S. Bi. Bi. T.), Unit of Forensic Medicine, University of Parma, Italy. 5. Department of Clinical and Experimental Medicine, Cardiac Surgery Unit, University of Parma, Italy. 6. Cardio-Thoracic Surgery Department, Heart and Vascular Centre, Maastricht University Medical Centre, Maastricht, The Netherlands. 7. Department of Biomedical, Biotechnological, and Translational Sciences (S. Bi. Bi. T.), Anatomy and Histology Unit, University of Parma, Parma, Italy; CoreLab Scientific Director, University Hospital, Parma, Italy. 8. Department of Biomedical, Biotechnological, and Translational Sciences (S. Bi. Bi. T.), Unit of Pathology, University of Parma, Italy. Electronic address: domenico.corradi@unipr.it.
Abstract
BACKGROUND: With age, aortic valve cusps undergo varying degrees of sclerosis which, sometimes, can progress to calcific aortic valve stenosis (AVS). To perform a retrospective clinico-pathologic investigation in patients with calcific AVS. METHODS: We characterized and graded the structural remodeling in 236 aortic valves (200 tricuspid and 36 bicuspid) from patients with calcific AVS (148 males; average 72years); possible relationships between general/clinical/echocardiographic characteristics and the histopathologic changes were explored. Twenty autopsy aortic valves served as controls. In 40 cases, we also tested the immunohistochemical expression of metalloproteinases and cytokines, and characterized the inflammatory infiltrate. In 5 cases, we cultured cusp stem cells and explored their potential to differentiate into osteoblasts/adipocytes. RESULTS: AVS cusps showed structural remodeling as severe fibrosis (100%), calcific nodules (100%), neoangiogenesis (81%), inflammation (71%), bone metaplasia with or without hematopoiesis (6% and 53%, respectively), adipose metaplasia (16%), and cartilaginous metaplasia (7%). At multivariate analysis, AVS degree and interventricular septum thickness were the only predictors of remodeling (barring inflammation). All the tested metalloproteinases (except MMP-13) and cytokines were expressed in AVS cusps. Inflammation mainly consisted of B and T lymphocytes (CD4+/CD8+ cell ratio 3:1) and plasma cells. AVS changes were mostly different from typical atherosclerosis. Cultured mesenchymal cusp stem cells could differentiate into osteoblasts/adipocytes. CONCLUSIONS: Structural remodeling in AVS is peculiar and considerable, and is related to the severity of the disease. However, the different newly formed tissues-where "valvular interstitial cells" play a key role-and their well-known slow turnover suggest a reverse structural remodeling improbable.
BACKGROUND: With age, aortic valve cusps undergo varying degrees of sclerosis which, sometimes, can progress to calcific aortic valve stenosis (AVS). To perform a retrospective clinico-pathologic investigation in patients with calcific AVS. METHODS: We characterized and graded the structural remodeling in 236 aortic valves (200 tricuspid and 36 bicuspid) from patients with calcific AVS (148 males; average 72years); possible relationships between general/clinical/echocardiographic characteristics and the histopathologic changes were explored. Twenty autopsy aortic valves served as controls. In 40 cases, we also tested the immunohistochemical expression of metalloproteinases and cytokines, and characterized the inflammatory infiltrate. In 5 cases, we cultured cusp stem cells and explored their potential to differentiate into osteoblasts/adipocytes. RESULTS: AVS cusps showed structural remodeling as severe fibrosis (100%), calcific nodules (100%), neoangiogenesis (81%), inflammation (71%), bone metaplasia with or without hematopoiesis (6% and 53%, respectively), adipose metaplasia (16%), and cartilaginous metaplasia (7%). At multivariate analysis, AVS degree and interventricular septum thickness were the only predictors of remodeling (barring inflammation). All the tested metalloproteinases (except MMP-13) and cytokines were expressed in AVS cusps. Inflammation mainly consisted of B and T lymphocytes (CD4+/CD8+ cell ratio 3:1) and plasma cells. AVS changes were mostly different from typical atherosclerosis. Cultured mesenchymal cusp stem cells could differentiate into osteoblasts/adipocytes. CONCLUSIONS: Structural remodeling in AVS is peculiar and considerable, and is related to the severity of the disease. However, the different newly formed tissues-where "valvular interstitial cells" play a key role-and their well-known slow turnover suggest a reverse structural remodeling improbable.
Authors: Marta Scatena; Melissa F Jackson; Mei Y Speer; Elizabeth M Leaf; Mary C Wallingford; Cecilia M Giachelli Journal: Cardiovasc Pathol Date: 2018-02-15 Impact factor: 2.185