The bicuspid aortic valve and thoracic aortic disease
Author: Granath, Carl
Date: 2023-12-08
Location: CMM Lecture Hall (L8:00), Center for Molecular Medicine, Visionsgatan 18, Karolinska University Hospital, Solna
Time: 09.00
Department: Inst för molekylär medicin och kirurgi / Dept of Molecular Medicine and Surgery
Abstract
About 1% of the population is born with an aortic valve composed of only two cusps, called a
bicuspid aortic valve. Bicuspid aortic valve is associated with a high risk of both aortic valve
disease and ascending aortic dilatation, which develop at a significantly earlier age than in
patients with a normal tricuspid aortic valve. No medical therapy exists for either of the
conditions and current surgical treatments have substantial limitations. Tissue engineering is a
potential future treatment option for valvular heart disease. However, clinical trials have shown
that engineered valves exhibit limited durability similarly to conventional biological valves. A
possible cause of their failure is an aberrant basement membrane in the scaffolds, but the
normal basement membrane in the aortic valve has not been characterized. Moreover, the type
and prevalence of valvular disease and aortic dilatation differs between anatomical variants, or
phenotypes, of the bicuspid aortic valve, and potential sex differences have not been addressed
in this context. Furthermore, the pathological process of ascending aortic dilatation differs
between patients with bicuspid and tricuspid aortic valves, which has important implications
for pharmacological targets, surveillance, and surgical management.
Study I investigated the expression of laminins, a key basement membrane component, in the aortic valve. Valves from deceased donors were studied with immunohistochemistry, which revealed expression of laminin chains ⍺4-5, β1-2, and 𝛾1. A decellularized rat aortic valve scaffold with a retained basement membrane was developed to facilitate studies on the role of basement membrane components in valve regeneration.
Study II described sex differences in bicuspid phenotype in relation to valvular and aortic disease in a surgical cohort. Right-left cusp fusion was associated with aortic regurgitation in males, whereas right-non-coronary cusp fusion was associated with regurgitation in females. Furthermore, the 2-sinus phenotype was associated with root phenotype aortic dilatation in males, while females with the 2-sinus phenotype had small aortic roots and no root dilatation.
Study III demonstrated an inverse association between acetylsalicylic acid therapy and ascending aortic dilatation in patients with tricuspid aortic valve in a retrospective surgical series. Furthermore, acetylsalicylic acid was associated with decreased aortic intima-media gene expression of Cyclooxygenase-2 in dilated aortas from patients with tricuspid aortic valve.
Study IV mapped the long-term outcome of the distal aorta (the arch to the abdominal aorta) after ascending aortic replacement in a prospective cohort of patients with bicuspid and tricuspid aortic valves. There was a high incidence of distal aortic complications in patients with tricuspid, but not bicuspid aortic, valves.
In conclusion, the present thesis provides novel insights about the aortic valve microstructure, clinical implications of bicuspid aortic valve disease and ascending aortic dilatation, and pharmacological therapy in ascending aortic dilatation. These findings may contribute to new treatment options for bicuspid aortic valve disease and ascending aortic dilatation, and an individualized clinical management.
Study I investigated the expression of laminins, a key basement membrane component, in the aortic valve. Valves from deceased donors were studied with immunohistochemistry, which revealed expression of laminin chains ⍺4-5, β1-2, and 𝛾1. A decellularized rat aortic valve scaffold with a retained basement membrane was developed to facilitate studies on the role of basement membrane components in valve regeneration.
Study II described sex differences in bicuspid phenotype in relation to valvular and aortic disease in a surgical cohort. Right-left cusp fusion was associated with aortic regurgitation in males, whereas right-non-coronary cusp fusion was associated with regurgitation in females. Furthermore, the 2-sinus phenotype was associated with root phenotype aortic dilatation in males, while females with the 2-sinus phenotype had small aortic roots and no root dilatation.
Study III demonstrated an inverse association between acetylsalicylic acid therapy and ascending aortic dilatation in patients with tricuspid aortic valve in a retrospective surgical series. Furthermore, acetylsalicylic acid was associated with decreased aortic intima-media gene expression of Cyclooxygenase-2 in dilated aortas from patients with tricuspid aortic valve.
Study IV mapped the long-term outcome of the distal aorta (the arch to the abdominal aorta) after ascending aortic replacement in a prospective cohort of patients with bicuspid and tricuspid aortic valves. There was a high incidence of distal aortic complications in patients with tricuspid, but not bicuspid aortic, valves.
In conclusion, the present thesis provides novel insights about the aortic valve microstructure, clinical implications of bicuspid aortic valve disease and ascending aortic dilatation, and pharmacological therapy in ascending aortic dilatation. These findings may contribute to new treatment options for bicuspid aortic valve disease and ascending aortic dilatation, and an individualized clinical management.
List of papers:
I. Granath C, Noren H, Björck H, Simon N, Olesen K, Rodin S, Grinnemo KH, Österholm C. Characterization of Laminins in Healthy Human Aortic Valves and a Modified Decellularized Rat Scaffold. Biores Open Access. 2020 Dec 7;9(1):269-278.
Fulltext (DOI)
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II. Granath C, Mohamed SA, Olsson C, Grattan M, Mertens L, Franco-Cereceda A, Björck HM. Valve disease and aortopathy associations of bicuspid aortic valve phenotypes differ between men and women. Open Heart. 2021 Oct;8(2):e001857.
Fulltext (DOI)
Pubmed
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III. Granath C*, Freiholtz D*, Bredin F, Olsson C, Franco-Cereceda A, Björck HM. Acetylsalicylic Acid Is Associated With a Lower Prevalence of Ascending Aortic Aneurysm and a Decreased Aortic Expression of Cyclooxygenase 2. J Am Heart Assoc. 2022 May 3;11(9):e024346. *Contributed equally.
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IV. Granath C, Dismorr M, Björck HM, Carlestål E, Olsson C, Bredin F. Fate of the Distal Aorta after Ascending Aortic Replacement in Patients with Bicuspid and Tricuspid Aortic Valves - A Ten-Year Follow-up. [Submitted]
I. Granath C, Noren H, Björck H, Simon N, Olesen K, Rodin S, Grinnemo KH, Österholm C. Characterization of Laminins in Healthy Human Aortic Valves and a Modified Decellularized Rat Scaffold. Biores Open Access. 2020 Dec 7;9(1):269-278.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Granath C, Mohamed SA, Olsson C, Grattan M, Mertens L, Franco-Cereceda A, Björck HM. Valve disease and aortopathy associations of bicuspid aortic valve phenotypes differ between men and women. Open Heart. 2021 Oct;8(2):e001857.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Granath C*, Freiholtz D*, Bredin F, Olsson C, Franco-Cereceda A, Björck HM. Acetylsalicylic Acid Is Associated With a Lower Prevalence of Ascending Aortic Aneurysm and a Decreased Aortic Expression of Cyclooxygenase 2. J Am Heart Assoc. 2022 May 3;11(9):e024346. *Contributed equally.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Granath C, Dismorr M, Björck HM, Carlestål E, Olsson C, Bredin F. Fate of the Distal Aorta after Ascending Aortic Replacement in Patients with Bicuspid and Tricuspid Aortic Valves - A Ten-Year Follow-up. [Submitted]
Institution: Karolinska Institutet
Supervisor: Björck, Hanna M
Co-supervisor: Österholm Corbascio, Cecilia; Franco-Cereceda, Anders
Issue date: 2023-11-14
Rights:
Publication year: 2023
ISBN: 978-91-8017-192-2
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