Team Hanna Björck

Molecular and epidemiological studies of ascending aortic aneurysms

Ascending aortic aneurysm (AscAA) is a silent disease and a potentially fatal condition if aortic wall rupture or dissection occurs. AscAA entails destructive changes of the medial layer of the aortic wall but the precise pathogenic mechanism behind its development is unclear. The most significant risk factor for AscAA formation, however, is being born with a bicuspid aortic valve (BAV), with as many as 50% of all BAV patients requiring ascending aortic surgical repair at some point during their lifetime. BAV is the most common congenital heart malformation with a prevalence of 0.5-1.5%.

A unique clinical cohort is the basis for our research, which aims to clarify the disease mechanisms underlying aortic aneurysm formation. Our biobank includes >2100 patients undergoing valve replacement and/or repair of the ascending aorta, and today, our cohort is one of the largest and most comprehensive in the world. The biobank consists of DNA, plasma, serum, and tissue biopsies from all patients. Uniquely, we have collected biopsies from multiple tissues from the same individual of the first 600 patients (ascending aorta, internal thoracic artery, heart, and liver). Also, smooth muscle cells and endothelial cells from patient ascending aortas have been isolated for functional in vitro studies. We integrate multiomic analysis, epidemiology, and genetics to identify candidategenes and pathways. Functional evaluations are performed using cell culture and in vitro analyses.

Ongoing Projects

What factors influence aneurysm susceptibility in the ascending aorta?

We will study molecular mechanisms involved in aneurysm formation in patients with BAV, particularly focusing on the endothelial/intimal layer, and in patients with degenerative AscAA (TAV-associated). The analyses in aortic biopsies from BAV and TAV patients will be combined with in vitro studies of primary aortic cells. Specific questions include: i) Does aneurysm formation in patients with BAV occur as a consequence of intimal instability, and which molecular players are involved? ii) what are the molecular mechanisms and regulatory factors behind degenerative AscAA?

Is there an association between pharmacological treatment and prevalence of AscAA, and does aortic surgery impact the need of post-operative medication therapy?

Pharmacological therapy in the management and prevention of aneurysmal disease would have great implications on patient care. In this project we will address the association between ongoing treatment with different pharmacological agents and the prevalence of ascending aortic dilatation, in BAV and TAV patients referred for aneurysmal surgical repair. Additionally, we aim to study pharmacological treatment one year following cardiac surgery to evaluate the impact of surgical intervention on subsequent cardiometabolic health and medication management.

Does a genetic background of BAV also increase aneurysm susceptibility?

We will use genetic tools to study the potential genetic background of BAV formation and its associated aortopathy. This is clinically important since this will strongly argue for screening of relatives to BAV cases and a continuous risk for aortopathy after BAV repair in patients with a non-dilated aorta.

Can plasma biomarkers predict further ascending aortic growth?

A 10-year follow-up of the ASAP cohort was initiated 2017 that will include imaging data, extensive anthropometric and chemical data. Plasma biomarkers will be retrospectively analyzed in relation to ascending aortic expansion. Causality will be determined using genotype data. Candidate proteins will be used in a prediction model of aortic growth together with genomic, transcriptomic, and clinical data.

Team members

• Otto Bergman, PhD, bioinformatician
• Per Eriksson, PhD, Senior professor
• David Freiholtz, MD, PhD student
• Carl Granath, MD, PhD-student
• Karin Lång, laboratory assistant
• Maria Sabater-Lleal, Senior researcher, affiliated

Cooperations

We have a close collaboration with the group of Professor Anders Franco-Cereceda and Docent Christian Olsson at the Cardiothoracic Surgery Unit at the Karolinska University Hospital Solna, as well as with Docent Joy Roy and Professor Rebecka Hultgren at the Vascular Surgery group, Karolinska University Hospital Solna. We are part of the Stockholm Aneurysm Research Group (STAR). We have previously been members of the EU-financed project FAD Health-F2-2008-200647 (Fighting Aneurysmal Disease) and the Leducq transatlantic network on BAV disease MIBAVA.

Affiliated to the team is Maria Sabater Lleal, PhD, Senior Researcher, Research Institute Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. Maria is an expert in genetic analyses.

We also have a close collaboration with Pelin Sahlén, SciLifeLab, on high-resolution mapping of promoter-enhancer interactions at a genome-wide level.

Research support

• The Swedish Research Council
• The Swedish Heart-Lung Foundation
• The Stockholm County Council
• Magnus Bergvall Foundation
• Mats Klebergs Foundation
• KI Research Foundation Grants
• Private donation by Mr. Fredrik Lundberg

Selected publications

Acetylsalicylic Acid Is Associated With a Lower Prevalence of Ascending Aortic Aneurysm and a Decreased Aortic Expression of Cyclooxygenase 2.
Granath C, Freiholtz D, Bredin F, Olsson C, Franco-Cereceda A, Björck HM
J Am Heart Assoc 2022 May;11(9):e024346

Sex Differences in Aortopathy and Valve Diseases Among Patients Undergoing Cardiac Surgical Procedure.
Vignac M, Björck HM, Olsson C, Eriksson MJ, Jouven X, Michos ED, Franco-Cereceda A, Eriksson P, Gaye B
Ann Thorac Surg 2022 Nov;114(5):1665-1670

Valve disease and aortopathy associations of bicuspid aortic valve phenotypes differ between men and women.
Granath C, Mohamed SA, Olsson C, Grattan M, Mertens L, Franco-Cereceda A, Björck HM
Open Heart 2021 Oct;8(2):

The mir-200 family regulates key pathogenic events in ascending aortas of individuals with bicuspid aortic valves.
Maleki S, Cottrill KA, Poujade FA, Bhattachariya A, Bergman O, Gådin JR, Simon N, Lundströmer K, Franco-Cereceda A, Björck HM, Chan SY, Eriksson P
J Intern Med 2019 Jan;285(1):102-114

ROBO4 variants predispose individuals to bicuspid aortic valve and thoracic aortic aneurysm.
Gould RA, Aziz H, Woods CE, Seman-Senderos MA, Sparks E, Preuss C, Wünnemann F, Bedja D, Moats CR, McClymont SA, Rose R, Sobreira N, Ling H, MacCarrick G, Kumar AA, Luyckx I, Cannaerts E, Verstraeten A, Björk HM, Lehsau AC, Jaskula-Ranga V, Lauridsen H, Shah AA, Bennett CL, Ellinor PT, Lin H, Isselbacher EM, Lino Cardenas CL, Butcher JT, Hughes GC, Lindsay ME, , , Mertens L, Franco-Cereceda A, Verhagen JMA, Wessels M, Mohamed SA, Eriksson P, Mital S, Van Laer L, Loeys BL, Andelfinger G, McCallion AS, Dietz HC
Nat Genet 2019 Jan;51(1):42-50

High-Resolution Regulatory Maps Connect Vascular Risk Variants to Disease-Related Pathways.
Åkerborg Ö, Spalinskas R, Pradhananga S, Anil A, Höjer P, Poujade FA, Folkersen L, Eriksson PP, Sahlén P
Circ Genom Precis Med 2019 Mar;12(3):e002353

Altered DNA methylation indicates an oscillatory flow mediated epithelial-to-mesenchymal transition signature in ascending aorta of patients with bicuspid aortic valve.
Björck HM, Du L, Pulignani S, Paloschi V, Lundströmer K, Kostina AS, Österholm C, Malashicheva A, Kostareva A, Evangelista A, Teixidó-Tura G, Maleki S, Franco-Cereceda A, Eriksson P,
Sci Rep 2018 Feb;8(1):2777

Protein-altering and regulatory genetic variants near GATA4 implicated in bicuspid aortic valve.
Yang B, Zhou W, Jiao J, Nielsen JB, Mathis MR, Heydarpour M, Lettre G, Folkersen L, Prakash S, Schurmann C, Fritsche L, Farnum GA, Lin M, Othman M, Hornsby W, Driscoll A, Levasseur A, Thomas M, Farhat L, Dubé MP, Isselbacher EM, Franco-Cereceda A, Guo DC, Bottinger EP, Deeb GM, Booher A, Kheterpal S, Chen YE, Kang HM, Kitzman J, Cordell HJ, Keavney BD, Goodship JA, Ganesh SK, Abecasis G, Eagle KA, Boyle AP, Loos RJF, Eriksson P, Tardif JC, Brummett CM, Milewicz DM, Body SC, Willer CJ
Nat Commun 2017 May;8():15481

Mesenchymal state of intimal cells may explain higher propensity to ascending aortic aneurysm in bicuspid aortic valves.
Maleki S, Kjellqvist S, Paloschi V, Magné J, Branca RM, Du L, Hultenby K, Petrini J, Fuxe J, , Lehtiö J, Franco-Cereceda A, Eriksson P, Björck HM
Sci Rep 2016 Oct;6():35712

Aneurysm development in patients with a bicuspid aortic valve is not associated with transforming growth factor-β activation.
Paloschi V, Gådin JR, Khan S, Björck HM, Du L, Maleki S, Roy J, Lindeman JH, Mohamed SA, Tsuda T, Franco-Cereceda A, Eriksson P
Arterioscler Thromb Vasc Biol 2015 Apr;35(4):973-80