Hanna Björck

Background: Ascending aortic aneurysm (AscAA) is a silent yet potentially fatal disease if the aortic wall ruptures or dissects. The underlying pathogenic mechanism remains poorly understood and the disease is only identified incidentally. Therapeutic agents to halt or reverse aortic wall deterioration are absent making prophylactic surgery the only treatment option. Moreover, the disease is highly heterogenous and associated with varying degree of aortic valve disease underscoring the need for clinical characterization and molecular phenotyping of disease processes to increase our understanding of disease pathology. Only then can we identify patients at risk, guide preventive strategies, and develop novel treatments. Aims and hypotheses: The overarching goal of our translational project is to advance patient care of aneurysmal disease by exploring molecular mechanisms, genetic background, and clinical outcomes of AscAA in conjunction with aortic valve disease. Specifically, we will study the molecular phenotype associated with degenerative AscAA and the role of extracellular vesicles (aim 1), and aortopathy associated with bicuspid aortic valve (aim 2), reveal the genetic contribution to AscAA (aim 3), identify plasma biomarkers associated with rapid aortic growth (aim 4), and explore multivalve heart disease in relation to surgical outcome following aortic valve repair. Workplan: All studies are based on our unique patient cohort (>2700 patients undergoing aortic valve and/or ascending aortic repair) and biobank of tissue biopsies. Aortic specimen is collected intera-operatively, and will be used to perform large-scale omics analyses but also detailed in vitro analyses using primary vascular cells. Clinical outcom studies and genetic investigations using state-of-the-art methods will be conducted. Uniquely, the first 600 patients have been followed for 10 years, with repeated echocargiography measurements at baseline, and 10 years after surgery. Plasma proteomic measurements at baseline are also available from these patents. Impact: Several unresolved questions related to AscAA and valve disease will be addressed with the ultimate goal of identifying targeted molecular therapies and tailor surveillance programs for individuals at high risk of life-threatening events.

Background An ascending aortic aneurysm is an abnormal dilation of the large artery (aorta) closest to the heart. In the worst-case scenario, the dilation can lead to a rupture of the blood vessel, which is a life-threatening condition. The cause of the disease is still unknown, and currently, there are no medical treatments that can stop or reverse the degradation of the aortic wall. The disease is also highly heterogeneous among different patient groups and is associated with varying degrees of valve disease. Aims Since the disease has a heterogeneous nature, it is important to characterize its underlying causes in order to better understand how it develops in different patient groups. The overall goal of the project is to investigate how aneurysms near the heart arise and how the phenotype of the heart valve affects the disease. We combine global tissue analysis with studies of the plasma proteome and genetics to identify biological processes and markers that can predict the disease and potentially become targets for treatment in the future. Workplan All four substudies are based on a unique patient cohort, currently consisting of over 2,900 patients who have undergone aortic valve and/or ascending aortic surgery, and associated biobank of tissue biopsies. In studies 1 3, we analyze the aortic wall at the molecular level from patients with bicuspid and tricuspid aortic valves, combined with in vitro analysis using primary cells, to determine the underlying pathogenic mechanism. In study 4, protein expression in plasma is analyzed to identify proteins associated with aneurysm growth. Significance The project addresses a major medical challenge: identifying which patients with aortic aneurysms are at high risk of developing serious complications. By understanding the underlying disease mechanisms and identifying markers associated with growth, we can improve treatment and risk assessment, and guide clinical decisions based on biological markers rather than imaging measurements. In the long term, this could reduce the number of life-threatening events and offer personalized care for affected individuals.

Backgrund: Ascending aortic aneurysm (AscAA) is a silent disease and a potentially fatal condition if the aortic wall rupture or dissect. AscAA primarily entails destructive changes of the medial layer of the aortic wall leading to aortic enlargement, but the underlying pathogenic mechanism remains poorly understood and the disease is only identified incidentally. Therapeutic agents to halt or reverse the aortic wall deterioration are absent. Both experimental and clinical studies have shown that the disease is highly heterogenous and associated with varying degree of aortic valve disease, highlighting the great need for clinical and molecular characterization of disease processes. Aims and hypotheses: The overarching goal of this translational project is to explore ascending aortic aortopathy and heart valve disease from a patient-specific perspective, with focus on molecular mechanisms, and clinical outcomes. Specifically, we will study the molecular phenotype associated with degenerative AscAA (aim 1) and AscAA occurring in combination with a bicuspid aortic valve (aim 2), identify plasma biomarkers associated with rapid ascending aortic growth (aim 3), reveal the long-term risk of distal aortic complications after ascending aortic surgery (aim 4), and explore other cardiac valve anomalies and surgical outcome in patients undergoing aortic valve repair. Workplan: All research aims are based on our unique patient cohort, including today >2300 patients undergoing aortic valve replacement and/or repair of the ascending aorta. Uniquely, the first 600 patients have been followed for up to 10 years, with repeated echocargiography and/or CT measurements at baseline, 1 year-, and 10 years after cardiac surgery. Plasma proteomic measurements at baseline are also available from all 600 patents. Aortic tissue specimen from all >2300 patients have been collected intera-operatively, and will be used to perform large scale omic analyses and detailed in vitro analyses using primary vascular cells. Impact: Several unresolved questions related to AscAA and valve disease will be addressed with the ultimate goal of identifying patient-specific molecular targets for future therapies and tailoring of prediction and surveillance programs for patients at high risk of life-threatening events.