__Abstract__



Aortic disease represents one of the major causes of morbidity and mortality in the

industrialized society. Approximately 2% of all deaths are caused by aortic aneurysm and

dissections [1]. Aneurysms are defined as a local widening of the artery with more than

50 percent of the normal diameter [2]. An aneurysm can result in a fatal aortic rupture or

in an aortic dissection, which is a tear in the wall of the artery that causes blood to flow

between the layers of the wall and forces the layers apart [3]. Dissections involving the

ascending aorta, Stanford type A dissections, have a mortality rate of 1-2% per hour and

should be immediately treated surgically [4], while dissections occurring in the descending

aorta are usually treated medically and have an in-hospital mortality of about 10% [5].

However, an acute aortic dissect

Ramnath, N.W.M. (Natasja )

Ramnath, Natasja

EUR Research Repository

English

Molecular pathogenesis of Fibulin-4 associated aortic aneurysms

__Abstract__



Aortic disease represents one of the major causes of morbidity and mortality in the

industrialized society. Approximately 2% of all deaths are caused by aortic aneurysm and

dissections [1]. Aneurysms are defined as a local widening of the artery with more than

50 percent of the normal diameter [2]. An aneurysm can result in a fatal aortic rupture or

in an aortic dissection, which is a tear in the wall of the artery that causes blood to flow

between the layers of the wall and forces the layers apart [3]. Dissections involving the

ascending aorta, Stanford type A dissections, have a mortality rate of 1-2% per hour and

should be immediately treated surgically [4], while dissections occurring in the descending

aorta are usually treated medically and have an in-hospital mortality of about 10% [5].

However, an acute aortic dissection may also result in a rupture and with thoracic aortic

rupture mortality is very high, approximately 94 to 100%. Both diseases have principles and

techniques of surgical treatment in common. Surgery of aneurysms of the ascending aorta

and arch, the descending aorta, and the thoracoabdominal aorta has been associated with

a reduced operative mortality of respectively 2.9%, 3.0% and 11.9% between 1995 and

2004 [6]. However, the diagnosis of aneurysms and dissections is at the moment limited

to computed tomography and echocardiography, usually in late and severe stages of the

diseases. The main mechanisms by which these diseases occur are largely unknown. It is

thought that aneurysm formation is the result of changes in the extracellular matrix (ECM)

of the aortic wall and signaling pathways of the vasculature [3]. However, more insight into

the molecular mechanisms leading to aneurysm formation is required in order to identify

predisposing factors and new detection protocols for earlier detection of aortic aneurysms

Erasmus University Digital Repository

Stellingen behorende bij het proefschrift 'Molecular pathogenesis of Fibu/in-4 associated aortic aneurysms' 1. In vivo non-invasive molecular imaging of matrix metalloproteinase activity using protease-activatable fluorescent sensors can identify the risk of developing an aartic aneurysm while the aortic di lation itself has not yet appeared . - this thesis 2. A generalized susceptibility to extracellular matrix delects and secondary inflammation can underlie the co-occurrence of aartic aneurysms and COPD. - this thesis 3. A subtie genetic defect in the extracellular matrix, in combination with specific lifestyle factors, can predispose to late-onset vascular, pulmonary and atherosclerotic diseases. - this thesis 4. lncreased secrelion of TGF-132 by Fibulin-4 deficient aortic smooth muscle cells plays an important role in thoracic aartic aneurysms and might prove relevant as a therapeutic target or biomarker. - this thesis 5. Fibulin-4 expression levels can determine the severity of cardiovascular diseases and therefore milder mutations affecting the expression level of the protein should also be considered as potentially pathogenie. - this thesis 6. "There is no disease more conducive to clinical humility than aneurysm of the aorta" - Sir William Osler, Founding professor Johns Hopkins Hospita/, 1900 7. "Longevity is a vascular question, which has been well expressed in the axiom that man is only as old as his arteries. The onset of what may be called physiological arterio-sclerosis depends, in the first place, on the quality of arterial tissue which the individual has inherited, and secondarily on the amount of wear and tear to which he has subjeeled it"- Sir William Osler, 1891 8. One of the key things that can be changed to reduce the risk for cardiovascular disease is diet; a diet lew in animal produels and processed foods, but with plenty of fresh fruits and vegetables, nuts, seeds, whole grains and soy is beneficia!. - Wortd Heart Federation, Cardiovascular disease risk factors 9. Since modern science is increasingly interdisciplinary, complex and costly, collaborative research activities are required for efficient scientific productivity. - The Impact of Research Collaboration on Scientific Productivity, Barry Bozeman, Sooho Lee, 2003 10. "The way we communieale withethers and with ourselves ultimately delermines the quality of our lives" - Unlimited Power: The new science of personaf achievement, Anthony Robbins, 1986 11. "Take up an idea, devote yourself te it, struggle on in patience, and the sun will rise for you" -Swami Vivekanand Natasja W.M. Ramnath, 2014 

Molecular Pathogenesis of Fibulin-4 Associated Aortic Aneurysms

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