Pharmaceutical treatment options for aortic root pathology in Mar.pdf (4.04 MB)

Pharmaceutical treatment options for aortic root pathology in Marfan syndrome

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posted on 22.11.2019, 18:24 by Darren McLoughlin

Aortic pathology can have devastating consequences with significant morbidity and mortality. Marfan syndrome patients have a profound predisposition to develop aortic root pathology and can develop complications of aortic root pathology such as aneurysm of the aorta (especially the aortic root), aortic dissection and aortic valve regurgitation.

Recent advances in understanding the pathophysiology of the consequences of fibrillin-1 deficiency in Marfan syndrome and the development of murine models of this condition have opened up the possibility for translational research to be conducted in this area. Potential pharmacological treatments can now be extensively researched prior to clinical trials.

Pravastatin, a 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitor has been shown to have a beneficial effect on atherosclerosis via “pleiotropic,” or noncholesterol related, anti-inflammatory mechanisms. These mechanisms may have a beneficial effect in aortic root pathology in Marfan syndrome.

The first aim of this research was to establish a natural history of aortic root pathology in Marfan syndrome and to study multiple aspects of aortic root pathology to gain an insight into the pathophysiology of the disease. The second aim was to compare the efficacy and mechanism of potential pharmacological treatments to attenuate aortic root pathology in Marfan syndrome, Pravastatin, Losartan and Doxycycline. The third aim was to optimise the dose and timing of administration of Pravastatin for aortic root pathology in Marfan syndrome. These aims were studied in a murine model of Marfan syndrome.

The results obtained demonstrate that Pravastatin is equipotent to Losartan in attenuation of aortic root dilatation in a murine model of Marfan syndrome. Doxycycline’s performance was inferior to both Pravastatin and Losartan in attenuation of aortic root pathology.

This research provides a basis for further study into the mechanisms of aortic pathology. It also provides evidence for a novel potential treatment for aortic root pathology in Marfan syndrome, namely, Pravastatin.

History

First Supervisor

Professor J.M. Redmond

Second Supervisor

Dr Jonathan McGuinness

Comments

A thesis submitted to the Royal College of Surgeons in Ireland for the degree of Doctor of Medicine from the National University of Ireland in 2012.

Published Citation

McLoughlin D. Pharmaceutical treatment options for aortic root pathology in Marfan syndrome. [MD Thesis]. Dublin: Royal College of Surgeons in Ireland; 2012.

Degree Name

Doctor of Medicine (MD)

Date of award

30/06/2012

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