A Randomized Double-blind Study Assessing the Effects of Losartan Versus Atenolol on Pulse Wave Velocity and the Biophysical Properties of the Aorta in Patients With Marfan Syndrome

The objective of the proposed research is to conduct a randomized, double-blind superiority feasibility study to compare the effects of two types of medication (Losartan, an Angiotensin Receptor Blocker, and Atenolol, a beta blocker) on vascular function in patients with Marfan syndrome (MFS). Our outcomes will include measuring the pulse wave velocity (PWV) and other biophysical properties of the aorta in the two groups of patients. This study will provide essential pilot data and development of logistics to enable a full multi-centre randomized controlled trial to test the hypothesis that Losartan will improve vascular function and, in the long-term, slow the rate of aortic root dilation.

MFS is an inherited disorder that affects 1:5000 of the population (i.e., 6000 people) in Canada alone. In MFS, mutations in the FBN1 gene lead to production of abnormal fibrillin 1 and to connective tissue abnormalities that impair skeletal, ocular, pulmonary and, most importantly, cardiovascular systems. Cardiovascular complications are also related to endothelial dysfunction, which has widespread implications for the health of large and muscular blood vessels and has effects on blood pressure, thrombosis, cholesterol levels and general vascular homeostasis. In MFS, progressive dilation, dissection and rupture of the aortic root may occur. This dilation is not solely due to the primary abnormality in collagen caused by the abnormal fibrillin protein. It remains unclear what the vascular mechanisms are that cause dilation of the aortic root. Eventual aortic rupture is a major cause of sudden death in MFS. If untreated, MFS significantly shortens the lifespan of affected individuals: half will succumb in their late 20s or early 30s, usually of aortic rupture. As such, it is crucial to develop effective treatments for cardiovascular disease in MFS and to improve our ability to detect critical changes in blood vessel (aortic) structure and function.

Clinical management of cardiovascular disease in individuals with MFS aims to decrease the rate of aortic root dilation and reduce the risk of dissection and rupture. Beta blockers (eg. Atenolol) have been the traditional medical treatment although some studies have cited the success of calcium antagonists or angiotensin converting enzyme (ACE) inhibitors, However, while beta blocker treatment has been successful in reducing the rate of dilation of the aorta, and its complications in MFS, studies report inconsistent responses to treatment and one pediatric study showed no benefit of beta blockers and better results with ACE inhibitors. Thus, it is still unclear whether one or the other of these pharmacological agents improves outcomes in regard to aortic dilation or rupture.

Recently, individuals with MFS have been shown to have dysregulation of transforming growth factor beta (TGF-beta) signaling that is postulated to result in the enlarged aortic root and other manifestations of the disease. Conversely, disorders of TGF beta 1 and 2 receptors have been shown to produce a Marfan phenotype. A study using a Marfan mouse model found that Losartan, an angiotensin 2 AT1 receptor blocker, prevented the development of aortic root dilation and other phenotypic manifestations of the syndrome. Among the actions of Losartan is the prevention of increased levels of TGF beta and its effects on stimulation of production of extracellular matrix in vascular smooth muscle. This evidence suggests that agents that alter TGF beta signalling, such as Losartan, might have significant potential to ameliorate endothelial dysfunction and aortic dilation in MFS. A clinical trial comparing the effects of Losartan with the current standard treatment regimen (beta blockers) is needed.

Ultimately, even treated individuals suffer from aortic dilation, so that surgical repair of the dilated aortic root is definitive in MFS. Elective surgery carries a low mortality and has significantly improved life expectancy; in contrast, emergency surgery for aortic root dissection or rupture carries a much higher mortality. Our earlier clinical studies and more recent work in a Marfan mouse model study suggest that aortic root dilation is a later stage in the disease process, which has involved cellular mechanisms (perhaps related to TGF beta) before aortic root dilation occurs. This suggests that, through research, one might enable clinicians to identify individuals who are in the early stages of vessel dilation and/or who are at risk for aortic rupture. If we could improve our capacity for early diagnosis of aortic root dilation, we could intervene in the pre-clinical stages and minimize the incidence of emergency surgery or sudden death.