Losartan Versus Atenolol for the Treatment of Marfan Syndrome
Condition: Marfan Syndrome
MeSH terms: Marfan Syndrome; Arachnodactyly; Syndrome
Study type: Interventional
Phase: Phase 2

Summary: 
      Marfan syndrome is a genetic disease of our connective tissue, which provides material and
      support for our skeleton, muscles, blood vessels and other parts of our bodies. People with
      Marfan syndrome may be tall and thin with slender, tapering fingers, long arms and legs, and
      spine curvature. They often have heart and eye problems. In some patients, the condition is
      very mild and the person has few or no symptoms. Others are always at risk of
      life-threatening problems, which usually involve damage to the valves in the heart or
      weakening of the large blood vessels leading from the heart. If the blood vessels become
      weak, they can balloon out (dilate) and break (rupture), which might cause the person to die
      suddenly. We have only a limited ability to stop the progression of disease in Marfan
      syndrome. Typically we use medicines that lower heart rate or blood pressure (or both). But
      this does not prevent the disease and very few drugs work well enough to keep patients from
      needing surgery or dying suddenly because a blood vessel has torn open. Our objective is to
      study two medicines to see if one, or both, can improve blood vessel function in patients
      with Marfan syndrome. One (Atenolol) belongs to a group of drugs called beta blockers and is
      often used to treat high blood pressure. It is the most common drug that is currently used to
      treat patients with Marfan syndrome. The other (Losartan) is also used for high blood
      pressure, but works in a different way. This study will help us to find better ways to treat
      people who have Marfan syndrome and to identify early changes in blood vessel function that
      may help to prevent long-term complications.
    

Detailed description: 
      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.

      Towards this goal, our group has developed a novel method of assessing the biophysical
      properties of the aorta by standard Echo Doppler techniques and have developed an accurate
      measure of PWV, which is considered the most important index of vascular function. In
      patients with MFS, we have demonstrated increased pulse wave velocity, reduced
      distensibility, increased stiffness in the large central arteries, and endothelial
      dysfunction-even if the aortic root had not yet dilated (see appended paper).

      On the basis of these studies, we have also been given access to proprietary GE software to
      analyze raw data and have developed a software program that analyses the Doppler pulse flow
      and external carotid artery pressure tracing raw data to obtain parameters that previously
      required invasive techniques or laborious manual techniques to calculate. Using this new
      technique, which is unique to our group and applicable to other conditions that affect the
      aorta, we can now measure several key variables of aortic vessel function, including vascular
      distensibility, stiffness indices, impedances, total arterial compliance, reflective wave
      index, left ventricular work and efficiency. We predict that using this method to make a
      comprehensive assessment of aortic vascular (dys)function will provide for early detection of
      vascular changes and enable an improved comparison of the effectiveness of pharmacological
      treatment of cardiovascular disease in MFS.

      Therefore, the objective of the proposed research is to use this methodology to compare
      aortic vascular function in individuals with MFS under conventional treatment using a beta
      blocker (Atenolol) or an angiotensin receptor blocker (Losartan). We propose a randomized,
      prospective, double-blinded superiority study to compare the actions of Losartan with
      Atenolol on vascular function in a group of 30 patients with MFS. Our research group has the
      unique capability to perform an analysis of the vascular effects of these therapies.

      The Specific Aims are as follows:

        1. To determine whether 12 months of treatment with Losartan decreases PWV more than 12
           months of treatment with Atenolol in a cohort of patients with MFS;

        2. To determine whether 12 months of treatment with Losartan will improve indices of
           distensibility, stiffness, arterial compliance, impedances and endothelial function more
           than 12 months of treatment with Atenolol in the same cohort of patients with MFS;

        3. To determine whether 12 months of treatment with Losartan slows the progression of
           aortic root dilation when compared to 12 months of treatment with Atenolol in the same
           cohort of patients with MFS.
    

Intervention name(s): Losartan; Atenolol
Intervention type(s): Drug; Drug
Intervention description(s): Losartan (25mg OD); Atenolol (25-50mg OD)
Intervention MeSH terms: Losartan; Atenolol
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Randomized; double-blind superiority trial