Marfan Syndrome Moderate Exercise Trial II

Overview

Marfan syndrome (MFS) is a distinctive connective tissue disorder that affects multiple organ systems including the heart, bones, ligaments, and eyes, and is associated with significant risk of aortic dissection. Given limited evidence from in-vitro studies, and theoretical concerns, the majority of patients with MFS are restricted from certain physical activities. The lack of exercise and deconditioning have detrimental effects including increasing weakness, joint pain, decreased endurance, and depressive symptoms. Given the significant paucity of data currently existing on the effects of exercise in humans with MFS, and the recent, optimistic findings in rodent models, this pilot trial was established to assess the effects of moderated dynamic exercise in adolescents and young adults with MFS.

Description

Marfan syndrome (MFS) is a distinctive connective tissue disorder with clinical phenotypes that affect multiple organ systems including the heart, bones, ligaments, and eyes, and are associated with significant risk of aortic dissection. Given anecdotal reports of aortic dissection, limited evidence from in-vitro studies, and theoretical concerns, the majority of patients with MFS are restricted from certain physical activities, most commonly isometric exercise and contact sports. Published guidelines also suggest restriction from highly dynamic competitive sports. While clinicians may mean to restrict patients only from competitive sports, often children and families interpret this caution as applying to almost all exercise, resulting in a large number of patients with MFS being sedentary. This lack of exercise and deconditioning likely has detrimental effects in increasing weakness and joint pain and decreasing endurance. Depressive symptoms are also not uncommon in patients with these syndromes, and may be triggered or exacerbated by guidance to acutely cease participation in sports at the time of diagnosis.

To date, as far as we are aware, there are no published controlled studies on the effects of dynamic exercise on human subjects. In 2017, Mas-Stachurska et al published a study suggesting that a moderate level of dynamic exercise mitigated progressive degradation of the cardiac structures typically seen in MFS in a rodent sample. This study suggests the possibility that the fears surrounding moderate exercise in humans may be unwarranted. In addition, this study suggests that moderate exercise may actually protect the aorta and myocardium, in addition to the numerous other physical and emotional benefits that have been shown to result from consistent exercise. We have unpublished trial results in a pilot study that also suggest benefit to adolecents and young adults.

Given the significant paucity of data currently existing on effects of exercise in humans with MFS, and the recent optimistic findings in rodent models, we plan to conduct a randomized control trial of moderate dynamic exercise in adolescents and young adults with MFS.

The objective is to:

1. Randomize 50 patients with Marfan syndrome from ages 10-25 years to current status and care (controls) versus a moderate dynamic exercise intervention, then 2) allow the control group patients to undergo the exercise intervention.The investigators will then compare outcomes between both the intervention and control groups, and between the baseline and post-intervention states. Specific outcome measures will include cardiovascular assessment: maximal oxygen uptake (max VO2), ambulatory blood pressure, segmental and central aortic stiffness, ventricular mass and volume, and endothelial function, physical assessment by the physical therapist, and quality of life/mental health assessment: health-related quality of life, depression and anxiety screening scales. The hypothesis is that the intervention of a moderate exercise program introduced by a licensed physical therapist will result in improvement in cardiovascular status, muscular health, and mental health without detrimental effects on the aortic wall.

Eligibility

Inclusion Criteria:

• Male and female patients diagnosed with Marfan syndrome (defined by Ghent criteria and either a pathogenic variant in FBN1 or ectopia lentis)
• Age 10-25 years at enrollment

Exclusion Criteria:

1. History of aortic surgery
2. History of spinal surgery with implanted materials that may negatively impact MRI safety or imaging quality.
3. Diagnosis of major congenital heart disease (ASD, VSD, bicuspid aortic valve, and mitral valve prolapse will not qualify as exclusion criteria)
4. Condition limiting the ability to perform moderate exercise.
5. Major concurrent diagnosis that may confound the interpretation of the effect of the proposed intervention on the proposed outcome measures.
6. Aortic dilation meeting threshold for prophylactic aortic surgical intervention (>/= 4.5 cm in diameter)