Mild aerobic exercise blocks elastin fiber fragmentation and aortic dilatation in a mouse model of Marfan syndrome associated aortic aneurysm

Abstract

Regular low-impact physical activity is generally allowed in patients with Marfan syndrome, a connective tissue disorder caused by heterozygous mutations in the fibrillin-1 gene. However, being above average in height encourages young adults with this syndrome to engage in high-intensity contact sports, which unfortunately increases the risk for aortic aneurysm and rupture, the leading cause of death in Marfan syndrome. In this study, we investigated the effects of voluntary (cage-wheel) or forced (treadmill) aerobic exercise at different intensities on aortic function and structure in a mouse model of Marfan syndrome. Four-week-old Marfan and wild-type mice were subjected to voluntary and forced exercise regimens or sedentary lifestyle for 5 mo. Thoracic aortic tissue was isolated and subjected to structural and functional studies. Our data showed that exercise improved aortic wall structure and function in Marfan mice and that the beneficial effect was biphasic, with an optimum at low intensity exercise (55-65% V̇o) and tapering off at a higher intensity of exercise (85% V̇o). The mechanism underlying the reduced elastin fragmentation in Marfan mice involved reduction of the expression of matrix metalloproteinases 2 and 9 within the aortic wall. These findings present the first evidence of potential beneficial effects of mild exercise on the structural integrity of the aortic wall in Marfan syndrome associated aneurysm. Our finding that moderate, but not strenuous, exercise protects aortic structure and function in a mouse model of Marfan syndrome could have important implications for the medical care of young Marfan patients. The present study provides conclusive scientific evidence that daily exercise can improve aortic health in a mouse model of Marfan syndrome associated aortic aneurysm, and it establishes the threshold for the exercise intensity beyond which exercise may not be as protective. These findings establish a platform for a new focus on promoting regular exercise in Marfan patients at an optimum intensity and create a paradigm shift in clinical care of Marfan patients suffering from aortic aneurysm complications.

Cardiac Rehabilitation Protects Against the Expansion of Abdominal Aortic Aneurysm

“…To date, few studies have reported the safety and effectiveness of exercise in patients with AAA. In a recent report on an exercise program in a mouse model of Marfan syndrome, mild aerobic exercise blocks elastin fiber fragmentation and aortic dilatation . Two pilot studies in 2009 and 2010 reported on the safety and tolerance of exercise in a few patients with AAA.…”

“…In a recent report on an exercise program in a mouse model of Marfan syndrome, mild aerobic exercise blocks elastin fiber fragmentation and aortic dilatation. 21 Two pilot studies in 2009 8 and 2010 22 reported on the safety and tolerance of exercise in a few patients with AAA. From the 12-week supervised program of moderate-intensity endurance exercise for patients (n=11) with small AAAs, no increases in AAA size nor any other adverse clinical events were observed at 12 weeks, 23 but there were no follow-up data on patients' clinical outcomes after the exercise program.…”

Inhibition of Marfan Syndrome Aortic Root Dilation by Losartan

“…29,50,51 Hence, prophylactic treatment of MFS aortic root disease may benefit from endothelial A B functioneoptimized approaches, a claim also supported by the protective effect of mild aerobic exercise on MFS aortic root disease. 52 Although exercise also reduces resting HR, the effect of ATR1a deletion on C1039G mice HR did not reduce aortic root remodeling, further supporting the role of endothelial NO in MFS. Hence, exercise and other welloptimized endothelial functioneenhancing approaches may prove superior to commonly used therapies, a controversial topic in a recent large-scale trial.…”

Marfan syndrome and exercise: A literature review

“…A total of 226 studies were found in the main search, 6 of which were selected for this review. One study was selected through review of reference lists, and 1 was included after first review of the article resulting in a total of 8 studies 9,18‐24 . Of the selected studies, 1 was an observational pilot study, 22 2 were case reports, 23,24 and 5 were case‐control studies 9,18‐21 .…”

“…In conclusion, their results indicated that moderate dynamic exercise mitigates a progression of cardiovascular deficits in MFS mice. Another case‐control study by Gibson et al 19 (2017) studied ~ 60 mice, divided into control groups of 6 to 16 mice and MFS groups of 6 to 16 mice. Both the control groups and the MFS groups were subjected to 6 different regimes, forced exercise at 55%, 65%, 75%, and 85% of VO 2 max, voluntary exercise and a sedentary regime, respectively.…”