Presenting Author Midwestern University/ University of Arizona
Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the fibrillin-1 (FBN1) gene. This mutation manifests in a variety of phenotypic changes in the musculoskeletal, cardiovascular, and pulmonary systems, with a notable vascular effect leading to aortic aneurysm, dissection, and rupture. This results in a significant increase in morbidity and mortality in these patients. Studies have shown that there is a connection between MFS and intracranial aneurysms (IA). The prevalence of IA in patients with aortic disease is quadrupled compared to that in the general population. There is a modestly increased prevalence of ischemic stroke in hospitalized patients with MFS when compared with healthy controls. The reduced cerebral blood flow triggered by cardiac and peripheral vascular dysfunction could further make the brain more vulnerable to vascular dementia and Alzheimer’s pathology. Studies have found that 50% school-age children with MFS had one or more neuropsychologic deficits. Despite the reported neurological complications in MFS patients, our understanding of cerebrovascular function and structure in MFS is very limited. Losartan, an AT1R blocker has shown positive effects on slowing the progression of aortic root aneurysm in the well-established mouse model of MFS (Fbn1 +/- p. Cys1041Gly). Alternatively, the cardiovascular benefits of moderate exercise training have been well documented in the literature. In addition, studies have shown that aerobic exercise can improve cognitive function, decrease neuropsychiatric and neurodegenerative symptoms. In this study we aim to investigate the impact of MFS pathogenesis and Losartan treatment and mild aerobic exercise on other vessels such as the posterior cerebral artery, coronary and pulmonary arteries.
At 4 weeks of age, male and female mice were divided into experimental groups: control (Ctrl), MFS, MFS + Losartan, MFS + exercise. MFS mice received 0.6 g/L of Losartan in drinking water or subjected to an exercise regimen of 8m/min, 30min/day, 5days/week. At 6 months of age, in vivo ultrasound imaging was performed to measure aortic pulse wave velocity (PWV), and peak blood flow of the coronary, pulmonary and posterior cerebral arteries. Blood pressure (BP) measurements were also taken using the tail-cuff method.
Our results showed that PWV, an index of aortic stiffness is increased in MFS mice compared to Ctrl, while Losartan and exercise reduced the PWV in MFS mice bringing it back to the values of healthy Ctrl. The posterior cerebral artery peak blood flow was significantly reduced in MFS and MFS + Losartan groups compared to Ctrl. No significant difference was observed in the MFS + exercise group compared to Ctrl. The coronary and pulmonary peak blood flow showed no significant change between MFS and control groups and MFS and intervention groups. There was also no statistical significance in the systolic and diastolic BP between the groups. This study provides an early insight into the disease progression of MFS as well as investigates the preliminary potential effects of Losartan and exercise on peak blood flow in coronary, pulmonary and cerebral arteries in the well-established MFS mouse model.
Midwestern University, NIH-R15HL145646, University of Arizona.
