P455Evidence for left ventricular dysfunction in a mouse model of marfan syndrome

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Purpose: Cardiovascular manifestations in Marfan syndrome (MFS) are mainly characterized by aortic root dilatation, ensuing aneurysm formation and finally (often) fatal aortic dissection. Primary cardiomyopathy with both systolic and diastolic ventricular dysfunction is clinically less pronounced in most cases, although well documented in recent literature. The underlying pathophysiology of this finding is largely unknown although it is likely that the TGFß pathway, which is implicated in most pleiotropic findings occurring in MFS, plays a role. One possibility to obtain insight into the pathophysiology of cardiomyopathy in MFS is to study a mouse model, allowing detailed in vivo and in vitro studies.Methods: We conducted detailed serial cardiovascular ultrasound studies in 10 MFS mice (fbn1 C1039G) and 10 age- and sex matched control mice. Both vascular (aortic dimensions) and cardiac (left ventricular diameters and diastolic function) parameters were obtained with a dedicated ultrasound apparatus (Vevo 2100, Visualsonics, Toronto, Canada) equipped with a high-frequency linear array probe (MS 550D, frequency 22-55 MHz).Results: MFS mice at six months and 1 year had significantly larger diameters versus controls at the level of the aortic sinus (2,26mm ± 0,33 vs 1,84mm ± 0,13; P = 0,003 and 2.57mm ± 0.53 vs 1.93mm ± 0.2; P = 0,004, resp.), ascending aorta (2,1 mm ± 0,5 vs 1,64mm ± 0,14; P = 0,007 and 2.34mm ± 0.74 vs 1.72mm ± 0.17; P = 0,015, resp.) and transverse aorta (1,9 ± 0,36mm vs 1,5 ± 0,2; P = 0,036 and 1.84 ± 0.2 vs 1.45 ± 0,14mm; P = 0,007, resp.). There was a non-significant trend towards larger aortic diameters at 1 and 3 months. Pulmonary artery diameters were not significantly different in MFS mice. Left ventricular ejection fraction (EF) was lower in MFS mice at all time points and evolved towards significant lower values at one year of age (62.57% ± 7.87 vs 71.48% ± 5.33; p=0,024).Conclusion: Developing animal models that accurately recapitulate the human phenotypic features that ensue as a result of mutant gene expression is essential to study underlying pathophysiological processes and ultimately develop targeted treatment. Here we provide evidence for involvement of the myocardium in a mouse model of MFS. This model may enable us not only to study the development and treatment strategies of cardiomyopathy in MFS but may ultimately also increase our insights into more common forms of cardiomyopathy.

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