Angiotensin II Promotes Mitral Valve and Left Atrial Pathology in Fibrillin-1 C1041G/+ Mice

Background Activation of the renin-angiotensin system (RAS) contributes to aortic diseases caused by fibrillin-1 haploinsufficiency ( Fbn1 C1041G/+ ). However, whether RAS activation influences mitral valve disease associated with FBN1 variants remains undefined. This study determined whether inhibition or augmentation of the RAS affects mitral valve pathology in Fbn1 C1041G/+ mice. Methods Angiotensinogen (AGT) antisense oligonucleotides (ASOs) were administered for 12 weeks to inhibit the RAS in male and female Fbn1 C1041G/+ mice. To augment the RAS, mice were infused with angiotensin II (AngII; 1,000 ng/kg/min) for 28 days. Mitral valve and heart function were monitored by ultrasound. At termination, hearts were dissected free and tissue sectioned to assess mitral valve leaflet thickness and pathology. Results Mitral valve leaflet thickness was significantly increased in Fbn1 C1041G/+ mice compared to Fbn1 +/+ littermates of both sexes. ASO-mediated AGT inhibition did not alter this phenotype despite markedly reduced plasma AGT concentrations. AngII infusion increased mitral valve leaflet thickness in Fbn1 C1041G/+ mice with increased proteoglycan and collagen content, while exerting minimal effects in Fbn1 +/+ mice. Twenty-five percent of AngII-infused Fbn1 C1041G/+ mice died of non-vascular causes. Ultrasound showed mitral valve dysfunction in AngII-infused Fbn1 C1041G/+ mice. Grossly expanded left atria were common in AngII-infused Fbn1 C1041G/+ mice. These markedly enlarged left atria contained increased fibrosis, macrophage accumulation, and platelet-rich masses. Conclusions Mitral valves of Fbn1 C1041G/+ mice did not respond to AGT inhibition but were markedly more susceptible to AngII infusion, with greater increases in thickness and compositional changes than mitral valves of Fbn1 +/+ mice. In addition, AngII promoted mitral valve dysfunction that were associated with pronounced left atrial pathology. What are the Clinical Implications? Manipulation of fibrillin-1 in mice leads to vascular pathology that is attenuated by sustained inhibition of the renin-angiotensin system and exacerbated by its activation. However, whether modulation of the RAS influences mitral valve disease in mice harboring fibrillin-1 variants remains unknown. This study demonstrated that the presence of a missense variant of fibrillin-1 greatly augments the effects of renin-angiotensin system activation on mitral valve pathology compared with wild-type mice, with increased leaflet thickness and enhanced accumulation of proteoglycan and collagen. These structural changes are accompanied by mitral valve dysfunction and pronounced left atrial pathology, likely attributable to angiotensin II-induced mitral valve prolapse. These findings provide an experimental basis for determining whether inhibition of the renin-angiotensin system attenuates the development or progression of mitral valve dysfunction in humans with fibrillin-1 variants.