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

The study investigated whether the renin-angiotensin system (RAS) influences mitral valve pathology in mice with a genetic mutation called Fbn1C1041G/+ that causes fibrillin-1 haploinsufficiency, a condition associated with aortic diseases. The researchers tested the effect of inhibiting or augmenting the RAS on mitral valve health in these mice.

They administered angiotensinogen antisense oligonucleotides (ASOs) to the mice for 12 weeks to block the RAS, and infused angiotensin II (AngII) into the mice for 28 days to boost the RAS. The team monitored the mitral valve and heart function using ultrasound, and examined the hearts after the experiment to assess the mitral valve leaflet thickness and any pathological changes.

The findings revealed that the mitral valve leaflet thickness was significantly larger in the Fbn1C1041G/+ mice compared to wild-type mice (Fbn1+/+). However, ASO-mediated inhibition of AGT, a component of the RAS, did not change the increased leaflet thickness in the Fbn1C1041G/+ mice, despite a substantial drop in plasma AGT levels.

In contrast, AngII infusion led to increased mitral valve leaflet thickness in the Fbn1C1041G/+ mice, accompanied by changes in the composition of the valve, including higher amounts of proteoglycan and collagen. The AngII infusion had a minimal impact on the mitral valves of Fbn1+/+ mice. Tragically, 25% of AngII-infused Fbn1C1041G/+ mice died from non-vascular causes.

Upon examination, ultrasound showed that the AngII-infused Fbn1C1041G/+ mice had dysfunctional mitral valves. Grossly enlarged left atria, a chamber of the heart, were a common finding in these mice. The enlarged left atria displayed increased fibrosis, accumulation of macrophages, and masses rich in platelets. These pathological changes were more pronounced in the AngII-infused Fbn1C1041G/+ mice compared to the Fbn1+/+ mice.

In conclusion, the study shows that Fbn1C1041G/+ mice do not respond to AGT inhibition, meaning the RAS is not regulated in this genetically altered group. However, these mice are particularly susceptible to AngII infusion, showing greater increases in mitral valve thickness and compositional changes compared to the Fbn1+/+ mice. Furthermore, AngII promotes mitral valve dysfunction and is associated with significant left atrial pathology in the Fbn1C1041G/+ mice.