Multimodality and molecular imaging to track valvular anatomy, physiology and biology in calcific aortic valve disease

Objectives Calcific aortic valve disease (CAVD) is the most frequent etiology of aortic stenosis. Combining molecular imaging with anatomic and physiologic imaging can provide a comprehensive picture of valvular pathology and may identify valves at high risk for progression. Matrix metalloproteinase (MMP) activation contributes to valvular remodeling and calcification. We evaluated MMP-targeted molecular imaging in conjunction with echocardiography and CT for assessing valvular pathology in CAVD.

Methods ApoE-/- mice were fed a Western diet (WD) up to 9 months to induce CAVD. Valvular function and anatomy were assessed by echocardiography and CT. 99mTc-RP805 which targets activated MMPs was used to image valvular biology in vivo by microSPECT/CT. In vivo microSPECT/CT imaging was followed by ex vivo planar imaging. Aortic valve was harvested for histology, morphometry and gene expression analysis.

Results The development of CAVD as evidenced by leaflet thickening and appearance of valvular calcification was noted after 6 months of WD. These features further increased after 9 months of WD. RP805 uptake in aortic valve area on in vivo microSPECT images was maximal at 6 months (control: 0.5±0.1, 3m: 0.6±0.1, 6m: 1.7±0.2, 9m: 1.1±0.1 cpv, n=9-13, p<0.01 for 6m vs control or 3m). There was a good correlation between in vivo and ex vivo quantification of tracer uptake (r=0.99). Tracer uptake specificity was established by pre-administration of excess non-labeled precursor (1.7±0.2 vs 0.7±0.1, p<0.05). MMP tracer uptake in vivo paralleled expression of calcification-related genes RANK (r=0.99) and RunX2 (r=0.91).

Conclusions MMP-targeted imaging can detect the calcification process in CAVD, and may serve as a potential predictor for disease progression. Thus, MMP imaging may help target potential novel therapeutic interventions to selected high risk patients and track their effect on valvular biology.