Disease Activity in Mitral Annular Calcification

Abstract

Background: Mitral annular calcification (MAC) is associated with cardiovascular events and mitral valve dysfunction. However, the underlying pathophysiology remains incompletely understood. In this prospective longitudinal study, we used a multimodality approach including positron emission tomography, computed tomography, and echocardiography to investigate the pathophysiology of MAC and assess factors associated with disease activity and progression.

Methods: A total of 104 patients (age 72±8 years, 30% women) with calcific aortic valve disease, therefore predisposed to MAC, underwent ¹⁸F-sodium fluoride (calcification activity) and ¹⁸F-Fluorodeoxyglucose (inflammation activity) positron emission tomography, computed tomography calcium scoring, and echocardiography. Sixty patients underwent repeat computed tomography and echocardiography after 2 years.

Results: MAC (mitral annular calcium score >0) was present in 35 (33.7%) patients who had increased ¹⁸F-fluoride (tissue-to-background ratio, 2.32 [95% CI, 1.81-3.27] versus 1.30 [1.22-1.49]; P<0.001) and ¹⁸F-Fluorodeoxyglucose activity (tissue-to-background ratio, 1.44 [1.37-1.58] versus 1.17 [1.12-1.24]; P<0.001) compared with patients without MAC. MAC activity (¹⁸F-fluoride uptake) was closely associated with the local calcium score and ¹⁸F-Fluorodeoxyglucose uptake, as well as female sex and renal function. Similarly, MAC progression was closely associated with local factors, in particular, baseline MAC. Traditional cardiovascular risk factors and calcification activity in bone or remote atherosclerotic areas were not associated with disease activity nor progression.

Conclusions: MAC is characterized by increased local calcification activity and inflammation. Baseline MAC burden was associated with disease activity and the rate of subsequent progression. This suggests a self-perpetuating cycle of calcification and inflammation that may be the target of future therapeutic interventions.

Keywords: disease progression; inflammation; mitral valve; positron emission tomography computed tomography.

Figure 1

Mitral annular calcification activity (18F-fluoride TBR_max) increased with the burden of baseline MAC (box plots by categories of baseline CT-MAC calcium score: zero/below median [<837 AU]/above median [≥837 AU]) (A) and was correlated with inflammatory activity (18F-FDG TBR_max), (B). Baseline CT-MAC was virtually absent in patients without 18F-fluoride activity (C).

Figure 2

Baseline CT-MAC, 18F-fluoride PET activity and 2-year progression in 3 patients First row: mild mitral annular calcification (MAC) at baseline (A), associated with mild mitral annular 18F-fluoride uptake (B), and modest progression after 2 years (change in CT-MAC 69 AU) (C). Second row: moderate MAC at baseline (A), moderate 18F-fluoride uptake (B), and intermediate progression after 2 years (change in CT-MAC 2404 AU) (C). Third row: severe MAC at baseline (A), bifocal high-intensity 18F-fluoride uptake (B), and rapid progression (change in CT-MAC 9446 AU) (C). Note de-novo areas of MAC that developed at the site of intense 18F-fluoride uptake in the lateral annulus.

Figure 3

Mitral annular calcification progression (AU/year) increased with the burden of baseline MAC (box plots by categories of baseline CT-MAC calcium score: zero/below median [<837 AU]/above median [≥837 AU]) (A) and was virtually absent in patients without 18F-fluoride activity (B). A steady increase in MAC progression was observed on moving from 18F-fluoride PET-CT- to PET-CT+, to PET+CT- and finally to PET+CT+ patients (C).