How to identify patients at risk for fast progressive aortic stenosis?

Mirac Senel (Tübingen)1, L. Baas (Tübingen)1, T. Harm (Tübingen)1, M. Sigle (Tübingen)2, A.-K. Rohlfing (Tübingen)1, D. Rath (Tübingen)1, K.-P. Kreisselmeier (Tübingen)1, T. Castor (Tübingen)1, S. Autenrieth (Heidelberg)3, M. Gawaz (Tübingen)2, K. A. L. Müller (Tübingen)2

1Universitätsklinikum Tübingen Innere Medizin III, Kardiologie und Angiologie Tübingen, Deutschland; 2Universitätsklinikum Tübingen Innere Medizin III, Kardiologie und Kreislauferkrankungen Tübingen, Deutschland; 3Deutsches Krebsforschungszentrum (DKFZ) Heidelberg, Deutschland


Background: Degenerative aortic stenosis(AS) is characterized by varying courses of disease progression in asymptomatic and symptomatic patients. The underlying mechanisms of fast disease progression is currently not well defined and understood. Clinical, echocardiographic, and laboratory risk parameters associated with disease progression remain unknown, especially in early stages of aortic valve disease.

Methods: We prospectively analyzed 687 consecutive patients with either mild (n=97), moderate (n=115), or severe (n=475) AS undergoing cardiac check-up. Cardiac workup included physical examination, echocardiography, blood sampling for laboratory parameters, chemokine profiling, and phenotyping of monocytes and platelets as well as collection of plasma and immune cell samples for further analysis of protein and gene expression. The diagnosis and severity of AS was classified according to current guidelines. Furthermore, we defined two subgroups of patients with symptomatic AS regarding fast (FP-AS) and slow (SP-AS) disease progression by repetitive transthoracic echocardiographic assessment in a retrospective analysis of our digital echocardiographic database. Here, we determined disease progression by the change of the maximum transvalvular flow velocity (∆Vmax) over time and established an annualized progression rate ∆Vmax. The median annualized ∆Vmax was used as cut-off and thereby two subgroups of patients were evident with either FP-AS (∆Vmax ≥0.45 m/s/year) or SP-AS (∆Vmax <0.45 m/s/year).

Results: We evaluated an all-comers cohort of patients with either mild(n=97), moderate (n=115), or severe (n=475) AS undergoing cardiac check-up. Patients showed a median age of 67 (59–76), 71% were men. Patients with FP-AS defined by ∆Vmax ≥0.45 m/s/year were significantly younger, were predominantly women, showed significantly lower peak velocity and peak pressure gradients over the aortic valve in echocardiography, while the aortic valve area (AVA) was significantly larger than in SP-AS (p<0.01). In a subgroup of 162 patients, morphological analysis of the calcification patterns was performed by computed tomography scans. Interestingly, here we found that patients with FP-AS showed less calcification (mm3) for trend when compared to SP-AS. Distribution patterns regarding calcification of non-coronary, left coronary, and right coronary cusps were not significantly different among groups. We also performed in-depth phenotyping of monocytes and platelets in these patients. Here, we found that altered numbers of non-classical monocytes were significantly associated with fast disease progression in women (p<0.001), but not in men. Numbers of intermediate monocytes were associated with disease progression by trend in both, men and women. Linear regression analysis revealed that young age <50 years, female gender, increased numbers of intermediate and non-classical monocytes, and peak velocity over the aortic valve were independently associated with the disease progression of AS. The presence of diabetes mellitus type 2, hypercholesterinemia, or severe renal insufficiency as typical cardiovascular risk factors were not associated with disease progression in our studied cohort.

Conclusion: Our findings suggest that patients at risk for rapid progression of degenerative aortic valve disease can be identified by an intensified risk assessment comprising clinical, echocardiographic, morphologic, and laboratory parameters of the immune response.

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