1Universitätsklinikum Frankfurt Med. Klinik III - Kardiologie, Angiologie Frankfurt am Main, Deutschland; 2Goethe Universität Frankfurt am Main Zentrum für Molekulare Medizin, Institut für Kardiovaskuläre Regeneration Frankfurt am Main, Deutschland; 3Goethe Universität Frankfurt am Main Institute of Cardiovascular Regeneration Frankfurt am Main, Deutschland
Background
The senescence-associated secretory phenotype (SASP) is a potential driver of age-related risk via reflecting advanced biological aging. Circulating SASP components mainly include pro-inflammatory cytokines, growth modulators and matrix remodelling proteases. Degenerative aortic valve stenosis (AVS) is the prototypical inflammatory age-associated cardiovascular disease.
Purpose
Our aim was to identify circulating SASP components, which are associated with worse prognosis in elderly patients undergoing TAVR for AVS.
Methods
In an initial derivation cohort of 120 AVS patients, we measured the circulating concentration of 24 SASPs using the Luminex Multiplex ELISA Assay (Biotechene, GmbH) at the time of TAVR. Receiver operating characteristic (ROC) curves and Youden-index derived optimal cut-off values were created to assess the predictive power for long-term mortality during 3 years of follow-up for each SASP component. Thereafter, in an additional validation cohort of 390 TAVR patients, the significant predictors of mortality identified in the derivation cohort as well as a panel of 3 independent predictors by multivariate analyses were prospectively validated.
Results
In the derivation cohort, 9 out of 24 SASP components were statistically significant individual predictors of mortality by univariate analysis with AUC > 0.62, while only 3 components remained independent predictors of death after multivariate analyses (all p<0.03). These 3 SASP components (GDF-15, ICAM-1, and Osteoprotegerin) were also confirmed as significant independent predictors of mortality in the prospective validation cohort. Most importantly, after adjustment for a variety of clinical variables as well as age, a score based on the cumulative number of these 3 SASP components being above the Youden-index derived optimal cut-off value documented a substantial increase in long-term mortality after TAVR for each additional positive marker (see Kaplan-Meier curves).
Conclusion
The present study validates elevated circulating concentrations of the 3 SASP components GDF-15, ICAM-1, and Osteoprotegerin as independent predictors of long-term mortality in patients undergoing TAVR. Importantly, the cumulative presence of these markers reflecting different pathophysiological pathways of senescence provides for profoundly improved discrimination power and, thus, may serve as a highly useful clinical risk stratification tool in these elderly patients undergoing TAVR.