Abstract

Background: Risk stratification in severe aortic valve stenosis (AVS), even after contemporary TAVR therapy, is a significant unmet need. General risk scores (STSscore) or heart status biomarkers (NTproBNP) are useful, but prognostic value of potential disease-specific and mechanistically-based indexes is still low. Myocardial replacement fibrosis, as assessed by cMRI, appears to be the most important prognostic factor after TAVR. Soluble ST2 (sST2), a general cardiac biomarker originally reported in inflammatory diseases, was shown to be an independent factor for myocardial fibrosis; and men have higher levels of sST2 in patients with AVS. Experimentally, mosaic loss of Y chromosome in monocytes (mLOY) was associated with increased diffuse myocardial fibrosis, and we recently reported that mLOY is associated with a worse prognosis in severe AVS. Aim: We aimed at assessing the prognostic value of sST2 added to mLOY as a disease-specific biological-genomic marker focused on fibrosis in male patients with severe AVS. Methods: A cohort of 243 consecutive elderly male patients undergoing TAVR was studied. mLOY (i.e., Y/X ratio) was assessed with a digital PCR method in peripheral blood cells DNA, by targeting a 6 bp sequence difference between genes AMELX and AMELY using TaqMan. The previously established mLOY cut-off value of 17% was used. sST2 serum levels were measured, and its optimal cut-off point was calculated based on ROC-curve and Youden index. 2-year survival in the following groups was compared using KM-curves: LOY-low/sST2-low, LOY-low/sST2-high, LOY-high/sST2-low, LOY-high/sST2-high. A multivariate Cox regression analysis was used to assess mortality risk independent from most important comorbidity, echocardiographic and laboratory risk factors. Results: Optimal cut-off value for sST2 was 32.665 ng/ml. Separately, both mLOY (HR: 2.9 [1,7-4.9] and sST2 (4.2 [2.5-7.0]) predicted mortality (both, p<0.0001), but prognosis in LOY-high/sST2-high patients was significantly worse than in all other groups (p<0.001) and showed a substantial risk difference over time (see K-M curves). Multivariate analysis confirmed the risk prediction to be independent from other risk factors (HR 4.620, 95% IC 2.35-9.07, p<0.0001). Conclusion: In male patients with severe AVS undergoing TAVR, LOY-high/sST2-high, a combined biological-genomic marker for fibrosis, is a strong disease-specific and mechanistically-based mortality predictor, independent from general and cardiac risk markers.