sST2 and mosaic loss of Y-chromosome: a combined biological-genomic prognostic marker related to fibrosis in aortic valve stenosis

Background
Even when being treated with modern TAVR techniques, risk stratification in patients with severe aortic valve stenosis (AVS), is still a key unmet medical need. No disease-specific and mechanistically-based scores showing a high prognostic value are available, and general biomarkers for heart condition (NTproBNP) or surgical risk scores (STSscore) are usually used instead.

After TAVR, cMRI studies have shown myocardial replacement fibrosis to be a critical prognostic factor. Initially reported as a biomarker for inflammatory disorders, soluble ST2 (sST2), a current general marker for heart condition, is an independent factor associated with myocardial fibrosis, with higher levels having been shown in men with AVS.

In experimental studies, an association of mosaic loss of Y-chromosome in monocytes (mLOY) with higher diffuse myocardial fibrosis has been reported. Our recent clinical findings have also shown mLOY to result in a poor prognosis in patients with severe AVS.

Aim
The prognostic value of sST2 added to mLOY (measured as Y/X ratio) as a fibrosis-related combined biological-genomic marker specific for AVS was investigated in male patients with severe AVS.

Methods
243 consecutive elderly men undergoing TAVR were included. Using a digital PCR method in DNA from peripheral blood cells, we measured mLOY by targeting a 6 bp sequence difference between genes AMELX and AMELY with TaqMan. Positivity was based on a previously determined mLOY threshold of 17%. The optimal threshold for sST2 levels was estimated based on a ROC curve.

Patients were classified into 4 categories according to low vs. high LOY and low vs. high sST2 results, and 2-year Kaplan-Meier curves for survival were analysed. Results were adjusted for key comorbidities and laboratory/echocardiographic risk factors using a multivariate Cox regression analysis.

Results
An optimal prognostic sST2 threshold of 32.7 ng/ml was established. Mortality was significantly predicted by both mLOY (HR: 2.9[1,7-4.9]; p<0.001) and sST2 (4.2[2.5-7.0] in separate analyses; p<0.001). The combination of high LOY/high sST2 resulted in a significantly higher mortality risk compared to the other 3 groups (high LOY/low sST2, low LOY/high sST2, and low LOY/low sST2) (p<0.001), with a substantial risk difference over time (see figure). These highly predictive findings were independent from other risk factors as shown by multivariate analysis (HR 4.620, 95% IC 2.35-9.07, p= p<0.001).

Conclusion
As a fibrosis-related biological-genomic marker, the combined use of high LOY plus high sST2 in men with severe AVS provides a strong mechanistically-based prognostic index for mortality which is independent from known clinical, echocardiographic, and laboratory risk factors and specific for AVS.