Dataset Information

Mosaic loss of Y chromosome in monocytes is associated with lower survival after transcatheter aortic valve replacement.

ABSTRACT:

Aims

Mosaic loss of Y chromosome (LOY) in blood cells is the most common acquired mutation, increases with age, and is related to cardiovascular disease. Loss of Y chromosome induces cardiac fibrosis in murine experiments mimicking the consequences of aortic valve stenosis, the prototypical age-related disease. Cardiac fibrosis is the major determinant of mortality even after transcatheter aortic valve replacement (TAVR). It was hypothesized that LOY affects long-term outcome in men undergoing TAVR.

Methods and results

Using digital PCR in DNA of peripheral blood cells, LOY (Y/X ratio) was assessed by targeting a 6 bp sequence difference between AMELX and AMELY genes using TaqMan. The genetic signature of monocytes lacking the Y chromosome was deciphered by scRNAseq. In 362 men with advanced aortic valve stenosis undergoing successful TAVR, LOY ranged from -4% to 83.4%, and was >10% in 48% of patients. Three-year mortality increased with LOY. Receiver operating characteristic (ROC) curve analysis revealed an optimal cut-off of LOY >17% to predict mortality. In multivariate analysis, LOY remained a significant (P < 0.001) independent predictor of death during follow-up. scRNAseq disclosed a pro-fibrotic gene signature with LOY monocytes displaying increased expression of transforming growth factor (TGF) β-associated signaling, while expression of TGFβ-inhibiting pathways was down-regulated.

Conclusion

This is the first study to demonstrate that LOY in blood cells is associated with profoundly impaired long-term survival even after successful TAVR. Mechanistically, the pro-fibrotic gene signature sensitizing the patient-derived circulating LOY monocytes for the TGFβ signaling pathways supports a prominent role of cardiac fibrosis in contributing to the effects of LOY observed in men undergoing TAVR.

SUBMITTER: Mas-Peiro S

PROVIDER: S-EPMC10232276 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Publications

Mosaic loss of Y chromosome in monocytes is associated with lower survival after transcatheter aortic valve replacement.

Mas-Peiro Silvia S Abplanalp Wesley T WT Rasper Tina T Berkowitsch Alexander A Leistner David M DM Dimmeler Stefanie S Zeiher Andreas M AM

European heart journal 20230601 21

<h4>Aims</h4>Mosaic loss of Y chromosome (LOY) in blood cells is the most common acquired mutation, increases with age, and is related to cardiovascular disease. Loss of Y chromosome induces cardiac fibrosis in murine experiments mimicking the consequences of aortic valve stenosis, the prototypical age-related disease. Cardiac fibrosis is the major determinant of mortality even after transcatheter aortic valve replacement (TAVR). It was hypothesized that LOY affects long-term outcome in men unde ...[more]

PMID: 36932691

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Project description:Abstract Aims After transcatheter aortic valve replacement (TAVR), cardiovascular and non-cardiovascular comorbidities may offset the survival benefit from the procedure. We aimed to describe the relationships between that benefit and patient comorbidities. Methods and results The study pooled two European cohorts of patients with severe aortic stenosis (AS-pooled): one with patients who underwent (cohort of AS patients treated by TAVR, N = 233) and another with patients who did not undergo TAVR (cohort of AS patients treated medically; N = 291). The investigators collected the following: calcification prognostic impact (CAPRI) and Charlson scores for cardiovascular and non-cardiovascular comorbidities, activities of daily living (ADL)/instrumental activities of daily living (IADL) scores for frailty as well as routine Society of Thoracic Surgeons (STS) score and Logistic Euroscore. Unlike ADL/IADL scores, CAPRI and Charlson scores were found to be independent predictors of 1-year all-cause death in the AS-pooled cohort, with and without adjustment for STS score or Logistic Euroscore; they were thus retained to define a three-level prognostic scale (good, intermediate, and poor). The survival benefit from TAVR—vs. no TAVR—was stratified according to these three prognosis categories. The beneficial effect of TAVR on 1-year all-cause death was significant in patients with good and intermediate prognosis, hazard ratio (95% confidence interval): 0.36 (0.18; 0.72) and 0.32 (0.15; 0.67). That effect was reduced and not statistically significant in patient with poor prognosis [0.65 (0.22; 1.88)]. Conclusion The study showed that, beyond a given comorbidity burden (as assessed by CAPRI and Charlson scores), the probability of death within a year was high and poorly reduced by TAVR. This indicates the futility of TAVR in patients in the poor prognosis category. Graphical Abstract Graphical Abstract Relationship between prognosis category and the transcatheter aortic valve replacement (TAVR) effect. Prognosis categories were defined using the tertiles of calcification prognostic impact and Charlson scores. The estimates of 1-year all-cause death probabilities in each cohort (cohort of AS patients treated medically and cohort of AS patients treated by TAVR) were obtained using a multivariable Cox regression model. The mortality curves were obtained using an interpolated polynomial of degree 2 based on those estimates. The hatched area indicates the difference in the probability of 1-year death between the two cohorts and illustrates mainly the TAVR effect. While both TAVR and the prognosis category contributed to 1-year all-cause death, the contribution of TAVR was not uniform across the range of prognoses; the poorer was the prognosis category, the lower was the benefit from TAVR.

Dataset Information

Mosaic loss of Y chromosome in monocytes is associated with lower survival after transcatheter aortic valve replacement.

Aims

Methods and results

Conclusion

Publications

Mosaic loss of Y chromosome in monocytes is associated with lower survival after transcatheter aortic valve replacement.

Similar Datasets

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