Abstract Body: Background
Chronic kidney disease represents one of the strongest risk factors for cardiovascular diseases, and particularly for heart failure. Despite improved pharmaceutical treatments mortality remains high. Recently, experimental studies demonstrated that mosaic loss of Y chromosome (LOY) associates with cardiac fibrosis in mice. Since diffuse cardiac fibrosis is the common denominator for progression of all forms of heart failure, we determined the association of LOY on mortality and cardiovascular disease outcomes in patients with chronic kidney disease.
Methods
LOY was quantified in patients with stable CKD (CARE for HOMe study, derivation cohort, N=279) and dialysis patients (4D study, validation cohort, N=544). The association between LOY and mortality, combined cardiovascular and heart failure-specific endpoints, and echocardiographic measures was assessed.
Results
In CARE for HOMe, mortality was higher in men as compared to women across the entire range of impaired renal function. The frequency of LOY increased with age. LOY was associated with increased mortality (HR 2.58, 95%CI 1.33-5.03) and risk for cardiac decompensation or death (HR 2.30, 95%CI 1.23-4.27). Patients with LOY >17 % showed a significant decline of ejection fraction and an increase of E/E’ within five years. Consistently, validation in the 4D study revealed that LOY was associated with increased mortality (HR 3.13, 95%CI 1.97-4.99), higher risk of death due to heart failure and sudden cardiac death (HR 4.14, 95%CI 2.00-8.57), but not atherosclerotic events (see figure). Patients with LOY >17 % showed significantly higher plasma levels of soluble ST2, a biomarker for myocardial fibrosis. Mechanistically, intermediate monocytes from patients with LOY >17 % showed significantly higher CCR2 expression and higher plasma levels of the CCR2 ligand CCL2, which may have contributed to increased heart failure events.
Conclusions
LOY identifies male patients with chronic kidney disease at high risk for mortality and heart failure events.