1Universitätsklinikum Frankfurt Med. Klinik III - Kardiologie, Angiologie Frankfurt am Main, Deutschland; 2Universitätsklinikum Frankfurt Frankfurt am Main, Deutschland; 3Agaplesion Markus Krankenhaus Frankfurt am Main, Deutschland; 4Universitätsklinikum Würzburg Medizinische Klinik und Poliklinik II Würzburg, Deutschland; 5Charité - Universitätsmedizin Berlin Berlin, Deutschland; 6Synlab Medizinisches Versorgungszentrum Heidelberg GmbH Eppelheim, Deutschland; 7Universitätsklinikum des Saarlandes Homburg/Saar, Deutschland; 8Goethe Universität Frankfurt am Main Zentrum für Molekulare Medizin, Institut für Kardiovaskuläre Regeneration Frankfurt am Main, Deutschland; 9Goethe Universität Frankfurt am Main Institute of Cardiovascular Regeneration Frankfurt am Main, Deutschland
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, mosaic loss of Y chromosome (LOY) emerged as an important driver of cardiac fibrosis in men. We determined the effects 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 2.90, 95%CI 1.50-5.60) and risk for cardiac decompensation and death (HR 2.54, 95%CI 1.37-4.69). Patients with LOY >17 % had higher NT-proBNP, troponin-T levels, and worse diastolic and systolic left ventricular function Consistently, validation in the 4D study revealed that LOY was associated with increased cardiovascular mortality (HR 3.00, 95%CI 1.89-4.78), higher risk of death due to heart failure and sudden cardiac death (HR 3.91, 95%CI 1.89-8.07), but not atherosclerotic events. Mechanistically, intermediate monocytes from patients with LOY >17 % showed significantly higher CCR2 expression, 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.