1Universitätsklinikum Frankfurt Med. Klinik III - Kardiologie, Angiologie Frankfurt am Main, Deutschland; 2Universitätsklinikum Frankfurt Kardiologie Frankfurt am Main, Deutschland; 3Goethe Universität Frankfurt am Main Zentrum für Molekulare Medizin, Institut für Kardiovaskuläre Regeneration Frankfurt am Main, Deutschland; 4Medizinische Klinik IV Nephrologie Frankfurt, Deutschland; 5Goethe Universität Frankfurt am Main Institute of Cardiovascular Regeneration Frankfurt am Main, Deutschland
Aims
Age-associated clonal hematopoiesis of indeterminate potential (CHIP) has been associated with increased incidence and worse prognosis of chronic heart failure. CHIP is driven by somatic mutations in hematopoietic stem and progenitor cells (HSPC). Mosaic loss of the Y chromosome (LOY), the most common somatic mutation in blood cells of men, also correlates with clonal expansion of myeloid cells, increases with age and was experimentally shown to lead to diffuse cardiac fibrosis and subsequent heart failure in mice. However, the prognostic significance of LOY as well as its potential interaction with CHIP in patients with chronic heart failure is unknown.
Methods and Results
We investigated the prevalence and prognostic significance of the extent of LOY and the two most common CHIP-driver mutations DNMT3A and TET2 in 705 male patients with established chronic heart failure across the entire spectrum of left ventricular ejection fraction. LOY was determined by digital PCR of peripheral blood cells by assessing the 6bp sequence difference between the AMELX and AMELY genes. ROC analysis relating the extent of LOY to mortality revealed a LOY of 17% as the optimal cut-off value to predict death during follow-up. LOY co-occurred with DNMT3A/TET2 mutations in 27.1% of men at age > 70 years. LOY >17% was observed in 18.6% of all patients, increased with age and was associated with increased mortality after three years (13,7% in patients without LOY compared to 29.0% in patients with LOY, p<0.001, Figure 1). LOY remained an independent predictor of death in multivariate analysis including, age, ejection fraction and nt-pro BNP (HR 1,67; 95% CI 1.08-2.57; p=0.017). Importantly, LOY was associated with increased mortality in patients with heart failure with reduced ejection fraction defined as < 50% (p<0.001) as well as in patients with preserved ejection fraction ≥ 50% (p=0.01). The co-occurrence of harboring LOY and DNMT3A/TET2 mutations significantly contributed to the observed increased mortality observed in carriers of DNMT3A/TET2 mutations
Conclusion
Among patients with heart failure, LOY in blood cells is associated with increased risk of death across the complete range of ejection fraction. Further studies are warranted to discern if LOY associates with cardiac fibrosis in men with heart failure and triggers increased profibrotic signaling. The results of this study may inform trials evaluating precision-targeted anti-fibrotic therapies in patients with chronic heart failure.