Abstract
BackgroundChronic kidney disease (CKD) is associated with increased propensity for arrhythmias. In this context, ventricular repolarization alterations have been shown to predispose to fatal arrhythmias and sudden cardiac death. Between mineral bone disturbances in CKD patients, increased fibroblast growth factor (FGF) 23 and decreased Klotho are emerging as important effectors of cardiovascular disease. However, the relationship between imbalanced FGF23-Klotho axis and the development of cardiac arrhythmias in CKD remains unknown.MethodsWe carried out a translational approach to study the relationship between the FGF23–Klotho signaling axis and acquired long QT syndrome in CKD-associated uremia. FGF23 levels and cardiac repolarization dynamics were analyzed in patients with dialysis-dependent CKD and in uremic mouse models of 5/6 nephrectomy (Nfx) and Klotho deficiency (hypomorphism), which show very high systemic FGF23 levels.ResultsPatients in the top quartile of FGF23 levels had a higher occurrence of very long QT intervals (> 490 ms) than peers in the lowest quartile. Experimentally, FGF23 induced QT prolongation in healthy mice. Similarly, alterations in cardiac repolarization and QT prolongation were observed in Nfx mice and in Klotho hypomorphic mice. QT prolongation in Nfx mice was explained by a significant decrease in the fast transient outward potassium (K+) current (Itof), caused by the downregulation of K+ channel 4.2 subunit (Kv4.2) expression. Kv4.2 expression was also significantly reduced in ventricular cardiomyocytes exposed to FGF23. Enhancing Klotho availability prevented both long QT prolongation and reduced Itof current. Likewise, administration of recombinant Klotho blocked the downregulation of Kv4.2 expression in Nfx mice and in FGF23-exposed cardiomyocytes.ConclusionThe FGF23–Klotho axis emerges as a new therapeutic target to prevent acquired long QT syndrome in uremia by minimizing the predisposition to potentially fatal ventricular arrhythmias and sudden cardiac death in patients with CKD.Graphical abstract
Highlights
Chronic kidney disease (CKD) is associated with increased propensity for arrhythmias
Higher circulating Fibroblast growth factor 23 (FGF23) levels are associated with longer QT interval in patients with dialysis-dependent CKD We analyzed the possible relation between serum FGF23 levels and QT interval duration in a cohort of patients with dialysis-dependent CKD
When we compared patients according to FGF23 quartile, we found no differences in heart rate (HR) or in HR variability metrics (SDANN, SDNN and MRSSD index) (Table 1)
Summary
Chronic kidney disease (CKD) is associated with increased propensity for arrhythmias. Between mineral bone disturbances in CKD patients, increased fibroblast growth factor (FGF) 23 and decreased Klotho are emerging as important effectors of cardiovascular disease. The risk of cardiovascular disease and mortality increases as renal function declines [1, 2], with the highest risk in patients with dialysis-dependent chronic kidney disease (CKD) [3]. Among the components of bone mineral metabolism, fibroblast growth factor (FGF) 23 appears to be an important contributor to the elevated cardiovascular risk in patients with CKD [5, 6], especially for those receiving dialysis [7]. Reduced Klotho expression in CKD leads to resistance to the phosphaturic effect of FGF23 [14], increasing serum phosphate levels that pathologically stimulate FGF23 synthesis. As aging is an independent cardiovascular disease risk factor [18], CKD-related premature aging may increase cardiovascular risk in patients with this pathology
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