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Abstract: TH-OR041

High Fibroblast Growth Factor 23 Levels Induce Ventricular Arrhythmogenesis via Intracellular Ca2+ Mishandling

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Navarro-Garcia, Jose Alberto, Research Institute 1+12, Hospital Universitario 12 de Octubre, Madrid, Madrid, Spain
  • Delgado, Carmen, Research Institute Alberto Sols, CSIC, Madrid, Spain
  • Fernandez velasco, Maria, Research Institute Idipaz, Hospital Universitario La Paz, Madrid, Madrid, Spain
  • Rodríguez-Sánchez, Elena, Research Institute 1+12, Hospital Universitario 12 de Octubre, Madrid, Madrid, Spain
  • Aceves-Ripoll, Jennifer, Research Institute 1+12, Hospital Universitario 12 de Octubre, Madrid, Madrid, Spain
  • González, Laura, Research Institute 1+12, Hospital Universitario 12 de Octubre, Madrid, Madrid, Spain
  • Kuro-o, Makoto, Jichi Medical University, Shimotsuke, Japan
  • Ruilope, Luis M., Research Institute 1+12, Hospital Universitario 12 de Octubre, Madrid, Spain
  • Ruiz-Hurtado, Gema, Research Institute 1+12, Hospital Universitario 12 de Octubre, Madrid, Madrid, Spain

Group or Team Name

  • Cardiorenal Translational Laboratory
Background

Fibroblast growth factor (FGF)23 is a phosphaturic hormone synthesized as response to increased serum phosphate levels. FGF23 action requires the presence of its cofactor Klotho (KL). Chronic kidney disease patients show decreased soluble KL and high FGF23 levels. High FGF23 levels have been associated to renal dysfunction and recently considered as a non-conventional cardiovascular risk factor. However, it is unknown whether FGF23 might alter cardiac contractile function and rhythm.Our study analyze FGF23 effect on calcium (Ca2+) handling, key regulator of contractile function and ventricular rhythm, and the Ca2+ handling in an animal model with high circulating levels of FGF23 (KL hypomorphic mice, kl/kl).

Methods

Isolated adult rat ventricular myocytes (ARVM) were perfused with FGF23 (100 ng/mL). To determinate FGF23-dependent pathways, ARVM were pre-incubated with the FGF-receptor inhibitor PD173074 (10 mM) or recombinant KL (rKL; 100 ng/mL). Adult mouse ventricular myocytes (AMVM) were isolated from Wildtype (WT, +/+) and kl/kl littermates mice. L-type Ca2+ current (ICaL) was recorded by the whole-cell patch-clamp technique. Ca2+ handling and contractile function were analyzed using confocal microscopy.

Results

FGF23 reduced ICaL (p<0.001), intracellular systolic Ca2+ transients amplitude (p<0.01) and sarcoplasmic reticulum (SR) Ca2+ load (p<0.01). These alterations were functionally translated to a deterioration of cellular contraction (p<0.01). FGF23 exposure increased diastolic Ca2+ leak (p<0.01) and ryanodine receptors activity. FGF23 perfusion induced a pro-arrhythmogenic phenotype in paced ARVM (p<0.05). FGF23 effects were blocked in PD173074- or rKL-pretreated ARVM. Moreover, kl/kl mice showed a significant increment of FGF23 serum levels versus WT (p<0.001). kl/kl AMVM presented a reduction of intracellular systolic Ca2+ transient amplitude (p<0.001), contraction (p<0.001) and SR-Ca2+ load (p<0.05). Diastolic Ca2+ release was increased in kl/k (p<0.01) which lead finally to a pro-arrhythmogenic phenotype in kl/kl AMVM (p<0.001).

Conclusion

Our study uncovers FGF23 as new target in the intracellular Ca2+ handling, able to induce contractile dysfunction and pro-arrhythmogenic phenotype in adult cardiomyocytes.

Funding

  • Private Foundation Support