Fibroblast growth factor 23 (FGF23) induces ventricular arrhythmias and prolongs QTc interval in mice in an FGF receptor 4-dependent manner

Graves, Jonah; Vallejo, Julian; Hamill, Chelsea S.; Wang, Derek; Ahuja, Rohan; Patel, Shaan; Faul, Christian; Wacker, Michael

doi:10.1152/ajpheart.00798.2020

Cited by 15 publications

(16 citation statements)

References 66 publications

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“…That being said, intraperitoneal administration of FGF23 in healthy mice demonstrated that it can directly induce QT interval prolongation. A recent study has demonstrated that this FGF23-induced prolongation of the QT interval in healthy mice was mediated by FGFR4 [ 71 ]. However, in our experimental model of CKD, we did not find any evidence of cardiac hypertrophy development, which is usually associated to FGFR4-mediated FGF23 signaling.…”

Section: Discussionmentioning

confidence: 99%

The anti-aging factor Klotho protects against acquired long QT syndrome induced by uremia and promoted by fibroblast growth factor 23

Navarro‐García

Salguero‐Bodes

González‐Lafuente

et al. 2022

BMC Med

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Background Chronic 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. Methods We 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. Results Patients 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. Conclusion The 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

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Section: Discussionmentioning

confidence: 99%

The anti-aging factor Klotho protects against acquired long QT syndrome induced by uremia and promoted by fibroblast growth factor 23

Navarro‐García

Salguero‐Bodes

González‐Lafuente

et al. 2022

BMC Med

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“…In terms of disease models, genetically modified mice ( 23 , 26 , 28 – 33 ) or specific rat strains (e.g., spontaneously hypertensive rat) ( 34 , 35 , 40 ) were most commonly assessed (∼37% of studies), and myocardial infarction, ischemia, or hypoxia were evaluated in ∼27% of studies ( 25 , 31 , 35 , 38 , 42 , 44 , 45 , 47 ). Around 16% of investigations used pharmacological modulation ( 24 , 43 , 49 , 50 , 52 ). A small number of studies investigated environmental effects [including herbicide ( 36 ), vaping ( 27 ), and alcohol ( 51 )], aging and development ( 25 , 28 , 41 ), nonischemic heart failure ( 39 ), and the remaining studies performed electrophysiological assessments in nondiseased hearts ( 37 , 46 , 48 ).…”

Section: Evaluation Of Current Literaturementioning

confidence: 99%

“…The most commonly used techniques to evaluate electrophysiological parameters and arrhythmia susceptibility were in vivo electrocardiogram (ECG) or electrode recordings in conscious or anesthetized animals (∼56% of studies) ( 23 – 28 , 30 , 32 , 36 , 38 , 40 – 42 , 46 – 48 , 52 ) or optical mapping in excised hearts or tissues (∼47% of studies) ( 27 , 30 , 31 , 33 – 35 , 39 , 41 , 43 – 45 , 49 – 51 ). The remaining studies used electrode-based or ECG recordings in excised hearts and tissues ( 24 , 25 , 29 , 31 , 32 , 35 , 40 , 41 , 50 ) or in vivo ECG telemetry ( 27 , 29 , 33 , 37 ), and often, a combination of multiple approaches were used to rigorously evaluate electrophysiological properties (including experiments in isolated cardiomyocytes, which are not covered in detail in these guidelines).…”

Section: Evaluation Of Current Literaturementioning

confidence: 99%

Guidelines for assessment of cardiac electrophysiology and arrhythmias in small animals

Ripplinger

Glukhov

Kay

et al. 2022

American Journal of Physiology-Heart and Circulatory Physiology

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Cardiac arrhythmias are a major cause of morbidity and mortality worldwide. Although recent advances in cell-based models, including human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM), are contributing to our understanding of electrophysiology and arrhythmia mechanisms, pre-clinical animal studies of cardiovascular disease remain a mainstay. Over the past several decades, animal models of cardiovascular disease have advanced our understanding of pathological remodeling, arrhythmia mechanisms, drug effects, and have led to major improvements in pacing and defibrillation therapies. There exist a variety of methodological approaches for assessment of cardiac electrophysiology, and a plethora of parameters may be assessed with each approach. This Guidelines article will provide an overview of the strengths and limitations of several common techniques used to assess electrophysiology and arrhythmia mechanisms at the whole animal, whole heart, and tissue level, with a focus on small animal models. We also define key electrophysiological parameters that should be assessed, along with their physiological underpinnings, and the best methods with which to assess these parameters.

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“…Interestingly, mechanistic investigations always indicate a hampered calcium handling, fibrosis formation, and a decreased Cx43 expression as the main potentiators of the pro‐arrhythmic parameters 93–95,97–99,102,103 . Perfusion of a single toxin is an alternative method to specifically investigate its effects, which in case of the non‐toxin FGF23 revealed to lead to increased arrhythmogenicity, via disturbed calcium handling 94,104 …”

Section: Current Electrophysiological Researchmentioning

confidence: 99%

“…[93][94][95][97][98][99]102,103 Perfusion of a single toxin is an alternative method to specifically investigate its effects, which in case of the non-toxin FGF23 revealed to lead to increased arrhythmogenicity, via disturbed calcium handling. 94,104 Unfortunately, the main drawback of these studies is that there are no data available on specific culprits for the electrophysiological changes and the mechanisms behind the effects have rarely been investigated. Ultimately, establishing a CKD model with consistent electrophysiological remodeling would be highly beneficial in the search for pharmacological interventions to treat or prevent the occurrence of arrhythmias.…”

Section: In Vivo Ckd Studies On Cardiac Electrophysiologymentioning

confidence: 99%

Uremic toxins in chronic kidney disease highlight a fundamental gap in understanding their detrimental effects on cardiac electrophysiology and arrhythmogenesis

2022

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Chronic kidney disease (CKD) and cardiovascular disease (CVD) have an estimated 700–800 and 523 million cases worldwide, respectively, with CVD being the leading cause of death in CKD patients. The pathophysiological interplay between the heart and kidneys is defined as the cardiorenal syndrome (CRS), in which worsening of kidney function is represented by increased plasma concentrations of uremic toxins (UTs), culminating in dialysis patients. As there is a high incidence of CVD in CKD patients, accompanied by arrhythmias and sudden cardiac death, knowledge on electrophysiological remodeling would be instrumental for understanding the CRS. While the interplay between both organs is clearly of importance in CRS, the involvement of UTs in pro‐arrhythmic remodeling is only poorly investigated, especially regarding the mechanistic background. Currently, the clinical approach against potential arrhythmic events is mainly restricted to symptom treatment, stressing the need for fundamental research on UT in relation to electrophysiology. This review addresses the existing knowledge of UTs and cardiac electrophysiology, and the experimental research gap between fundamental research and clinical research of the CRS. Clinically, mainly absorbents like ibuprofen and AST‐120 are studied, which show limited safe and efficient usability. Experimental research shows disturbances in cardiac electrical activation and conduction after inducing CKD or exposure to UTs, but are scarcely present or focus solely on already well‐investigated UTs. Based on UTs data derived from CKD patient cohort studies, a clinically relevant overview of physiological and pathological UTs concentrations is created. Using this, future experimental research is stimulated to involve electrophysiologically translatable animals, such as rabbits, or in vitro engineered heart tissues.

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Fibroblast growth factor 23 (FGF23) induces ventricular arrhythmias and prolongs QTc interval in mice in an FGF receptor 4-dependent manner

Cited by 15 publications

References 66 publications

The anti-aging factor Klotho protects against acquired long QT syndrome induced by uremia and promoted by fibroblast growth factor 23

The anti-aging factor Klotho protects against acquired long QT syndrome induced by uremia and promoted by fibroblast growth factor 23

Guidelines for assessment of cardiac electrophysiology and arrhythmias in small animals

Uremic toxins in chronic kidney disease highlight a fundamental gap in understanding their detrimental effects on cardiac electrophysiology and arrhythmogenesis

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