The Effect of FGF23 on Cardiac Hypertrophy Is Not Mediated by Systemic Renin-Angiotensin- Aldosterone System in Hemodialysis

Dörr, Katharina; Kammer, Michael; Reindl‐Schwaighofer, Roman; Lorenz, Matthias; Marculescu, Rodrig; Poglitsch, Marko; Beitzke, Dietrich; Oberbauer, Rainer

doi:10.3389/fmed.2022.878730

Cited by 4 publications

(4 citation statements)

References 47 publications

(51 reference statements)

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“…Finally, a recent clinical study showed that etelcalcetide reduces the circulating concentration of FGF23 and inhibits the progression of LVH (33). In this study, the concentration of FGF23, but not the levels of renin-angiotensin-aldosterone system (RAAS)related parameters, showed a clear association with left ventricular mass index (34).…”

Section: Fgf23 and Lvhmentioning

confidence: 52%

Direct and indirect effects of fibroblast growth factor 23 on the heart

2023

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Fibroblast growth factor (FGF)23 is a bone-derived phosphotropic hormone that regulates phosphate and mineral homeostasis. Recent studies have provided evidence that a high plasma concentration of FGF23 is associated with cardiac disease, including left ventricular hypertrophy (LVH), heart failure, atrial fibrillation, and cardiac death. Experimental studies have shown that FGF23 activates fibroblast growth factor receptor 4 (FGFR4)/phospholipase Cγ/calcineurin/nuclear factor of activated T-cells signaling in cardiomyocytes and induces cardiac hypertrophy in rodents. Activation of FGFR4 by FGF23 normally requires the co-receptor α-klotho, and klotho-independent signaling occurs only under conditions characterized by extremely high FGF23 concentrations. Recent studies have demonstrated that FGF23 activates the renin-angiotensin-aldosterone system (RAAS) and induces LVH, at least in part as a result of lower vitamin D activation. Moreover, crosstalk between FGF23 and RAAS results in the induction of cardiac hypertrophy and fibrosis. In this review, we summarize the results of studies regarding the relationships between FGF23 and cardiac events, and describe the potential direct and indirect mechanisms whereby FGF23 induces LVH.

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Section: Fgf23 and Lvhmentioning

confidence: 52%

Direct and indirect effects of fibroblast growth factor 23 on the heart

2023

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“…Patient characteristics at baseline are reported in Table 1 and have been described previously [ 9 , 28 , 29 ]. The degree of overhydration, assessed through body composition monitoring at the screening stage and subsequently measured at two-month intervals throughout the trial, was found to be similar between the groups [ 9 ].…”

Section: Resultsmentioning

confidence: 99%

Effect of etelcalcetide versus alfacalcidol on left ventricular function and feature-tracking cardiac magnetic resonance imaging in hemodialysis—a post-hoc analysis of a randomized, controlled trial

Dörr,

Kammerlander,

Lauriero

et al. 2023

Journal of Cardiovascular Magnetic Resonance

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Background Calcimimetic therapy with etelcalcetide (ETEL) has been shown to attenuate the advancement of left ventricular (LV) hypertrophy in hemodialysis patients measured by cardiac magnetic resonance (CMR). The aim of the study was to evaluate whether this effect is accompanied by alterations in LV function and myocardial composition. Methods This was a post-hoc analysis of a randomized-controlled trial of ETEL versus Alfacalcidol (ALFA) in 62 hemodialysis patients. LV function was assessed using LV ejection fraction (LVEF) and LV global longitudinal strain (GLS) on feature-tracking (FT) CMR. Myocardial tissue characteristics were analyzed using parametric T1 and T2 mapping. Results Of the total study cohort (n = 62), 48 subjects completed both CMR scans with sufficient quality for FT analysis. In the one-year follow-up, LV GLS deteriorated in the ALFA group, whereas the ETEL group remained stable (LV GLS change: + 2.6 ± 4.6 versus + 0.3 ± 3.8; p = 0.045 when adjusting for randomization factors and baseline LV GLS). We did not observe a difference in the change of LVEF between the two groups (p = 0.513). The impact of ETEL treatment on LV GLS over time remained significant after additional adjustment for the change in LV mass during the study period. ETEL treatment did not significantly affect other CMR parameters. There were no changes in myocardial composition between treatment groups (T1 time change: + 15 ± 42 versus + 10 ± 50; p = 0.411; T2 time change: − 0.13 ± 2.45 versus − 0.70 ± 2.43; p = 0.652). Conclusions In patients undergoing hemodialysis, treatment with ETEL was protective against deterioration of LV longitudinal function, as evaluated through FT CMR, when compared to the control therapy of ALFA. This effect was not mediated by the change in LV mass. Trial registration URL: https://clinicaltrials.gov/ct2/show/NCT03182699. Unique identifier: NCT03182699.

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“…In line with this notion, we found unchanged renin concentrations in CPD mice, relative to mice kept on ND. However, it is unclear whether this is also true for humans because a recent study in hemodialysis patients with LVH failed to find an association between FGF23 levels and components of the RAAS [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

Long-Term Excessive Dietary Phosphate Intake Increases Arterial Blood Pressure, Activates the Renin–Angiotensin–Aldosterone System, and Stimulates Sympathetic Tone in Mice

et al. 2022

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Increased dietary phosphate intake has been associated with severity of coronary artery disease, increased carotid intima–media thickness, left ventricular hypertrophy (LVH), and increased cardiovascular mortality and morbidity in individuals with normal renal function as well as in patients suffering from chronic kidney disease. However, the underlying mechanisms are still unclear. To further elucidate the cardiovascular sequelae of long-term elevated phosphate intake, we maintained male C57BL/6 mice on a calcium, phosphate, and lactose-enriched diet (CPD, 2% Ca, 1.25% P, 20% lactose) after weaning them for 14 months and compared them with age-matched male mice fed a normal mouse diet (ND, 1.0% Ca, 0.7% P). Notably, the CPD has a balanced calcium/phosphate ratio, allowing the effects of elevated dietary phosphate intake largely independent of changes in parathyroid hormone (PTH) to be investigated. In agreement with the rationale of this experiment, mice maintained on CPD for 14 months were characterized by unchanged serum PTH but showed elevated concentrations of circulating intact fibroblast growth factor-23 (FGF23) compared with mice on ND. Cardiovascular phenotyping did not provide evidence for LVH, as evidenced by unchanged LV chamber size, normal cardiomyocyte area, lack of fibrosis, and unchanged molecular markers of hypertrophy (Bnp) between the two groups. However, intra-arterial catheterization revealed increases in systolic pressure, mean arterial pressure, and pulse pressure in mice fed the CPD. Interestingly, chronically elevated dietary phosphate intake stimulated the renin–angiotensin–aldosterone system (RAAS) as evidenced by increased urinary aldosterone in animals fed the CPD, relative to the ND controls. Furthermore, the catecholamines epinephrine, norepinephrine, and dopamine as well as the catecholamine metabolites metanephrine. normetanephrine and methoxytyramine as measured by mass spectrometry were elevated in the urine of mice on CPD, relative to mice on the ND. These changes were partially reversed by switching 14-month-old mice on CPD back to ND for 2 weeks. In conclusion, our data suggest that excess dietary phosphate induces a rise in blood pressure independent of secondary hyperparathyroidism, and that this effect may be mediated through activation of the RAAS and stimulation of the sympathetic tone.

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The Effect of FGF23 on Cardiac Hypertrophy Is Not Mediated by Systemic Renin-Angiotensin- Aldosterone System in Hemodialysis

Cited by 4 publications

References 47 publications

Direct and indirect effects of fibroblast growth factor 23 on the heart

Direct and indirect effects of fibroblast growth factor 23 on the heart

Effect of etelcalcetide versus alfacalcidol on left ventricular function and feature-tracking cardiac magnetic resonance imaging in hemodialysis—a post-hoc analysis of a randomized, controlled trial

Long-Term Excessive Dietary Phosphate Intake Increases Arterial Blood Pressure, Activates the Renin–Angiotensin–Aldosterone System, and Stimulates Sympathetic Tone in Mice

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