Chronic kidney disease (CKD) is a worldwide public health threat that increases risk of death due to cardiovascular complications, including left ventricular hypertrophy (LVH). Novel therapeutic ...targets are needed to design treatments to alleviate the cardiovascular burden of CKD. Previously, we demonstrated that circulating concentrations of fibroblast growth factor (FGF) 23 rise progressively in CKD and induce LVH through an unknown FGF receptor (FGFR)-dependent mechanism. Here, we report that FGF23 exclusively activates FGFR4 on cardiac myocytes to stimulate phospholipase Cγ/calcineurin/nuclear factor of activated T cell signaling. A specific FGFR4-blocking antibody inhibits FGF23-induced hypertrophy of isolated cardiac myocytes and attenuates LVH in rats with CKD. Mice lacking FGFR4 do not develop LVH in response to elevated FGF23, whereas knockin mice carrying an FGFR4 gain-of-function mutation spontaneously develop LVH. Thus, FGF23 promotes LVH by activating FGFR4, thereby establishing FGFR4 as a pharmacological target for reducing cardiovascular risk in CKD.
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•In the absence of α-klotho, FGF23 induces binding of FGFR4 to PLCγ•FGF23 activates calcineurin/NFAT signaling in cardiac myocytes via FGFR4•FGFR4 blockade protects CKD rats with high serum FGF23 from cardiac hypertrophy•Knockin mice carrying a FGFR4 gain-of-function mutation develop cardiac hypertrophy
Grabner et al. reveal that FGFR4 mediates the pro-hypertrophic cardiac effects of FGF23, a phosphate-regulating hormone elevated in patients with chronic kidney disease (CKD). Activation of FGFR4/calcineurin/NFAT signaling is sufficient to induce cardiac hypertrophy in mice, while FGFR4 blockade attenuates cardiac hypertrophy in a rat model of CKD.
Cardiac dysfunction in CKD is characterized by aberrant cardiac remodeling with hypertrophy and fibrosis. CKD is a state of severe systemic Klotho deficiency, and restoration of Klotho attenuates ...vascular calcification associated with CKD. We examined the role of Klotho in cardiac remodeling in models of Klotho deficiency-genetic Klotho hypomorphism, high dietary phosphate intake, aging, and CKD. Klotho-deficient mice exhibited cardiac dysfunction and hypertrophy before 12 weeks of age followed by fibrosis. In wild-type mice, the induction of CKD led to severe cardiovascular changes not observed in control mice. Notably, non-CKD mice fed a high-phosphate diet had lower Klotho levels and greatly accelerated cardiac remodeling associated with normal aging compared with those on a normal diet. Chronic elevation of circulating Klotho because of global overexpression alleviated the cardiac remodeling induced by either high-phosphate diet or CKD. Regardless of the cause of Klotho deficiency, the extent of cardiac hypertrophy and fibrosis correlated tightly with plasma phosphate concentration and inversely with plasma Klotho concentration, even when adjusted for all other covariables. High-fibroblast growth factor-23 concentration positively correlated with cardiac remodeling in a Klotho-deficient state but not a Klotho-replete state. In vitro, Klotho inhibited TGF-β1-, angiotensin II-, or high phosphate-induced fibrosis and abolished TGF-β1- or angiotensin II-induced hypertrophy of cardiomyocytes. In conclusion, Klotho deficiency is a novel intermediate mediator of pathologic cardiac remodeling, and fibroblast growth factor-23 may contribute to cardiac remodeling in concert with Klotho deficiency in CKD, phosphotoxicity, and aging.
An increased circulating level of fibroblast growth factor 23 (FGF23) is an independent risk factor for mortality, cardiovascular disease, and progression of chronic kidney disease (CKD), but its ...role in transplant allograft and patient survival is unknown. We tested the hypothesis that increased FGF23 is an independent risk factor for all-cause mortality and allograft loss in a prospective cohort of 984 stable kidney transplant recipients. At enrollment, estimated GFR (eGFR) was 51 ± 21 ml/min per 1.73 m(2) and median C-terminal FGF23 was 28 RU/ml (interquartile range, 20 to 43 RU/ml). Higher FGF23 levels independently associated with increased risk of the composite outcome of all-cause mortality and allograft loss (full model hazard ratio: 1.46 per SD increase in logFGF23, 95% confidence interval: 1.28 to 1.68, P<0.001). The results were similar for each component of the composite outcome and in all sensitivity analyses, including prespecified analyses of patients with baseline eGFR of 30 to 90 ml/min per 1.73 m(2). In contrast, other measures of phosphorus metabolism, including serum phosphate and parathyroid hormone (PTH) levels, did not consistently associate with outcomes. We conclude that a high (or elevated) FGF23 is an independent risk factor for death and allograft loss in kidney transplant recipients.
Plasminogen activator inhibitor 1 (PAI-1) is a functional biomarker of the metabolic syndrome. Previous studies have demonstrated that PAI-1 is a mechanistic contributor to several elements of the ...syndrome, including obesity, hypertension and insulin resistance. Here we show that PAI-1 is also a critical regulator of hepatic lipid metabolism. RNA sequencing revealed that PAI-1 directly regulates the transcriptional expression of numerous genes involved in mammalian lipid homeostasis, including PCSK9 and FGF21. Pharmacologic or genetic reductions in plasma PAI-1 activity ameliorates hyperlipidemia in vivo. These experimental findings are complemented with the observation that genetic deficiency of PAI-1 is associated with reduced plasma PCSK9 levels in humans. Taken together, our findings identify PAI-1 as a novel contributor to mammalian lipid metabolism and provides a fundamental mechanistic insight into the pathogenesis of one of the most pervasive medical problems worldwide.
FGF23 induces left ventricular hypertrophy Faul, Christian; Amaral, Ansel P; Oskouei, Behzad ...
The Journal of clinical investigation,
11/2011, Letnik:
121, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Chronic kidney disease (CKD) is a public health epidemic that increases risk of death due to cardiovascular disease. Left ventricular hypertrophy (LVH) is an important mechanism of cardiovascular ...disease in individuals with CKD. Elevated levels of FGF23 have been linked to greater risks of LVH and mortality in patients with CKD, but whether these risks represent causal effects of FGF23 is unknown. Here, we report that elevated FGF23 levels are independently associated with LVH in a large, racially diverse CKD cohort. FGF23 caused pathological hypertrophy of isolated rat cardiomyocytes via FGF receptor-dependent activation of the calcineurin-NFAT signaling pathway, but this effect was independent of klotho, the coreceptor for FGF23 in the kidney and parathyroid glands. Intramyocardial or intravenous injection of FGF23 in wild-type mice resulted in LVH, and klotho-deficient mice demonstrated elevated FGF23 levels and LVH. In an established animal model of CKD, treatment with an FGF-receptor blocker attenuated LVH, although no change in blood pressure was observed. These results unveil a klotho-independent, causal role for FGF23 in the pathogenesis of LVH and suggest that chronically elevated FGF23 levels contribute directly to high rates of LVH and mortality in individuals with CKD.
Elevated fibroblast growth factor 23 (FGF23) is associated with cardiovascular disease in patients with chronic kidney disease. As a potential mediating mechanism, FGF23 induces left ventricular ...hypertrophy; however, its role in arterial calcification is less clear. In order to study this, we quantified coronary artery and thoracic aorta calcium by computed tomography in 1501 patients from the Chronic Renal Insufficiency Cohort (CRIC) study within a median of 376 days (interquartile range 331–420 days) of baseline. Baseline plasma FGF23 was not associated with the prevalence or severity of coronary artery calcium after multivariable adjustment. In contrast, higher serum phosphate levels were associated with prevalence and severity of coronary artery calcium, even after adjustment for FGF23. Neither FGF23 nor serum phosphate were consistently associated with thoracic aorta calcium. We could not detect mRNA expression of FGF23 or its coreceptor, klotho, in human or mouse vascular smooth muscle cells, or normal or calcified mouse aorta. Whereas elevated phosphate concentrations induced calcification in vitro, FGF23 had no effect on phosphate uptake or phosphate-induced calcification regardless of phosphate concentration or even in the presence of soluble klotho. Thus, in contrast to serum phosphate, FGF23 is not associated with arterial calcification and does not promote calcification experimentally. Hence, phosphate and FGF23 promote cardiovascular disease through distinct mechanisms.
Cardiac implantable electronic device (CIED) infection has a high mortality. Previous investigations showed reduced postoperative infections using skin preparation with chlorhexidine, preoperative ...intravenous antibiotics, and a TYRX-a antibacterial envelope. The additional benefit of antibiotic pocket wash and postoperative antibiotics has not been systematically studied.
The ENVELOPE trial (A Randomized trial of Stand-Alone Use of the Antimicrobial Envelope in High-Risk Cardiac Device Patients) was a prospective, multicenter, randomized, controlled trial enrolling patients undergoing CIED procedures with ≥2 risk factors for infection. The control arm received standard chlorhexidine skin preparation, intravenous antibiotics, and the TYRX-a antibiotic envelope. The study arm received pocket wash (500 mL antibiotic solution) and postoperative antibiotics for 3 days along with the prophylactic control measures. The primary end point was CIED infection and system removal at 6 months.
One thousand ten subjects (505 per arm) were enrolled and randomized. Patients were seen in person for a wound check with digital photo 2 weeks postimplant and at 3 and 6 months. CIED infection rate was low in both groups (1.0% control arm and 1.2% study arm,
=0.74). In the 11 subjects with infection and system removal, the time to study end point was 107±92 days with a PADIT (Prevention of Arrhythmia Device Infection Trial) score of 7.4 and a 64% 1-year mortality. Prior history of CIED infection independently predicted CIED system removal at 6 months in all subjects (odds ratio, 9.77,
=0.004). Of 11 infections requiring system removal, 5 were in the setting of pocket hematoma.
The use of antibiotic pocket irrigation and postoperative oral antibiotics provides no additional benefit to the prophylactic measures of chlorhexidine skin preparation, preoperative intravenous antibiotics, and an antibiotic envelope in reducing CIED infection. Postoperative hematoma is a major risk factor for infection, driven by the use of antiplatelet and anticoagulant medications. The strongest predictor of CIED removal at 6 months, regardless of intervention, was prior CIED infection.
URL: https://www.
gov; Unique identifier: NCT02809131.
Fibroblast growth factor 23 (FGF23) is an endocrine hormone that is secreted by bone and acts on the kidney and parathyroid glands to regulate phosphate homeostasis. The effects of FGF23 on phosphate ...homeostasis are mediated by binding to FGF receptors and their coreceptor, αklotho, which are abundantly expressed in the kidney and parathyroid glands. However, the mechanisms of how FGF23 regulates phosphate handling in the proximal tubule are unclear because αklotho is primarily expressed in the distal nephron in humans and rodents. The purpose of this study was to gain additional insight into the FGF23-αklotho system by investigating the spatial and temporal aspects of the expression of fgf23 and αklotho in the zebrafish, Danio rerio. Here, we report that zebrafish fgf23 begins to be expressed after organogenesis and is continually expressed into adulthood in the corpuscles of Stannius, which are endocrine glands that lie in close proximity to the nephron and are thought to contribute to calcium and phosphate homeostasis in fish. Zebrafish αklotho expression can be detected by 24-h postfertilization in the brain, pancreas and the distal pronephros, and by 56-h postfertilization in liver. Expression in the distal pronephros persists throughout development, and by Day 5, there is also strong expression in the proximal pronephros. αklotho continues to be expressed in the tubules of the metanephros of the adult kidney. These data indicate conservation of the FGF23-αklotho system across species and suggest a likely role for αklotho in the proximal and distal tubules.
Introduction
Focal impulse and rotor modulation (FIRM) ablation can be used to target nonpulmonary vein (PV) sources of atrial fibrillation (AF). No published studies have compared freedom from ...atrial fibrillation (FFAF) after pulmonary vein reisolation (PVRI) plus FIRM to PVRI alone in patients with reconnected PVs undergoing repeat ablation.
Methods
A 3:1 matched retrospective cohort study was performed on 21 patients with recurrent AF and PV reconnection who underwent PVRI plus FIRM‐guided ablation and 63 patients with recurrent AF treated with PVRI alone at a single institution. All patients in the PVRI‐alone cohort had cryoballoon PVRI at the time of repeat ablation without additional lesion sets for AF. Cases were matched based on the type of AF (paroxysmal vs nonparoxysmal), left atrial diameter (±4 mm), left ventricular ejection fraction (±10%), duration of AF (±18 months), and age (±5 years). The primary endpoint was FFAF after a 3‐month blanking period.
Results
Out of 53 total FIRM cases performed at Northwestern Memorial Hospital between 2015 and 2017, 21 patients had PVRI plus FIRM for recurrent AF with PV reconnection. These patients had an average of 3.3 ± 2.1 rotors (60% left atrial) ablated. Over a median follow‐up time of 24.7 months (interquartile range, 13‐36 months), patients in the PVRI‐alone cohort demonstrated a higher rate of FFAF (n = 35; 55.6%) than patients in the PVRI plus FIRM‐guided ablation cohort (n = 7; 33.3%) (logrank P = .049).
Conclusion
In patients undergoing repeat ablation for AF with PV reconnection, PVRI plus FIRM did not increase FFAF compared to PVRI alone.
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