Decoding FGF23: How This Hormone Impacts Your Heart Health
"New research uncovers the role of FGF23 in promoting myocardial fibrosis, offering potential targets for future heart disease treatments."
Fibroblast growth factor 23 (FGF23) has traditionally been recognized for its vital role in maintaining phosphate balance and vitamin D metabolism within the body. Produced by bone cells, FGF23 acts on the kidneys and parathyroid glands to ensure these levels stay within a healthy range. However, emerging research is revealing a darker side to this hormone, linking elevated FGF23 levels to various pathological effects, especially concerning heart health.
One significant area of concern is the connection between FGF23 and left ventricular hypertrophy (LVH), a condition where the heart's main pumping chamber thickens, making it harder for the heart to function effectively. Studies have shown that individuals with chronic kidney disease often exhibit markedly elevated FGF23 levels, and this, in turn, can directly contribute to LVH. But the story doesn't end there.
A new study is shedding light on FGF23's potential role in promoting myocardial fibrosis, a condition characterized by the excessive buildup of scar tissue in the heart muscle. This process can stiffen the heart, impair its ability to relax and fill with blood, and ultimately lead to diastolic dysfunction, a type of heart failure. Understanding how FGF23 contributes to myocardial fibrosis could pave the way for novel therapeutic strategies to protect heart health.
Assessing Cardiac Fibrosis
Myocardial fibrosis, whether focal or diffuse, is common in many cardiac diseases and is associated with a poor prognosis for major adverse cardiovascular events. Histological analysis remains the gold standard for confirming fibrosis, but endomyocardial biopsy is invasive, subject to sampling errors, and impractical for routine clinical use. Reviews therefore emphasize non-invasive imaging techniques and circulating biomarkers for characterizing fibrosis, phenotyping heart failure, and tracking its clinical impact. Non-invasive detection methods have expanded because fibrosis is also associated with arrhythmia, heart failure, and sudden cardiac death.
How Does FGF23 Promote Heart Fibrosis?
To investigate the role of FGF23 in myocardial fibrosis, researchers conducted a series of experiments using both in vitro (cell-based) and in vivo (animal) models. They observed that myocardial and plasma FGF23 levels, as well as levels of FGF receptor 4 (FGFR4), were increased in mice with heart failure. Similar increases were seen in cultured adult mouse cardiac fibroblasts (AMCFs) when exposed to substances like angiotensin II, phenylephrine, and soluble fractalkine – all known to contribute to cardiac stress and remodeling.
- Increased FGF23: Elevated levels of FGF23 in heart failure models.
- Fibroblast Response: Cardiac fibroblasts (AMCFs) show increased FGF23 and FGFR4 when exposed to stress factors.
- Collagen Production: FGF23 boosts procollagen I and III expression, leading to fibrosis.
- Beta-Catenin Activation: FGF23 activates β-catenin, a key fibrosis promoter.
Recent FGF23 Evidence
The Cardiovascular Health Study reports that elevated FGF23 levels are associated with left ventricular hypertrophy and heart failure in people with and without kidney disease. Another cited study found that FGF23 overexpression worsened heart failure, while high FGF23 levels were significantly associated with heart-failure severity. In a mouse model of nephrotic syndrome, one week of disease was accompanied by elevated serum FGF23, reduced cardiac function, and cellular cardiac hypertrophy without significant increases in cardiac mass or fibrosis. A 2026 review describes myocardial fibrosis as a major contributor to cardiovascular disease progression and highlights the need for early, non-invasive biomarker diagnosis.
Limits of the Evidence
In mice, baseline myocardial FGF23 mRNA and protein expression was relatively low but became significantly elevated during heart failure induced by transverse aortic constriction. This experimental finding supports a relationship between cardiac stress and myocardial FGF23 expression, but it does not by itself establish the same mechanism in humans. A 2025 review also states that much work remains necessary to fully understand myocardial fibrosis, including its assessment, quantification, predictive value, and future therapies. Clinical descriptions characterize fibrosis as excess scar-like tissue that can make heart tissue stiff and poorly conducting, but these descriptions do not resolve how FGF23 causes those changes.
Fibrosis and Treatment Response
The progression from physiological to pathological fibrosis is especially evident in myocardial ischemia and infarction, which the cited review identifies as the most common cause of cardiovascular disease resulting from reduced myocardial perfusion. Fibrosis is also prevalent in cardiomyopathies that lead to heart failure with reduced ejection fraction. Although left ventricular assist devices provide hemodynamic unloading and may allow partial cardiomyocyte recovery, contemporary studies report no consistent reductions in persistent myocardial fibrosis. These findings distinguish improved circulatory support from reliable reversal of established fibrotic remodeling.
Looking Ahead: Targeting FGF23 for Heart Health
This research provides compelling evidence that FGF23 plays a significant role in promoting myocardial fibrosis and exacerbating diastolic dysfunction in the context of MI and IR. The key mechanism appears to involve the upregulation of active β-catenin and TGF-β, both of which are known drivers of fibrotic processes. While more research is needed to fully elucidate the intricate details of this pathway, these findings suggest that targeting FGF23 signaling could be a promising therapeutic strategy for preventing or treating myocardial fibrosis and improving heart function. Future studies should focus on developing specific FGF23 inhibitors or β-catenin antagonists that can be safely and effectively used in humans to combat heart disease.
From Mechanism to Therapy
Current research examines the molecular pathways involved in myocardial fibrosis alongside emerging therapeutic approaches. Recent single-cell and spatial transcriptomic studies are being used to investigate heterogeneity in fibrotic signaling and the challenges of translating mechanistic findings into treatment. Pathologic fibrosis expands the myocardial interstitium, disrupts structural integrity, and promotes cardiac dysfunction. Identifying and targeting cardiac fibroblasts before fibrosis causes irreversible injury is therefore presented as a potentially important clinical strategy.
Disease in Context
Rheumatic heart disease and endomyocardial fibrosis are major causes of cardiac disease in low-income countries. A reported patient had mitral stenosis and restrictive cardiomyopathy initially attributed to severe rheumatic heart disease. The disease progressed despite valve replacement, and the progression was considered likely secondary to previously undiagnosed endomyocardial fibrosis. The case illustrates how overlapping cardiac conditions can complicate diagnosis and treatment.