Allograft Vasculopathy in Transplanted Hearts and the Role of FGF 23-Klotho Axis

Research Article

Austin J Clin Cardiolog. 2022; 8(1): 1088.

Allograft Vasculopathy in Transplanted Hearts and the Role of FGF 23-Klotho Axis

Evlice M*

Department of Cardiology, Bingol State Hospital, Bingol, Turkey

*Corresponding author: Mert Evlice, Department of Cardiology, Bingol State Hospital, 12000 Bingol, Turkey

Received: February 18, 2022; Accepted: March 12, 2022; Published: March 19, 2022


Background: There are increasing evidences in the role of the involvement of the fibroblast growth factor 23 (FGF 23) - clotho axis in the pathogenesis of endothelial disfunction and cardiovascular disease. This study intended to explore the role of FGF 23 - clotho axis in the development of allograft vasculopathy.

Methods: A total of 38 biatrial heart transplant patients who were operated were included in the study (20 males, 11 females; mean age: 44 ± 7 years). CFR was measured in all patients and the patients were divided into two groups according to respective CFR values. CFR > 2 patients constituted CAV (-) group, CFR < 2 patients were enrolled into CAV (+) group. FGF 23 and clotho levels were analyzed and compared in both groups.

Results: FGF 23 levels were significantly higher in CAV (+) group (264.0±114.4 vs. 183.5±56.0 p=0.04). There was a good but inverse correlation between CFR and FGF 23 levels in CAV (+) group (r= - 0.71 p=0.03). Clotho levels were significantly lower in patients who have CAV (2.76±1.6 vs. 4.77±0.87 p=0.01). There was a moderate correlation between CFR and clotho levels in CAV (+) group (r=0.62 p=0.04). There was an inverse correlation between clotho and FGF 23 levels in both CAV (+) and CAV (-) groups.

Conclusion: In transplanted patients, there was a good but negative correlation between CFR and FGF 23 levels. Conversely, there was a good correlation between CFR and clotho levels. These results gave rise to the thought clotho-FGF 23 axis has a role in the development of CAV.

Keywords: Fibroblast growth factor 23; Cardiac allograft vasculopathy; Nitric oxide


Accelerated arteriosclerosis has emerged as a major lifethreatening complication in long-term survivors of cardiac transplantation. Both cardiac allograft vasculopathy (CAV) and atherosclerosis are atheromatous diseases with some common features, but there are also many distinctive characteristics of both diseases such as sites and degree of involvement, progression rate and more prominent autoimmune involvement in transplanted hearts. Conventional risk factors such as diabetes, hypertension, age, smoking and chronic kidney disease partly, but not entirely explain the increase in morbidity and mortality. Despite successful interventions on traditional risk factors, risk remains high in cardiovascular disease. Endothelial dysfunction is regarded as an important contributor to increased cardiovascular risk [1].

Endothelial dysfunction is a systemic pathological condition which can be defined as a condition resulting from an imbalance between the actions of vasorelaxing and vasoconstrictor factors. The imbalance is mainly caused by reduced nitric oxide (NO) bioavailability and/or increased generation of reactive oxygen species (ROS) [2].

Fibroblast Growth Factor 23 (FGF 23) is a mutated gene identified in autosomal dominant hypophosphatemic rickets with 251-amino acid residuals in the protein [3]. The FGF family has 23 proteins that regulate cell proliferation, migration, differentiation and survival. Several known subgroups of human FGFs have been defined. The FGF19 subfamily comprises FGF19, FGF21 and FGF 23. FGF 23 is produced by osteocytes, and regulates phosphate homeostasis via FGFR1 receptor signaling in the presence of klotho. Klotho gene represents a type I single-pass transmembrane protein that is associated with Β-glucuronidases. Membrane klotho interacts with FGF receptors (especially FGFR1) to form a high-affinity for FGF 23, stimulates phosphate excretion into the urine and decreases the level of serum 1,25(OH)2D3, and inhibits secretion of parathyroid hormone. Secreted klotho protein functions as a humoral factor that modifies several ion channels and transporters, and other processes, including insulin and insulin-like growth factor-1 signaling. Soluble klotho also plays an important role in the regulation of NO production and the integrity and permeability of endothelium [4]. In cooperation with klotho, FGF 23 regulates blood calcium level by suppressing the synthesis of 1,25(OH)D3 and reabsorption of phosphate in the proximal convoluted part of the nephron. FGF 23 also can negatively regulate the secretion of parathyroid hormone [5].

There are also increasing evidences in the role of the involvement of the FGF 23-klotho-vitamin D axis in the pathogenesis of endothelial disfunction and cardiovascular disease. Klotho and FGF 23 may function in a common single transduction pathway to accelerate vascular calcification and cardiac hypertrophy. Klotho-null mice or FGF 23-deficient mice shows early atherosclerosis, vascular calcifications, impaired angiogenesis, and vasculogenesis, suggesting the impact of this pairing on the pathophysiology of cardiovascular disorders [6].

In this study, we aimed to explore the role of FGF 23-klotho axis in allograft vasculopathty in patients with heart transplantation.


Study population

A total of 52 heart transplant patients were included in the study (36 males, 20 females; mean age: 46.5 ± 9.7 years). 4 patients were excluded due to poor echo imaging, unsatisfactory coronary flow reserve (CFR) measurements or meeting other exclusion criteria. 50 eligible patients continued to the study. Study protocol was designed as prospective clinical cohort study. Baseline CFR measurement were done in the first or second month postoperatively. 2 patients with abnormal baseline CFR results (CFR ≤ 2) were excluded. 46 patients with normal baseline CFR results (CFR > 2) continued study. 8 patients developed antibody mediated rejection (AMR) or cell mediated rejection (CMR) (5 AMR and 3 CMR) during follow up. Initially, those patients excluded from main cohort to prevent overlapping results. 6 of those were evaluated (4 AMR and 2 CMR) after completion of study. After median 4 years follow up, CFR and FGF 23-Klotho analyses were done. CAV (+) group consisted of patients with CFR ≤ 2. CAV (-) group consisted of patients with CFR ≤ 2. During follow up, Coronary angiography was performed in 12 individuals out of 38 patients. Patients were followed median four years. At the end of at least 1 year follow up period, CFR and FGF 23-klotho values were measured.

Patients with moderate to severe left ventricular (LV) wall motion abnormality, rejection, LV ejection fraction (EF) less than 50%, atrioventricular conduction abnormalities on ECG, pericarditis, thyroid dysfunction (TSH >4.0mIU/l or < 0.4mIU/l) , anemia (Hb < 13gr/dl) hypercholesterolemia (LDL > 190mg/dl) , electrolyte imbalance (Na levels greater than 145mEq/l or lower than 135mEq/l, K levels greater than 3.5mEq/l or lower than 5mEq/l, calcium levels greater than 8.5mg/dl or lower than 10.5mg/dl ), renal dysfunction (glomerular filtration rate lower than 90ml/min), pulmonary disease (obstructive physiology defined as FEV1/FVC < 70% or reduced vital capacity and/or reduced total lung volume), moderate to severe valvular dysfunction (moderate to severe mitral, aortic, tricuspid or pulmonary valve stenosis and/or regurgitation defined by echocardiography according to AAC/AHA Management of Valvular Heart Disease Guidelines), echocardiographic image that was technically insufficient were excluded from the study. All of the study patients were taking respective immunosuppressive medication (Table 1). Written, detailed, informed consent was obtained from all patients. The institutional ethics committee approved the study protocol. The demographic and baseline characteristics of patients in the study and control groups were given in Table 1.