GALECTIN-3 STRONGLY ASSOCIATES WITH RENAL FUNCTION, CARDIOMYOPATHY AND FIBROSIS IN PATIENTS WITH FABRY DISEASE

Abstract Background and Aims Patients with Fabry disease frequently develop cardiac hypertrophy and progressive Fabry nephropathy. The progress of cardiac hypertrophy can lead to replacement fibrosis and heart failure. Galectin-3 is expressed in the heart, kidneys, blood vessels, and macrophages. It marks activated macrophages in failure-prone hypertrophied hearts and contributes to cardiac dysfunction. Experimental data suggest that galectin-3 is involved in fibrosis and inflammation also associated with renal failure. Galectin-3 inhibitor therapy tested in a phase 2 clinical trial in chronic kidney disease lead to an improvement of the estimated glomerular filtration rate. Given the role of Galectin-3 in cardiac hypertrophy, heart and renal failure, we hypothesized that it may be of potential relevance particularly for Fabry disease patients. Method This study investigated the galectin-3 concentrations in 172 patients with genetically proven Fabry disease. We studied the association of galectin-3 concentrations with renal function, left ventricular mass, and adverse clinical symptoms in patients with Fabry disease. Galectin-3 was measured by FDA-approved ELISA. GFR was determined by DTPA clearance. Left ventricular mass and cardiomyopathy were assessed by magnetic resonance imaging and echocardiography. In cross-sectional analysis, associations with adverse clinical outcomes were determined by correlation analysis and linear and binary logistic regression analysis, respectively. Data was adjusted for age and sex. Results Patients had a mean age of 39±14 years and 41% were male. The mean galectin-3 concentration was 17±12 ng/mL (normal value is approx. 11 ng/mL). Patients had a mean BMI of 23.7±4.5 kg/m2 and a mean GFR of 92±38 ml/min. Galectin-3 was strongly correlated with GFR, creatinine and urea. With higher galectin-3 concentrations of the patients, their GFR was lower (r=-0.63, p<0.001) and creatinine and urea were higher (r=0.68 and r=0.53, respectively, both p<0.001). Furthermore, cardiac hypertrophy was significantly higher with higher concentrations of galectin-3. The correlation coefficient for septal hypertrophy was r=0.43 (p<0.001) and for posterior hypertrophy r=0.39 (p<0.001), respectively. Similarly, cardiac fibrosis was significantly higher with higher galectin-3 levels (r=0.34, p<0.001). Patients of the highest galectin-3 tertile furthermore had significantly higher risks of adverse clinical symptoms. The adjusted odds ratio to suffer from angina pectoris was increased > 6-fold and the odds ratio to suffer from neuropathic pain was increased > 3-fold for patients of the highest galectin-3 tertile as compared to patients of the lowest galectin-3 tertile. Conclusion Increased galectin-3 concentrations were strongly associated with cardiac hypertrophy, cardiac fibrosis, decreased renal function, and adverse clinical symptoms in patients with Fabry disease. Galectin-3 can be useful as biomarker for cardiac and renal complications in Fabry disease. Galectin-3 inhibitor treatment may reduce complications of Fabry disease, and requires a randomized controlled trial.