Digital Theses Archive


Tesi etd-11222016-220643

Type of thesis
Galectin-3 and aldosterone profibrotic pathways in the failing heart
SCIENZE MEDICHE - Translational Medicine
  • aldosterone
  • fibrosis
  • galectin-3
  • heart failure
  • remodeling
Exam session start date
Background<br>Natriuretic peptides represent, nowadays, the most widely used biomarkers for heart failure (HF) management and risk stratification, though they do not reflect directly a specific pathway of cardiac damage. Differently, galectin-3 (Gal-3), a soluble β-galactoside binding lectin which holds relevant prognostic value as well, is biologically linked to the process of inflammation and fibrosis and may thus be a marker of a peculiar mechanism of cardiac damage and remodelling, and a potential therapeutic target.<br> In past years, the renin-angiotensin-aldosterone system (RAAS) has been largely demonstrated to exert profibrotic, prohypertrophic and proinflammatory effects in the pathophysiology of HF, and the elevation of circulating levels of its effectors (in particular plasma renin activity and aldosterone) is associated with a worse outcome in HF patients, despite optimal pharmacological and non-pharmacological therapy. Both Gal-3 and RAAS effectors may thus be considered as culprit biomarkers. Further, there is initial experimental evidence that Gal-3 and RAAS may interplay in the development of cardiovascular damage in hypertensive models. However, such interaction has not been investigated in the setting of left ventricular (LV) dysfunction and HF, nor there is clinical demonstration that Gal-3 is associated with cardiac fibrosis or with the evolution of cardiac remodeling.<br> With the present translational project, we aimed therefore to test the following hypotheses:<br>1. Gal-3 participates in the mechanisms of aldosterone mediated cardiac fibrosis and tissue remodeling in a murine model of LV dysfunction;<br>2. Gal-3 level is associated with the development of LV remodeling and fibrosis and can predict the effects of neurohormonal antagonism in patients with chronic HF due to non-ischemic dilated cardiomyopathy (NIDCM).<br><br>Materials and Methods<br>Animal study. Adult male mice with cardiac-specific hyperaldosteronism (AS) underwent isoproterenol subcutaneous injections (200 mg/kg x 2/day over two consecutive days), to be then randomized to receive placebo, a Gal-3 inhibitor (modified citrus pectin, MCP), an aldosterone antagonist (potassium canrenoate), or MCP+canrenoate for 14 days. The effects of different pharmacological approaches were assessed by serial echocardiographies, analysis of gene expression and protein content of key determinants of inflammation and fibrosis, and by histology.<br>Clinical study. We prospectively enrolled 150 consecutive patients referred for HF management, with a diagnosis of NIDCM. Patients with malignancies, acute or chronic inflammatory diseases, hematological and autoimmune disorders and severe chronic kidney disease (estimated glomerular filtration rate &lt;30 ml/Kg/min) were excluded. All patients underwent a comprehensive clinical evaluation, a biohumoral characterization, including the assay of Gal-3, 2-D echocardiography, and a contrast-enhanced cardiac magnetic resonance (CMR) for the assessment of LV volumes and fibrosis by the late gadolinium enhancement (LGE) technique. A smaller cohort of 70 patients also received soluble suppression of tumorigenicity protein 2 (sST2) assay at baseline as well as a follow-up CMR after 24 months for the evaluation of LV reverse remodeling, defined as a &gt;10 percentage units increase in LV ejection fraction or a &gt;10% decrease in LV end-diastolic volume indexed.<br><br>Results<br>Isoproterenol induced a rapid and persistent decrease in LV systolic function which was markedly improved by treatment with either MCP or canrenoate. MCP and canrenoate also reduced cardiac hypertrophy and fibrosis and the expression of genes involved in fibrogenesis (Coll-1 and Coll-3) and macrophage infiltration (CD-68 and MCP-1). Further, after treatment with isoproterenol, Gal-3 gene expression and protein levels were decreased by both canrenoate and MCP. The combined use of antagonists of Gal-3 and aldosterone resulted in enhanced effects on cardiac hypertrophy, inflammation, and fibrosis, when compared to MCP or canrenoate alone.<br> In our cohort of NIDCM patients, median Gal-3 value was 14.4 ng/mL (IQR 11.7–19.0 ng/mL); LGE was detected in 106 (71%). Patients with LGE had higher Gal-3 than those without (15.4, 11.8–21.0 vs 13.1, 11.7–16.4 ng/mL, p=0.006). Among univariate predictors of LGE presence (Gal-3, male sex, disease duration, arterial hypertension, left and right ventricular ejection fraction, left ventricular stroke volume), Gal-3 maintained its predictive value at multivariate analysis, together with sex, hypertension, disease duration and right ventricular ejection fraction. At follow-up CMR, 35 patients (50%) showed reverse remodeling. Gal-3, but not sST2 resulted as an independent predictor of LV reverse remodeling at multivariate analysis.<br><br>Conclusion<br>Data from animal experiments suggest that Gal-3 participates in mechanisms of aldosterone-mediated myocardial damage in murine model of HF. Likewise, in the clinical setting of NIDCM, Gal-3 seems to be associated with LV fibrosis and to the evolution of cardiac remodeling, possibly identifying the subset of patients with a more pronounced response to pharmacological neurohormonal antagonism. On a whole, our data may support the use of Gal-3 as a biomarker for the management of HF and as a potential therapeutical target.