PROTECTIVE ROLE OF NEUROTROPHIN-3 IN HUMAN FAILING HEART

D Vicente1, F Montó1, J Rueda2, J Agüero2, L Almenar2, A Delgado3, I Fariñas3, P D\'Ocon1. 1University of Valencia, Departmento de Farmacologia, 46100, Spain, 2Hospital la Fe, Valencia, 46009, Spain, 3University of Valencia, Departamento de Biología Celular and CIBER en Enfermedades Neurodegenerativas, 46100, Spain

BACKGROUND: Neurotrophin-3 (NT-3) is an essential factor in the development and maturation of sympathetic neurons in heart and vessels and has been also implicated in cardiac development (1), but little is known about its role in the mature cardiovascular system nor in pathologies as heart failure (HF). In fact, the potential functions of NT-3 in the context of the cardiovascular system are only beginning to emerge. OBJECTIVE: To examine the expression of NT-3, its receptor TrkC, and α1 and β- adrenoceptors in the left ventricle (LV) from patients with HF and healthy donors.METHODS/PATIENTS: Forty heart transplant patients were consecutively recruited. Heart failure was due to ischemic heart disease in 10 patients, dilated myocardiopathy in 21 patients and to other forms of cardiopathy in 9 patients. All the patients received pharmacological therapy for HF with diuretics, β-blockers, ACE inhibitors or intravenous β-agonist drugs (dobutamine) according to hemodynamic status. Non-failing heart tissues were obtained from 4 donor hearts, which could not be transplanted for technical reasons and had no apparent signs of cardiac failure. mRNAs encoding NT-3, TrkC, β1, β2, α1A and GAPDH (as a housekeeping gene) were quantified by TaqMan® real-time PCR using the TaqMan® Gene Expression Assays (Applied Biosystems). This research conforms with the principles outlined in the Declaration of Helsinki and was performed with the approval of the Ethics Committee of the Universitat de Valencia and the Hospital Universitario La Fe de Valencia. One-way ANOVA followed by a Student’s t-test was performed using the Graph Pad Software. Lineal regression and Pearson’s correlation test were used to establish associations between mRNA and different clinical/anthropometric variables (age, body mass index, ejection fraction, cardiac index, LV-end systolic and diastolic diameter, pulmonary arterial pressure) in HF patients.RESULTS: Significantly increased expression of NT-3, but not TrkC, was observed in the LV of HF patients compared to controls (P<0.05). There was a significant correlation between mRNA levels for NT-3 and β2-adrenoceptor (P<0.01) and for NT-3 and α1A-adrenoceptor (P<0.01). A direct correlation was also observed between NT-3 expression and the ejection fraction (P<0.01). No significant correlation was observed between NT-3 and the other clinical variables studied. CONCLUSION: The increased expression of NT-3 in LV from HF patients and its correlation to α1A and β2-adrenoceptor expression as well as to the ejection fraction suggests a protective role of NT-3 in the sympathetic regulation of the failing heart.

(1) Caporali A and Emanueli C, Physiol Rev, 89: 279-308, 2009

Study supported by a grant from Universitat de València (nº2011-0739). D Vicente received a fellowship from the Spanish Ministry of Education and Science