I005 Chemical denervation of sympathetic nervous system induces abnormal myocardial architecture

Abstract

The role of autonomic nervous system (ANS) on heart function modulation is well-known. By contrast, ANS role on myocardial tissue architecture has scarcely been investigated. The aim of the present work was to investigate changes in heart tissue architecture after chemical sympathetic denervation by 6OH-Dopamine (6OH-DA) in mice. Two months old mice (n=18) received 3 injections of 6OHDA (200 mg/kg, ip) or saline (n = 6) at 3 days of interval. At 15 and 30 days after first injection, ECG was recorded (PowerLab, DSI) under anaesthesia and heart rate spectral variability (HRV) was performed (FFT) in low frequency (LF: 0.15-1.5 Hz) and high frequency (HF: 1.5-5 Hz) ranges; LH/HF ratio was also calculated. After sacrifice, blood was withdrawn for plasma catecholamine determination (HPLC). Heart tissue was fixed (formaldehyde 10 %) for histology or frozen for western blot analysis (tyrosine hydroxylase, TH). When compared to controls (1410±145 pg/ml) plasma norepinephrine levels were significantly lower at D15 (766±186 pg/ml) and D30 (675±288 pg/ml) after 6OH-DA without significant change in epinephrine levels. TH expression was absent at D15 and present but significantly lower than in controls at D30. When compared to controls (48.5±6.2 %), LF HRV was significantly reduced at D15 (31.6±5.4 %) but not at D30 (58.2±16.2 %) without any change in HF. LF/HF ratio was lower in 6OH-DA treated mice at D15 (0.49±0.13 vs 1.29±0.17 in controls) but was normal at D30 (1.63±0.31). At D15, hearts from 6-OH-DA treated mice exhibited mild structural abnormalities with wavy cardiomyocyte appearance in septum. At D30, histological abnormalities concerned whole myocardium with myocytes intersecting at various angles with bundles wavy appearance. Variability in cell size with anisocaryosis, attenuated myocytes with perinuclear halo and shaped nuclei were observed. No inflammation, interstitial fibrosis or necrosis were noticed. This study suggests that heart denervation induces myocardial tissue disorganization. Relationship between these pathological changes and sympathetic nerve destruction and/ or catecholamine depletion remains to be elucidated. Apart from physiological significance, these results also bring new structural basis to explain increased risk of cardiac disease during human autonomic failure.