Mani, A.; (2007) Cardiac rhythm abnormalities in cirrhosis. Doctoral thesis , University of London.

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Abstract

Liver cirrhosis is associated with cardiovascular dysfunction including decreased heart rate variability and impaired acceleration of the heart rate in response to sympathetic activation (chronotropic incompetence). In this thesis, the hypothesis that increased formation of reactive nitrogen species in cirrhosis causes nitration or S-nitrosation of cardiac proteins and leads to impaired chronotropic function was assessed in an experimental model of cirrhosis. Cardiac chronotropic responsiveness to fi-adrenergic stimulation was assessed in vitro using spontaneous beating rat isolated atria. A novel mass spectrometric method was developed for dynamic assessment of nitration reactions based on the nitration of deuterium-labelled pra-hydroxyphenyl acetic acid. Nitration of cardiac proteins was measured by mass spectrometry and located by immunogold electron microscopy. Marked impairment of chronotropic responses of isolated atria to isoproterenol was observed in rats with cirrhosis, which normalized after the administration of N-acetylcysteine (a scavenger of reactive oxygen and nitrogen species) or L-NAME (a nitric oxide synthase inhibitor). The levels of protein-bound nitrotyrosine in atrial tissue increased from 16 1 to 23 3 pg/g tyrosine in rats with cirrhosis, and decreased to 15 1 and 17 1 pg/g after treatment with L-NAME and N-acetylcysteine, respectively (P<0.05). Immunogold electron microscopy demonstrated increased nitration of filaments and mitochondria in the atria of rats with cirrhosis. A chemiluminescence- based method was developed to stabilise and measure S-nitrosothiols in tissues. There was no difference in cardiac S-nitrosothiols following induction of cirrhosis, and neither N-acetylcysteine nor L-NAME had any effect on the cardiac levels of S-nitrosothiols. Autonomic regulation of cardiac function was assessed by analysis of heart rate variability in anesthetized rats using Fast Fourier Transformation. Heart rate variability analysis showed impaired sympathovagal balance towards increase of cardiac sympathetic activity in rats with cirrhosis (P<0.05). However there was no change in the sympathovagal balance following N-acetylcysteine or L-NAME adminstration in cirrhotic rats. In conclusion, abnormal cardiac chronotropic function in cirrhosis is associated with increased nitration of cardiac proteins. Two independent treatments (N-acetylcysteine and L-NAME) that decrease nitration of cardiac proteins led to normalization of cardiac responses. Nitration of critical proteins in cardiac tissue may lead to abnormal cardiac function.

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