Effect of endotoxin on heart rate dynamics in rats with cirrhosis

Reduced heart rate variability (HRV) is a hallmark of systemic inflammation which carries negative prognostic information in sepsis. Decreased HRV is associated with partial uncoupling of cardiac pacemaker from cholinergic neural control during systemic inflammation. Sepsis is a common complication in liver cirrhosis with high mortality. The present study was aimed to explore the hypothesis that endotoxin uncouples cardiac pacemaker from autonomic neural control and reduces HRV in an experimental model of cirrhosis. Cirrhosis was induced by surgical ligation of the bile duct in rats. Cirrhotic rats were given intraperitoneal injection of either saline or lipopolysaccharide (endotoxin, 1 mg/kg). Changes in HRV indices were studied in conscious rats using implanted telemetric probes. The atria were isolated and chronotropic responsiveness to cholinergic stimulation was assessed in vitro. Endotoxin injection induced a significant tachycardia and decreased short-term and long-term HRV indices in control rats. However, endotoxin was unable to increase heart rate in cirrhotic animals. In contrast with control rats, endotoxin induced biphasic changes in short-term HRV in cirrhotic rats. Acute endotoxin challenge reduced long-term HRV with 60-min delay in comparison with control animals. Endotoxin injection was associated with a significant hypo-responsiveness to cholinergic stimulation in control rats in vitro. Endotoxin did not change atrial chronotropic responsiveness to cholinergic stimulation in cirrhotic rats. Our data shows that cirrhosis is associated with development of tolerance to cardiac chronotropic effect of endotoxin in rats.