Increased sample asymmetry and memory of cardiac time-series following endotoxin administration in cirrhotic rats.

Sepsis, and other causes of acute systemic inflammation, can reduce heart rate variability (HRV) and increase cardiac cycle regularity in mammals. Thus, HRV monitoring has been used for early detection of sepsis in adults and neonates. Liver cirrhosis is associated with reduced basal HRV and the development of tolerance to the cardiac chronotropic effects of bacterial endotoxin. This may pose limitations on the use of heart rate monitoring in early detection of sepsis in this patient population. In a study to develop a physiomarker for the detection of sepsis in cirrhosis, we observed that endotoxin administration in adult cirrhotic rats leads to the development of transient heart rate decelerations, a phenomenon which has been reported in neonates with sepsis, and quantified using sample asymmetry analysis. In the present study, cirrhosis was induced by surgical ligation of the bile duct in rats. Cirrhotic rats were given intraperitoneal injections of either saline or endotoxin (1 mg kg-1). Changes in sample asymmetry and memory length of cardiac time-series were studied in conscious rats using implanted telemetric probes. Cirrhotic (but not control) rats exhibited increased sample asymmetry following endotoxin injection, which was consistent with the development of transient heart rate deceleration. Endotoxin administration in cirrhotic rats was associated with prolongation of memory length for observing decelerating perturbations in the cardiac rhythm. These findings may have application in the development of an HRV monitoring system for early detection of sepsis in cirrhosis.

LRP6 mutation in a family with early coronary disease and metabolic risk factors.

Coronary artery disease (CAD) is the leading cause of death worldwide and is commonly caused by a constellation of risk factors called the metabolic syndrome. We characterized a family with autosomal dominant early CAD, features of the metabolic syndrome (hyperlipidemia, hypertension, and diabetes), and osteoporosis. These traits showed genetic linkage to a short segment of chromosome 12p, in which we identified a missense mutation in LRP6, which encodes a co-receptor in the Wnt signaling pathway. The mutation, which substitutes cysteine for arginine at a highly conserved residue of an epidermal growth factor-like domain, impairs Wnt signaling in vitro. These results link a single gene defect in Wnt signaling to CAD and multiple cardiovascular risk factors.