can lead to liver dysfunction and damage. How unexpected In cirrhosis, cardiac contractile function has been exand gratifying, therefore, to find a voice as eloquent as the tensively documented to be abnormal. At baseline, carlate Chilean Nobel laureate's to not only extoll the many diac output is increased, and this is one of the charactervirtues of the liver, but also remind us that sometimes the istics of hyperdynamic circulation. However, when liver takes precedence over the heart, i.e., that liver failure cirrhotic patients are challenged by pharmacological or can also lead to cardiac dysfunction. physiological stress, ventricular hyporesponsiveness is It has been known for more than four decades that hepatic revealed. Similar patterns have been noted in cirrhotic cirrhosis is associated with a host of cardiovascular abnoranimal models. This phenomenon has been termed ''cirmalities. The initial studies in the early 1950s documented rhotic cardiomyopathy.'' Although alcohol abuse may the existence of hyperdynamic circulation in cirrhosis, manicontribute to some cases of cirrhotic cardiomyopathy, it has been clearly documented to occur even in the ab-fested by increased cardiac output and reduced systemic vassence of alcohol ingestion. Diminished myocardial b-ad-cular resistance. This latter phenomenon, the peripheral varenergic receptor signal transduction function, possibly sodilatation, continues to fascinate investigators even up to caused by a persistent elevation in norepinephrine con-the present, and recent studies have examined the possible tent, has been shown to play an important role. Alter-role of nitric oxide and other endothelium-dependent factors ation in cardiac plasma membrane properties due to im-in mediating the vasodilatation. The heart itself was not expaired lipid metabolism is also crucial. Other possible amined until about three decades ago, and around that time pathogenic factors are reviewed, including accumula-studies of cardiac contractile function in patients with alcotion of cardiodepressant substances caused by hepato-holic-induced liver disease started consistently showing that cellular insufficiency, and ventricular overload sec-despite the increased baseline cardiac output, when ventricuondary to increased blood volume and hyperdynamic lar contractile responses were tested under conditions of circulation. Because the cardiac reserve function is bor-pharmacological or physiological stress, the heart behaved derline in patients with cirrhosis, cardiovascular status abnormally in a blunted manner. For many years, this was should be carefully monitored, especially when patients ascribed to the well-known direct toxic effects of alcohol on undergo stresses such as liver transplantation or porto-cardiac muscle, i.e., as a manifestation of latent or subclinical systemic shunting procedures. (HEPATOLOGY 1996;24: alcoholic cardiomyopathy, and relegated to the scientific 451-459.)backwaters as a clinically insignificant curiosity. However, recently several studies have emerged in both ...

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The underlying mechanisms for the electrophysiological abnormalities that develop as a consequence of cirrhosis of the liver have been studied by recording three different K+ currents in mammalian heart tissue. Single myocytes from the atria and ventricles of sham-operated and bile ductligated (BDL) cirrhotic adult rats were current and voltage clamped using standard whole cell methods. In ventricular myocytes from cirrhotic animals, measurements of the current-voltage relationships, voltage dependence of inactivation, and reactivation kinetics of K+ currents showed that the only significant functional changes (within the physiological range of membrane potentials) were decreases in the density of expression of 1) I(t), a Ca(2+)-independent transient outward K+ current, and 2) Isus, a delayed rectifier K+ current. The decreases in I(t) and Isus contribute to the prolonged Q-T interval of the electrocardiogram that has been described in cirrhotic patients. Measurement of K+ currents in atrial myocytes demonstrated that there were no significant differences in any of the K+ current densities between sham and BDL animals, although reactivation kinetics of I(t) were slowed somewhat.

To elucidate the basic membrane mechanisms underlying cirrhotic cardiomyopathy, cardiac sarcolemmal plasma membrane physical properties, chemical composition, beta-adrenoceptor density, binding affinity, and isoproterenol-stimulated adenosine 3',5'-cyclic monophosphate (cAMP) production were studied. Cirrhosis was induced by chronic bile duct ligation, while controls underwent a sham operation. The cardiac plasma membrane of cirrhotic rats was found to be more rigid than controls, primarily due to an increased cholesterol-to-phospholipid ratio. In cirrhotic animals, beta-adrenergic dysfunction was evident with a 21% decrease in beta-adrenoceptor density but no alteration in binding affinity. Despite the modest decrease in receptor number, beta-adrenoceptor-stimulated cAMP production was decreased by 37% in cirrhotic rats. When the membrane physical properties of the cirrhotic rats were restored to normal, by incubation with the fluidizing agent 2-(2-methoxy-ethoxy)ethyl 8-(cis-2-n-octylcyclopropyl)octanoate (A2C), isoproterenol-stimulated cAMP production also increased to levels indistinguishable from control animals. Restoration of membrane physical properties had no effect on either beta-adrenoceptor density or binding affinity. These results suggest that the increased rigidity of cardiomyocyte plasma membranes seen with cirrhosis is associated with decreased beta-adrenoceptor function. Moreover, restoring normal physical properties may result in restoration of beta-adrenoceptor-mediated contractile function.