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 ...

Silymarin from the milk thistle herb (Silybum marianum) is used by many patients with chronic viral hepatitis, but its efficacy remains unknown. We performed a systematic review of silymarin for the treatment of chronic viral hepatitis B and C. An exhaustive search strategy identified 148 papers that studied silymarin compounds in liver disease. Of these, four trials included patients with hepatitis C, one included hepatitis B patients, and two, unspecified chronic viral hepatitis. However, only one trial exclusively studied patients with hepatitis C, and none involved patients with only hepatitis B. Silymarin treatment resulted in a decrease in serum transaminases compared with baseline in four studies, and compared with placebo in only one study. There is no evidence that silymarin affects viral load or improves liver histology in hepatitis B or C. No studies were found that investigated the use of silymarin concomitantly with interferon, nucleoside analogues, or other conventional treatments for hepatitis B or C. In conclusion, silymarin compounds likely decrease serum transaminases in patients with chronic viral hepatitis, but do not appear to affect viral load or liver histology. Nevertheless it may be worthwhile to determine its effects in conjunction with standard antiviral treatment.

Background and purpose: Hyperdynamic circulation and mesenteric hyperaemia are found in cirrhosis. To delineate the role of endocannabinoids in these changes, we examined the cardiovascular effects of anandamide, AM251 (CB 1 antagonist), AM630 (CB 2 antagonist) and capsazepine (VR1 antagonist), in a rat model of cirrhosis. Experimental approach: Cirrhosis was induced by bile duct ligation. Controls underwent sham operation. Four weeks later, diameters of mesenteric arteriole and venule (intravital microscopy), arterial pressure, cardiac output, systemic vascular resistance and superior mesenteric artery (SMA) flow were measured after anandamide, AM251 (with or without anandamide), AM630 and capsazepine administration. CB 1 , CB 2 and VR1 receptor expression in SMA was assessed by western blot and RT-PCR. Key results: Anandamide increased mesenteric vessel diameter and flow, and cardiac output in cirrhotic rats, but did not affect controls. Anandamide induced a triphasic arterial pressure response in controls, but this pattern differed markedly in cirrhotic rats. Pre-administration of AM251 blocked the effects of anandamide. AM251 (without anandamide) increased arterial pressure and systemic vascular resistance, constricted mesenteric arterioles, decreased SMA flow and changed cardiac output in a time-dependent fashion in cirrhotic rats. Capsazepine decreased cardiac output and mesenteric arteriolar diameter and flow, and increased systemic vascular resistance in cirrhotic rats, but lacked effect in controls. Expression of CB 1 and VR1 receptor proteins were increased in cirrhotic rats. AM630 did not affect any cardiovascular parameter in either group. Conclusions and implications: These data suggest that endocannabinoids contribute to hyperdynamic circulation and mesenteric hyperaemia in cirrhosis, via CB 1 -and VR1-mediated mechanisms.

defective myocardial contractility is seen under various pharThe pathogenesis of cirrhotic cardiomyopathy remacological and physiological stimuli. [2][3][4] This condition has mains unclear. Because ventricular contractility is debeen termed cirrhotic cardiomyopathy, but the mechanisms pendent on the interplay of stimulatory b-adrenergic underlying these cardiac abnormalities remain poorly underand inhibitory muscarinic receptors, we aimed to examstood. Various hypotheses have been proposed, including abine a possible role of muscarinic M2 receptor overactinormalities in neural factors, mechanoreceptor-mediated revity in a rat model of cirrhotic cardiomyopathy. Cirrhosponses, and the cardiac muscle itself (reviewed in Lee, 4 Ma, ). controls underwent sham operations. Contractile reCardiac contractile function is regulated mainly by the sponses to the muscarinic agonist carbachol were measympathetic and parasympathetic branches of the autonomic sured in situ in the autonomic-denervated pithed rat nervous system through the guanine nucleotide binding reguand in vitro in isolated ventricular papillary muscles.latory protein (G-protein)-coupled b-adrenergic and muscaVentricular sarcolemmal plasma membranes were isorinic receptors. Attenuation in the b-adrenergic-stimulated lated by sucrose density gradients, and muscarinic chronotropic and inotropic responses has been shown in cirreceptor characteristics were studied using 1-[N-methylrhotic patients and animal models of cirrhosis. 6-9 3 H]scopolamine (NMS). Membrane adenylyl cyclaseBecause ventricular contractility is dependent on the interactivity was tested by a protein binding assay. Maximum play of stimulatory b-adrenergic and inhibitory muscarinic first time derivative of peak ventricular systolic presreceptor function, we hypothesized that the abnormalities sure (/dP/dt) for sham-operated and cirrhotic rats at seen in the cirrhotic heart could be caused by changes in baseline was 3,599 { 296 versus 1,226 { 63 mm Hg/sec muscarinic receptor activity. Specifically, the blunted ven-(P õ .01). Maximum first time derivative of ventricular tricular responsiveness of cirrhotic cardiomyopathy might be diastolic relaxation (0dP/dt) for sham and cirrhotic rats caused by overactivity of inhibitory muscarinic receptors. at basal levels was 03,040 { 235 versus 0864 { 59 (P õ However, this hypothesis has not previously been examined. .01). The /dP/dt max , and 0dP/dt max responses to carbaTherefore, we aimed to clarify this issue, using different in chol were blunted in the cirrhotic rats. The cirrhotic situ and in vitro protocols to test muscarinic receptor function papillary muscles showed significantly less inhibition to and characteristics in a rat model of cirrhotic cardiomyopaincremental doses of carbachol than control rat muscles.thy. Likewise, isoproterenol-stimulated membrane adenylyl cyclase activity was significantly less inhibited by carba- MATERIALS AND METHODSchol doses in the cirrhotic rats. Membrane M2 receptor density and binding affinity in cirrhotic rat he...

SUMMARY. Chronic hepatitis C virus (HCV) infections with genotype 2 or 3 are associated with favourable sustained virologic response (SVR) rates. However, genotype 3 may respond less well. We reassessed all treatment-naive patients with genotype 2 and 3 participating in a large expandedaccess, non-randomized, open-label trial, evaluating 180lg pegylated interferon (peg-IFN) alpha-2a (40kD) once weekly and 800 mg/day ribavirin for 24-48 weeks. Factors measured prior to initiation of antiviral therapy were considered in the multiple logistic regression model for predicting SVR. In total, 180 patients were analysed of which 72 (40%) were infected by genotype 2 and 108 (60%) genotype 3. The baseline characteristics between patients infected by genotype 2 or 3 were no different including the distribution of hepatic fibrosis stages by METAVIR score. Overall SVR was lower in those patients infected with genotype 3. The significant multivariate predictors of lack of SVR were hepatic fibrosis (P = 0.014) and genotype 3 (P = 0.030). The negative impact of cirrhosis (METAVIR score F4) on treatment response was more evident among subjects with genotype 3 than those with genotype 2 (P = 0.027). There is significant interaction between cirrhosis and genotype 3 leading to a poor antiviral response in such patients requiring an alternate management strategy. This finding should be confirmed in a larger population.