This study was aimed to evaluate demographic, clinical, histological, and virological characteristics of 46 hepatitis C virus (HCV) carriers with persistently normal alanine transaminase (ALT) levels and to compare the results with those obtained in a group of 52 HCV-RNA-positive patients with elevated ALT levels. Subjects with normal ALT were more often females (P < .001), were more likely to be asymptomatic (P < .001), and have a lower incidence of risk factors for HCV transmission (P < .01). All patients with normal ALT had significant histological liver damage. The mean grading and staging did not differ between patients with normal and those with raised ALT concentrations. Moderate to severe hepatitis was more frequently found among subjects with normal than with elevated ALT. HCV genotype 2a was far more common in subjects with normal (43%) than with abnormal ALT levels (6%; P < .002), genotype 1b being more frequent in these latter (50% vs. 17%; P < .001). Patients with normal ALT levels had similar serum HCV-RNA titers than subjects with raised ALT. Neither HCV genotype distribution nor viral load correlated with the severity of liver damage. We conclude that significant liver disease may occur irrespective of clinical symptoms, ALT levels, HCV genotypes, and viral load.

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BACKGROUND AND PURPOSEPropranolol is a vasoactive drug that shows antiangiogenic and antitumour activities in melanoma. However, it is unknown whether these activities are dose-dependent and whether there is a relationship between systemic vascular effects of propranolol and anti-melanoma activity. EXPERIMENTAL APPROACHEffects of increasing doses of propranolol (10, 20, 30 and 40 mg·kg À1 ·day À1 ) on tumour growth were studied in B16F10 melanoma-bearing mice. Histological and biochemical analyses were used to assess propranolol effects on angiogenesis and cancer cell proliferation. Systemic vascular resistance (SVR) was evaluated by measuring cardiac output and arterial BP. KEY RESULTSIn vitro analyses revealed that B16F10 cells expressed β-adrenoceptors, but neither isoprenaline, a β-adrenoceptor agonist, nor the β-blocker propranolol affected cancer cell proliferation. In vivo studies showed that the antitumour efficacy of propranolol follows a U-shaped biphasic dose-response curve. Low doses (10 and 20 mg·kg À1 ·day À1 ) significantly inhibit tumour growth, whereas higher doses are progressively less effective. We also found that high-dose propranolol stimulates tumour arteriogenesis whereas no effect on angiogenesis was observed at any dose. Based on these data and considering that propranolol is a vasoactive drug, we hypothesized that it causes systemic vasoconstriction or vasodilation depending on the dose and thus alters tumour perfusion and growth. Consistent with this hypothesis, we found that propranolol has a biphasic effect on SVR with low and high doses producing vasoconstriction and vasodilation respectively. CONCLUSIONS AND IMPLICATIONSPropranolol inhibits melanoma growth in a U-shaped biphasic manner. A direct relationship exists between SVR and antimelanoma activity.Abbreviations α-SMA, α-smooth muscle actin; CO, cardiac output; GAPDH, Glyceraldehyde-3-phosphate dehydrogenase; HR, heart rate; IB4, isolectin B4; SV, stroke volume; SVR, systemic vascular resistance; vWF, Von Willebrand Factor Introduction β-Adrenoceptors are a family of G-protein coupled receptors comprising three subtypes, β 1 , β 2 and β 3 , which act by activating a Gs protein. These receptors play a role in the regulation of peripheral vascular resistance, heart function and airway reactivity, as well as a variety of metabolic and CNS functions. β-Adrenoceptors also regulate cellular processes involved in cancer and angiogenesis and are the molecular target of β-blockers, a class of drugs which inhibits the interaction of catecholamines with β-adrenoceptors.In vitro studies indicate that propranolol, the prototype of β-blockers, reduces melanoma cell proliferation in human and murine melanoma cell lines (Dal Monte et al., 2013;Moretti et al., 2013;Calvani et al., 2015;Wrobel and Le Gal, 2015). Furthermore, the systemic administration of propranolol slows down tumour development in immunodeficient mice transplanted with human melanoma cells (Wrobel and Le Gal, 2015) and inhibits the effects of stress on the growth and metast...

Cardiac dysfunction is often observed in patients with cancer also representing a serious problem limiting chemotherapeutic intervention and even patient survival. In view of the recently established role of the immune system in the control of cancer growth, the present work has been undertaken to investigate the effects of a panel of the most important inflammatory cytokines on the integrity and function of mitochondria, as well as of the cytoskeleton, two key elements in the functioning of cardiomyocytes. Either mitochondria features or actomyosin cytoskeleton organization of in vitro‐cultured cardiomyocytes treated with different inflammatory cytokines were analyzed. In addition, to investigate the interplay between tumor growth and cardiac function in an in vivo system, immunocompetent female mice were inoculated with cancer cells and treated with the chemotherapeutic drug doxorubicin at a dosing schedule able to suppress tumor growth without inducing cardiac alterations. Analyses carried out in cardiomyocytes treated with the inflammatory cytokines, such as tumor necrosis factor α (TNF‐α), interferon γ (IFN‐γ), interleukin 6 (IL‐6), IL‐8, and IL‐1β revealed severe phenotypic changes, for example, of contractile cytoskeletal elements, mitochondrial membrane potential, mitochondrial reactive oxygen species production and mitochondria network organization. Accordingly, in immunocompetent mice, the tumor growth was accompanied by increased levels of the inflammatory cytokines TNF‐α, IFN‐γ, IL‐6, and IL‐8, either in serum or in the heart tissue, together with a significant reduction of ventricular systolic function. The alterations of mitochondria and of microfilament system of cardiomyocytes, due to the systemic inflammation associated with cancer growth, could be responsible for remote cardiac injury and impairment of systolic function observed in vivo.

In HCV carriers with normal aminotransferase levels viraemia does not predict the grade of HCV-related chronic liver disease (CLD), although subjects with higher HCV RNA levels seem to have more severe fibrosis. Although these data suggest that patients with higher viraemia might have more intense architectural changes and more severe progression of liver disease than those with lower levels of HCV replication, the weak and imprecise correlation leads us to conclude that HCV RNA quantitation is not a useful indicator in clinical practice in the selection of patients for liver biopsy.

1 Cardiac hypertrophy is a homeostatic response to elevated afterload. Na þ /H þ exchanger (NHE) inhibition reduces the hypertrophic response in animal models of left ventricular hypertrophy (LVH) and myocardial infarction. We examined the effect of chronic treatment with cariporide, a selective inhibitor of Na þ /H þ exchanger isoform 1 (NHE-1), on left ventricular (LV) systolic and diastolic function under pressure overload conditions. 2 Male CD-1 mice were randomized to receive either a control diet or an identical diet supplemented with 6000 p.p.m. of cariporide. Cardiac pressure overload was induced by thoracic aortic banding. LV dimension and systolic and diastolic function were assessed in sham and banded mice by echocardiography and cardiac catheterization 2 and 5 weeks after surgery. Histological analysis was also performed. 3 After 2 weeks of pressure overload, the vehicle-treated banded mice (Veh-Bd) had enhanced normalized LV weight (about þ 50%) and normal chamber size and function, whereas cariporidetreated banded mice (Car-Bd) showed a preserved contractility and systolic function despite a marked attenuation of LVH. Diastolic function did not differ significantly among groups. After 5 weeks, the Veh-Bd developed LV chamber enlargement and systolic dysfunction as evidenced by a 16% increase in LV end-diastolic diameter, a 36% decrease in myocardial contractility, and a 26% reduction in percent fractional shortening. In contrast, Car-Bd showed an attenuated increase in LV mass, normal chamber size, and a maintained systolic function. A distinct histological feature was that in banded mice, cariporide attenuated the development of cardiomyocyte hypertrophy but not the attendant myocardial fibrosis. 4 In conclusion, the results of the present study indicate that (i) the hypertrophic response to pressure overload is dependent on NHE-1 activity, and (ii) at the 5-week stage, banding-induced deterioration of LV performance is prevented by NHE-1 inhibition. British Journal of Pharmacology (2004) 141, 526-532. doi:10.1038/sj.bjp.0705631 Keywords: Pressure overload; Na þ /H þ exchanger; cardiac remodeling; systolic function Abbreviations: BW, body weight; Car, cariporide; Car-Bd, cariporide-treated, banded mice; Car-Sh, cariporide-treated, shamoperated mice; CSA, cardiomyocyte cross-sectional area; Ees, end-systolic elastance; HR, heart rate; LVEDD, left ventricular end-diastolic diameter; LVEDP, left ventricular end-diastolic pressure; LV FS, left ventricular fractional shortening; LVSP, left ventricular systolic pressure; LVW/BW, left ventricular weight-to-body weight ratio; NHE-1, Na þ /H þ exchanger isoform 1; RWT, posterior-wall thickness-to-left ventricular end-diastolic diameter ratio; s s , end-systolic left ventricular wall stress; Veh-Sh, vehicle-treated, sham-operated mice; Veh-Bd, vehicle-treated, banded mice

Background and purpose: Pathological cardiac hypertrophy is associated with the expression of a gene profile reminiscent of foetal development. The non selective b-adrenoceptor antagonist propranolol is able to blunt cardiomyocyte hypertrophic response in pressure-overloaded hearts. It remains to be determined whether propranolol also attenuates the expression of hypertrophy-associated foetal genes. Experimental approach: To address this question, the foetal gene programme, of which atrial natriuretic peptide (ANP), the b-isoform of myosin heavy chain (b-MHC), and the a-skeletal muscle isoform of actin (skACT) are classical members, was induced by thoracic aortic coarctation (TAC) in C57BL/6 mice, or by phenylephrine, a selective a 1 -adrenoceptor agonist, in cultured rat neonatal cardiomyocytes. Key results: In TAC mice, the left ventricular weight-to-body weight (LVW/BW) ratio increased by 35% after 2 weeks. Levels of ANP, b-MHC and skACT mRNA in the left ventricles increased 2.2-fold, 2.0-fold and 12.1-fold, respectively, whereas a-MHC and SERCA mRNA levels decreased by E 50%. Although propranolol blunted cardiomyocyte growth, with approximately an 11% increase in the LVW/BW ratio, it enhanced the expression of ANP, b-MHC and skACT genes (10.5-fold, 27.7-fold and 22.7-fold, respectively). Propranolol also enhanced phenylephrine-stimulated ANP and b-MHC gene expression in cultured cardiomyocytes. Similar results were obtained with metoprolol, a selective b 1 -adrenoceptor antagonist, but not with ICI 118551, a b 2 -adrenoceptor antagonist. Conclusions and implications: Propranolol enhances expression of the hypertrophy-associated foetal genes mainly via the b 1 -adrenoceptor blockade. Our results also suggest that, in pressure-overloaded hearts, cardiomyocyte growth and foetal gene expression occur as independent processes.

Cardiovascular diseases (CVDs) are a major burden on the healthcare system: indeed, over two million new cases are diagnosed every year worldwide. Unfortunately, important drawbacks for the treatment of these patients derive from our current inability to stop the structural alterations that lead to heart failure, the common endpoint of many CVDs. In this scenario, a better understanding of the role of epigenetics – hereditable changes of chromatin that do not alter the DNA sequence itself – is warranted. To date, hyperacetylation of histones has been reported in hypertension and myocardial infarction, but the use of inhibitors for treating CVDs remains limited. Here, we studied the effect of the histone deacetylase inhibitor Givinostat on a mouse model of acute myocardial infarction. We found that it contributes to decrease endothelial-to-mesenchymal transition and inflammation, reducing cardiac fibrosis and improving heart performance and protecting the blood vessels from apoptosis through the modulatory effect of cardiac fibroblasts on endothelial cells. Therefore, Givinostat may have potential for the treatment of CVDs.