Focus
Authors: Scott L. Friedman
Journal: Journal of Hepatology (2012)

Given the widespread impact of hepatic disease on other organs including the kidney, lungs, and the immune and central nervous systems, it's been interesting that the heart is rarely mentioned. A study in this month's issue of the Journal of Hepatology by Maruyama et al. identifies a common effect of hepatitis C virus (HCV) infection on myocardial function that is reversible following viral eradication. Unlike the effect on other organs, however, this cardiac connection does not reflect a consequence of advanced liver disease but rather a direct result of HCV infection. A second study by Marrone et al. explores the benefit and mechanisms by which statins, which are widely used to lower cholesterol and reduce risk of coronary disease, improve hepatic sinusoidal cell function. In the study by Maruyama and colleagues, extensive cardiac evaluation was performed in 217 consecutive patients with chronic HCV infection, including EKG, echocardiography, serum brain-derived and atrial natriuretic peptides, and myocardial thallium scintigraphy. Remarkably, 87% of patients with HCV but not normal controls had abnormal thallium scans, although no clinical manifestations of heart disease were reported. Of 92 patients who had a sustained virologic response following treatment with either interferon alone or interferon plus ribavirin, all had improved myocardial function on follow-up thallium scan, whereas 57 patients who relapsed following either treatment had only a transient improvement at the end of therapy, while all patients who were non-responders (either to mono-therapy with interferon or combined interferon–ribavirin) had no improvement at all. Although earlier studies have reported that HCV infection may affect myocardial function and can be present in the tissue [1Matsumori A. Yutani C. Ikeda Y. Kawai S. Sasayama S. Hepatitis C virus from the hearts of patients with myocarditis and cardiomyopathy.Lab Invest. 2000; 80: 1137-1142Crossref PubMed Scopus (79) Google Scholar, 2Omura T. Yoshiyama M. Hayashi T. Nishiguchi S. Kaito M. Horiike S. et al.Core protein of hepatitis C virus induces cardiomyopathy.Circ Res. 2005; 96: 148-150Crossref PubMed Scopus (41) Google Scholar, 3Demir M. Demir C. Effect of hepatitis C virus infection on the left ventricular systolic and diastolic functions.South Med J. 2011; 104: 543-546Crossref PubMed Scopus (17) Google Scholar], this report is remarkable by demonstrating improvement in cardiac function following SVR, implicating the presence of virus in causing the abnormalities. Still, lots of questions remain. Are the findings in heart unique to HCV or are they a common, albeit rarely sought, consequence of any systemic viral infection? Since no myocardial biopsies were obtained, the authors could not link the findings to the presence of HCV in heart tissue, but even if HCV was detected, this would not exclude the impact of systemic consequences of HCV infection, for example, due to immune dysregulation or systemic inflammation, since the latter can reduce myocardial function [[4]Ungureanu-Longrois D. Balligand J.L. Kelly R.A. Smith T.W. Myocardial contractile dysfunction in the systemic inflammatory response syndrome: role of a cytokine-inducible nitric oxide synthase in cardiac myocytes.J Mol Cell Cardiol. 1995; 27: 155-167Abstract Full Text PDF PubMed Scopus (187) Google Scholar]. This might indeed be the case in this study, since the severity of cardiac abnormalities correlated with the histologic activity in the liver and indocyanine green clearance (a measure of liver function); thus, more liver injury and dysfunction might lead to greater systemic inflammation that impairs myocardial function, even in non-cirrhotics, since cirrhotics were excluded in the Maruyama report. It would have been interesting to assess markers of systemic inflammation, for example C-reactive protein. This suggestion, however, underscores how primitive our ability is to rigorously quantify immune function in clinical practice. Immune dysregulation associated with HCV is widely recognized [[5]Fallahi P. Ferri C. Ferrari S.M. Corrado A. Sansonno D. Antonelli A. Cytokines and HCV-related disorders.Clin Dev Immunol. 2012; 2012: 468107Crossref PubMed Scopus (95) Google Scholar], but its assessment is not part of the clinical management of the disease. Because this report and almost all prior studies describing HCV effects on heart were performed in Japanese patients, it is also worth considering whether there are genetic polymorphisms common to this ethnicity that make cardiac abnormalities more likely to occur with HCV infection. Of course, the simplest way to address this possibility is by performing similar studies in non-Japanese with HCV to assess the prevalence of cardiac dysfunction. Finally, are the abnormalities clinically important, since cardiac dysfunction is not a common clinical problem in HCV-infected patients? It is possible, as the authors point out, that HCV or its consequences affect the potassium pump (which is also required for cellular uptake of thallium), leading to a defect in potassium homeostasis that impedes endothelial cell function. Moreover, does HCV-related endothelial cell dysfunction in heart reflect a broader impact of HCV on vascular homeostasis systemically? At the very least, evidence of a bona fide impact of chronic HCV infection on either myocytes or endothelium might help clarify its impact on other tissues where there is a greater clinical concern. For example, HCV infection has been linked to neurocognitive deficits [[6]McAndrews M.P. Farcnik K. Carlen P. Damyanovich A. Mrkonjic M. Jones S. et al.Prevalence and significance of neurocognitive dysfunction in hepatitis C in the absence of correlated risk factors.Hepatology. 2005; 41: 801-808Crossref PubMed Scopus (165) Google Scholar], and a recent study demonstrated infection of endothelial cells of the blood–brain barrier [[7]Fletcher N.F. Wilson G.K. Murray J. Hu K. Lewis A. Reynolds G.M. et al.Hepatitis C virus infects the endothelial cells of the blood–brain barrier.Gastroenterology. 2012; 142 (e636): 634-643Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar], focusing attention on this critical cell type as a mediator of HCV's effects in other tissues. The endothelium is also a focus of the study by Marrone et al., but in this case the work addresses the biology of the hepatic sinusoidal endothelium. Specifically, the investigators build upon an earlier study [[8]Gracia-Sancho J. Russo L. Garcia-Caldero H. Garcia-Pagan J.C. Garcia-Cardena G. Bosch J. Endothelial expression of transcription factor Kruppel-like factor 2 and its vasoprotective target genes in the normal and cirrhotic rat liver.Gut. 2011; 60: 517-524Crossref PubMed Scopus (92) Google Scholar] that demonstrated induction of the zinc finger transcription factor, Krüppel-like factor 2 (KLF2), within sinusoidal endothelial cells of cirrhotic liver. KLF2 is one of a large family of related Krüppel-like transcription factors that share the same DNA binding domain but have divergent amino-terminal activation domains that confer a broad range of biologic activities [9Bieker J.J. Kruppel-like factors: three fingers in many pies.J Biol Chem. 2001; 276: 34355-34358Crossref PubMed Scopus (531) Google Scholar, 10Brey C.W. Nelder M.P. Hailemariam T. Gaugler R. Hashmi S. Kruppel-like family of transcription factors: an emerging new frontier in fat biology.Int J Biol Sci. 2009; 5: 622-636Crossref PubMed Scopus (68) Google Scholar]. The contribution of KLF2 to vascular endothelial cell homeostasis has been well established [11Atkins G.B. Jain M.K. Role of Kruppel-like transcription factors in endothelial biology.Circ Res. 2007; 100: 1686-1695Crossref PubMed Scopus (311) Google Scholar, 12Lin Z. Natesan V. Shi H. Dong F. Kawanami D. Mahabeleshwar G.H. et al.Kruppel-like factor 2 regulates endothelial barrier function.Arterioscler Thromb Vasc Biol. 2010; 30: 1952-1959Crossref PubMed Scopus (83) Google Scholar], and much of the data in the Marrone paper recapitulates an earlier study in vascular endothelial cells demonstrating a potent effect of statins in promoting KLF2-dependent nitric oxide and thrombomodulin induction [[13]Sen-Banerjee S. Mir S. Lin Z. Hamik A. Atkins G.B. Das H. et al.Kruppel-like factor 2 as a novel mediator of statin effects in endothelial cells.Circulation. 2005; 112: 720-726Crossref PubMed Scopus (252) Google Scholar]. Marrone and colleagues similarly demonstrate that several statins induce KLF2 in cultured sinusoidal endothelial cells, which leads to up-regulation of endothelial nitric oxide synthase and thrombomodulin. The effect was blunted by providing mevalonate to overcome the inhibition of HMG-CoA reductase by statins (their main mechanism of action), and was also inhibited by using siRNA to KLF2 to reduce its expression. Moreover, this effect on endothelial cells led to reduced paracrine activation in culture of a human hepatic stellate cell line (LX-2), as assessed by expression of alpha smooth muscle actin, consistent with a recent study that underscores the importance of endothelial cells in regulating stellate cell activation [[14]Xie G. Wang X. Wang L. Atkinson R.D. Kanel G.C. Gaarde W.A. et al.Role of differentiation of liver sinusoidal endothelial cells in progression and regression of hepatic fibrosis in rats.Gastroenterology. 2012; 142 (e916): 918-927Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar]. The findings foreshadow interesting new molecular and translational directions. From the molecular perspective, a complete readout of KLF2's transcriptional targets and the impact of statins in sinusoidal endothelium could be assessed using a range of techniques including cDNA array, chromosomal IP-sequencing (ChIP-seq) or even direct transcriptome or exome deep sequencing [15Gorreta F. Carbone W. Barzaghi D. Genomic profiling: cDNA arrays and oligoarrays.Methods Mol Biol. 2012; 823: 89-105Crossref PubMed Scopus (15) Google Scholar, 16Ku C.S. Wu M. Cooper D.N. Naidoo N. Pawitan Y. Pang B. et al.Exome versus transcriptome sequencing in identifying coding region variants.Expert Rev Mol Diagn. 2012; 12: 241-251Crossref PubMed Scopus (28) Google Scholar]. Such unbiased approaches might reveal other cytoprotective targets downstream of KLF2 that have not previously been uncovered. In addition, the mechanism linking inhibition of HMG-CoA reductase (i.e., reduced cholesterol biosynthesis) to KLF2 induction in this cell type is entirely obscure and merits further inquiry. From a translational perspective, the findings could lead to long-term studies of statin usage, building upon an earlier report by the same group in cirrhotics [[17]Zafra C. Abraldes J.G. Turnes J. Berzigotti A. Fernandez M. Garca-Pagan J.C. et al.Simvastatin enhances hepatic nitric oxide production and decreases the hepatic vascular tone in patients with cirrhosis.Gastroenterology. 2004; 126: 749-755Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar], to determine their effect not only on portal hypertension, but also on fibrosis and vascular remodeling. While unlikely to be sufficiently potent alone to treat fibrosis, statins might provide synergistic activities when combined with either existing or new antifibrotic agents. Statins are also likely to have many other cellular and molecular targets of action in liver besides KLF2, in particular through down-regulation of inflammation [[18]Antonopoulos A.S. Margaritis M. Lee R. Channon K. Antoniades C. Statins as anti-inflammatory agents in atherogenesis: molecular mechanisms and lessons from the recent clinical trials.Curr Pharm Des. 2012; 18: 1519-1530Crossref PubMed Scopus (305) Google Scholar]. Nonetheless, by clarifying their mechanisms of action, more potent and selective inducers of vasoprotection could be discovered, whether or not they exert their effects through KLF2. Together, these two studies link liver disease with vascular biology, and reinforce a connection that is likely to yield further insights with continued exploration using molecular methods and in vivo models. The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. Myocardial injury in patients with chronic hepatitis C infectionJournal of HepatologyVol. 58Issue 1PreviewThe existence of a direct pathogenic link between hepatitis C virus (HCV) infection and myocardial injury has not been confirmed. We investigated the association between myocardial conditions and HCV in patients with HCV-related chronic hepatitis using thallium-201 myocardial scintigraphy. Full-Text PDF The transcription factor KLF2 mediates hepatic endothelial protection and paracrine endothelial–stellate cell deactivation induced by statinsJournal of HepatologyVol. 58Issue 1PreviewStatins improve hepatic endothelial function and liver fibrosis in experimental models of cirrhosis, thus they have been proposed as therapeutic options to ameliorate portal hypertension syndrome. The transcription factor Kruppel-like factor 2 (KLF2) may be induced by statins in liver sinusoidal endothelial cells (SEC), orchestrating an efficient vasoprotective response. The present study aimed at characterizing whether KLF2 mediates statins-derived hepatic protection. Full-Text PDF