Cardiovascular Disease and Hepatitis C Virus ... - IngentaConnect

Review Article

Cardiovascular Disease and Hepatitis C Virus Infection An Irrelevant Statement or a Hot Relationship? Vasiliki Katsi, MD, PhD,* Ioannis Felekos, MD, PhD,† Stamatios Skevofilax, MD,‡ Constantina Aggeli, MD, PhD,† Dimitris Tousoulis, MD, PhD,* Christodoulos Stefanadis, MD, PhD,† and Ioannis Kallikazaros, MD, PhD*

Abstract: Hepatitis C virus (HCV) is well known for being the leading cause of hepatocellular carcinoma and cirrhosis, contributing to a devastating array of metabolic dysfunctions associated with hepatic failure. However, the cardiac manifestations of HCV and chronic hepatitis C (CHC) are being explored, thus illuminating the connection between HCV infection and cardiac disease. Although not all studies agree, the evidence in favor of CHC promoting major risk factors for cardiovascular disease such as hypertension, insulin resistance, diabetes mellitus, and atherosclerosis is compelling. Similarly, properly warranted attention is being guided towards CHC as an independent risk factor for the development of atherosclerotic heart disease and cardiomyopathy. This review provides a synopsis on the relationship between (HCV) infection and cardiac disease, emphasizing on some of the key possible mechanisms and population derived data. Key Words: Hepatitis C virus, cardiovascular system (Cardiology in Review 2015;23: 11–17)

T

he liver represents a major inflammation regulator, including both local and systemic inflammation, through the production and excretion of molecules with inflammatory-inducing properties. It was discovered in 1989 that hepatitis c virus (HCV) belongs to the genus hepacivirus and is a small positive-sense, single-stranded, enveloped ribonucleic acid (RNA) virus. According to the World Health Organization, 3% of the world’s population is infected by this virus. To date, there are 6 major genotypes of HCV, with each genotype consisting of a mixture of species, termed as quasispecies.1 HCV infection can be difficult to treat due to its ability to mutate and, therefore, evade current treatments, with the first genotype being the most resistant strain.1–3 HCV is long considered as the major culprit for hepatocellular carcinoma and cirrhosis. Novel data, however, indicate that the specific virus may be held responsible for a paramount of extrahepatic manifestations.

PATHOPHYSIOLOGY OF HEPATITIS C VIRUS INFLAMMATION: OVERVIEW OF POTENTIAL DISEASE MECHANISMS HCV infection is the initial event in a chronic inflammatory cascade. The production of proinflammatory and inflammatory cytokines, such as interleukin (IL) 1-beta, tumor necrosis factor (TNF)-α and -β, leads to local inflammation and fibrosis.4 Moreover, the

From the *1st Cardiology Department, Hippokration Hospital/Athens Medical School, Athens, Greece; †Cardiology Department Hippokration Hospital, Athens, Greece; and ‡General Hospital, Chios, Greece. Disclosure: The authors have no conflicts of interest to report. Correspondence: Ioannis Felekos, MD, PhD, Kasomouli 63, Neos Kosmos, 11744, Athens. E-mail: [email protected]. Copyright © 2014 Lippincott Williams & Wilkins ISSN: 1061-5377/15/2301-0011 DOI: 10.1097/CRD.0000000000000031

alterations in intestinal flora that is noted in patients with chronic HCV infection lead to increased levels of endotoxins, which further augment cytokine production.5 In addition, steatosis is a major contribution to the mechanisms of HCV hepatic and extrahepatic manifestations, via the increased expression of inflammatory markers including IL-6 and TNF-α. These molecules signify the inhibition of insulin signaling and adiponectin levels which in turn result in insulin resistance and steatosis progression.6 Specifically, obese patients with steatosis tend to sustain more severe hepatic injury and become more resistant to HCV infection treatment. The metabolic syndrome shares many clinical elements with hepatic steatosis. It has also been noted that there are elevated levels of inflammatory markers and endothelial dysfunction in hepatic steatosis, perhaps explaining at least a portion of the HCV patients’ elevated risk for coronary artery disease.7 A set of proinflammatory and anti-inflammatory cytokines guide the growing atherosclerotic lesion toward rupture. Inflammatory markers such as high sensitivity C-reactive protein, IL-6, and TNF-α are elevated in HCV-infected patients compared to HCVuninfected control subjects.8 On the contrary, insulin resistance and glucose metabolism abnormalities tend to promote metabolic syndrome in this subset of patients. A 4-fold and even 11-fold increase in some cohorts has been indicated from previous studies.9 A recent population based on the NHANES 10-year data has demonstrated that HCV infection is independently associated with insulin resistance, type 2 diabetes mellitus, and hypertension, and congestive heart failure.9 Although the association of HCV infection, insulin resistance, and diabetes mellitus type 2 is certain, the mechanism of disease presentation remains elusive. Not until recently, the role of cannabinoid receptors became known. These receptors are in abundance in various organ tissues including the liver, with the cannabinoid receptor-1 subtype being upregulated in patients with chronic hepatitis C (CHC). Polymorphisms in these receptors promote liver inflammation and necrosis.10 Another important pathophysiologic path is the development of cryoglobulinemia that accompanies HCV infection. Cryoglobulins are detected in 50% of infected persons and are the product of a complex interaction between the host and the pathogen. Their presence signifies the formation of immune complexes that are deposited in the vascular endothelium causing vasculitis.11 A recent article by Terrier et al12 suggests that mixed cryoglobulinemia could affect the heart in 7% of the screened patients who presented with symptoms of chest pain and heart failure. The administration of immunosuppressive therapy led to reversal of cardiac injury with good early prognosis. However, according to the authors, long-term outcomes were poor. Last, but not least, the presence of oxidative stress is another implicated pathway of HCV-mediated inflammation. The loss of equilibrium between antioxidants and reactive oxygen species is associated with local and systemic inflammation. Ischemia, apoptosis, necrosis, and tissue regeneration, along with fibrogenesis, represent a vast array of oxidative stress-induced damage.13 A schematic synopsis of HCV infection inflammatory pathways is provided in Figure 1.

Cardiology in Review • Volume 23, Number 1, January/February 2015

www.cardiologyinreview.com | 11

Katsi et al


FIGURE 1. Pathophysiology of Hepatitis C virus infection and cardiovascular disease. HCV indicates hepatitis C virus; IL, interleukin; TNF-α, tumor necrosis factor-alpha.

Atherosclerosis An immune mechanism for atherosclerosis has been indicated. In the early 1970s, the monoclonal hypothesis was established, suggesting an infectious role in atherosclerosis. More specifically, this theory proposes that a mutation or a viral agent may convert a smooth muscle cell into a precursor proliferative clone. This suggests that an atherosclerotic plaque may be considered as a monoclonal benign neoplasm.14 Arteriosclerosis combined with endothelial dysfunction eventually leads to vascular wall stiffness. Pulse wave velocity has emerged as a valuable tool for the assessment of arterial stiffness and is found to be increased in various disease states, in addition to being prognostic for cardiovascular events.15 In the literature, there are conflicting data regarding the causal relationship between CHC infection and hypertension. In fact, several studies have shown that there was no correlation with CHC and hypertension, while other studies have shown that HCV (+) patients are less likely to have hypertension.7,8 Seropositivity of HCV has a significant association with pulse wave velocity independent of other risk factors of atherosclerosis. The same is not true for patients seropositive for hepatitis B virus.16 It is possible that the viral infection itself and/or the immune response to the HCV infection leads to arterial wall damage and resultant arterial wall stiffness. Cryoglobulinemia in HCV patients, suggesting an immunological mechanism of disease, is associated with a higher risk for arterial hypertension compared to patients without cryoglobulinemia.17 Liver fibrosis, a consequence of CHC infection, induces an array of metabolic changes, which may be partially responsible for an observed increase in the prevalence of atherosclerosis. One interesting study evaluated the prevalence of carotid atherosclerosis to determine its potential association with host, viral factors, and liver histology. Carotid plaques were independently associated with CHC patients compared with control patients. CHC patients also had higher intima media thickness compared to control patients. Older age and severe hepatic fibrosis were the most prevalent risk factors for carotid plaque formation. In patients older than 55 years, there was a similar prevalence in both groups.18 A previous HIV/HCV coinfection study did not concur with an increased atherosclerosis risk. The study examined carotid plaques among participants from the Women’s Interagency HIV Study. After adjustment for demographic traditional cardiovascular risk factors, there was no significant increased risk for carotid intima media thickness in HIV/HCV coinfected patients and HCV-monoinfected patients. An interesting finding was that the association of HIV/ HCV coinfection and HIV monoinfection with carotid plaques was positive in comparison to a negative association pattern with common carotid artery/carotid intima media thickness. It was also noted that the caution is warranted when looking at these data due to a small number of HCV-monoinfected patients included in the study.19 However, one 12 | www.cardiologyinreview.com

should be skeptical as findings regarding HCV/HIC coinfection may not be extrapolated for HCV-monoinfected people.

Insulin Resistance and Hepatitis C Virus According to epidemiological studies, HCV infection seems to be related to the development of insulin resistance.20 This in turn could lead to an increased incidence of type II diabetes mellitus that accounts for many of the CHC infection complications. A recent meta-analysis examining 34 studies and more than 300,000 patients has shown that HCV patients have about 1.7-fold increased risk of type 2 diabetes compared to noninfected controls, both in retrospective and prospective studies.21 Other researchers, however, seem to contradict this statement. A recent US study involving 15,000 persons did not show any causative relationship between HCV and diabetes.22 Perhaps the discrepancies between various reports could be attributed to the effect of elevated liver enzymes or to the absence of adjusted multivariate analysis. There is cumulative evidence that HCV insulin resistance may be the culprit for hepatic steatosis, which is one of the characteristic histopathologic features of HCV caused by chronic liver disease, and is also closely related to insulin resistance. Insulin resistance is one of the leading factors for severe fibrosis in CHC infections. Moreover, hyperinsulinemia has a deleterious effect on the management of CHC.23 The underlying mechanisms of this complex interaction are not fully understood. A direct cytopathic effect of HCV has been suggested. The genomic structure of HCV, lipid metabolism, the molecular links between the HCV core protein, lipid droplets and increased neolipogenesis, and inhibited fatty acid degradation in mitochondria have been investigated. HCV mediates dysfunction of the insulin signaling pathways through several distinct mechanisms, such as upregulating the expression of suppressors of cytokine signaling 3 expression, downregulation of peroxisome proliferator–activated receptors gamma (PPARγ), activation of mammalian target of the rapamycin (mTOR)/S6K1 pathway, and increased TNF-α secretion.24–27 Treatment options involve the administration of metformin as first-line drug therapy. Most of the patients will need concomitant use of other insulin sensitizers such as PPARγ agonists. On the contrary, chronic HCV treatment with antivirals seems to ameliorate insulin resistance and decrease the incidence of diabetes.28

HEPATITIS C VIRUS INFECTION AND CORONARY ARTERY DISEASE Several studies have suggested that some infectious agents may cause cellular and molecular changes that contribute to the pathogenesis of atherosclerosis (Table 1). The data obtained indicate the identification of viral genomes in the atherosclerotic plaques and © 2014 Lippincott Williams & Wilkins


CVD and Hep C Virus Infection

TABLE 1. Relationship Between Hepatitis C Virus and Atherosclerosis/Coronary Artery Disease Freidberg et al30 Vassalle et al14 Butt et al7 Oliveira et al31 Mostafa et al18 Tien et al19

Sample Size

Population

Outcomes

8579 686 171665 62 329 1695

HCV/HIV coinfection HCV infection HCV infection HCV infection HCV infection HCV/HIC coinfection

High risk for CAD Correlation with multi-vessel CAD Higher prevalence of CAD among infected persons Intermediated risk for CAD Higher prevalence of atherosclerosis No relation of HCV and carotid disease

HCV indicates hepatitis C virus; HIV, human immunodeficiency virus; CAD, coronary artery disease.

also pro-atherogenic effects of viral infection in cells relevant to atherogenesis (smooth muscle cells, monocyte macrophages, T cells, endothelial cells). Experimental models have also shown promotion and acceleration of atherosclerosis by infectious agents.29 Currently, little is known about the correlation between HCV infection and the development of CAD. Freidberg et al30 sought to investigate the potential of such relationship in a study population consisting of 8579 HIV-infected individuals who had been coinfected with HCV. After a follow-up of about 7 years, a higher incidence of CAD in the HIV(+)/HCV(+) cohort was noticed, implying that HCV coinfection posed an additional risk for CAD development. Moreover, after adjusting for additional factors such as traditional coronary heart disease risk factors, administration of antiretroviral therapy, and HIV viral load and CD4 count, it was found that HIV(+)/ HCV(+) patients continued to have a significantly higher risk for coronary heart disease. It should be stated that the inflammatory burden of HIV/HCV coinfection is higher compared to the HCV infection alone. Therefore, the above finding cannot be easily applied to HCVmonoinfected persons. In a recent population study, Vassalle et al14 evaluated the association between HCV seropositivity and coronary artery disease. It was found that HCV seropositivity was prevalent in 6.3% of patients with coronary artery disease as compared to 2% of the controlled group. In addition, an increasing correlation was shown with the number of vessels affected, reaching up to 8.4% for 3-vessel disease. Similar results were shown by another study using the Modified Reardon Severity Score System to evaluate patients with angiographically documented coronary artery disease. Among HCV seropositive patients, the Reardon Score was higher. Both groups of patients exhibited no statistical significant differences with regard to the frequencies of traditional risk factors. However, fibrinogen and C-reactive protein were significantly higher in the HCV seropositive patients. After adjustment for other risk factors, HCV seropositive patients still had higher Reardon severity score.8 Butt et al7 published a large observational study for coronary arterial disease risk amongst veterans comparing HCV (+) and HCV (–) subjects. It was shown that although HCV-infected patients were younger and displayed lower lipid levels with a lower risk for hypertension, this group was associated with a higher risk of coronary artery disease after adjustment for traditional risk factors. In fact, lower lipid levels were found among HCV (+) persons, being consistent with other studies. Postulated mechanisms for this are binding of HCV particles to lipid fractions, impaired hepatocyte assembly of very-low-density lipoprotein, and HCV entry into hepatocytes through the low-density lipoprotein-cholesterol receptors. Both HCV(+) and HCV() groups had similar risk for hyperlipidemia. The study did fail to find a correlation between HCV(+) patients and diabetes mellitus; however, this may be attributed to the lack of adjustment for body mass index. Similar cardiovascular risk was reported by Oliveira et al.31 The authors demonstrated that HCV-infected persons had an intermediate risk (according to the Framingham risk score). It should be © 2014 Lippincott Williams & Wilkins

stated that the HCV cohort had no diabetes, while body mass index and cholesterol profile were within normal ranges, and according to histology examinations they were not cirrhotic. Laboratory results unveiled higher levels of cytokines in HCV patients, underlying the role of inflammation for the pathogenesis of atherosclerosis.

HEPATITIS C VIRUS MYOCARDITIS AND CARDIOMYOPATHY HCV affects the myocardium in various ways, resulting in different phenotypes of cardiomyopathies. Myocardial involvement includes hypertrophic cardiomyopathy (HCM) perhaps due to proliferative stimuli from the HCV infection causing hypertrophic changes and myopathy. It can also provoke dilated cardiomyopathy (DCM) when myocardial necrosis is diffuse, inducing congestive heart failure, while focal myocardial damage results in ventricular wall aneurysms which may result in arrhythmogenic right ventricular cardiomyopathy. Restrictive cardiomyopathy is sometimes seen with myocardial necrosis in the subendocardium.32 Moreover, HCVrelated mixed cyoglobulinemia vasculitis could rarely be linked to cardiomyopathy. It was illustrated by echocardiography and magnetic resonance imaging that a complete remission of disease appeared after treatment for vasculitis.12 DCM is characterized by chamber dilatation and systolic dysfunction. With regard to disease pathogenesis, viral causes have been identified through sustained viral and host immune mechanisms.29 Various investigators have addressed the role of HCV infection. Matsumori et al33 were the first in Japan to identify HCV as a potential myocardial insult, when viral RNA in myocardial tissue of patients with DCM was found in 16.7%. The same researchers have uncovered HCV RNA strains in 6.3% of persons with DCM during a collaborative research project of the Committees for the Study of Idiopathic Cardiomyopathy in Japan, as well as after analyzing postmortem specimens.34 Since then, several studies have been published with conflicting findings. Indeed, there is no agreement that HCV could be replicated in myocardial cells, thus implying that the viral RNA unveiled in cardiac tissue could actually reflect infected material from neighboring or plasma cells, or viral transmission due to frequent hospitalizations. Dalekos et al35 and Reis et al36 found no causal relation between chronic HCV infection and DCM. Therefore, routine screening of patients with DCM for HCV infection is not warranted. Apart from DCM, HCV cardiomyopathy could manifest as HCM and myocarditis. According to a collaborative study during which autopsied hearts were histologically examined, HCV RNA was detected in 26% with HCM, 11.5% with DCM, and 33.3% with myocarditis.37 In the Myocarditis Treatment Trial, anti-HCV antibodies were established in 4.4% of 1355 patients, including 5.9% of 102 patients using biopsy to diagnose myocarditis.38 The underlying mechanisms that could result in a specific phenotype remain elusive. To this direction, Matsumori et al39 noted their involvement with the major histocompatibility complex. The major histocompatibility www.cardiologyinreview.com | 13


Katsi et al

complex II may influence the development of different phenotypes of HCV cardiomyopathies: current studies found that different alleles had relevance to liver HCV disease, HLADQB1*0303 and HLADRB1*0901 alleles were found predominately in higher levels in patients with HCM. No allele was increased in patients with DCM except for a minor increase in DRB1*1201.40 Beyond cardiomyopathies, few studies in the literature link HCV to heart failure syndromes. Antonelli et al41 were the first to assess the clinical value of N terminal-pro-B-natriuretic peptide (NTpro-BNP) determinations in infected patients with otherwise normal cardiac function and structure. The authors illustrated higher levels of NT-pro-BNP in HCV(+) individuals, suggesting a subclinical cardiac dysfunction. However, no correlation was made to echocardiographic parameters or magnetic resonance image findings and therefore no data exist with regard to baseline ejection fraction. This limitation was addressed in another study which attempted to assess correlations between echocardiography and NT-pro-BNP levels.42 Again, NT-pro-BNP measurements were reported higher in infected individuals. Of note, patients with elevated levels of NT-pro-BNP exhibited diastolic impairment. These findings seem to enhance the results reported by Antonelli et al.41 In addition, similar echocardiographic findings were shown by Demir et al43 who found diastolic impairment in HCV(+) persons. Maruyama et al44 attempted to explore the presence and extent of myocardial injury in 217 consecutive patients with CHC infection with the implementation of SPECT as the screening tool. Myocardial perfusion defects were found in 87% of the patients and were improved by viral eradication with interferon therapy. Of note, patients were reported to be asymptomatic, suggesting that patients with CHC infection might have extremely mild cardiomyopathy as an extrahepatic manifestation of their infection. These studies have clinical value since they underline the importance of subclinical myocardial dysfunction.

HEPATITIS C VIRUS AND HEART TRANSPLANTATION OUTCOMES HCV infection is prevalent in recipients of and candidates for solid organ transplants. Several investigators have studied the role of HCV with rather conflicting findings (Table 2). According to Lee et al,45 patients who were HCV(+) prior to transplantation exhibited higher mortality rates as compared to HCV() counterparts. It has been postulated that immunosuppressant therapy could be the main culprit of adverse outcomes in this specific patient population, since it may accelerate progression to liver fibrosis and reduce the time interval for liver regeneration. Moreover, chronic immunosuppression could exacerbate chronic inflammation, which in turn could lead to vasculopathy. A small retrospective study by Lin et al46 involving 385 patients suggested that there was no significant difference in patient survival or graft function between HCV(+) and HCV() heart transplant recipients. Additionally, HCV-positive recipients were not at an increased risk of hepatic failure or accelerated transplant coronary artery disease. Another retrospective study comprised of 96 HCV(+) heart transplant recipients reported no difference in mortality rates,

but an increased incidence of liver-related deaths when compared to uninfected patients.47 Transplantation of HCV antibody-positive donor organs into uninfected recipients almost uniformly results in CHC infection in the immunocompromised host, with reported transmission rates ranging from 7% to 82%. Marelli et al48 reported HCV transmission in only 25% of recipients, while Ong et al49 found that 82% of recipients of donor HCV(+) hearts became HCV RNA positive. More recently, a multicenter cohort study was performed to assess all-cause mortality in 261 patients who received an HCV(+) donor heart. Short- and long-term mortality was higher among recipients of HCV(+) donor hearts, who were more likely to die of liver disease and coronary vasculopathy, even when data were adjusted for age and patient status.50 There is limited published experience with interferon therapy for HCV before cardiac transplantation, which may be due to the concerns regarding the safety and tolerability of interferon and ribavirin in this population. Furthermore, post-transplant interferon therapy in the cardiac and pulmonary transplant setting may be associated with an increased risk of graft rejection. Data from DuranteMangoni et al52 suggested that combined treatment with ribavirin and interferon can be offered safely provided that the patient is stable with regard to heart and liver disease. However, it must be stated that their data cannot be extrapolated in the general HCV(+) population since they only monitored 3 patients. Only 2 small pilot studies demonstrated that interferon monotherapy might be effective and well-tolerated in the treatment of HCV in heart transplant recipients. Recently, a novel regimen consisting of sofosbuvir plus ribavirin has received a class II indication for the management of HCV patients receiving liver transplantation according to the guidelines published by the American Association for the Study of Liver Diseases. The regimen proved to be both efficacious and safe in the specific clinical application. However, in the setting of cardiac transplant there is no hard evidence addressing the efficacy and safety of this combination. Large randomized clinical trials are needed to provide data for this specific patient group. Beyond the field of heart transplantation, Palaniswamy et al51 sought to investigate the impact of HCV infection on patient outcomes after percutaneous coronary intervention with either drugeluting or bare-metal stenting. The rationale for this study was that patients with chronic liver infection are prone to bleeding, thus making bare-metal stents an attractive option. However, chronic inflammation and endothelial dysfunction that accompanies HCV infection would render the implantation of drug-eluting stents as a more preferable choice. In this retrospective study, 78 patients were monitored and the authors concluded that there were no differences in terms of adverse events between patients who received revascularization with either type of stent. All the above-mentioned studies are retrospective in design, thus unknown and unmeasured confounders could exist. Randomized controlled trials are needed to obtain more robust results. Moreover, the utilization of large databases suffers from missing data and the inability to validate the accuracy of the obtained information.

TABLE 2. Hepatitis C Virus and Cardiovascular Intervention Outcomes Study Lee et al Lin et al46 Palaniswamy et al51 Gasink et al50 45

Sample Size

Type of Study

20687 385 78 10915

Retrospective analysis Retrospective analysis Retrospective analysis Multicenter cohort study

Intervention Heart transplantation Heart transplantation Percutaneous coronary intervention Heart transplantation

Outcomes Decreased survival after heart transplantation No significant difference in patient survival or graft function No difference in MACE between BMS and DES Receipt of a heart from an HCV-positive donor is associated with decreased survival in heart transplant recipients

MACE indicates major adverse cardiac events; BMS, bare-metal stents; DES, drug-eluting stents; HCV, hepatitis C virus.

14 | www.cardiologyinreview.com

© 2014 Lippincott Williams & Wilkins


The outcomes of HCV in recipients of cardiac and lung transplants have yet to be clearly established, and future prospective studies are needed.

HEPATITIS C VIRUS TREATMENT AND CARDIOVASCULAR DRUGS: CARDIAC AND LIVER TOXICITY Of the most commonly used regimens in cardiology are the hydroymethyl-glutaryl-coenzyme A inhibitors (statins), known for their lipid-lowering properties and for their pleiotropic actions on inflammation. Henderson et al53 sought to determine the effect of statin therapy on serum AST and ALT levels in a cohort of HCVinfected veterans with well-characterized liver disease, using liver biopsy specimens. They concluded that among HCV-infected patients, AST and ALT levels for those prescribed statins decreased over a 6- to 12-month follow-up period compared to patients not taking statins. Gibson et al54 reported that statin administration was not related to liver enzyme elevation. Those findings come in accordance with those reported by other studies, thus verifying that statins do not present a major risk for severe hepatotoxicity in HCV-infected persons.55,56 As concerns about statin therapy toxicity are being thoroughly addressed, interest in a possible beneficial effect of statins has emerged over the last decade. Statins have been shown in experimental studies to inhibit hepatic stellate cells proliferation and their production of collagens through a dose-dependent mechanism.57,58 Statins may also have an effect specific to HCV. It has been shown that HCV RNA replication can be disrupted in vitro by high concentrations of statins by depleting mevalonic acid, which in turn leads to low cellular levels of geranylgeranyl pyrophosphates, thus interrupting the cycle of viral genome replication.59 However, it needs to be clarified whether these in vitro effects of statins on HCV have any clinical relevance. Furthermore, data from the literature suggest that statins may lower the risk of hepatocellular carcinoma, especially in person with diabetes. Several mechanisms have been implicated for this including the mevalonic acid metabolism disruption mentioned above. Most of the available data are derived from experimental and observational studies, which have not been verified by large metanalyses.60 Diabetes in particular poses a greater risk for hepatic carcinoma, regardless of the presence of HCV infection.61 This has led El-Serag et al62 to conduct a retrospective study to exploit potential favorable outcomes of statin administration in peerson with diabetes. The authors did show an inverse relationship between statin use and the risk of hepatocellular carcinoma.62 Stronger evidence is still needed to support these findings. Another drug with hepatotoxic potential is amiodarone, which is widely used for the suppression of supraventricular and ventricular arrhythmias. Surprisingly Cheng et al63 illustrated a beneficial effect of the drug on the HCV life cycle. According to the authors, the administration of amiodarone appeared to inhibit HCV entry independent of genotypes, which was attributed to the downregulation of CD81 receptor expression. The inhibitory effect of amiodarone also manifested in the HCV assembly step, via the suppression of microsomal triacylglycerol transfer protein activity. Amiodarone revealed no effects on HCV replication and translation. With the host factortargeting characteristics, amiodarone may be an attractive agent for the treatment of HCV infection. However, drug therapies for HCV infection have been implicated for cardiac toxicity (Table 3). Although regimens that include interferon-α have been associated with marked improvement in important therapeutic outcomes, including reductions in mortality, liver cancer, and other serious liver-related events, they are not always © 2014 Lippincott Williams & Wilkins


TABLE 3. HCV Treatment and Cardiac Toxicity Drug Protease inhibitors Simeprevir Telaprevir Boceprevir

Peg-interferon

Ribavirin

Side Effects From Cardiovascular System Dyspnea-exertional dyspnea QT prolongation QT prolongation Acute myocardial infarction, Atrial fibrillation Coronary artery disease Pericarditis, pericardial effusion Hypotension, hypertension Deep vein thrombosis Pericarditis Myocarditis QT prolongation Potentiation of warfarin effect Ischemic heart disease Supraventricular arrhythmias Ventricular arrhythmias Palpitations, arrhythmias(mainly supraventricular) Myocardial infarction, Cardiomyopathy, Pericardial effusion, pericarditis Hypotension, hypertension, flushing Vasculitis

successful and have been associated with considerable toxicity and morbidity. Interferon forms the mainstay of treatment for HCV infection. Nearly every organ system is affected by interferon formulations. With regard to the cardiovascular system, a variety of adverse events have been reported, most commonly including arrhythmias (58%), acute coronary syndromes (21%), cardiomyopathies (12%), and pericarditis (9%). These side effects are related neither to dose nor to age. However, patients with known coronary artery disease tend to be at higher risk for acute coronary syndromes and arrhythmic events.64 Currently, the 3 main groups of HCV drugs are protease inhibitors (ie, telaprevir, boceprevir, and faldapevir), NS5A-acting agents (deleobuvir), and nucleos(t)ide RdRp inhibitors. There are several investigative studies that have assessed the efficacy of interferonfree regimens involving combination therapies with encouraging results.65,66 In addition, recent reports suggest that interferon-free combinations exhibit a favorable safety and side effect profile. A recent phase II trial assessed the efficacy and safety of a combination regimen of the NS5A inhibitor ledipasvir, NS3 protease inhibitor vedroprevir, nonnucleoside NS5B inhibitor tegobuvir, and ribavirin in treatment-naive patients with CHC genotype 1 without cirrhosis. The most common adverse events were fatigue, headache, nausea, rash, and diarrhea, and the regimen was well-tolerated.67 Almawardy et al68 conducted a small study with 120 infected individuals who were on a combination regimen and concluded that this therapeutic approach did not display any major adverse event in patients with normal function. In light of the new guidelines, simeprevir is now the only protease inhibitor included for the management of HCV patients because telaprevir and boceprevir are markedly inferior to the novel alternative regimens. This drug shows a better adverse reaction profile as compared to previous agents and seems to be effective in multiple HCV genotypes. However, possible interactions of these novel agents, especially with statins, could be a major issue in patients with concomitant HCV infection and dyslipidemia. Most statins are also CYP3A substrates and, not surprisingly, CYP3A inhibitors such as telaprevir and boceprevir are expected to increase statin levels and the associated risk of severe toxicity such as rhabdomyolysis.69 Some clinicians have the opinion that, given the relatively short treatment duration with direct-acting antivirals, at least with telaprevir (12 weeks), one www.cardiologyinreview.com | 15


Katsi et al

can also temporarily stop the statin to avoid toxicity associated with a potential drug–drug interaction. An alternative option might be pravastatin as this statin is not a CYP substrate.70,71 There are limitations, however, regarding the application of these data in the general HCV-infected population because most studies are conducted in persons without cirrhosis or hepatic impairment.

CONCLUSIONS HCV infection represents a disease state concerning not only hepatologists but cardiovascular physicians as well. Existing data point to this direction since HCV is responsible for a vast array of cardiovascular manifestations. Moreover, drug therapies affecting HCV infection display variable adverse events on the myocardium and vice versa. Given the high prevalence of HCV worldwide and the burden of cardiovascular disease, clinicians should be alert when encountering patients suffering from both maladies. ACKNOWLEDGMENT This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. REFERENCES 1. Irshad M, Mankotia DS, Irshad K. An insight into the diagnosis and pathogenesis of hepatitis C virus infection. World J Gastroenterol. 2013;19:7896–7909. 2. Ko HM, Hernandez-Prera JC, Zhu H, et al. Morphologic features of extrahepatic manifestations of hepatitis C virus infection. Clin Dev Immunol. 2012;2012:740138. 3. Zignego AL, Ferri C, Pileri SA, et al.; Italian Association of the Study of Liver Commission on Extrahepatic Manifestations of HCV infection. Extrahepatic manifestations of Hepatitis C Virus infection: a general overview and guidelines for a clinical approach. Dig Liver Dis. 2007;39:2–17. 4. Zampino R, Marrone A, Restivo L, et al. Chronic HCV infection and inflammation: clinical impact on hepatic and extra-hepatic manifestations. World J Hepatol. 2013;5:528–540. 5. Sandler NG, Koh C, Roque A, et al. Host response to translocated microbial products predicts outcomes of patients with HBV or HCV infection. Gastroenterology. 2011;141:1220–1230, 1230.e1. 6. Leandro G, Mangia A, Hui J, et al.; HCV Meta-Analysis (on) Individual Patients’ Data Study Group. Relationship between steatosis, inflammation, and fibrosis in chronic hepatitis C: a meta-analysis of individual patient data. Gastroenterology. 2006;130:1636–1642. 7. Butt AA, Xiaoqiang W, Budoff M, et al. Hepatitis C virus infection and the risk of coronary disease. Clin Infect Dis. 2009;49:225–232. 8. Alyan O, Kacmaz F, Ozdemir O, et al. Hepatitis C infection is associated with increased coronary artery atherosclerosis defined by modified Reardon severity score system. Circ J. 2008;72:1960–1965. 9. Younossi ZM, Stepanova M, Nader F, et al. Associations of chronic hepatitis C with metabolic and cardiac outcomes. Aliment Pharmacol Ther. 2013;37:647–652. 10. Coppola N, Zampino R, Bellini G, et al. Association between a polymorphism in cannabinoid receptor 2 and severe necroinflammation in patients with chronic hepatitis C. Clin Gastroenterol Hepatol. 2014;12:334–340. 11. Sansonno D, Tucci FA, Ghebrehiwet B, et al. Role of the receptor for the globular domain of C1q protein in the pathogenesis of hepatitis C virus-related cryoglobulin vascular damage. J Immunol. 2009;183:6013–6020. 12. Terrier B, Karras A, Cluzel P, et al. Presentation and prognosis of car diac involvement in hepatitis C virus-related vasculitis. Am J Cardiol. 2013;111:265–272. 13. Poli G. Pathogenesis of liver fibrosis: role of oxidative stress. Mol Aspects Med. 2000;21:49–98. 14. Vassalle C, Masini S, Bianchi F, et al. Evidence for association between hepatitis C virus seropositivity and coronary artery disease. Heart. 2004;90:565–566. 15. Millasseau SC, Stewart AD, Patel SJ, et al. Evaluation of carotid-femoral pulse wave velocity: influence of timing algorithm and heart rate. Hypertension. 2005;45:222–226. 16. Tomiyama H, Arai T, Hirose K, et al. Hepatitis C virus seropositivity, but not hepatitis B virus carrier or seropositivity, associated with increased pulse wave velocity. Atherosclerosis. 2003;166:401–403.

16 | www.cardiologyinreview.com

17. Cacoub P, Poynard T, Ghillani P, et al. Extrahepatic manifestations of chronic hepatitis C. MULTIVIRC Group. Multidepartment Virus C. Arthritis Rheum. 1999;42:2204–2212. 18. Mostafa A, Mohamed MK, Saeed M, et al. Hepatitis C infection and clearance: impact on atherosclerosis and cardiometabolic risk factors. Gut. 2010;59:1135–1140. 19. Tien PC, Schneider MF, Cole SR, et al. Association of hepatitis C virus and HIV infection with subclinical atherosclerosis in the women’s interagency HIV study. AIDS. 2009;23:1781–1784. 20. Moucari R, Asselah T, Cazals-Hatem D, et al. Insulin resistance in chronic hepatitis C: association with genotypes 1 and 4, serum HCV RNA level, and liver fibrosis. Gastroenterology. 2008;134:416–423. 21. White DL, Ratziu V, El-Serag HB. Hepatitis C infection and risk of diabetes: a systematic review and meta-analysis. J Hepatol. 2008;49:831–844. 22. Ruhl CE, Menke A, Cowie CC, Everhart JE. The Relationship of Hepatitis C Virus Infection with Diabetes in the United States Population. Hepatology. 2014;60:1139–1149. 23. El-Zayadi AR, Anis M. Hepatitis C virus induced insulin resistance impairs response to anti viral therapy. World J Gastroenterol. 2012;18:212–224. 24. Kawaguchi T, Yoshida T, Harada M, et al. Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through up-regulation of suppressor of cytokine signaling 3. Am J Pathol. 2004;165:1499–1508. 25. Pazienza V, Clément S, Pugnale P, et al. The hepatitis C virus core protein of genotypes 3a and 1b downregulates insulin receptor substrate 1 through genotype-specific mechanisms. Hepatology. 2007;45:1164–1171. 26. Banerjee S, Saito K, Ait-Goughoulte M, et al. Hepatitis C virus core protein upregulates serine phosphorylation of insulin receptor substrate-1 and impairs the downstream akt/protein kinase B signaling pathway for insulin resistance. J Virol. 2008;82:2606–2612. 27. Bose SK, Shrivastava S, Meyer K, et al. Hepatitis C virus activates the mTOR/ S6K1 signaling pathway in inhibiting IRS-1 function for insulin resistance. J Virol. 2012;86:6315–6322. 28. Romero-Gómez M, Fernández-Rodríguez CM, Andrade RJ, et al. Effect of sustained virological response to treatment on the incidence of abnormal glucose values in chronic hepatitis C. J Hepatol. 2008;48:721–727. 29. Shah PK. Link between infection and atherosclerosis: who are the culprits: viruses, bacteria, both, or neither? Circulation. 2001;103:5–6. 30. Freiberg MS, Chang CC, Skanderson M, et al.; Veterans Aging Cohort Study. The risk of incident coronary heart disease among veterans with and without HIV and hepatitis C. Circ Cardiovasc Qual Outcomes. 2011;4:425–432. 31. Oliveira CP, Kappel CR, Siqueira ER, et al. Effects of hepatitis C virus on cardiovascular risk in infected patients: a comparative study. Int J Cardiol. 2013;164:221–226. 32. Matsumori A. Role of hepatitis C virus in cardiomyopathies. Ernst Schering Res Found Workshop. 2006; 55:99–120. 33. Matsumori A, Shimada T, Chapman NM, et al. Myocarditis and heart failure associated with hepatitis C virus infection. J Card Fail. 2006;12:293–298. 34. Matsumori A. Hepatitis C virus and cardiomyopathy. Intern Med. 2001;40:78–79. 35. Dalekos GN, Achenbach K, Christodoulou D, et al. Idiopathic dilated cardiomyopathy: lack of association with hepatitis C virus infection. Heart. 1998;80:270–275. 36. Reis FJ, Viana M, Oliveira M, et al. Prevalence of hepatitis C and B virus infection in patients with idiopathic dilated cardiomyopathy in Brazil: a pilot study. Braz J Infect Dis. 2007;11:318–321. 37. Matsumori A, Yutani C, Ikeda Y, et al. Hepatitis C virus from the hearts of patients with myocarditis and cardiomyopathy. Lab Invest. 2000;80:1137–1142. 38. Mason JW, O’Connell JB, Herskowitz A, et al. A clinical trial of immunosuppressive therapy for myocarditis. The Myocarditis Treatment Trial Investigators. N Engl J Med. 1995;333:269–275. 39. Matsumori A. Hepatitis C virus infection and cardiomyopathies. Circ Res. 2005;96:144–147. 40. Matsumori A, Ohashi N, Ito H, et al. Genes of the major histocompatibility complex class II influence the phenotype of cardiomyopathies associated with hepatitis C virus infection. In: Matsumori A, ed. Cardiomyopathies and Heart Failure. Boston, MA: Kluwer Academic Publishers; 2003: 515–521. 41. Antonelli A, Ferri C, Ferrari SM, et al. High levels of circulating N-terminal pro-brain natriuretic peptide in patients with hepatitis C. J Viral Hepat. 2010;17:851–853. 42. Che W, Liu W, Wei Y, et al. Increased serum N-terminal pro-B-type natriuretic peptide and left ventricle diastolic dysfunction in patients with hepatitis C virus infection. J Viral Hepat. 2012;19:327–331.



43. Demir M, Demir C. Effect of hepatitis C virus infection on the left ventricular systolic and diastolic functions. South Med J. 2011;104:543–546. 44. Maruyama S, Koda M, Oyake N, et al. Myocardial injury in patients with chronic hepatitis C infection. J Hepatol. 2013;58:11–15. 45. Lee I, Localio R, Brensinger CM, et al. Decreased post-transplant survival among heart transplant recipients with pre-transplant hepatitis C virus positivity. J Heart Lung Transplant. 2011;30:1266–1274. 46. Lin MH, Chou NK, Chi NH, et al. The outcome of heart transplantation in hepatitis C-positive recipients. Transplant Proc. 2012;44:890–893. 47. Lake KD, Smith CI, Milfred-La Forest SK, et al. Outcomes of hepatitis C positive (HCV+) heart transplant recipients. Transplant Proc. 1997;29:581–582. 48. Marelli D, Bresson J, Laks H, et al. Hepatitis C-positive donors in heart transplantation. Am J Transplant. 2002;2:443–447. 49. Ong JP, Barnes DS, Younossi ZM, et al. Outcome of de novo hepatitis C virus infection in heart transplant recipients. Hepatology. 1999;30:1293–1298. 50. Gasink LB, Blumberg EA, Localio AR, et al. Hepatitis C virus seropositivity in organ donors and survival in heart transplant recipients. JAMA. 2006;296:1843–1850. 51. Palaniswamy C, Aronow WS, Sukhija R, et al. Major adverse cardiac events in patients with hepatitis C infection treated with bare-metal versus drug-eluting stents. Clin Cardiol. 2010;33:367–370. 52. Durante-Mangoni E, Ragone E, Pinto D, et al. Outcome of treatment with pegylated interferon and ribavirin in heart transplant recipients with chronic hepatitis C. Transplant Proc. 2011;43:299–303. 53. Henderson LM, Patel S, Giordano TP, et al. Statin therapy and serum transaminases among a cohort of HCV-infected veterans. Dig Dis Sci. 2010;55:190–195. 54. Gibson K, Rindone JP. Experience with statin use in patients with chronic hepatitis C infection. Am J Cardiol. 2005;96:1278–1279. 55. Segarra-Newnham M, Parra D, Martin-Cooper EM. Effectiveness and hepatotoxicity of statins in men seropositive for hepatitis C virus. Pharmacotherapy. 2007;27:845–851. 56. Cohen DE, Anania FA, Chalasani N; National Lipid Association Statin Safety Task Force Liver Expert Panel. An assessment of statin safety by hepatologists. Am J Cardiol. 2006;97(8A):77C–81C. 57. Rombouts K, Kisanga E, Hellemans K, et al. Effect of HMG-CoA reductase inhibitors on proliferation and protein synthesis by rat hepatic stellate cells. J Hepatol. 2003;38:564–572. 58. Wang C, Gale M Jr, Keller BC, et al. Identification of FBL2 as a geranylgeranylated cellular protein required for hepatitis C virus RNA replication. Mol Cell. 2005;18:425–434.



59. Lok AS, Everhart JE, Chung RT, et al.; HALT-C Trial Group. Evolution of hepatic steatosis in patients with advanced hepatitis C: results from the hepatitis C antiviral long-term treatment against cirrhosis (HALT-C) trial. Hepatology. 2009;49:1828–1837. 60. Kaye JA, Jick H. Statin use and cancer risk in the General Practice Research Database. Br J Cancer. 2004;90:635–637. 61. Dhar D, Seki E, Karin M. NCOA5, IL-6, type 2 diabetes, and HCC: The deadly quartet. Cell Metab. 2014;19:6–7. 62. El-Serag HB, Johnson ML, Hachem C, et al. Statins are associated with a reduced risk of hepatocellular carcinoma in a large cohort of patients with diabetes. Gastroenterology. 2009;136:1601–1608. 63. Cheng YL, Lan KH, Lee WP, et al. Amiodarone inhibits the entry and assembly steps of hepatitis C virus life cycle. Clin Sci (Lond). 2013;125:439–448. 64. Odashiro K, Hiramatsu S, Yanagi N, et al. Arrhythmogenic and inotropic effects of interferon investigated in perfused and in vivo rat hearts: influences of cardiac hypertrophy and isoproterenol. Circ J. 2002;66:1161–1167. 65. Zeuzem S, Soriano V, Asselah T, et al. Interferon (IFN)-free combination treatment with the HCV NS3/4A protease inhibitor BI 201335 and the nonnucleoside NS5B inhibitor BI 207127 +/- ribavirin (R): final results of the SOUND-C2 and predictors of response [Abstract 232]. 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD). November 9–13, 2012; Boston, Massachusetts. 66. Poordad F, Lawitz E, Kowdley KV, et al. Exploratory study of oral combination antiviral therapy for hepatitis C. N Engl J Med. 2013;368:45–53. 67. Wyles DL, Rodriguez-Torres M, Lawitz E, et al. All-oral combination of ledipasvir, vedroprevir, tegobuvir, and ribavirin in treatment-naive patients with genotype 1 HCV infection. Hepatology. 2014;60:56–64. 68. Almawardy R, Elhammady W, Mousa N, et al. Is combination therapy for chronic hepatitis C toxic for cardiac function? Hepat Mon. 2012;12:e6254. 69. Lee JE, van Heeswijk R, Alves K, et al. Effect of the hepatitis C virus protease inhibitor telaprevir on the pharmacokinetics of amlodipine and atorvastatin. Antimicrob Agents Chemother. 2011;55:4569–4574. 70. Hulskotte E, Gupta S, Xuan Y, et al. Pharmacokinetic evaluation of the interaction between the HCV protease inhibitor boceprevir and the HMG-CoA reductase inhibitors atorvastatin and pravastatin. In: Sixteenth annual meeting of HEP DART, Koloa, Hawaii, December 4–8, 2011 [poster 122]. 71. Chu X, Cai X, Cui D, et al. In vitro assessment of drug–drug interaction potential of boceprevir as an inhibitor and inducer of drug metabolizing enzymes and transporters. In: Sixty second annual meeting of the American Association for the Study of Liver Diseases, San Francisco, California, November 4–8, 2011 [poster 378].

www.cardiologyinreview.com | 17