Hepatitis C virus (HCV) infection represents a major health issue worldwide due to its burden of chronic liver disease and extrahepatic manifestations including cardiovascular diseases, which are associated with excess mortality. Analysis of published studies supports the view that HCV infection should be considered a risk factor for the development of carotid atherosclerosis, heart failure and stroke. In contrast, findings from studies addressing coronary artery disease and HCV have yielded conflicting results. Therefore, meta-analytic reviews and prospective studies are warranted. The pathogenic mechanisms connecting HCV infection, chronic liver disease, and atherogenesis are not completely understood. However, it has been hypothesized that HCV may promote atherogenesis and its complications through several direct and indirect biological mechanisms involving HCV colonization and replication within arterial walls, liver steatosis and fibrosis, enhanced and imbalanced secretion of inflammatory cytokines, oxidative stress, endotoxemia, mixed cryoglobulinemia, perturbed cellular and humoral immunity, hyperhomocysteinemia, hypo-adiponectinaemia, insulin resistance, type 2 diabetes and other components of the metabolic syndrome. Understanding these complex mechanisms is of fundamental importance for the development of novel therapeutic approaches to prevent and to treat vascular complications in patients with chronic HCV infection. Currently, it seems that HCV clearance by interferon and ribavirin treatment significantly reduces non-liver-related mortality; moreover, interferon-based treatment appears to decrease the risk of ischemic stroke.

Hepatitis C virus (HCV) infection is endemic worldwide, with an estimated global prevalence of 3%, resulting in approximately 170 million infected people[1]. HCV infection is the major cause of chronic liver diseases leading to a wide range of hepatic diseases, including cirrhosis and hepatocellular carcinoma. In addition, there is a growing body of data concerning the role of HCV in extrahepatic manifestations[2], including metabolic derangements[3], and, more recently, accelerated atherosclerosis eventually triggering cardiovascular events[4].

Atherosclerosis, either subclinical or manifest, is a chronic inflammatory disease. The chief clinical manifestations are coronary artery disease (CAD), stroke and ischemic limbs. In addition to the “traditional” factors of atherosclerosis other “novel” factors have been hypothesized. The possible role of an infectious agent in the development of experimental atherosclerosis in rodents was first reported more than 120 years ago[5], and this concept has gained new life in recent years[6]. In the last few years, a strict association between atherosclerosis and non-alcoholic fatty liver disease (NAFLD) has been reported, challenging the old paradigm that ‘‘chronic liver disease protects from atherosclerosis”[7,8]. Similar to NAFLD, HCV infection is increasingly identified as a potential atherogenic condition. In fact, chronic HCV infection causes hepatic and systemic inflammation[4] via increased levels of pro-atherogenic chemokines and cytokines[4] and hepatic steatosis, a distinguishing feature of this infection[9]. In addition, it has been demonstrated that HCV colonizes and replicates within carotid plaques[10,11] likely causing vascular inflammation. Earlier studies conducted in the general population showed that HCV markers were independently associated with atherosclerosis[12,13]. Subsequent research, however, yielded conflicting results, some studies confirming[14,15] and others denying such an association[16,17]. However, recent data have shown excess cardiovascular mortality during the course of chronic HCV infection[18,19]. Given the high prevalence of HCV infection on a worldwide basis and the primacy of cardiovascular diseases among the causes of mortality, the role of HCV as a cardiovascular risk factor needs to be analysed in-depth.

Accordingly, in this review we evaluated the literature regarding the association between chronic HCV infection and atherosclerosis, the clinical impact on the development of cardiovascular diseases and the possible pathogenic mechanisms underlying increased cardiovascular risk in those with HCV infection.

Table 1 reports the findings of the studies evaluating the association between HCV and carotid atherosclerosis. Ishizaka et al[12,13], assessing a large number of subjects in two studies conducted in the general population, were first in reporting an association between HCV infection and atherosclerosis. The first study was published in 2002 and showed that HCV infection was associated with an increased risk of carotid atherosclerosis[12]. Similar results were obtained in a second study published in 2003[13]. Irrespective of known atherogenic risk factors, Ishizaka et al[12,13] found that HCV was an independent predictor of carotid atherosclerosis. Another study, which enrolled a large cohort of Japanese subjects from the general population, showed that HCV-infected subjects had increased arterial stiffness compared to HCV-negative controls[20]. Fukui et al[21] confirmed these results in a series of patients with type 2 diabetes in which anti-HCV positivity was demonstrated to be an independent risk factor of both increased carotid intima-media-thickness (IMT) and plaque. Following these pioneer Japanese reports, two Italian studies further confirmed the independent association between HCV infection and atherosclerosis. Boddi et al[10] showed that the prevalence of an IMT greater than 1 mm was significantly higher in anti-HCV positive subjects than in controls. At multivariate analysis, anti-HCV positivity was an independent predictor of IMT. Similarly, Targher et al[15] showed that HCV positivity was an independent predictor of increased carotid IMT.

A large study in Egyptian individuals, including HCV infected patients, HCV subjects with viral clearance, and subjects never infected (controls), showed that the prevalence of carotid atherosclerosis did not vary when patients with active infection were compared to those with past infection. However, HCV infected patients showed a higher risk of atherosclerosis following adjustment for known cardiovascular risk factors[22].

Petta et al[23] evaluating carotid atherosclerosis in a cohort of biopsy-proven chronic hepatitis C genotype 1 patients, reported that HCV patients had a significantly higher prevalence of atherosclerosis than matched control subjects (41.9% vs 22.9%, respectively). In addition, the severity of hepatic fibrosis was independently associated with a higher risk of carotid plaques.

Recently, our group assessed carotid atherosclerosis in a large cohort of consecutive liver biopsy-proven chronic hepatitis C patients with and without steatosis[24]. HCV patients showed a significantly higher prevalence of atherosclerosis than that observed in the HCV-negative control group (53.7% vs 34.3%, respectively, P < 0.0001). HCV patients without steatosis showed a higher prevalence of atherosclerosis than that observed in the HCV-negative control group without steatosis (26.0% vs 14.8%, P < 0.015). HCV patients with steatosis had a prevalence of atherosclerosis significantly higher than NAFLD patients (77.7% vs 57.8%, P < 0.0001). These results provided definite evidence that HCV was strictly associated with the development of atherosclerosis and that patients with HCV-related steatosis, irrespective of HCV genotype, age, gender and degree of histological liver damage, exhibited the highest prevalence of atherosclerosis. Moreover, at multivariate analysis, HCV-related steatosis was an independent risk factor for carotid atherosclerosis (OR = 32.35; 95%CI: 5.4-230, P < 0.0001). HCV-related steatosis predicted atherosclerosis with an AUC of 0.78 (95%CI: 0.71-0.85, P < 0.0001; with a positive specificity of 81.7% and sensitivity of 74.2%). These data suggest that steatosis is both a good marker for identifying atherosclerosis-prone individuals and an early mediator of atherosclerosis. Evidence for the latter role is based on steatosis being associated with traditional pro-atherogenic factors such as metabolic syndrome, insulin resistance, hyper-homocysteinaemia, liver inflammation and fibrosis scores, hypo-adiponectinaemia and hyper-tumour necrosis factor-alpha (TNF-α)[25] and oxidative stress[26]. In brief, our study[24] suggests that HCV-related steatosis modulates atherogenic factors such as inflammation and the dysmetabolic milieu, therefore, favouring development of atherosclerosis. Furthermore, our study[24] showed that amongst the younger HCV population (e.g., < 50 years old) about 34% showed atherosclerosis and a significant proportion (24.1%) had plaques, whereas in the control group the prevalence of atherosclerosis was significantly lower (16.0%) and the presence of plaques (3.9%) was a relatively uncommon finding. Such data support the view that chronic HCV infection predisposes individuals to the premature development of atherosclerosis and advanced carotid changes despite the more favourable cardiovascular risk profile featuring lower lipid levels and lower prevalence of metabolic syndrome[24].

An increased risk of carotid atherosclerosis was also demonstrated in HIV-infected patients. In this setting, Sosner et al[27] reported an increased prevalence of carotid plaque in HIV/HCV co-infected patients, strengthening the view that HCV infection is an independent risk factor of atherosclerosis.

In contrast to the above studies which highlighted a strict association between chronic HCV infection and carotid atherosclerosis, other studies did not confirm such an association. For example, Bilora et al[28] and Caliskan et al[29], in the setting of hemodialysis patients, did not find any association between HCV infection and atherosclerosis. Similarly, in a cohort of HCV-infected women, with and without HIV co-infection, Tien et al[30], after adjustment for confounding factors, were unable to demonstrate an association between HCV infection and atherosclerosis. Likewise, Masiá et al[31] did not observe any association between HCV infection and atherosclerosis in a cohort of HIV co-infected patients.

It is important to underline that those studies showing a positive association, generally included a very large population of subjects, whereas the studies showing no association were generally conducted in smaller cohorts of patients at high risk for atherosclerosis (e.g., either hemodialysed or HCV/HIV co-infected) (Table 1). Considering that atherosclerosis is a multi-factorial disorder, studies with low power may have generated false negative results of doubtful clinical significance. In addition, inconsistency among studies may be the result of different features in the populations under examination, differences in the assessment of HCV infection and stage of liver disease, technique used to evaluate atherosclerosis and, of primary importance, comparator control groups and adjustment for confounding factors. Overall, we deem that an analysis of available studies supports the view that HCV infection should be considered a risk factor for the development of atherosclerosis. Meta-analytic reviews and adequate prospective studies are eagerly awaited to gauge the impact of HCV on the development of atherosclerosis more precisely.

A consistent body of evidence indicates that chronic HCV infection should be considered a risk factor for subclinical atherosclerosis. Accordingly, the question is: is there evidence that HCV is a risk factor for the development of cardiac and cerebral vascular diseases? Clearly the answer is not straightforward and involves different levels of assessment. First, it is important to evaluate a hard outcome, such as mortality related to cardiovascular diseases in those with HCV infection, and next, studies evaluating such an association need to be weighted.

Evidence for a significant excess of cardiovascular mortality among anti-HCV positive subjects is provided by a large study which assessed HCV-associated all-cause mortality in the general United States population[32]. Moreover, a study conducted in the general population showed that HCV infection was an independent predictor of cerebrovascular deaths and that such mortality was correlated with serum HCV RNA levels[33]. Of importance, HCV clearance by interferon and ribavirin treatment significantly reduces non-liver-related mortality in these patients[34]. The above data suggest a possible direct impact of HCV infection on cardiovascular diseases.

The precise pathogenic mechanisms connecting HCV infection, chronic liver disease, and atherogenesis are not completely understood. Figure 1 depicts the potential pathogenic factors involved. It is logical to hypothesize that HCV may promote atherogenesis through several direct and indirect biological mechanisms. Atherosclerotic plaques are widely recognized to develop and to destabilize as a result of persistent inflammatory changes. Chronic HCV infection is associated with both hepatic and systemic inflammation, which is triggered by HCV either directly or indirectly. Such inflammatory pathways involve cytokines release and increased oxidative stress. HCV RNA sequences have been isolated within carotid plaques, supporting the hypothesis that HCV plays a direct pro-atherogenic role by inducing arterial inflammation, likely via the pro-inflammatory cytokine interleukin 1β[47]. In addition, HCV structural and non-structural proteins play a major role in initiating and maintaining chronic inflammation. HCV promotes an imbalanced T helper (Th)1/Th2 cytokines ratio perturbing the equilibrium between cellular immunity, promoted and maintained by interleukin (IL)-2, TNF-α and interferon-γ, and humoral immunity, sustained by IL-4, IL-5, IL-6 and IL-10[48]. Compared to HCV negative individuals, patients with chronic HCV infection have been shown to exhibit higher TNF-α levels which are associated with an increased risk of heart failure and death[49]. Moreover, an intermediate cardiovascular risk, higher levels of pro-inflammatory cytokines (IL-6 and TNF-α), and a higher ratio of pro-inflammatory/anti-inflammatory cytokines (TNF-α/IL-10 and IL-6/IL-10) have been reported in non-obese, non-diabetic, HCV-infected patients than that observed in the control group[50]. HCV-driven secretion of inflammatory cytokines may contribute to the development of cardiovascular disease through several effector mechanisms, including enhanced synthesis of matrix metalloproteinase-9, intracellular adhesion molecules, expression of anti-endothelium antibodies, and generation of oxidative stress and insulin resistance.

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Figure 1 Pathogenic mechanisms associated with the development of atherosclerosis in chronic hepatitis C infection. HCV: Hepatitis C virus; IR: Insulin resistance.

The higher prevalence of atherosclerosis observed in chronic HCV infection is correlated with liver steatosis[24], a key feature of HCV infection which is associated with several pro-atherogenic factors including inflammatory cytokines, hyper-homocysteinaemia, hypo-adiponectinaemia, insulin resistance, and components of the metabolic syndrome[24].

Atherosclerosis in HCV patients is also associated with liver fibrosis[23] which is an expected finding given the tight association between steatosis and fibrosis in those with chronic hepatitis C[9]. Histological hepatic changes play a pivotal role in regulating local and systemic inflammation through proteins secreted by the diseased liver[4].

HCV is considered a metabolic virus and is associated with metabolic disorders, in particular insulin resistance and type 2, which are diabetes pro-atherogenic conditions.

HCV infection is associated with increased levels of endotoxaemia, which promotes a strong inflammatory reaction via TNF-α and toll-like receptors, which are both able to induce a marked inflammatory reaction. Of interest, HCV is also the agent causing mixed cryoglobulinaemia a paradigmatic vasculitic condition[4].

Based on the above considerations it is clear that chronic HCV infection represents a condition directly and indirectly promoting a milieu of pro-atherogenic factors, mainly pro-inflammatory molecules, which trigger atherogenesis and favour its complications eventually leading to an increased prevalence of cardiovascular diseases. A more detailed understanding of the complex mechanisms underlying HCV-related inflammation and atherogenesis is of key importance for the development of novel therapeutic approaches targeting the different steps of the inflammatory response to prevent and treat atherosclerosis in patients with chronic HCV infection.

The literature seems to support the view that chronic HCV infection is a risk factor for atherosclerosis, the development of cardiovascular diseases and significant cardiovascular mortality. However, further well-conducted studies are necessary to better assess the impact of HCV on the different cardiovascular conditions, in particular on myocardial infarction. The pathogenic mechanisms should be further elucidated due to their potential impact on the development of novel therapeutic approaches to prevent and to treat cardiovascular complications in patients with chronic HCV infection.

Based on the evidence discussed in the present article, we feel it reasonable to recommend to screen noninvasively for atherosclerosis all patients with chronic HCV infection. Knowledge of the whole pathologic burden will be of help in making a reasoned decision for the management of chronic HCV infection. In this respect, it is important to underline that existing data seem to indicate that interferon-based treatment reduces the risk of stroke and of cardiovascular-related mortality. Future studies should clarify the full impact and the right timing of antiviral treatment in preventing, improving or reversing HCV-related atherosclerosis.