To our knowledge, this is the largest study to determine the role of HCV infection in the risk of CAD. We found that HCV-infected subjects were at a significantly higher risk of developing CAD, compared with HCV-uninfected subjects, even after adjustment for traditional risk factors for cardiovascular disease. The reason for the increased risk is unclear, especially because several cardiovascular risk factors were less prevalent in the HCV-infected subjects. For example, HCV-infected subjects were younger; had lower total cholesterol, LDL-C, and triglyceride levels; and had a lower prevalence of hypertension. Because the risk of CAD was higher after adjustment for the traditional risk factors, HCV infection itself or other unknown factors are at least partly responsible for the increased risk.
Recent studies support the role of inflammation in the pathogenesis of CAD [29
]. According to these studies, a complex balance between proinflammatory and anti-inflammatory cytokines dictates the initiation, propagation, and rupture of atherosclerotic lesions. Some studies have shown that the levels of inflammatory markers (e.g., high sensitivity to C-reactive protein, interleukin 6, and tumor necrosis factor α
) are higher in HCV-infected subjects, compared with HCV-uninfected control subjects [33
]. Since inflammation and thrombosis are critical pathways in the genesis of CAD and since HCV infection is also associated with alterations in inflammatory markers, this might be the common pathway that increases CAD risk. Markers of thrombosis and inflammation have also been associated with more-severe CAD, and the malnutrition inflammation scores are elevated in HCV-infected persons with CAD, compared with those without CAD [36
]. Most studies have shown an increased prevalence of diabetes among HCV-infected persons, which is a major cardiovascular risk factor. Although we did not find an increased prevalence of diabetes among the HCV-infected persons in the current study, we did not adjust for body mass index in the 2 groups. In our previous work, we found that HCV-infected persons have a lower body mass index, compared with HCV-uninfected persons (authors’ unpublished data), which could at least partly explain this finding. Another possibility is that HCV-infected persons are seen less frequently for care and are less likely to receive a diagnosis of diabetes. In fact, nonadherence to follow-up visits was the most common reason that HCV-infected people were not prescribed treatment for HCV infection in one study [38
]. Although diabetes was not more prevalent among the HCV-infected group in our study, when present, it was associated with a significantly higher risk of CAD in both groups.
The proportion of subjects with evidence of liver injury was higher among the HCV-infected persons. This finding is intuitive and confirms multiple previous studies. Liver injury was associated with an increased risk of CAD, but this risk was contributed to by the HCV-uninfected subjects and was not significant for the HCV-infected subjects. Furthermore, the lack of association between HCV infection and CAD in the subset of persons with liver injury (in the absence of a diagnosis of alcohol abuse or dependence) suggests a role for liver injury in determining the risk of CAD.
Our finding of lower lipid levels in the HCV-infected persons is consistent with previous studies [39
]. Postulated mechanisms for lower lipid levels in HCV-infected persons include binding of HCV particles to various lipid fractions, impaired hepatocyte assembly of very-low-density lipoprotein because of inhibition of microsomal transfer protein, and entry of HCV into hepatocytes through the LDL-C receptors [39
]. Although the lipid levels were lower in the HCV-infected subjects, the risk of CAD associated with hyperlipidemia was similar in the HCV-infected and -uninfected subjects.
Other traditional risk factors (e.g., age, male sex, hypertension, COPD [a surrogate for heavy smoking], and diabetes) were associated with a higher risk of CAD in both HCV-infected and -uninfected groups, as shown in other studies. Unanticipated was the association of black race with a lower risk of CAD. Numerous studies indicate that minority race is associated with a higher risk of cardiovascular risk factors (e.g., hypertension and diabetes), but this did not translate into a higher risk of CAD in our study. Whether the lower risk of CAD found in our study is related to access-to-care issues or other factors needs further study. The finding of a positive association between drug abuse or dependence and CAD in the HCV-infected persons is an interesting finding. Cocaine use has been well established as a risk factor for acute myocardial infarction in persons with and without preexisting coronary disease [42
]. Although coronary vasospasm has been implicated as the most likely mechanism, arrhythmias and increased atherosclerosis due to adventitial mast cells have also been proposed to effect such risk [43
]. Whether our observation is associated with such behavioral risk factors is unclear at this time.
There are many strengths to our study. We studied a large national population, rather than a geographically limited sample. The VA health care system is a unique population that offers significant advantages for large studies of outcomes. Foremost is the availability of data at centralized centers, from which appropriate clinical, laboratory, pharmacy, and outcome parameters can be retrieved. The VA is the largest single provider of comprehensive health care to HCV-infected persons in the United States. Its extensive electronic medical information–gathering system is linked nationally and provides unparalleled opportunity for longitudinal follow-up of patients. The patients at the VA medical centers are cared for regardless of their ability to pay. Patients may relocate multiple times and will still be cared for by the same system, with health care providers having access to patient information from other sites.
A limitation of our study is the use of ICD-9-CM codes for the diagnosis of CAD. Although it would be ideal to use adjudicated clinical measures for the diagnosis of CAD, it would not be possible in such a large national study. ICD-9-CM codes have been used in other large national studies for cardiovascular outcomes. Another limitation is the lack of inclusion of body mass index and family history of CAD, which are important risk factors for CAD. Although we do not believe that family history of CAD may be different in HCV-infected and -un-infected persons, the former are more likely to have a lower body mass index. If true, the higher risk found in our study is actually an underestimation of the true risk. We used the diagnosis of COPD as a surrogate for heavy smoking status, because it is likely to pick up only a subset of smokers with the most severe consequences of smoking. It may be argued that persons who receive a diagnosis of an acute coronary event may not have presented to a VA facility for care and instead may have been taken to the nearest emergency facility. If true, this is likely to affect both HCV-infected and -uninfected persons equally.
To summarize, the increased risk of CAD in HCV-infected persons may be related to a differential level of cytokines, which are markers of inflammation, thrombosis, and endothelial dysfunction [33
]; behavioral and social risk profile [42
]; malnutrition and/or inflammation pathway activation [36
]; or liver injury. More likely, a combination of these factors acts in concert to negate the protective effect of a favorable risk profile and increases the overall risk of CAD.
In conclusion, in a comparison of HCV-infected subjects with HCV-uninfected control subjects, HCV infection is associated with a higher risk of CAD, even after adjustment for traditional risk factors. The reason(s) and mechanism(s) of this association need further study.