Despite a lack of overt cardiovascular disease, increased cIMT and hsCRP were strongly related to all-cause mortality in this study. To our knowledge, this study provides the first report of an association between cIMT, a surrogate marker of atherosclerosis, and mortality in HIV-infected patients. The significant association of hsCRP with mortality in HIV corroborates previous findings, but expands it to a broader population of HIV-infected patients.
CIMT measured using B-mode carotid ultrasonography is a well-recognized surrogate marker of generalized atherosclerosis19
. A large number of studies in non-HIV infected patients have reported positive correlations of cardiovascular events with common carotid wall thickness and thus support its use in cardiovascular risk assessment10
. CIMT also has been associated with both cardiovascular death and all-cause mortality in the general population. Several investigations have shown that HIV-infected individuals have more abnormal surrogate markers of atherosclerosis and a faster rate of progression when compared to HIV-negative controls12;13;20-24
. Traditional risk factors remain most strongly associated with asymptomatic atherosclerosis in HIV-positive patients and the impact of HAART remains controversial. Since cardiovascular hard end-points remain overall rare, there have been no studies to date in HIV-positive individuals correlating cardiovascular events with cIMT. While we were not able to show that cIMT was associated with cardiovascular-specific mortality in this analysis, we believe that the association with all-cause mortality may be a valid proxy for the relationship of atherosclerotic CV disease and longterm HIV infection and hypothesize that the combined effects of vascular aging and HIV on chronic inflammation and immune activation may accelerate the progression of cardiac complications. We speculate that age is not significantly associated with all-cause mortality in our cohort as this is a relatively young patient population and inflammation from chronic HIV infection, as well as cardiac risk factors introduced by unfavorable lifestyles and possibly the treatment of HIV infection, may predominate the pathogenesis of atherosclerosis in this population. It has previously been shown that increased vascular age is common among HIV-infected patients25,26
. In our cohort, the mean increase in vascular age is estimated to be 12 years higher than the chronologic age. Overall, any observed difference in all-cause mortality may be a reasonable reflection of the risk of future adverse events, including cardiac mortality.
Although not yet routinely incorporated into cardiovascular risk assessment, CRP, a novel cardiovascular risk factor, may provide additional assistance in predicting cardiovascular disease in the general population27
. Higher CRP has been found to be associated with higher cIMT in HIV-negative patients and the association with stroke is strengthened in the presence of higher cIMT28
. The use of this inflammatory biomarker is currently being investigated in individuals with chronic inflammatory infections, such as HIV disease. CRP has previously been found to be a marker of HIV disease progression, independent of CD4 count and viral load 29
. Additionally, CRP has been shown to be a predictor of mortality in HIV-infected women 30
. In our study, hsCRP was found to be significantly higher in those who died compared to those who are alive, indicating that it could be useful a clinical marker to predict poorer outcomes in HIV-infected men and women. When applied in combination with cIMT, it may improve risk stratification for adverse outcomes in this population.
Atherogenic dyslipidemia (elevated triglycerides and low HDL cholesterol) is common in HIV-infected patients, which is seen prior to treatment as well as in those on long-term HAART. Similar to the general population, one of the essential steps in cardiovascular risk assessment in HIV infection is the determination of lipid levels, however very few are treated with lipid-lowering agents1
. Statins, which target mainly hypercholesterolemia and elevated LDL-cholesterol, are the most commonly used lipid-lowering medications used in HIV-infected patients31
, but do not target the predominant lipid abnormalities see in HIV. In our cohort, total cholesterol and LDL-cholesterol were significantly lower in those who died compared to those who are alive, reflecting more advanced HIV disease in those who died, supported further by lower CD4 counts and higher viral loads in decedents. Poorly controlled HIV infection has previously been shown to increase the risks for cardiovascular morbidity32
. Conversely, low HDLcholesterol, an independent risk factor for cardiovascular disease and a component of the metabolic syndrome, is common among HIV-infected patients, but treatments that specifically target this abnormality are difficult and rarely used in this population33
. Our data indicate a trend towards lower HDL-cholesterol in those who died compared to those who are alive. However, even after adjusting for these abnormalities, cIMT and hsCRP remained strongly associated with mortality in our cohort.
We recognize the limitations of the present study. First, this is not a large enough cohort to study cause-specific mortality. Although deaths were rigorously ascertained in this study, few of our participants had cardiac-related death listed as a primary or contributory cause of death. However, all-cause mortality is not subject to misclassification bias and may therefore be a “harder” end point than cause-specific mortality in this at-risk population with many concurrent comorbid illnesses 34
. While cardiovascular events remain overall rare in this population and follow-up times are short, it is known that there is a high prevalence of asymptomatic cardiovascular disease in HIV-infected patients and vascular disease may be present and significant at the time of death, but was not recognized as the underlying cause. CRP, a marker of chronic inflammation, may further contribute to all-cause mortality in the HIV-infected population, as it may reflect both cumulative HIV and cardiovascular disease burden. Although our mortality analysis could not disentangle confounding of more advanced HIV disease in those who died, even after removing the four AIDS death, cIMT remained significantly associated with mortality in this study (HR=2.75, 95% CI 1.21 to 6.25). Further, substance abuse may have obscured some of the association of atherosclerosis with mortality as it could be hypothesized that drug users who died had significant underlying cardiac pathology which may have increased their susceptibility to overdose. Overall, all-cause death is an objective, unbiased end point and may therefore be more appropriate in the setting of a complex disease process. Second, we recognize the ongoing debate in both the general and HIV population as to which carotid segment is most associated with CV risk. However, our choice to use the common carotid measurement instead of the internal segment for this survival analysis was recently corroborated by a publication from the CARDIA cohort, which has a similar age and race distribution as our HIV-positive cohort and showed that a greater proportion of the variability in common carotid IMT can be explained by traditional cardiovascular risk factors than for the carotid artery bulb and internal carotid arteries (27% vs. 8%)35
. Further, the FRAM cohort recently published results indicating that the common, but not the internal, cIMT is a better predictor of HIV-related risk factors36
. In summary, we a priori chose to use only the common carotid measurement for this analysis due to the difficulty in visualization and lesser stability of measurements of the internal carotid segment. Third, this is a fixed covariate analysis at a single timepoint and conclusions are therefore limited to associations. We hope to provide more information about factors affecting mortality in HIV infection in longitudinal studies in the future. Fourth, there is a concern of overfitting the data by using too many independent variables in a model when the sample size is small and there are not many outcomes. However, adding age, an important predictor of cardiovascular disease and death, into the model did not significantly improve the model nor change any of the model coefficients by more than 5% compared to the model that did not include age as a covariate.
In conclusion, abnormal carotid IMT and elevated hsCRP identify HIV-infected individuals at high risk of death. These findings support a complex relationship among inflammation, subclinical atherosclerosis and immune activation in HIV-infected patients and suggest the need for further study. However, identification of carotid artery atherosclerosis and elevated hsCRP levels among asymptomatic HIV-infected persons helps identify a high-risk group for death and may allow for the introduction of early interventions aimed at asymptomatic atherosclerosis and inflammation to prevent future adverse cardiovascular events and death in this population.