In our HIV-infected cohort, we found a statistically significant longitudinal association between increased levels of P. gingivalis and increased (worsened) levels of carotid artery IMT. Furthermore, we found a statistically significant longitudinal association between increased gingival REC and increased (improved) levels of brachial artery FMD. CD4+ T cell count and level of HIV RNA improved significantly during the study, implying successful therapy and immune reconstitution on HAART.
The longitudinal association between levels of P. gingivalis
and levels of IMT emerged only after adjusting for preselected CVD-specific and HIV-specific potential confounding covariates (see Supplementary Tables S1A and B
; Supplementary Data are available online at www.liebertonline.com/aid
). P. gingivalis,
an anaerobic gram-negative bacterium, has consistently been associated with severe PD in HIV-uninfected cohorts.37
We previously reported that P. gingivalis
was a statistically significant predictor of periodontal disease in HIV+
adults (standardized β
<0.001, adjusted R2
In an ApoE-/-
mouse model, oral infection with P. gingivalis
resulted in accelerated atheroma formation, which could be prevented by immunization to P. gingivalis
prior to oral P. gingivalis
These and other studies suggest that P. gingivalis
may be able to induce specific innate immune inflammatory pathways and maintain a state of chronic inflammation at sites distant from oral infection.44
Exploring such mechanisms was beyond the scope of this study; however, murine models suggest that major and minor fimbriae of P. gingivalis
can directly or indirectly (through platelets and/or antigen-presenting cells) interact with endothelial cells eliciting inflammatory cascades that promote atherogenesis.44–46
Our data concerning the association between P. gingivalis
and increased carotid artery IMT support the growing literature showing a connection between periodontal disease and atherosclerosis in general populations.47
Historically, clinical measures of PD were developed to quantify clinical signs of PD,48
not the mucosal exposure to microbes and their byproducts that could trigger systemic effects. Therefore, it is not surprising that clinical measures of PD in our cohort were unrelated to IMT; these findings are consistent with a study of almost 5000 subjects by Beck et al.
in the Atherosclerosis Risk in Communities (ARIC) Study. These authors found that clinical measures of PD were not associated with coronary heart disease (CHD) while serum IgG antibodies to known periodontal pathogens were significantly associated with CHD.49
Our data herein support the growing literature that quantification of periodontopathogenic bacteria in subgingival biofilm50,51
is a more direct and specific measure of PD as an exposure contributing to CVD risk. Comparing our longitudinal findings in an HIV-infected cohort to the general population is limited at present because ongoing studies such as The Oral Infections and Vascular Disease Epidemiology Study (INVEST) have, to our knowledge, published only cross-sectional reports.50–53
These authors have linked the cumulative level of periodontopathogenic microbial DNA to increased IMT,50
hypertension, and blood pressure.51
Our findings support these earlier cross-sectional associations50,51
and extend them into an HIV-infected population examined longitudinally.
While it is plausible that P. gingivalis could have increased virulence in an HIV-infected host, our limited sample size did not permit us to analyze whether or not P. gingivalis is acting as an independent risk factor for IMT. Our present longitudinal study, “Immune and Inflammatory Consequences of Intensive Periodontal Disease Treatment in HIV-Infected Adults,” is designed to more effectively address the mechanisms of our finding linking PD to IMT in this population.
Our finding of an association between apparently worsening REC and improving FMD over time deserves further attention (see Supplementary Tables S2A and 2B
for a time-adjusted model and the model adjusted for time and CVD-specific covariates; Supplementary Data are available online at www.liebertonline.com/aid
). One possible explanation is that local gingival inflammation and swelling at baseline may have resolved
during the study due to the initiation of HAART and resulting increase in CD4+
T cell count. This reduction in local swelling may have manifested itself clinically as an increase
in gingival recession (REC), although it may not represent periodontal disease progression (i.e., tissue destruction) per se. Another explanation is that a process similar to immune reconstitution inflammatory syndrome (IRIS) may have hastened or promoted gingival REC at specific sites, although we expect that the impact of potential IRIS-like phenomena, which occur in a relatively small proportion of persons initiating HAART and are typically short-lived, would be small in this 24-month longitudinal follow-up study. Thus, in the context of HIV infection, periodontal REC may be influenced by multiple mechanisms.
Beck et al.
proposed that when examining the connection between periodontal disease and systemic disease, components of PD (i.e., PPD, REC, and CAL) may individually influence outcome measures.54
This concept was clearly demonstrated in our earlier work wherein immune-related and metabolic independent variables were differentially associated with the dependent outcome variables PPD, REC, and CAL in a cross-sectional cohort of 112 HIV+
Herein, our study findings that components of traditionally defined PD are differentially related to established markers of cardiovascular disease (i.e., IMT and FMD) further support this concept. Whether REC, a component of PD, is related to brachial artery FMD in HIV-uninfected cohorts is, to our knowledge, unknown.
This study revealed that defining PD more broadly (i.e., microbiologically and as several clinical constructs) uncovered associations linking PD to markers of cardiovascular disease. It is possible that the associations detected herein may be due to residual confounding; however, we identified and included a priori many critical confounding variables in our analytic model. Based on our results, including both CVD-specific and HIV-specific confounding covariates appears to be critical when examining markers of CVD in an HIV-infected cohort.
Our results showing a slight improvement in FMD over time in HIV-infected adults on HAART () are in agreement with findings of improved FMD at 4 and 24 weeks after HAART initiation as reported by Torriani et al.
but differ from findings of worsened FMD over 1 year in a more heterogeneous cohort of HIV-infected adults as reported by Obueyungbo et al
We propose that our results are more similar to those of Torriani et al
. because, like their cohort, ours had recently started HAART, had a relatively low baseline CD4+
T cell count, and most but not all of our subjects (59%) achieved plasma HIV RNA levels <50 copies/ml at the final study visit. In the context of other longitudinal studies, our findings suggest that the stage of HIV disease and the specific immune profile of an HIV-infected cohort may influence the trajectory of change in subclinical CVD markers across time.
Our finding that IMT worsened by 0.0035
mm per year (i.e., 0.007
mm/2 years) agree with four previous longitudinal studies of HIV-infected cohorts,14–17
but are closest to findings by Currier et al.
indicating that IMT progressed a median of 0.0096
mm/year in a PI-treated group and 0.0058
mm/year in a non-PI-treated group.15
Among several pooled HIV-negative cohorts, the annual mean change in common carotid IMT is 0.015
; thus, the institution of HAART and possibly other unmeasured effects (i.e., improved care, health education) might have played a role in putting our subjects at a risk profile similar to the general population. The fact that FMD improved but IMT worsened during our study may represent either that the time frame of change is longer for IMT than for FMD or that FMD and IMT may be influenced by different mechanisms in HIV-infected adults. Longitudinal findings in an HIV-infected cohort reported by Obueyungbo et al.
, wherein traditional risk factors for CVD (i.e., age, male gender, and smoking status) were significantly related to IMT but not FMD, would tend to support the latter interpretation.17
Our study had several strengths. We followed a relatively homogeneous cohort in terms of stage of HIV disease—as most of our cohort had recently started HAART. We measured PD thoroughly and often (a median of four times over 2 years) and were able to quantify this exposure as a continuous variable. We defined PD microbiologically as well as clinically—as a variable broken down into separate readouts (i.e., PPD, REC, and CAL) as advised by Beck et al.54,56
We measured both IMT and FMD longitudinally, and collected and quantified numerous potential confounding variables. We reported a thorough immunological profile of our cohort (including time on HAART, time since first seropositive, nadir CD4+
T cell count, and time since nadir CD4+
T cell count). Finally, this is the first report relating PD to IMT and FMD in an HIV-infected cohort. CVD is a leading cause of death in HIV-infected adults.1,57,58
We have previously found high levels of severe PD in a predominantly black urban male cohort of HIV-infected adults,31
and since black males are disproportionately affected with HIV/AIDS in the United States,59
these findings may be broadly generalizable. Finally, if PD represents a previously unrecognized modifiable risk factor for CVD in HIV-infected adults, this finding could have great public health importance.
Our study also had a number of limitations. Foremost, the sample size is small and, against the backdrop of significant immune reconstitution, may be underpowered to detect clinically significant cross-sectional and longitudinal associations between measures of PD and markers of CVD risk. Given the complexity of our statistical model, the necessity to include both cross-sectional and longitudinal effects of PD exposure on markers of CVD risk as well as our small sample size, the number of confounders that could be included in our final analytic model was limited; however, we included many previously identified confounding variables.4,5,10,13–17,40,41
Another limitation is that most subjects in our cohort had moderate to severe PD since a comparison group of HIV+
adults on HAART with low levels of PD was not readily available.31
Thus, our within-subjects study design controlling for time on HAART is a reasonable and practical approach to addressing this question.
This study suggests a potential link between PD and CVD risk in HIV-infected adults on HAART. Since PD is a chronic oral infection that can be reduced or eliminated, an intervention study designed to reduce PD in HIV-infected adults would help determine whether this association reflects a modifiable risk factor for CVD.