We assessed the relation of inflammatory and coagulation biomarkers with electrocardiographic (ECG) evidence of myocardial ischemia. High-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and D-dimer levels were measured at study entry for 3,085 human immunodeficiency virus-infected participants (mean age 44 years; 26.4% women; 24.6% black) in the Strategies for Management of Antiretroviral Therapy trial. Logistic regression models were used to examine the associations of these biomarkers with prevalent and incident myocardial ischemia. The latter analyses were performed for 1,411 participants who were randomly assigned to receive continuous antiretroviral therapy during follow-up to suppress the human immunodeficiency virus viral load and had ≥1 ECG reading during the follow-up period. The median hsCRP, IL-6, and D-dimer level was 1.65 μg/ml (interquartile range 0.69 to 4.11), 1.60 pg/ml (interquartile range 1.00 to 2.75), and 0.18 μg/ml (interquartile range 0.11 to 0.32), respectively. At baseline, the prevalence of major or minor Q-QS or ST-T ECG abnormalities was 18.6%. The biomarker levels were associated with prevalent major or minor ischemic abnormalities on the univariate analyses; however, adjustment for traditional risk factors attenuated these associations. The adjusted odds ratio for major or minor ischemic abnormalities and 95% confidence intervals for the greatest versus lowest quartiles was 1.3 (95% confidence interval 0.9 to 1.7) for hsCRP, 1.0 (95% confidence interval 0.7 to 1.3) for IL-6, and 1.1 (95% confidence interval 0.9 to 1.5) for D-dimer. During a median follow-up of 2.3 years, new definite or probable ischemic ECG abnormalities developed in 11.7% of participants receiving continuous antiretroviral therapy. Biomarker levels were not associated with incident abnormalities on unadjusted or adjusted analyses. In conclusion, higher levels of hsCRP, IL-6, and D-dimer were not associated with ischemic ECG abnormalities. Elevated biomarker levels and ECG abnormalities indicating myocardial ischemia might reflect different risk pathways for cardiovascular disease.
After completion of the Strategies for Management of Antiretroviral Therapy (SMART) trial, the acute-phase reactant high-sensitivity C-reactive protein (hsCRP), the proinflammatory cytokine interleukin-6 (IL-6), and the coagulation marker, D-dimer, were measured from stored baseline specimens. These baseline biomarker levels predicted cardiovascular disease (CVD) and all-cause mortality and were higher compared to the general population, even among participants taking antiretroviral therapy and with human immunodeficiency virus (HIV) RNA <400 copies/ml. The elevation of these biomarkers, even with successful treatment of HIV, has been attributed to persistent chronic immune activation. Similar to studies of the general population, the presence of a major electrocardiographic (ECG) abnormality at baseline in the SMART trial was associated with developing CVD. We hypothesized that the severity of the chronic proinflammatory state evident during treated HIV infection, as measured by these 3 biomarkers, would be associated with a greater prevalence of ischemic ECG abnormalities at baseline and a greater incidence of ischemic abnormalities during follow-up among participants receiving continuous antiretroviral therapy and without evidence of clinical CVD.
Methods
The study design, methods, and primary results of the SMART study have been previously reported ( ClinicalTrials.gov identifier: NCT00027352 ). In brief, 5,472 HIV-infected participants with baseline CD4-positive T-cell counts ≥350 cells/mm 3 were randomized to receive either continuous antiretroviral therapy (viral suppression arm; n = 2,752) or CD4-positive T-cell count–guided antiretroviral therapy (drug conservation arm; n = 2,720).
For the cross-sectional analyses, we focused on 3,085 participants with baseline biomarker data and a 12-lead electrocardiogram at rest who were receiving antiretroviral therapy at study entry, had a plasma HIV RNA level of ≤400 copies/ml, and did not have a history of CVD (previous myocardial infarction, stroke, or coronary artery disease requiring surgery or drug treatment or a history of stroke, peripheral vascular disease, or congestive heart failure). For the longitudinal analyses, we further restricted our analysis to 1,411 participants with ≥1 follow-up electrocardiogram at rest, who were randomized to continuous antiretroviral therapy (viral suppression group) because these participants reflect the current standard of care for HIV.
The biomarkers, hsCRP, IL-6, and D-dimer, were studied, because they were shown to be strongly related to all-cause mortality and CVD clinical outcomes in the SMART study and because they were centrally measured from stored plasma for all consenting participants. IL-6 was measured using the chemiluminescent sandwich enzyme-linked immunosorbent assay (R&D Systems, Minneapolis, Minnesota); hsCRP using the NM II nephelometer, N Antiserum to Human CRP (Siemens Diagnostics, Deerfield, Illinois); and D-dimer levels using immunoturbidometric methods on the Sta-R analyzer, Liatest D-DI (Diagnostica Stago, Parsippany, New Jersey). The institutional review board at the University of Minnesota approved the plans for the analysis of the stored specimens.
An electrocardiogram at rest was recorded at baseline and the annual visits. The standard protocol used by all clinical sites for the collection of standard 12-lead electrocardiograms at rest in the SMART study has been previously described. Prevalent ECG abnormalities and the development of incident myocardial ischemia were classified using the Minnesota Code ECG classification. Prevalent ECG abnormalities were grouped into major or any (major or minor) ischemic abnormalities. Major abnormalities were defined as the presence of major Q-QS or major ST-T abnormalities. Minor abnormalities were defined as presence of isolated minor Q-QS or isolated minor ST-T abnormalities in the absence of any major ischemic abnormalities ( Supplemental Table 1 ). Definite incident myocardial ischemia was defined as a change from no or less severe myocardial ischemia to more severe myocardial ischemia, reflected as a change in the severity of the Minnesota Code plus an ≥50% to 100% change in the duration or amplitude of the Q/ST-T waves. Probable incident myocardial ischemia was defined as new or worsening of an existing myocardial ischemia, but not a 50% to 100% change in the duration or amplitude of the Q/ST-T waves ( Supplemental Table 2 ).
We used logistic regression models to study the associations of hsCRP, IL-6, and D-dimer with the prevalent ischemic ECG abnormalities. Odds ratios (ORs) were used to compare the risk of an ECG abnormality in patients with a biomarker level in the greatest quartile relative to the lowest, and p values correspond to a 1 SD higher level of the log-transformed biomarker to standardize the interpretation of the relative strength of the associations. ORs are presented unadjusted and adjusted for age, gender, race, baseline body mass index, smoking history, ratio of total cholesterol to high-density lipoprotein, diabetes, blood pressure-lowering medication use, lipid-lowering medication use, abacavir use history, protease inhibitor history, CD4-positive T-cell count at study entry, and hepatitis B and C co-infection.
The number of annual ECG assessments varied among the participants because of the rolling enrollment over several years. Therefore, we used conditional logistic regression models stratified by the number of ECG assessments to examine the association between the baseline biomarker values and the incident ischemic ECG changes. We also fit a Cox model for discrete failure time (annual ECG measurements) that took into account the follow-up visit at which the ECG abnormality was first observed in computing the ORs. Data were analyzed using Stata, version 12.1 (StataCorp, College Station, Texas).
Results
The average age of the 3,085 participants was 44 years (interquartile range 38 to 50); 813 (26%) were women, and 755 (25%) were black. The median CD4-positive T-cell count was 650 cells/mm 3 (interquartile range 497 to 846), 1,162 (38%) were current smokers, the median body mass index was 25 kg/m 2 (interquartile range 22 to 28), the median total cholesterol was 198 mg/dl (interquartile range 171 to 229), and the median high-density lipoprotein level was 42 mg/dl (interquartile range 34 to 52). The median duration of antiretroviral therapy was 4 years (interquartile range 3 to 5).
The median hsCRP, IL-6, and D-dimer level at study entry was 1.65 μg/ml (interquartile range 0.69 to 4.11), 1.60 pg/ml (interquartile range 1.00 to 2.75), and 0.18 μg/ml (interquartile range 0.11 to 0.32), respectively.
Major abnormalities were present in 5.9% of the 3,085 participants, and 19% had at least a major or minor abnormality (i.e., any ECG abnormality; Table 1 ). Most of the abnormalities were isolated ST-T (14.3% of the participants). The biomarker levels were greater among those with major or minor ischemic abnormalities than in those with no abnormalities ( Table 1 ), and these associations were significant in the unadjusted analyses ( Table 2 ). However, none of the biomarkers remained significantly associated with the presence of ischemic ECG abnormalities after covariate adjustment ( Table 2 ).
| ECG Abnormality | DC and VS Participants (n = 3,085) | hsCRP (μg/ml) | IL-6 (pg/ml) | D-dimer (μg/ml) |
|---|---|---|---|---|
| Prevalent abnormality | ||||
| Major abnormality | 181 (5.9%) | 2.13 (0.77–5.29) | 1.68 (1.07–3.25) | 0.22 (0.13–0.39) |
| Minor (but no major) abnormality | 392 (12.7%) | 2.16 (0.84–4.65) | 1.81 (1.00–3.08) | 0.20 (0.13–0.34) |
| Any abnormality (minor or major) | 573 (18.6%) | 2.16 (0.82–4.88) | 1.77 (1.01–3.13) | 0.20 (0.13–0.34) |
| No minor or major abnormality | 2512 (81.4%) | 1.59 (0.67–3.95) | 1.57 (1.00–2.65) | 0.18 (0.11–0.31) |
| Incident serial change (VS only) | VS participants (n = 1,411) | |||
| Definite incident change | 97 (6.9%) | 2.45 (0.73–5.26) | 1.84 (1.14–3.40) | 0.25 (0.12–0.40) |
| Probable incident change | 68 (4.8%) | 2.08 (0.77–4.51) | 1.81 (1.03–3.13) | 0.22 (0.13–0.34) |
| Definite or probable change | 165 (11.7%) | 2.19 (0.75–4.99) | 1.81 (1.10–3.29) | 0.22 (0.12–0.38) |
| No definite or probable change | 1246 (88.3%) | 1.63 (0.68–3.94) | 1.57 (0.97–2.67) | 0.18 (0.11–0.31) |
| ECG Abnormality | Unadjusted | Adjusted | ||
|---|---|---|---|---|
| OR (95% CI) | p Value ∗ | OR (95% CI) | p Value ∗ | |
| Prevalent ECG abnormalities | ||||
| Major abnormality | ||||
| hsCRP | 1.39 (0.91–2.12) | 0.10 | 1.13 (0.71–1.80) | 0.69 |
| IL-6 | 1.33 (0.88–2.00) | 0.23 | 1.02 (0.64–1.63) | 0.96 |
| D-dimer | 1.94 (1.26–3.00) | 0.02 | 1.39 (0.87–2.23) | 0.44 |
| Any abnormality | ||||
| hsCRP | 1.52 (1.17–1.96) | 0.01 | 1.25 (0.95–1.65) | 0.48 |
| IL-6 | 1.31 (1.02–1.68) | 0.02 | 0.95 (0.72–1.26) | 0.99 |
| D-dimer | 1.54 (1.19–2.00) | 0.007 | 1.13 (0.86–1.50) | 0.61 |
| Incident ECG serial change | ||||
| Definite change | ||||
| hsCRP | 1.24 (0.70–2.19) | 0.62 | 1.30 (0.68–2.45) | 0.55 |
| IL-6 | 1.47 (0.82–2.64) | 0.53 | 1.44 (0.75–2.77) | 0.66 |
| D-dimer | 1.48 (0.84–2.61) | 0.18 | 1.19 (0.64–2.19) | 0.51 |
| Definite or probable change | ||||
| hsCRP | 1.25 (0.61–1.60) | 0.69 | 1.05 (0.63–1.74) | 0.72 |
| IL-6 | 1.45 (0.91–2.29) | 0.28 | 1.11 (0.66–1.86) | 0.95 |
| D-dimer | 1.53 (0.97–2.42) | 0.09 | 1.21 (0.74–1.99) | 0.42 |
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