Objective- We evaluated the biological effects of low-dose methotrexate on 3 novel brachial artery grayscale ultrasound measures that may indicate subclinical arterial injury. Approach and Results- Exploratory analysis from a clinical trial of people with HIV infection at increased cardiovascular disease risk who were randomly assigned to low-dose methotrexate (target dose 15 mg/wk) or placebo. Brachial artery ultrasound grayscale median, gray level difference statistic texture-contrast (GLDS-CON), and gray level texture entropy were measured at baseline and after 24 weeks of intervention. Findings from the intention-to-treat (N=148) and adequately-dosed (N=118) populations were consistent, so the adequately-dosed population results are presented. Participants were a median (Q1, Q3) age of 54 (50, 60) years. After 24 weeks, the low-dose methotrexate intervention was associated with a 25.4% (-18.1, 58.6; P=0.007) increase in GLDS-CON compared with 1.3% (-29.1, 44.7; P=0.97) with placebo ( P=0.05) and a 0.10 u (-0.06, 0.23; P=0.026) increase in entropy compared with 0.02 u (-0.11, 0.14; P=0.54) with placebo ( P=0.14). At week 24, changes in CD4+ T cells correlated inversely with changes in GLDS-CON (ρ=-0.20; P=0.031), and entropy (ρ=-0.21; P=0.023). Changes in D-dimer levels, but no other inflammatory biomarkers, also correlated inversely with changes in GLDS-CON (ρ=-0.23; P=0.014) and entropy (ρ=-0.26; P=0.005). Conclusions- Brachial artery GLDS-CON and entropy increased after 24 weeks of low-dose methotrexate, though the latter was not significantly different from placebo. Grayscale changes were associated with decreases in CD4+ T-cell and D-dimer concentrations and may indicate favorable arterial structure changes.

Objectives

In the general population, the lower socioeconomic status (SES) associates with greater systemic and arterial inflammation and a greater risk of cardiovascular disease. Because arterial inflammation is heightened in individuals living with HIV, we tested the hypothesis that SES associates with arterial inflammation in this population.

Settings

Prospective cohort study.

Methods

Men living with HIV were recruited. Arterial inflammation and leukopoietic activity (ie, bone marrow activity) were measured using 18F-fluorodeoxyglucose positron emission tomography/computed tomography. Zip code-level SES measures were derived from the US Census Bureau. Linear regression and mediation analyses were used to assess associations between SES, arterial inflammation, leukopoietic activity, C-reactive protein (CRP), and interleukin-6.

Results

Thirty-nine virologically suppressed men living with HIV were studied (mean ± SD age 50.5 ± 11.1 years). The median CD4 count was 663 cells/mm3 (interquartile range: 399-922); 82% were receiving antiretroviral therapies. Local median income inversely associated with arterial inflammation [standardized β (95% confidence interval): -0.42 (-0.76 to -0.08)] after adjusting for age, Framingham risk score, statin use, antiretroviral use, and nadir CD4 count. The high-school graduation rate independently associated with arterial inflammation [-0.45 (-0.78 to -0.12)] and CRP [-0.49 (-0.86 to -0.012)]. Mediation analysis demonstrated the impact of SES on arterial inflammation was partially mediated by heightened circulating inflammatory levels: ↓SES (as high school graduation rate) →↑CRP →↑arterial inflammation accounting for 44% of the total effect (P < 0.05).

Conclusion

In individuals living with HIV, lower SES independently associated with higher leukopoietic activity, circulating markers of inflammation, and arterial inflammation. Furthermore, the link between SES and arterial inflammation was mediated by increased systemic inflammation.

Background

While growing evidence suggests a link between periodontal disease (PD) and cardiovascular disease (CVD), the independence of this association and the pathway remain unclear. Herein, we tested the hypotheses that: (1) inflammation of the periodontium (PD_inflammation ) predicts future CVD independently of disease risk factors shared between CVD and PD, and (2) the mechanism linking the two diseases involves heightened arterial inflammation.

Methods

¹⁸ F-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸ F-FDG-PET/CT) imaging was performed in 304 individuals (median age 54 years; 42.4% male) largely for cancer screening; individuals without active cancer were included. PD_inflammation and arterial inflammation were quantified using validated ¹⁸ F-FDG-PET/CT methods. Additionally, we evaluated the relationship between PD_inflammation and subsequent major adverse cardiovascular events (MACE) using Cox models and log-rank tests.

Results

Thirteen individuals developed MACE during follow-up (median 4.1 years). PD_inflammation associated with arterial inflammation, remaining significant after adjusting for PD and CVD risk factors (standardized β [95% CI]: 0.30 [0.20-0.40], P < 0.001). PD_inflammation predicted subsequent MACE (standardized HR [95% CI]: 2.25 [1.47 to 3.44], P <0.001, remaining significant in multivariable models), while periodontal bone loss did not. Furthermore, mediation analysis suggested that arterial inflammation accounts for 80% of the relationship between PD_inflammation and MACE (standardized log odds ratio [95% CI]: 0.438 [0.019-0.880], P = 0.022).

Conclusion

PD_inflammation is independently associated with MACE via a mechanism that may involve increased arterial inflammation. These findings provide important support for an independent relationship between PD_inflammation and CVD.

Importance

Human immunodeficiency virus (HIV) infection is associated with a high risk of cardiovascular disease and increased arterial inflammation. In HIV, inflammation is also increased within lymph nodes (LNs), tissues known to harbor the virus even among treated and suppressed individuals.

Objective

To test the hypothesis that arterial inflammation is linked to HIV disease activity and to inflammation within HIV-infected tissues (LNs).

Design, setting, and participants

For this case-control study, participants were recruited from the SCOPE (Observational Study of the Consequences of the Protease Inhibitor Era) cohort, a clinic-based cohort of individuals receiving care at San Francisco General Hospital and the San Francisco Veteran's Affairs Medical Center. Arterial and LN inflammation were measured using 18F-fluorodeoxyglucose positron emission tomography. Detailed immunophenotyping was performed, along with measurement of viral activity/persistence and of circulating inflammatory biomarkers.

Main outcomes and measures

Arterial and LN inflammation.

Results

A total of 74 men were studied (45 HIV-infected men with a median age of 53 years [interquartile range, 49-59 years] and 29 uninfected male controls with a median age of 52 years [interquartile range, 46-56 years]). Lymph node inflammation was higher in HIV-infected individuals and correlated with markers of viral disease activity (viral load, CD8+ T cells, and CD4/CD8 ratio) and CD4+ T-cell activation. Uninfected controls had the lowest LN activity (mean [SD] maximum axillary LN standardized uptake value, 1.53 [0.56]), the elite controller and ART-suppressed groups had intermediate levels of LN (mean [SD] maximum axillary LN standardized uptake value, 2.12 [0.87] and 2.32 [1.79], respectively), and the noncontrollers had the highest activity (mean [SD] maximum axillary LN standardized uptake value, 8.82 [3.08]). Arterial inflammation was modestly increased in HIV-infected individuals and was positively correlated with circulating inflammatory biomarkers (high-sensitivity C-reactive protein and IL-6) and activated monocytes (CD14dimCD16+; nonclassical) but not with markers of HIV. While LN and arterial inflammation were increased in HIV, inflammatory activity in these tissues was not related (r = 0.09, P = .56).

Conclusions and relevance

While LNs and, to a lesser degree, the arterial wall are inflamed in HIV, inflammation in these tissues is not closely linked. Namely, measures of HIV disease activity are strongly associated with LN inflammation but not with arterial inflammation. These data suggest that LN and arterial inflammation do not share underlying pathways of immune activation and also that therapeutic interventions that reduce viral disease activity may not predictably reduce arterial inflammation in HIV or its downstream consequence (ie, cardiovascular disease).

Background

Chronic inflammation in treated HIV infection is associated with mortality and atherosclerotic cardiovascular disease (ASCVD). We evaluated the safety and potential efficacy of low-dose methotrexate (LDMTX) in treated HIV.

Methods

This was a phase 2 randomized, double-blind, multicenter trial in adults ≥40 years old with treated HIV, with CD4+ T-cell count ≥400 cells/μL and with/at increased risk for ASCVD. Participants received LDMTX (5-15 mg/week) or placebo (plus folic acid) for 24 weeks and were followed for an additional 12 weeks. Primary endpoints were safety and brachial artery flow-mediated dilation (FMD).

Results

The 176 participants (90% male) had a median (Q1, Q3) age of 54 (49, 59) years. LDMTX was associated with decreases in CD4+ T cells at week 24 and CD8+ T cells at weeks 8, 12, and 24. Eleven participants (12.8%) experienced safety events in the LDMTX group vs 5 (5.6%) in placebo (Δ = 7.2%, upper 1-sided 90% CI, 13.4%; Pnoninferiority = .037). Week 24 change in FMD was 0.47% with LDMTX and 0.09% with placebo (P = .55). No inflammatory markers changed differentially with LDMTX compared to placebo.

Conclusions

Adults with HIV and increased ASCVD risk treated with LDMTX had more safety events than with placebo, but the prespecified noninferiority margin of 15% was not exceeded. LDMTX had no significant effect on endothelial function or inflammatory biomarkers but was associated with a significant decrease in CD8+ T cells. The balance of risks and potential benefits of LDMTX in this population will require additional investigation.

Clinical trials registration

NCT01949116.

Aim

High-density lipoproteins (HDLs) have several potentially protective vascular effects. Most clinical studies of therapies targeting HDL have failed to show benefits vs. placebo.

Objective

To investigate the effects of an HDL-mimetic agent on atherosclerosis by intravascular ultrasonography (IVUS) and quantitative coronary angiography (QCA).

Design and setting

A prospective, double-blinded, randomized trial was conducted at 51 centres in the USA, the Netherlands, Canada, and France. Intravascular ultrasonography and QCA were performed to assess coronary atherosclerosis at baseline and 3 (2-5) weeks after the last study infusion.

Patients

Five hundred and seven patients were randomized; 417 and 461 had paired IVUS and QCA measurements, respectively.

Intervention

Patients were randomized to receive 6 weekly infusions of placebo, 3 mg/kg, 6 mg/kg, or 12 mg/kg CER-001.

Main outcome measures

The primary efficacy parameter was the nominal change in the total atheroma volume. Nominal changes in per cent atheroma volume on IVUS and coronary scores on QCA were also pre-specified endpoints.

Results

The nominal change in the total atheroma volume (adjusted means) was -2.71, -3.13, -1.50, and -3.05 mm(3) with placebo, CER-001 3 mg/kg, 6 mg/kg, and 12 mg/kg, respectively (primary analysis of 12 mg/kg vs. placebo: P = 0.81). There was also no difference among groups for the nominal change in per cent atheroma volume (0.02, -0.02, 0.01, and 0.19%; nominal P = 0.53 for 12 mg/kg vs. placebo). Change in the coronary artery score was -0.022, -0.036, -0.022, and -0.015 mm (nominal P = 0.25, 0.99, 0.55), and change in the cumulative coronary stenosis score was -0.51, 2.65, 0.71, and -0.77% (compared with placebo, nominal P = 0.85 for 12 mg/kg and nominal P = 0.01 for 3 mg/kg). The number of patients with major cardiovascular events was 10 (8.3%), 16 (13.3%), 17 (13.7%), and 12 (9.8%) in the four groups.

Conclusion

CER-001 infusions did not reduce coronary atherosclerosis on IVUS and QCA when compared with placebo. Whether CER-001 administered in other regimens or to other populations could favourably affect atherosclerosis must await further study. Name of the trial registry: Clinicaltrials.gov; Registry's URL: https://clinicaltrials.gov/ct2/show/NCT01201837?term=cer-001&rank=2;

Trial registration number

NCT01201837.