Objective:
This study aimed to evaluate the relationship between inflammatory biomarkers and endothelial dysfunction (ED), as measured by brachial artery flow-mediated dilation (FMD).
Methods:We conducted a cross-sectional analysis utilizing baseline data of 135 participants with HIV infection on stable antiretroviral therapy (ART) in the Hawaii Aging with HIV-Cardiovascular (HAHC-CVD) study who had available baseline inflammatory biomarkers and brachial artery FMD measurements.
Results:We observed significant associations between brachial artery FMD and baseline brachial artery diameter, age, male gender, traditional cardiovascular disease (CVD) risk factors such as BMI, waist to hip ratio, hypertension, systolic blood pressure (BP), diastolic BP, and LDL cholesterol, and 10-year coronary heart disease (CHD) risk estimated by Framingham risk score (FRS). Of all biomarkers tested, higher level of C-reactive protein (CRP) (beta = − 0.695, P = 0.030) and serum amyloid P (SAP) (beta = − 1.318, P = 0.021) were significantly associated with lower brachial artery FMD in univariable regression analysis. After adjusting for baseline brachial artery diameter, age, and selected traditional CVD risk factors in multivariable model, SAP remained significantly associated with brachial artery FMD (beta = − 1.094, P = 0.030), while CRP was not (beta = − 0.391, P = 0.181).
Discussion:Serum amyloid P was independently associated with impaired brachial artery FMD and may potentially relate to ED and increased CVD risk in HIV-infected patients on stable ART.
Introduction
Human immunodeficiency virus (HIV) infection has been associated with increased risk of atherosclerotic cardiovascular diseases (ASCVD), even among patients with well-suppressed HIV infection on ART.Citation1,Citation2 Endothelial dysfunction (ED) is considered to play an important role in the development of atherosclerosisCitation3,Citation4 and when assessed by brachial artery flow-mediated dilation (FMD) has been shown to independently predict future ASCVDs.Citation5–Citation7 Paralleling clinical observation, studies assessing ED by brachial artery FMD in HIV-infected patients have consistently demonstrated ED relative to patients without HIV infection.Citation8–Citation10
Human immunodeficiency virus-infected patients, including those with well-suppressed HIV infection on ART, are in the state of chronic inflammation as evidenced by elevated levels of inflammatory biomarkers, such as C-reactive protein (CRP) and interleukin (IL)-6.Citation11 Although the role of these inflammatory biomarkers as markers of cardiovascular risk remains uncertain in HIV-infected patients, several studies have reported the association of these inflammatory biomarkers with cardiovascular disease (CVD) events.Citation12–Citation14 It has, therefore, been hypothesized that persistent immune activation and inflammation contribute to atherosclerosis in HIV-infected patients.Citation15,Citation16 However, studies previously assessing inflammatory biomarkers, such as CRP, for their association with brachial artery FMD yielded inconsistent results.Citation9,Citation17–Citation22 Thus, the relationship between inflammation and ED in HIV-infected patients remains uncertain.
In this study, we hypothesized that persistent inflammation is related to ED in HIV-infected patients. We examine biomarkers reflecting several aspects of inflammation, including cytokines: IL-1b, IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma; acute phase proteins such as CRP and serum amyloid A (SAA); soluble adhesion molecules such as soluble E-selectin (sE-selectin), soluble vascular cell adhesion molecule-1 (sVCAM-1), and soluble intercellular adhesion molecule-1 (sICAM-1); chemokine monocyte chemoattractant protein (MCP)-1; and other inflammatory markers including serum amyloid P (SAP), matrix metalloproteinase (MMP)-9, and myeloperoxidase (MPO), for their association with ED as measured by brachial artery FMD in HIV-infected participants on stable ART.
Materials and Methods
Study participants
This is a cross sectional analysis utilizing the baseline data of participants from the Hawaii Aging with HIV-Cardiovascular (HAHC-CVD) study. We included only participants who had available baseline inflammatory biomarkers and brachial artery FMD measurements. The details of study design and enrollment have been published previously.Citation23 Briefly, the study enrolled adults, age ≥ 40 years with documented HIV infection who were on stable ART for ≥ 3 months, from 2009 to 2012. The study was approved by the Committee on Human Subjects at our institution and was performed in accordance with the Declaration of Helsinki, all International Conference on Harmonization Good Clinical Practice guidelines, and applicable local regulatory requirements and laws. Written informed consents were obtained from all participants.
Clinical assessment
General medical history with special emphasis on CVD and HIV infection was obtained. Clinical parameters including blood pressure (BP), height, weight, body mass index (BMI), and waist to hip ratio were measured. Smoking history was defined as a dichotomous variable of ever smoked or never smoked. Routine HIV blood tests, including CD4+T-cell count and HIV RNA, as well as CVD blood tests, including fasting blood tests for total, high-density lipoprotein (HDL), directly measured low-density lipoprotein (LDL) cholesterol, triglycerides, and glucose were performed.
Hypertension was defined as systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg on entry visit, self-reported history of hypertension, or use of antihypertensive medications. Diabetes mellitus was defined by FBS ≥ 126 mg/dl, 2-hour OGTT ≥ 200 mg/dl, or self-reported history of diabetes mellitus. Ten-year coronary heart disease (CHD) risk was calculated by Framingham Risk Score (FRS) based on a model comprised of age, gender, total cholesterol, HDL cholesterol, systolic BP, treatment of hypertension, and any cigarette smoking in the past month using the National Cholesterol Education Program website (http://hp2010.nhlbihin.net/atpiii/calculator.asp).Citation24 Participants with diabetes (as a CVD equivalent) or clinical CVD (history of myocardial infarction, angina, coronary disease-related cardiac surgery, or ischemic stroke) were automatically classified as having 10-year CHD risk by FRS of 20%. Clinical CVD events were adjudicated by two physician-researchers (CMS and DCC). Undetectable plasma HIV RNA was defined as HIV RNA < 50 copies/ml.
Brachial artery FMD
Flow-mediated dilation testing was performed in the morning following a 12-hour fast utilizing previously published methodology.Citation18,Citation23,Citation25 Those who regularly used tobacco products refrained for at least 8 hours prior to the test. The test was conducted by forearm occlusion using a high-resolution linear array vascular ultrasound transducer (Siemens ACUSON Cypress) after a 10-minutes rest in a temperature-controlled room (70–76°F). Each study was recorded digitally and measured in triplicate by a single blinded reader at the core FMD laboratory at the University of Wisconsin at Madison. Flow-mediated dilation testing was obtained between 2 and 14 days of the biomarker assessments.
Biomarkers assessment
Plasma was assayed for inflammatory biomarkers, including sE-selectin, sVCAM-1, sICAM-1, MMP-9, MPO, CRP, SAA, SAP, IL-1b, IL-6, IL-8, IL-10, TNF-alpha, MCP-1, and IFN-gamma, using antibody-coated beads in a high sensitivity Milliplex Human CVD biomarker panel (Millipore, Billerica, MA, USA) as previously described.Citation26 The minimum detectable concentration of CRP of this assay is 0.001 ng/ml. Standard curves and samples were tested in duplicate. Samples were acquired on a Labscan 200 analyzer (Luminex, Austin, TX, USA) using Bio-Plex manager software (Bio-Rad, Hercules, CA, USA). The average coefficient of variation of all biomarker measurements was < 10%.
Statistical analyses
Demographic, cardiovascular, and HIV-related characteristics, as well as inflammatory biomarkers and brachial artery FMD measurements were described using the median, first quartile (Q1), and third quartile (Q3) for continuous variables and frequency and percent for categorical variables.
Univariable linear regression analyses were performed to assess inflammatory biomarkers as well as demographic, cardiovascular, and HIV-related characteristics for their associations with brachial artery FMD. Significant unadjusted associations between inflammatory biomarkers and brachial artery FMD were further evaluated in multivariable linear regression analyses adjusting for participants’ characteristics that were significantly associated with brachial artery FMD and selected traditional CVD risk factors that were previously reported to be associated with brachial artery FMD.Citation27 Final model included adjustment for baseline brachial artery diameter, age, systolic BP, LDL cholesterol, waist to hip ratio, diabetes mellitus, and smoking history. All inflammatory biomarkers were log transformed to normalization for analyses. All statistical analyses were conducted using SPSS (IBM, Version 21, Armonk, NY, USA). A two-sided probability of P-value < 0.05 was considered statistically significant.
Results
Participant characteristics
Of all participants enrolled into the HAHC-CVD cohort, a total of 135 participants had available baseline inflammatory biomarkers and brachial artery FMD measurements and were included in this analysis. The demographic, cardiovascular, HIV-related, and brachial artery FMD characteristics of the participants are presented in the . Participants were predominantly white (58.5%) and male (88.1%), with median age of 50 years. History of CVD events was presented in 7.4% of participants. The median 10-year CHD risk estimated by FRS was 6%. Most participants (85.9%) had undetectable HIV RNA and the median CD4+T-cell count of all participants was 480 cells/mm3. Nucleoside Reverse Transcriptase Inhibitors (NRTI), Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI), Protease Inhibitors (PI), and Integrase Inhibitor were currently used by 94.8, 48.9, 47.4, and 12.6% of participants, respectively. The median (Q1, Q3) of brachial artery FMD in this cohort was 3.72% (2.36%, 6.01%). The median (Q1, Q3) of sE-selectin, sVCAM-1, sICAM-1, MMP-9, MPO, CRP, SAA, SAP, IL-1b, IL-6, IL-8, IL-10, TNF-alpha, MCP-1, and IFN-gamma are shown in .
Table 1 Clinical, laboratory, and brachial artery FMD characteristics of study participants
Association between Participant characteristics, Inflammatory biomarkers, and Brachial artery FMD
In univariable linear regression analysis (), larger baseline brachial artery diameter (beta = − 20.777, P = < 0.001), older age (beta = − 0.064, P = 0.033), male gender (beta = − 1.640, P = 0.025), higher BMI (beta = − 0.128, P = 0.017), higher waist to hip ratio(beta = − 11.358, P = 0.012), hypertension (beta = − 1.674, P = 0.001), higher systolic (beta = − 0.048, P = 0.001) and diastolic BP (beta = − 0.084, P = 0.001), higher LDL cholesterol (beta = − 0.015, P = 0.032), and higher 10-year CHD risk estimated by FRS (beta = − 6.595, P = 0.049) were significantly associated with lower brachial artery FMD (reflecting worse ED). However, HIV-related factors (CD4+T-cell count, CD4+T-cell nadir, and undetectable HIV RNA), current use of cardiovascular medications (angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, beta blockers, aspirin, and statins) and antiretroviral medications (NRTIs, NNRTIs, PIs, and integrase inhibitor) were not associated with brachial artery FMD.
Table 2 Univariable linear regression for brachial artery FMD
Higher CRP (beta = − 0.695, P = 0.030) and SAP (beta = − 1.318, P = 0.021) levels were significantly associated with lower brachial artery FMD in univariable linear regression analysis (). While sE-selectin, sVCAM-1, sICAM-1, MMP-9, MPO, SAA, IL-1b, IL-6, IL-8, IL-10, TNF-alpha, MCP-1, and IFN-gamma were not significantly associated with brachial artery FMD.
The association between inflammatory biomarkers, CRP and SAP, and brachial artery FMD was further explored in multivariable linear regression analysis (). In the model adjusting for baseline brachial artery diameter, age, systolic BP, LDL cholesterol, waist to hip ratio, diabetes mellitus, and smoking history, higher level of SAP remained significantly associated with lower brachial artery FMD (beta = − 1.094, P = 0.030), while CRP was not (beta = − 0.391, P = 0.181). Exclusion of 10 participants with history of CVD did not affect the significance of these associations (data not shown).
Table 3 Multivariable linear regression for brachial artery FMD (%)
Discussion
Endothelial dysfunction has been proposed to be a precursor in development of atherosclerosis and an integrative marker of the net effect of all cardiovascular risk factors, both traditional and emerging.Citation3,Citation4 In this cohort of HIV-infected patients on stable ART for ≥ 3 months, we found significant associations between higher levels of inflammatory biomarkers, CRP and SAP, and lower brachial artery FMD, a marker of ED. After adjusting for baseline brachial artery diameter, age, and traditional CVD risk factors, SAP remained significantly associated with brachial artery FMD.
Both CRP and SAP are members of pentraxin, a family of serum proteins that serve as pattern recognition molecules and can activate an immune system and modulate inflammatory response.Citation28 C-reactive protein is widely utilized as a marker of acute and chronic inflammation. It is considered to be an acute phase protein as its serum level varies widely in response to inflammatory cytokines IL-1 and IL-6,Citation28,Citation29 especially in acute inflammatory processes. Serum amyloid P is a lesser-known inflammatory biomarker that has been associated with subclinical atherosclerosis and clinical ASCVDs in non-HIV patients.Citation30 Although its expression is influenced by the inflammatory cytokines IL-1 and IL-6, it is not considered to be an acute phase protein because its serum level is relatively stable and only weakly influenced by acute inflammatory processes.Citation28,Citation29
C-reactive protein was previously reported to be associated with impaired brachial artery FMD in one study in HIV-infected children.Citation20 Most studies previously assessing CRP and brachial artery FMD in patients with HIV failed to demonstrate this association.Citation9,Citation17–Citation19,Citation22,Citation31,Citation32 One study enrolled 331 ART-naïve HIV-infected participants also failed to demonstrate the association between CRP and brachial artery FMD.Citation21 The difference in the results of this study and our study may be due to different participants’ demographic as well as ART utilization. To our knowledge, the association between SAP and brachial artery FMD has never been demonstrated. This association might not be entirely unexpected given that pentraxin 3 (PTX3), another member of pentraxin, was also reported to be associated with brachial artery FMD.Citation33
Overall, the association of CRP and SAP with brachial artery FMD demonstrated in our study is consistent with the hypothesis that inflammation is related to ED in HIV-infected patients. However, the association between CRP and brachial artery FMD is not independent of traditional CVD risk factors given attenuation of the association in the multivariable regression model. This finding is consistent with the result of a large cohort of non-HIV patientsCitation34 and suggests that, similar to non-HIV patients, traditional CVD risk factors remain important driving force of inflammation in HIV-infected patients on stable ART.
Higher levels of SAP remained significantly associated with lower brachial artery FMD after adjustment for traditional CVD risk factors. This suggests that SAP may reflect different pathological processes from CRP. The difference in ligand binding and functional response between CRP and SAPCitation28,Citation29 may partly explain this observed difference. For example, CRP has been demonstrated to promote native and oxidized LDL uptake by macrophages,Citation35,Citation36 while SAP was reported to prevent oxidized LDL uptake by macrophages.Citation37 Thus, CRP and SAP may have different effects on foam cell formation and early development of atherosclerosis. Serum amyloid P was also reported to bind to HDL and inhibit HDL-mediated neutralization of lipopolysaccharide (LPS).Citation38 This issue may be especially important as higher LPS levels has been associated with lower brachial artery FMD in HIV-infected on ART.Citation39 In addition, SAP may modulate the degradation of and inflammatory response to amyloid fibrils,Citation29,Citation40 which can be found in atherosclerosis.
Although the role and incremental value of brachial artery FMD in cardiovascular risk stratification remains uncertain, lower brachial artery FMD has been shown to independently predict future ASCVDs in a number of studies.Citation5–Citation7 Thus, given the independent association between SAP and brachial artery FMD, SAP may provide additional predictive power to traditional CVD risk factors for ED and, potentially, ASCVDs in HIV-infected patients. Given different kinetics of CRP and SAP in relation to acute inflammatory processes,Citation28,Citation29,Citation41 CRP and SAP may be more suitably utilized at different stages of atherosclerosis. C-reactive protein is sensitive to acute inflammatory processes and may be more useful as a marker of acute ASCVD events. Serum amyloid P may be more useful as a marker of ASCVD risk during the chronic asymptomatic stage of atherosclerosis as its level is less likely to be confounded by other acute inflammatory processes.
This study is limited by its cross-sectional design and observational nature of surrogate markers. The association between the inflammatory markers, CRP and SAP, and ED cannot imply causation. Both CRP and SAP have been shown to accumulate in atherosclerotic plaques.Citation28,Citation42,Citation43 However, it remains uncertain if they are markers or active mediators of the pathologic process leading to the development of ED. The potential for chance findings on multiple comparisons of the different biomarkers is a possibility. However, the study initially analyzed only pentraxin biomarkers such as CRP and SAP a priori in influencing FMD. The limited comparison between these two biomarkers was consistent with one another in their overall effect on FMD. The significant findings document an opportunity to further explore pentraxin biomarkers as a marker of arterial injury. This study was limited by its ability to assess affects from other infections such as cytomegalovirus (CMV) co-infection, as well as translocation of gut microbial products. Host genetics were also not examined in this study, as well as comparison to a comparable HIV negative group. Additionally, FMD can be a technically challenging test that requires locating consistent vascular landmarks. Our sonographers underwent training through the University of Wisconsin at Madison and had regular quality assurance evaluations to insure consistency in repeated measures. The core FMD laboratory at the University of Wisconsin at Madison oversaw the FMD acquisitions and measures at the University of Hawaii. Despite these limitations, the strength of this study is the careful clinical characterization and brachial artery FMD measurement performed in the cohort in association with detailed biomarker assays performed in plasma using in a sensitivity CVD biomarker panel.
Conclusion
Serum amyloid P was independently associated with brachial artery FMD and may potentially relate to ED and increased ASCVD risk in HIV-infected patients on stable ART. This association warrants validation in future studies.
Disclaimer statements
The findings and conclusions of this study do not necessarily represent the views of The Queen's Medical Center.
Contributors
All authors were involved in study conception or design, or acquisition of data or analysis, and interpretation of data. All authors participated in revising the manuscript critically for important intellectual content, and approved the final version for publication.
Funding
This research was supported by grants R01HL095135 and U54MD007584.
Conflict of interest
None of the authors have any relevant conflicts of interest to disclose.
Ethics approval
The study was approved by the University of Hawaii Committee on Human Subjects and was performed in accordance with the Declaration of Helsinki, all International Conference on Harmonization Good Clinical Practice guidelines, and applicable local regulatory requirements and laws. Written informed consents were obtained from all participants.
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