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Inflammation Associates With Impaired Small Arterial Elasticity Early in HIV Disease

Inflammation Associates With Impaired Small Arterial Elasticity Early in HIV Disease Open Forum Infectious Diseases BRIEF REPORT elasticity and vice versa. However, arterial elasticity impairment Inflammation Associates With typically precedes changes in blood pressure (BP) [9], predicts Impaired Small Arterial Elasticity Early incident hypertension [10], and is responsive to treatment [11]. in HIV Disease e S Th trategic Timing of AntiRetroviral Treatment (START) 1 2 2 Trial is an international randomized trial investigating the opti- Tess E. Peterson, Katherine Huppler Hullsiek, Nicole Wyman Engen, 3 4 5 Nagalingeswaran Kumarasamy, Anne-Mette Lebech, Angelike Liappis, mal timing for ART initiation and represents a unique asymp- 6 7 1 8 Antonios Papadopoulos, Mark N. Polizzotto, Pamela J. Schreiner, Daniel Duprez, tomatic HIV-positive, ART-naïve population with preserved 8,9 and Jason V. Baker ; for the INSIGHT START (Strategic Timing of AntiRetroviral Treatment) Study Group immunity (CD4+ counts >500 cells/µL) and global distribu- 1 2 Division of Epidemiology and Community Health and Division of Biostatistics, University tion [12]. Biomarker levels were assessed in START reflective of Minnesota, Minneapolis, Minnesota; YRGCARE Medical Centre, VHS, Chennai, India; of systemic inflammation (high-sensitivity C-reactive protein Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Copenhagen, [hsCRP], interleukin-6 [IL-6], and serum amyloid A  [SAA]), Denmark; Section of Infectious Diseases, Washington DC Veterans Affairs Medical Center, Washington, DC; 4th Department of Internal Medicine, School of Medicine, National and adaptive immune activation (interleukin-27 [IL-27]), vascular Kapodistrian University of Athens, Athens, Greece; Kirby Institute for Infection and Immunity, injury (soluble intercellular adhesion molecule-1 [sICAM-1] University of New South Wales, Sydney, Australia; Department of Medicine, University of Minnesota, Minneapolis, Minnesota; Infectious Diseases, Hennepin County Medical Center, and soluble vascular adhesion molecule-1 [sVCAM-1]), and Minneapolis, Minesota coagulation (D-dimer). The START Arterial Elasticity substudy co-enrolled and consented START participants in 10 countries We estimated small arterial elasticity and used linear regres- over 6 continents, collecting data on arterial elasticity [6]. The sion to evaluate its association with inflammatory biomark- aim of this study was to explore cross-sectional baseline asso- ers among antiretroviral therapy–naïve, HIV-positive patients ciations between the biomarkers noted above and measures with high CD4+ counts. Aer ad ft justment, high-sensitivity of small arterial elasticity in this START substudy population. C-reactive protein and interleukin-6 were inversely associated with small arterial elasticity. es Th e data suggest that systemic Evaluating these associations could inform future research inflammation may contribute to vascular dysfunction even in strategies and potentially contribute to our understanding of very early HIV disease. early HIV-related CVD pathogenesis apart from the complex Keywords. arterial elasticity; cardiovascular disease; HIV effects of ART. infection; systemic inflammation; vascular dysfunction. METHODS HIV infection is associated with higher risk of cardiovascular Study Design disease (CVD) [1], which is a leading cause of morbidity and The International Network for Strategic Initiatives in Global HIV mortality in the era of effective antiretroviral therapy (ART) Trials (INSIGHT) START trial is an international randomized [2]. HIV-associated factors that have been suggested to contrib- clinical trial comparing immediate vs deferred initiation of ART, ute to higher risk of CVD include immune activation, chronic and the design and primary results have been reported [12]. inflammation, and activation of coagulation pathways [3, 4]. Participants at entry in START were HIV-positive and ART-naïve Small arterial elasticity (SAE) is an established measure of with no prior AIDS event and CD4+ counts >500 cells/μL. microvascular (dys)function [5, 6] associated with future CVD e A Th rterial Elasticity substudy co-enrolled START partici- events in the general population [7] and is impaired in HIV pants to ascertain ancillary measurements of SAE, estimated via infection [8]. Clinical hypertension leads to impaired arterial BP waveform analysis. Clinical and plasma biomarker data were collected as part of the main START trial [12, 13]. The study presented here is of a cross-sectional design among persons at entry into the START Arterial Elasticity substudy. Received 19 March 2018; editorial decision 9 May 2018; accepted 17 May 2018; published online 19 May 2018. Arterial Elasticity Measurement Correspondence: T.  E. Peterson, MPH, Hennepin County Medical Center, 914 South 8th Participants were asked to refrain from caffeine, nicotine, alco- Street, S2.305, Minneapolis, MN 55415 (pete9123@umn.edu). hol, antihistamines, and nonsteroidal anti-inflammatory med- Open Forum Infectious Diseases © The Author(s) 2018. Published by Oxford University Press on behalf of Infectious Diseases ications for 8 hours before the study visit. The HDI/PulseWave Society of America. This is an Open Access article distributed under the terms of the Creative CR-2000 (Hypertension Diagnostics, Inc., Eagan, MN) was used Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any to estimate the radial artery BP waveform. A  tonometer was medium, provided the original work is not altered or transformed in any way, and that the placed over the radial artery of the participant’s dominant arm work is properly cited. For commercial re-use, please contact journals.permissions@oup.com to record the BP contour while an oscillatory BP measurement DOI: 10.1093/ofid/ofy117 BRIEF REPORT • OFID • 1 Downloaded from https://academic.oup.com/ofid/article-abstract/5/6/ofy117/4999820 by Ed 'DeepDyve' Gillespie user on 19 June 2018 was taken at the brachial artery of the contralateral arm. As pre- (mg/dL). Other relevant factors, such as hepatitis B or C diag- viously described, arterial elasticity was then estimated using a nosis, diabetes, and use of lipid-lowering therapy, occurred modified Windkessel model [5–7]. too infrequently in this sample to include. Finally, because these biomarkers do not exist in isolation in vivo, an add- Biomarker Measurements itional model was fit with all biomarkers included simulta- Seven plasma biomarkers were measured: D-dimer, IL-6, IL-27, neously, controlling for the same set of covariates in the fully hsCRP , SAA, sICAM-1, and sVCAM-1. Plasma was stored at –70°C adjusted models described above. after isolation from nonfasting blood collected in EDTA tubes. Coefficients of determination (R ) were used to assess D-dimer was measured using an enzyme-linked fluores- model fit, interpreted as the proportion of the variance in SAE cence assay (VIDAS bioMerieux), IL-6 using a high-sensitiv- explained by the predictors in the model. All analyses were con- ity enzyme-linked immunosorbent assay (R&D Systems), and ducted using SAS, version 9.4, and a 2-sided type I error prob- IL-27 using an electro-chemiluminescence (ECL) immuno- ability of .05. assay (Meso Scale Diagnostics). A  multiplex ECL was used to measure hsCRP, SAA, sICAM-1, and sVCAM-1 concurrently RESULTS (Vascular Injury Panel 2, Meso Scale Diagnostics). These meth- Baseline demographic, clinical characteristics, and their asso- ods are consistent with those used in previous work [13]. ciations with SAE in this study have been presented previously Statistical Methods [6]. This sample was both young and diverse, with a median The START Arterial Elasticity substudy co-enrolled 337 par- (interquartile range [IQR]) age of 33 (28–41) years and 34% ticipants [6]. Excluded from analyses were those with HIV- white, 24% black, and 37% Asian self-identified race/ethni- negative testing (n = 1), prior CVD (n = 4), missing waveform city. Seventy percent of participants were male, and 29% were measurements (n  =  4), or missing biomarker measurements self-reported current smokers. The median (IQR) CD4+ count (n = 2), resulting in a final sample size of 326. was 625 (562–728) cells/µL, and the HIV viral load was 4.2 SAE was approximately normally distributed, and crude (3.7–4.7) log RNA copies/mL. The overall mean (SD) SAE was associations were all reasonably linear; no continuous variables 7.4 (3.0) mL/mmHg×100. were therefore categorized. Biomarkers were transformed on a Table  1 presents 15 linear regression models: 7 univariable log scale for all analyses to aid interpretation of model output. models, 7 fully adjusted multivariable models assessing bio- Specifically, regression coefficients for biomarker predictors will markers individually, and 1 fully adjusted multivariable model estimate the difference in SAE per log -unit increment in, or assessing all biomarkers simultaneously. In unadjusted mod- 2-fold higher, biomarker level. els, SAE was associated with log -hsCRP (ß  =  –0.18, P  =  .04), SAE was modeled using linear regression. Fully adjusted log -IL-6 (ß  =  –0.49, P  =  .006), log -sICAM-1 (ß  =  –0.59, 2 2 models included predictors for sex, age, race/ethnicity, P  =  .05), and log -D-dimer (ß  =  –0.99, P  <  .001). Aer ft full CD4+ count (cells/µL), HIV viral load (log RNA copies/ adjustment for age, sex, race/ethnicity, CD4+ count, HIV viral mL), current smoking, hypertension (defined as systolic BP load, smoking, hypertension, BMI, HDL-c, and total choles- ≥140 mmHg, diastolic BP ≥90 mmHg, or use of BP-lowering terol, log -hsCRP (ß = –0.18, P = .03) and log -IL-6 (ß = –0.56, 2 2 therapy), body mass index (BMI; kg/m ), high-density lipo- P  <  .001) had independent associations with SAE at baseline. protein cholesterol (HDL-c; mg/dL), and total cholesterol e Th confounding effects of age and sex largely account for the Table 1. Associations of Baseline Biomarker Levels and Small Arterial Elasticity Evaluated via Linear Regression a a Multivariable Model, Markers Multivariable Model, Markers Univariable Models Studied Individually Studied Simultaneously Biomarker, log ß (SE) P Value ß (SE) P Value ß (SE) P Value D-dimer, µg/mL –0.99 (0.19) <.001 –0.07 (0.20) .74 0.18 (0.21) .40 –0.18 (0.09) .04 –0.18 (0.08) .03 –0.08 (0.13) .51 hsCRP, µg/mL IL-6, pg/mL –0.49 (0.18) .006 –0.56 (0.16) <.001 –0.52 (0.18) .003 SAA, µg/mL –0.14 (0.11) .21 –0.13 (0.09) .18 0.07 (0.14) .63 IL-27, pg/mL 0.04 (0.10) .66 –0.06 (0.09) .49 –0.04 (0.09) .61 –0.59 (0.29) .05 –0.45 (0.26) .09 –0.70 (0.42) .10 sICAM-1, µg/mL sVCAM-1, µg/mL 0.07 (0.31) .82 –0.14 (0.28) .63 0.57 (0.44) .20 Regression coefficient (ß) estimates the difference in small arterial elasticity per log -unit increment in (or 2-fold higher) biomarker level. Abbreviations: hsCRP, high-sensitivity C-reactive protein; IL-6, interleukin-6; IL-27, interleukin-27; SAA, serum amyloid A; SE, standard error of ß estimate; sICAM-1, soluble intercellular adhesion molecule–1; sVCAM-1, soluble vascular adhesion molecule–1. Adjusted for sex at birth, age, race/ethnicity, CD4+ count, HIV viral load, smoking, hypertension (systolic BP ≥140 mmHg, diastolic BP ≥90 mmHg, or use of BP-lowering therapy), body mass index, high-density lipoprotein cholesterol, and total cholesterol. 2 • OFID • BRIEF REPORT Downloaded from https://academic.oup.com/ofid/article-abstract/5/6/ofy117/4999820 by Ed 'DeepDyve' Gillespie user on 19 June 2018 2 substantial difference in coefficient estimates observed for log - size, particularly in fully adjusted models; however, the large R D-dimer in the univariable vs fully adjusted models. observed in the simultaneously adjusted model suggests good When biomarkers were considered simultaneously, only model fit. log -IL-6 (ß  =  –0.52, P  =  .003) had an association with SAE Caution should be taken in generalizing results to other HIV- independent of the other biomarkers and demographic and positive populations, such as those who have initiated ART or clinical characteristics. That is, holding demographics, clinical are older with more substantial vascular disease. We are una- characteristics, and other measured biomarkers constant, there ble to determine whether inflammation continues to be asso- was, on average, a 0.52-unit decrement in SAE per 2-fold higher ciated with impaired arterial elasticity once viral suppression is IL-6. Overall, this final model fit well (R  = 0.368). achieved on long-standing continuous ART. In summary, this study demonstrated a significant cross- DISCUSSION sectional association between higher levels of systemic inflammation and impaired small arterial elasticity in an HIV- We explored associations between levels of inflammatory bio- positive, ART-naïve population with preserved immunity and markers and small arterial elasticity—which reflects early CVD at relatively low risk for both AIDS and CVD. These findings pathogenesis—in an asymptomatic HIV-positive, ART-naïve support the relevance of IL-6 as a potential contributor to HIV- population with high CD4+ counts. When individually evalu- associated CVD—including hypertension—and have implica- ated, participants with higher levels of 2 biomarkers of systemic tions for targeted prevention strategies. inflammation (IL-6 and hsCRP) were found to have signifi- cantly more impaired (lower) SAE after adjustment for tradi- Acknowledgments tional CVD risk factors. When all biomarkers were evaluated We would like to thank all the START Arterial Elasticity Substudy simultaneously, however, only the association between SAE and participants. IL-6 persisted after full adjustment. Please see N Engl J Med 2015; 373:795–807 for the complete list of START investigators. Inflammatory pathways contribute to CVD risk not only via Financial support. This work was supported by the National Institute their role in the initiation, progression, and rupture of athero- of Allergy and Infectious Diseases (grant numbers UM1-AI068641, sclerotic plaques [14] but also via blood pressure elevation and UM1-AI120197; United States); Agence Nationale de Recherches sur le SIDA et les Hipatites Virales (France); National Health and Medical hypertension [15]. Our study population had a very short dur- Research Council (Australia); National Research Foundation (Denmark); ation of HIV diagnosis (median, 1  year) and was also largely Bundes Ministerium f|r Bildung und Forschung (Germany); European normotensive (87%) without known CHD. HIV infection is AIDS Treatment Network, Medical Research Council (United Kingdom); characterized by higher levels of IL-6 and hsCRP compared with National Institute for Health Research, National Health Service (United Kingdom); and the University of Minnesota. uninfected controls, even aer v ft iral suppression [4 ]. Given this, Potential coni fl cts of interest. Dr. Lebech reports nonfinancial support hypertension may become an important manifestation of HIV- from Gilead for conference registration and personal fees from GSK for associated CVD. A recent study using insurance claims data sup- serving on an advisory board. Both are outside this submitted work. No other authors have commercial or other associations that might pose a con- ports this, suggesting that hypertension prevalence ranges from flict of interest. All authors have submitted the ICMJE Form for Disclosure 25% to 65% among HIV-positive persons [16]. These observa- of Potential Conflicts of Interest. Conflicts that the editors consider relevant tions, combined with new guidance on the diagnosis and man- to the content of the manuscript have been disclosed. agement of hypertension [17], suggest that BP management may References require increased priority in HIV clinical practice. 1. Freiberg MS, Chang CC, Kuller LH, et  al. HIV infection and the risk of acute er Th e are limitations to this study. First, analyses are cross- myocardial infarction. JAMA Intern Med 2013; 173:614–22. sectional. There is therefore temporal ambiguity of these rela- 2. Grund B, Baker JV, Deeks SG, et al. Relevance of interleukin-6 and D-dimer for serious non-AIDS morbidity and death among HIV-positive adults on suppres- tionships, and no causality can be inferred from the results. sive antiretroviral therapy. PLoS One 2016; 11:e0155100. Additionally, though SAE is an established measure of micro- 3. Nordell AD, McKenna M, Borges ÁH, et  al. Severity of cardiovascular disease outcomes among patients with HIV is related to markers of inflammation and vascular (dys)function, there are presently no well-validated coagulation. J Am Heart Assoc 2014; 3:e000844. reference values. We did, however, make an informal compari- 4. Neuhaus J, Jacobs DR Jr, Baker JV, et al. Markers of inflammation, coagulation, son with participants of similar age in the general population and renal function are elevated in adults with HIV infection. J Infect Dis 2010; 201:1788–95. cohort CARDIA (mean [SD] SAE, 8.1 [2.7] mL/mmHg×100; 5. Zimlichman R, Shargorodsky M, Boaz M, et al. Determination of arterial compli- n  =  1250), which suggested that values in this HIV-positive ance using blood pressure waveform analysis with the CR-2000 system: reliability, repeatability, and establishment of normal values for healthy European popula- study population may be low (P. Schreiner, April 2018, personal tion–the Seven European Sites Study (SESS). Am J Hypertens 2005; 18:65–71. communication). 6. Baker JV, Engen NW, Huppler Hullsiek K, et al; International Network for Strategic Initiatives in Global HIV Trials (INSIGHT) START Study Group. Assessment of Statistical limitations include relatively narrow biomarker arterial elasticity among HIV-positive participants with high CD4 cell counts: a interquartile ranges, limiting prediction power and possibly substudy of the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial. HIV Med 2015; 16:109–18. threatening validity. These were also exploratory analyses, lead- 7. Duprez DA, Jacobs DR Jr, Lutsey PL, et al. Association of small artery elasticity ing to use of several modeling approaches and inflation of type with incident cardiovascular disease in older adults: the multi-ethnic study of ath- I  error. Overadjustment may be of concern with this sample erosclerosis. Am J Epidemiol 2011; 174:528–36. BRIEF REPORT • OFID • 3 Downloaded from https://academic.oup.com/ofid/article-abstract/5/6/ofy117/4999820 by Ed 'DeepDyve' Gillespie user on 19 June 2018 8. Solages A, Vita JA, Thornton DJ, et al. Endothelial function in HIV-infected per- 13. Baker JV, Sharma S, Grund B, et  al; INSIGHT START (Strategic Timing of sons. Clin Infect Dis 2006; 42:1325–32. AntiRetroviral Treatment) Study Group. Systemic inflammation, coagu- 9. Payne RA, Wilkinson IB, Webb DJ. Arterial stiffness and hypertension: emerging lation, and clinical risk in the START trial. Open Forum Infect Dis 2017; concepts. Hypertension 2010; 55:9–14. 4:ofx262. 10. Peralta CA, Adeney KL, Shlipak MG, et  al. Structural and functional vascular 14. Libby P, Ridker PM, Hansson GK. Progress and challenges in translating the biol- alterations and incident hypertension in normotensive adults: the Multi-Ethnic ogy of atherosclerosis. Nature 2011; 473:317–25. Study of Atherosclerosis. Am J Epidemiol 2010; 171:63–71. 15. Duprez DA, Hearst MO, Lutsey PL, et  al. Associations among lung function, 11. Duprez DA, Florea ND, Jones K, Cohn JN. Beneficial effects of valsartan in arterial elasticity, and circulating endothelial and inflammation markers: the asymptomatic individuals with vascular or cardiac abnormalities: the DETECTIV multiethnic study of atherosclerosis. Hypertension 2013; 61:542–8. Pilot Study. J Am Coll Cardiol 2007; 50:835–9. 16. Gallant J, Hsue PY, Shreay S, Meyer N. Comorbidities among US patients with 12. Lundgren JD, Babiker AG, Gordin F, et  al; INSIGHT START Study Group. prevalent HIV infection—a trend analysis. J Infect Dis 2017; 216:1525–33. Initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl J 17. Cifu AS, Davis AM. Prevention, detection, evaluation, and management of high Med 2015; 373:795–807. blood pressure in adults. JAMA 2017; 318:2132–4. 4 • OFID • BRIEF REPORT Downloaded from https://academic.oup.com/ofid/article-abstract/5/6/ofy117/4999820 by Ed 'DeepDyve' Gillespie user on 19 June 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Open Forum Infectious Diseases Oxford University Press

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Abstract

Open Forum Infectious Diseases BRIEF REPORT elasticity and vice versa. However, arterial elasticity impairment Inflammation Associates With typically precedes changes in blood pressure (BP) [9], predicts Impaired Small Arterial Elasticity Early incident hypertension [10], and is responsive to treatment [11]. in HIV Disease e S Th trategic Timing of AntiRetroviral Treatment (START) 1 2 2 Trial is an international randomized trial investigating the opti- Tess E. Peterson, Katherine Huppler Hullsiek, Nicole Wyman Engen, 3 4 5 Nagalingeswaran Kumarasamy, Anne-Mette Lebech, Angelike Liappis, mal timing for ART initiation and represents a unique asymp- 6 7 1 8 Antonios Papadopoulos, Mark N. Polizzotto, Pamela J. Schreiner, Daniel Duprez, tomatic HIV-positive, ART-naïve population with preserved 8,9 and Jason V. Baker ; for the INSIGHT START (Strategic Timing of AntiRetroviral Treatment) Study Group immunity (CD4+ counts >500 cells/µL) and global distribu- 1 2 Division of Epidemiology and Community Health and Division of Biostatistics, University tion [12]. Biomarker levels were assessed in START reflective of Minnesota, Minneapolis, Minnesota; YRGCARE Medical Centre, VHS, Chennai, India; of systemic inflammation (high-sensitivity C-reactive protein Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Copenhagen, [hsCRP], interleukin-6 [IL-6], and serum amyloid A  [SAA]), Denmark; Section of Infectious Diseases, Washington DC Veterans Affairs Medical Center, Washington, DC; 4th Department of Internal Medicine, School of Medicine, National and adaptive immune activation (interleukin-27 [IL-27]), vascular Kapodistrian University of Athens, Athens, Greece; Kirby Institute for Infection and Immunity, injury (soluble intercellular adhesion molecule-1 [sICAM-1] University of New South Wales, Sydney, Australia; Department of Medicine, University of Minnesota, Minneapolis, Minnesota; Infectious Diseases, Hennepin County Medical Center, and soluble vascular adhesion molecule-1 [sVCAM-1]), and Minneapolis, Minesota coagulation (D-dimer). The START Arterial Elasticity substudy co-enrolled and consented START participants in 10 countries We estimated small arterial elasticity and used linear regres- over 6 continents, collecting data on arterial elasticity [6]. The sion to evaluate its association with inflammatory biomark- aim of this study was to explore cross-sectional baseline asso- ers among antiretroviral therapy–naïve, HIV-positive patients ciations between the biomarkers noted above and measures with high CD4+ counts. Aer ad ft justment, high-sensitivity of small arterial elasticity in this START substudy population. C-reactive protein and interleukin-6 were inversely associated with small arterial elasticity. es Th e data suggest that systemic Evaluating these associations could inform future research inflammation may contribute to vascular dysfunction even in strategies and potentially contribute to our understanding of very early HIV disease. early HIV-related CVD pathogenesis apart from the complex Keywords. arterial elasticity; cardiovascular disease; HIV effects of ART. infection; systemic inflammation; vascular dysfunction. METHODS HIV infection is associated with higher risk of cardiovascular Study Design disease (CVD) [1], which is a leading cause of morbidity and The International Network for Strategic Initiatives in Global HIV mortality in the era of effective antiretroviral therapy (ART) Trials (INSIGHT) START trial is an international randomized [2]. HIV-associated factors that have been suggested to contrib- clinical trial comparing immediate vs deferred initiation of ART, ute to higher risk of CVD include immune activation, chronic and the design and primary results have been reported [12]. inflammation, and activation of coagulation pathways [3, 4]. Participants at entry in START were HIV-positive and ART-naïve Small arterial elasticity (SAE) is an established measure of with no prior AIDS event and CD4+ counts >500 cells/μL. microvascular (dys)function [5, 6] associated with future CVD e A Th rterial Elasticity substudy co-enrolled START partici- events in the general population [7] and is impaired in HIV pants to ascertain ancillary measurements of SAE, estimated via infection [8]. Clinical hypertension leads to impaired arterial BP waveform analysis. Clinical and plasma biomarker data were collected as part of the main START trial [12, 13]. The study presented here is of a cross-sectional design among persons at entry into the START Arterial Elasticity substudy. Received 19 March 2018; editorial decision 9 May 2018; accepted 17 May 2018; published online 19 May 2018. Arterial Elasticity Measurement Correspondence: T.  E. Peterson, MPH, Hennepin County Medical Center, 914 South 8th Participants were asked to refrain from caffeine, nicotine, alco- Street, S2.305, Minneapolis, MN 55415 (pete9123@umn.edu). hol, antihistamines, and nonsteroidal anti-inflammatory med- Open Forum Infectious Diseases © The Author(s) 2018. Published by Oxford University Press on behalf of Infectious Diseases ications for 8 hours before the study visit. The HDI/PulseWave Society of America. This is an Open Access article distributed under the terms of the Creative CR-2000 (Hypertension Diagnostics, Inc., Eagan, MN) was used Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any to estimate the radial artery BP waveform. A  tonometer was medium, provided the original work is not altered or transformed in any way, and that the placed over the radial artery of the participant’s dominant arm work is properly cited. For commercial re-use, please contact journals.permissions@oup.com to record the BP contour while an oscillatory BP measurement DOI: 10.1093/ofid/ofy117 BRIEF REPORT • OFID • 1 Downloaded from https://academic.oup.com/ofid/article-abstract/5/6/ofy117/4999820 by Ed 'DeepDyve' Gillespie user on 19 June 2018 was taken at the brachial artery of the contralateral arm. As pre- (mg/dL). Other relevant factors, such as hepatitis B or C diag- viously described, arterial elasticity was then estimated using a nosis, diabetes, and use of lipid-lowering therapy, occurred modified Windkessel model [5–7]. too infrequently in this sample to include. Finally, because these biomarkers do not exist in isolation in vivo, an add- Biomarker Measurements itional model was fit with all biomarkers included simulta- Seven plasma biomarkers were measured: D-dimer, IL-6, IL-27, neously, controlling for the same set of covariates in the fully hsCRP , SAA, sICAM-1, and sVCAM-1. Plasma was stored at –70°C adjusted models described above. after isolation from nonfasting blood collected in EDTA tubes. Coefficients of determination (R ) were used to assess D-dimer was measured using an enzyme-linked fluores- model fit, interpreted as the proportion of the variance in SAE cence assay (VIDAS bioMerieux), IL-6 using a high-sensitiv- explained by the predictors in the model. All analyses were con- ity enzyme-linked immunosorbent assay (R&D Systems), and ducted using SAS, version 9.4, and a 2-sided type I error prob- IL-27 using an electro-chemiluminescence (ECL) immuno- ability of .05. assay (Meso Scale Diagnostics). A  multiplex ECL was used to measure hsCRP, SAA, sICAM-1, and sVCAM-1 concurrently RESULTS (Vascular Injury Panel 2, Meso Scale Diagnostics). These meth- Baseline demographic, clinical characteristics, and their asso- ods are consistent with those used in previous work [13]. ciations with SAE in this study have been presented previously Statistical Methods [6]. This sample was both young and diverse, with a median The START Arterial Elasticity substudy co-enrolled 337 par- (interquartile range [IQR]) age of 33 (28–41) years and 34% ticipants [6]. Excluded from analyses were those with HIV- white, 24% black, and 37% Asian self-identified race/ethni- negative testing (n = 1), prior CVD (n = 4), missing waveform city. Seventy percent of participants were male, and 29% were measurements (n  =  4), or missing biomarker measurements self-reported current smokers. The median (IQR) CD4+ count (n = 2), resulting in a final sample size of 326. was 625 (562–728) cells/µL, and the HIV viral load was 4.2 SAE was approximately normally distributed, and crude (3.7–4.7) log RNA copies/mL. The overall mean (SD) SAE was associations were all reasonably linear; no continuous variables 7.4 (3.0) mL/mmHg×100. were therefore categorized. Biomarkers were transformed on a Table  1 presents 15 linear regression models: 7 univariable log scale for all analyses to aid interpretation of model output. models, 7 fully adjusted multivariable models assessing bio- Specifically, regression coefficients for biomarker predictors will markers individually, and 1 fully adjusted multivariable model estimate the difference in SAE per log -unit increment in, or assessing all biomarkers simultaneously. In unadjusted mod- 2-fold higher, biomarker level. els, SAE was associated with log -hsCRP (ß  =  –0.18, P  =  .04), SAE was modeled using linear regression. Fully adjusted log -IL-6 (ß  =  –0.49, P  =  .006), log -sICAM-1 (ß  =  –0.59, 2 2 models included predictors for sex, age, race/ethnicity, P  =  .05), and log -D-dimer (ß  =  –0.99, P  <  .001). Aer ft full CD4+ count (cells/µL), HIV viral load (log RNA copies/ adjustment for age, sex, race/ethnicity, CD4+ count, HIV viral mL), current smoking, hypertension (defined as systolic BP load, smoking, hypertension, BMI, HDL-c, and total choles- ≥140 mmHg, diastolic BP ≥90 mmHg, or use of BP-lowering terol, log -hsCRP (ß = –0.18, P = .03) and log -IL-6 (ß = –0.56, 2 2 therapy), body mass index (BMI; kg/m ), high-density lipo- P  <  .001) had independent associations with SAE at baseline. protein cholesterol (HDL-c; mg/dL), and total cholesterol e Th confounding effects of age and sex largely account for the Table 1. Associations of Baseline Biomarker Levels and Small Arterial Elasticity Evaluated via Linear Regression a a Multivariable Model, Markers Multivariable Model, Markers Univariable Models Studied Individually Studied Simultaneously Biomarker, log ß (SE) P Value ß (SE) P Value ß (SE) P Value D-dimer, µg/mL –0.99 (0.19) <.001 –0.07 (0.20) .74 0.18 (0.21) .40 –0.18 (0.09) .04 –0.18 (0.08) .03 –0.08 (0.13) .51 hsCRP, µg/mL IL-6, pg/mL –0.49 (0.18) .006 –0.56 (0.16) <.001 –0.52 (0.18) .003 SAA, µg/mL –0.14 (0.11) .21 –0.13 (0.09) .18 0.07 (0.14) .63 IL-27, pg/mL 0.04 (0.10) .66 –0.06 (0.09) .49 –0.04 (0.09) .61 –0.59 (0.29) .05 –0.45 (0.26) .09 –0.70 (0.42) .10 sICAM-1, µg/mL sVCAM-1, µg/mL 0.07 (0.31) .82 –0.14 (0.28) .63 0.57 (0.44) .20 Regression coefficient (ß) estimates the difference in small arterial elasticity per log -unit increment in (or 2-fold higher) biomarker level. Abbreviations: hsCRP, high-sensitivity C-reactive protein; IL-6, interleukin-6; IL-27, interleukin-27; SAA, serum amyloid A; SE, standard error of ß estimate; sICAM-1, soluble intercellular adhesion molecule–1; sVCAM-1, soluble vascular adhesion molecule–1. Adjusted for sex at birth, age, race/ethnicity, CD4+ count, HIV viral load, smoking, hypertension (systolic BP ≥140 mmHg, diastolic BP ≥90 mmHg, or use of BP-lowering therapy), body mass index, high-density lipoprotein cholesterol, and total cholesterol. 2 • OFID • BRIEF REPORT Downloaded from https://academic.oup.com/ofid/article-abstract/5/6/ofy117/4999820 by Ed 'DeepDyve' Gillespie user on 19 June 2018 2 substantial difference in coefficient estimates observed for log - size, particularly in fully adjusted models; however, the large R D-dimer in the univariable vs fully adjusted models. observed in the simultaneously adjusted model suggests good When biomarkers were considered simultaneously, only model fit. log -IL-6 (ß  =  –0.52, P  =  .003) had an association with SAE Caution should be taken in generalizing results to other HIV- independent of the other biomarkers and demographic and positive populations, such as those who have initiated ART or clinical characteristics. That is, holding demographics, clinical are older with more substantial vascular disease. We are una- characteristics, and other measured biomarkers constant, there ble to determine whether inflammation continues to be asso- was, on average, a 0.52-unit decrement in SAE per 2-fold higher ciated with impaired arterial elasticity once viral suppression is IL-6. Overall, this final model fit well (R  = 0.368). achieved on long-standing continuous ART. In summary, this study demonstrated a significant cross- DISCUSSION sectional association between higher levels of systemic inflammation and impaired small arterial elasticity in an HIV- We explored associations between levels of inflammatory bio- positive, ART-naïve population with preserved immunity and markers and small arterial elasticity—which reflects early CVD at relatively low risk for both AIDS and CVD. These findings pathogenesis—in an asymptomatic HIV-positive, ART-naïve support the relevance of IL-6 as a potential contributor to HIV- population with high CD4+ counts. When individually evalu- associated CVD—including hypertension—and have implica- ated, participants with higher levels of 2 biomarkers of systemic tions for targeted prevention strategies. inflammation (IL-6 and hsCRP) were found to have signifi- cantly more impaired (lower) SAE after adjustment for tradi- Acknowledgments tional CVD risk factors. When all biomarkers were evaluated We would like to thank all the START Arterial Elasticity Substudy simultaneously, however, only the association between SAE and participants. IL-6 persisted after full adjustment. Please see N Engl J Med 2015; 373:795–807 for the complete list of START investigators. Inflammatory pathways contribute to CVD risk not only via Financial support. This work was supported by the National Institute their role in the initiation, progression, and rupture of athero- of Allergy and Infectious Diseases (grant numbers UM1-AI068641, sclerotic plaques [14] but also via blood pressure elevation and UM1-AI120197; United States); Agence Nationale de Recherches sur le SIDA et les Hipatites Virales (France); National Health and Medical hypertension [15]. Our study population had a very short dur- Research Council (Australia); National Research Foundation (Denmark); ation of HIV diagnosis (median, 1  year) and was also largely Bundes Ministerium f|r Bildung und Forschung (Germany); European normotensive (87%) without known CHD. HIV infection is AIDS Treatment Network, Medical Research Council (United Kingdom); characterized by higher levels of IL-6 and hsCRP compared with National Institute for Health Research, National Health Service (United Kingdom); and the University of Minnesota. uninfected controls, even aer v ft iral suppression [4 ]. Given this, Potential coni fl cts of interest. Dr. Lebech reports nonfinancial support hypertension may become an important manifestation of HIV- from Gilead for conference registration and personal fees from GSK for associated CVD. A recent study using insurance claims data sup- serving on an advisory board. Both are outside this submitted work. No other authors have commercial or other associations that might pose a con- ports this, suggesting that hypertension prevalence ranges from flict of interest. All authors have submitted the ICMJE Form for Disclosure 25% to 65% among HIV-positive persons [16]. These observa- of Potential Conflicts of Interest. Conflicts that the editors consider relevant tions, combined with new guidance on the diagnosis and man- to the content of the manuscript have been disclosed. agement of hypertension [17], suggest that BP management may References require increased priority in HIV clinical practice. 1. Freiberg MS, Chang CC, Kuller LH, et  al. HIV infection and the risk of acute er Th e are limitations to this study. First, analyses are cross- myocardial infarction. JAMA Intern Med 2013; 173:614–22. sectional. There is therefore temporal ambiguity of these rela- 2. Grund B, Baker JV, Deeks SG, et al. Relevance of interleukin-6 and D-dimer for serious non-AIDS morbidity and death among HIV-positive adults on suppres- tionships, and no causality can be inferred from the results. sive antiretroviral therapy. PLoS One 2016; 11:e0155100. Additionally, though SAE is an established measure of micro- 3. Nordell AD, McKenna M, Borges ÁH, et  al. Severity of cardiovascular disease outcomes among patients with HIV is related to markers of inflammation and vascular (dys)function, there are presently no well-validated coagulation. J Am Heart Assoc 2014; 3:e000844. reference values. We did, however, make an informal compari- 4. Neuhaus J, Jacobs DR Jr, Baker JV, et al. 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Journal

Open Forum Infectious DiseasesOxford University Press

Published: May 19, 2018

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