Infectious Diseases
ISSN: 2374-4235 (Print) 2374-4243 (Online) Journal homepage: http://www.tandfonline.com/loi/infd20
Low prevalence of peripheral arterial disease in a cross-sectional study of Danish HIV-infected patients Andreas Knudsen, Catarina Anna Evelina Malmberg, Andreas Kjær & AnneMette Lebech To cite this article: Andreas Knudsen, Catarina Anna Evelina Malmberg, Andreas Kjær & AnneMette Lebech (2015) Low prevalence of peripheral arterial disease in a cross-sectional study of Danish HIV-infected patients, Infectious Diseases, 47:11, 776-782 To link to this article: http://dx.doi.org/10.3109/23744235.2015.1061204
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Published online: 26 Jun 2015.
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Date: 05 November 2015, At: 13:46
Infectious Diseases, 2015; 47: 776–782
ORIGINAL ARTICLE
Low prevalence of peripheral arterial disease in a cross-sectional study of Danish HIV-infected patients
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ANDREAS KNUDSEN1,2*, CATARINA ANNA EVELINA MALMBERG1,2*, ANDREAS KJÆR2 & ANNE-METTE LEBECH1 From the 1Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre and 2Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark
Abstract Background: Patients infected with human immunodeficiency virus (HIV) appear to be at increased risk of cardiovascular disease (CVD). The ankle-brachial index (ABI) is a well-established screening tool for peripheral arterial disease (PAD) and future cardiovascular events in the general population. However, controversies exist on the prevalence of PAD among HIV-infected patients. In this study we aimed to measure the prevalence of PAD among HIV-infected patients and compare the ABI with carotid intima-media thickness (cIMT) and other known CVD risk predictors. Methods: We prospectively included HIV-infected patients from an outpatient clinic at the Department of Infectious Diseases, Hvidovre University Hospital, Denmark. We assessed the ABI pre- and post-exercise with a threshold for PAD defined as ABI ⱕ 0.9. All patients had cIMT measured at the far wall of the distal common carotid artery. Results: Of 102 patients included (mean age 52 years, 75% male, 94% receiving antiretroviral therapy (ART), 33% active smokers), 1 had a pre-exercise ABI ⱕ 0.9 and in addition 3 patients had a post-exercise ABI ⱕ 0.9. We found a poor correlation between ABI and traditional CVD risk factors other than body mass index. In contrast, a strong correlation was found between cIMT and traditional risk factors. Values of post-exercise ABI and cIMT were not correlated. The current ART did not influence ABI values. Conclusions: We found a low prevalence of PAD in HIV-infected patients. ABI did not correlate with CVD risk factors or cIMT. Based on these results ABI does not seem valuable as a screening tool for CVD among HIV-infected patients.
Keywords: HIV infection; peripheral arterial disease; atherosclerosis; carotid intima-media thickness
Introduction In countries with free access to antiretroviral treatment (ART), infection with human immunodeficiency virus (HIV) has become a chronic, manageable disease with a life expectancy approaching that of the general population [1]. However, non-AIDS co-morbidities are now of growing concern. In particular, cardiovascular diseases (CVD) seem to be overrepresented in the HIV-infected population [2], with the most striking finding being a 50% increased risk of myocardial infarction beyond that explained by traditional risk factors [3]. Possible explanations for this increased risk include ART [4] and chronic inflammation [5]. However, recent studies report
decreasing rates of cardiovascular events among optimally treated HIV-infected patients with high CD4 cell counts and full viral suppression during the last few years [6–8]. Many studies have investigated the peripheral endothelial function and early atherosclerosis in HIV-infected patients by different modalities including flow-mediated dilation [9], arterial stiffness [10] and carotid intima-media thickness (cIMT) [11,12]. The general findings were an overall tendency towards impaired endothelial function and signs of early atherosclerosis due to both traditional risk factors [12] and HIV-related immunodeficiency [10], and possibly certain ART regimens, most notably
*These authors contributed equally to the manuscript. Correspondence: Andreas Knudsen PhD, Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Kettegaard Allé 30, DK-2650 Hvidovre, Denmark. Tel: ⫹ 45 38626061. Fax: ⫹ 45 36474979. E-mail: [email protected]. © 2015 Informa UK Ltd. This is an open-access article distributed under the terms of the CC-BY-NC-ND 3.0 License which permits users to download and share the article for non-commercial purposes, so long as the article is reproduced in the whole without changes, and provided the original source is credited. (Received 4 February 2015 ; accepted 1 June 2015) ISSN 2374-4235 print/ISSN 2374-4243 online © 2015 Informa Healthcare DOI: 10.3109/23744235.2015.1061204
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HIV and peripheral arterial disease abacavir (ABC) [9] and the early protease inhibitors (PIs) [4]. But also here recent studies suggest that optimally treated patients may not be as prone to vascular changes as previously described [13,14]. A simple method to assess atherosclerosis is the ankle-brachial index (ABI), which is the ratio of systolic arterial pressure measured at the ankle to that measured at the brachial artery. This has been well validated in the general population, initially as an indicator of peripheral arterial disease (PAD) [15], and later as a predictor of cardiovascular events in asymptomatic patients [16]. The sensitivity of the ABI has been shown to increase when measured after mild exercise [17]. Traditionally, an ABI ⱕ 0.9 is taken as an indicator of PAD and increased risk of CVD [18], but studies have shown that even modest reductions in post-exercise ABI with a normal pre-exercise ABI are associated with increased risk of death [19]. In contrast to the general population, studies of ABI in HIV patients have been conflicting [20–22]. We therefore wanted to establish the prevalence of PAD in an unselected group of HIV-infected patients and assess the rationale of using ABI as a screening method for CVD risk in this population. To do so, we compared ABI with other known CVD risk predictors, including the Framingham risk score (FRS) and cIMT.
Materials and Methods Study design The study was a prospective cross-sectional study. A total of 102 patients were consecutively recruited during routine visits to the outpatient clinic at the Department of Infectious Diseases, Hvidovre University Hospital between October 2013 and May 2014. The clinic has an HIV-infected patient population of approximately 1500, which constitutes ≈30% of the Danish HIV-infected population. Inclusion criteria were (i) HIV infection and (ii) age ⬎ 18 years. Exclusion criteria were (i) inability to perform plantar flexion, (ii) immeasurable cIMT or (iii) alcohol or drug abuse hampering the ability to adhere to the protocol. All included patients were given oral and written information, and written informed consent was obtained from them all. The Danish National Committee on Biomedical Research Ethics approved the study (H-2-2011-042). Cardiovascular risk factors and Edinburgh claudication questionnaire The patients’ demographic and clinical characteristics were obtained by interviewing and examining medical
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records. The data included: age, gender, height, weight, smoking habits, alcohol use, renal disease, hepatitis, known diabetes or CVD and family history of CVD. Cardiac risk factors were used to calculate the 10-year risk of developing coronary heart disease (CHD) according to the FRS [23]. Patients’ use of medication specified as statins, antihypertensive or other cardiovascular medication, antidiabetic agents and ART were registered. All patients answered the Edinburgh claudication questionnaire to note symptoms related to peripheral vascular disease [24].
Pre- and post-exercise ABI measurement Patients rested comfortably on a bed in a dark room for 5 min, after which blood pressure was measured at the right and left ankle at the posterior tibial artery, followed by measurements at the right and left arm at the brachial artery. All patients had palpable peripheral pulses. The blood pressure was measured with a semiautomated cuff-oscillometric sphygmomanometer (A&D Co. Ltd, Saitama, Japan) with cuff size adapted to the circumference of the extremity [25]. Thereafter, the patient was asked to perform 50 consecutive repetitions of active ankle plantar flexion while standing with fully extended knees. Patients were allowed fingertip support against a wall to assist with balance. The exercises were carried out under supervision [26]. Immediately after the exercise, the patient lay down and the blood pressure measurement was repeated in the same manner as previously. The ABI was calculated by dividing the highest pressure recorded at the ankles with the highest systolic pressure of the arms. In accordance with the American Heart Association guidelines, the threshold for peripheral vascular disease diagnosed by ABI measurements was defined as ⱕ 0.9 [27]. Patients with ABI ⱕ 0.9 were referred to the Department of Clinical Physiology, Hvidovre University Hospital, for further clinical work-up.
Carotid intima-media thickness cIMT was measured bilaterally at the far wall of the distal common carotid artery caudally of the sinus caroticus covering 10 mm using a Sonosite M-Turbo (Sonosite Inc., Bothell, WA, USA) with a 13.6 MHz linear transducer and automated software (SonoCalc IMT 5.0; Sonosite Inc.). The measurement was performed in one projection in a longitudinal view with both the near and far wall visible. An increased cIMT was defined as an average thickness of ⬎ 900 μm. All patients had measurable cIMT. Average measurements ⬎ 900 μm or visible plaques resulted in referral to the Department of Clinical Physiology for further evaluation.
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Biochemical and immunological analyses and ART Levels of lipids, glucose, creatinine, HIV viral load and CD4 cell counts were extracted from analyses performed on blood samples from the routine visit, where patients were included in the study. Data on viral load and CD4 cell counts before treatment were taken from patients’ medical records and represent HIV RNA zenith and CD4 cell count nadir. ART represents the current treatment regimen at time of examination.
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Statistics Values are presented as mean ⫾ SEM unless otherwise specified. Correlation analyses were performed using Spearman’s rho. Intergroup differences were assessed by unpaired t test or ANOVA when analyzing more than two groups. A p value of ⬍ 0.05 was considered significant. All statistical analyses were made using SPSS22 (IBM, Armonk, NY, USA).
Results Baseline characteristics of all the patients are shown in Table I. A total of 94% of patients received ART at time of the study. The HIV parameters of the patients on ART at time of investigation showed that 93% of the patients had CD4 cell counts ⬎ 400 (106/L) and viral load below 40 (copies/ml). In all, 28% of the patients had been diagnosed with hypertension, and 7% had been diagnosed with other type of CVD (unstable angina, n ⫽ 1; ischaemic heart disease, n ⫽ 1; minor stroke, n ⫽ 1; myocardial infarction, n ⫽ 1; and coronary bypass graft surgery, n ⫽ 3). Also, 50% of the patients had elevated total cholesterol above 5 mmol/L, 12% had high density lipoprotein (HDL) values ⬍ 0.9 mmol/L and 2% had high values of low density lipoprotein (LDL) ⬎ 5 mmol/L. Sixty-three percent of patients had a low FRS (⬍ 10%), 18% had an intermediate FRS (⬎ 10 and ⬍ 20%) and 19% had a high FRS (⬎ 20%). Thirty-nine percent of patients had a systolic blood pressure of 140 mmHg or more on the day of the examination. Carotid intima-media thickness The results showed that 15% of patients had a high mean value of cIMT (⬎ 900 μm). Eight patients had minor, non-obstructive plaques on one or both sides of the common carotid artery or the bifurcation, three of which had cIMTvalues ⬍ 900 μm.
Table I. Baseline characteristics of patients in the study (n ⫽ 102). Parametersa
Value
Male/female Age (years) BMI (kg/m2) Smoking: active, former, never Systolic blood pressure (mmHg) Blood glucose (mmol/L) Total cholesterol (mmol/L) HDL (mmol/L) LDL (mmol/L) Diabetes Hypertension CVD other Positive Edinburgh questionnaire Framingham risk score (CHD 10 years) Intima media thickness (μm) CD4 cell count, median (range) HIV RNA, median (range) Duration of HIV infection (years) ⱖ 2 NRTIs ⫹ 1 NNRTI ⱖ 2 NRTIs ⫹ ⱖ 1 PI ⱖ 2 NRTIs ⫹ 1 II PI monotherapy PIs ⫹ 1 II 3 NRTIs Other No ART
77 (75%)/25 (25%) 52 ⫾ 1 26 ⫾ 0.5 33%, 25%, 42% 156 ⫾ 2 5.7 ⫾ 0.1 5.2 ⫾ 0.1 1.3 ⫾ 0.4 3.0 ⫾ 0.1 7% 28% 7% 7% 9.5 ⫾ 0.9 750 ⫾ 13 644 (57–1540) 19 (19–131 100) 12.5 ⫾ 0.6 53%b 23%b 9%b 4%b 3%b 2%b 6%b 6%
ART, antiretroviral therapy; BMI, body mass index; CHD, coronary heart disease; CVD, cardiovascular disease; HDL, high density lipoprotein; II, integrase inhibitor; LDL, low density lipoprotein; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor. aValues are presented as mean ⫾ SEM, unless otherwise indicated. bPercentage of patients receiving ART.
Ankle-brachial index and Edinburgh questionnaire One patient had an ABI ⱕ 0.9 both pre- and post-exercise and one patient had an ABI ⱕ 0.9 preexercise, but had normal ABI post-exercise. An additional three patients had ABI ⱕ 0.9 only after exercise. These four patients are described in Table II. A decrease in ABI from pre- to post-exercise ⱖ 15% was found in 14% of patients. Three patients had Table II. Characteristics of the four patients with post-exercise ABI of ⱕ 0.9. Patient
Sex
Age (years)
Risk factors
eABI
FRS
IMT (μm)
1 2 3 4
F M F M
38 72 40 52
Smoker Smoker, UAP Smoker Smoker, HT
0.83 0.75 0.84 0.89
0.3 26 1 21
494 906 583 988
eABI, post-exercise ankle-brachial index; F, female; FRS, Framingham risk score; HT, hypertension; IMT, intima-media thickness; M, male; UAP, unstable angina pectoris.
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pre-exercise ABI ⱖ 1.3 and three had post-exercise ABI (eABI) ⬎ 1.3. Six of the patients had a positive Edinburgh claudication questionnaire, but only one of these had eABI ⱕ 0.9.
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Correlation between post-exercise ABI and traditional cardiovascular risk factors We found a tendency towards a correlation between eABI and FRS (ρ ⫽ 0.2; p ⫽ 0.07), whereas none was found between eABI and lipids, blood pressure, or HIV parameters. There was a significant, positive correlation between age and eABI (ρ ⫽ 0.2, p ⫽ 0.03) and eABI and BMI (ρ ⫽ 0.2; p ⫽ 0.03). The smokers tended to have lower values of eABI, as shown in Figure 1. We found no correlation between eABI and cIMT (Figure 2). cIMT values were highly correlated with traditional risk factors and HIV viral load before treatment, but none of the other HIV parameters, as presented in Table III. A comparison of the 14% of patients who experienced a drop in ABI ⱖ 15% post-exercise with the patients who did not, revealed no difference in age, BMI, total cholesterol, LDL, HDL, FRS or cIMT (data not shown). ART had no obvious influence on eABI, since the groups did not differ significantly (PI ⫹ 1.08 ⫾ 0.03 vs PI– 1.10 ⫾ 0.01; p ⫽ 0.35; and ABC⫹ ⫽ 1.1 ⫾ 0.02 vs ABC– 1.08 ⫾ 0.01; p ⫽ 0.24).
Discussion In this study of 102 HIV-infected patients we found a low prevalence of PAD as determined by reduced
Figure 2. Scatterplot of the carotid intima-media thickness (cIMT) values versus post-exercise ankle-brachial index (ABI) values showing no correlation.
pre- or post-exercise ABI (ⱕ 0.9). Further, the ABI values did not correlate with traditional CVD risk factors other than BMI. In contrast, cIMT was significantly correlated with both CVD risk factors and pre-ART HIV viral load. Previous studies of PAD among HIV-infected patients have reported prevalences ranging from 2–6% [20,21,28–31] to values ⬎ 10% [22,32]. The prevalence of asymptomatic PAD in the general population has been estimated to be between 2 and 4% in two large studies from the USA [33,34], but somewhat higher (7–10%) in a Danish study [35]. The study cohort consisted of consecutive patients with HIV infection as the only inclusion criterion; they were generally well treated, with normal CD4 cell counts and viral load, and baseline characteristics were representative of the population in general [35]. We hypothesized that values of Table III. Correlation between cardiovascular risk factors and post-exercise ABI and intima-media thickness.
Figure 1. Post-exercise values of ankle-brachial index (ABI) according to smoking status. Analysis of variance showed a tendency towards lower values across the groups (p ⫽ 0.06).
Correlation analysis
Post-exercise ABI
FRS Total cholesterol HDL LDL IMT Systolic BP BMI Age CD4 HIV RNA
0.2, p ⫽ 0.07 NS NS NS NS NS 0.2b 0.2b NS NS
Intima-media thickness 0.6a 0.2b ⫺0.3b 0.2b – 0.4a NS 0.6a NS NS
Values are Spearman’s ρ: ap value ⬍ 0.005, bp value ⬍ 0.05. ABI, ankle-brachial index; BMI, body mass index; BP, blood pressure; CVD, cardiovascular disease; FRS, Framingham risk score; HDL, high density lipoprotein; IMT, intima-media thickness; LDL, low density lipoprotein; NS, not significant.
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ABI would reflect the amount of cardiac risk factors [18]. However, the only risk factor that the 4% of patients with an eABI ⱕ 0.9 had in common was smoking. Smoking is an acknowledged risk factor for PAD [36], but in this study we found only a tendency towards a difference in mean eABI between the current, former smokers and never smokers (p ⫽ 0.06). This was probably due to the low occurrence of ABI ⱕ 0.9 in our patient group. The Edinburgh claudication questionnaire did not predict low ABI well in this study, since only one of the positive responders proved to have an eABI ⱕ 0.9. In comparison, other studies in HIVinfected patients found around 50% of the positive responders to have low ABI [22,32]. The post-exercise measurement was correlated to BMI (ρ ⫽ 0.2; p ⫽ 0.03) and marginally correlated to FRS (ρ ⫽ 0.2; p ⫽ 0.07), but further correlations between eABI and lipids, blood pressure, or HIV infection parameters were absent. However, we did find eABI to be positively correlated to age (ρ ⫽ 0.22; p ⫽ 0.03). Normally, an aging population displays decreasing values of ABI [18,37], and our values in the older patients may be artificially high due to an increased arterial stiffening found in HIV-infected patients [10]. In healthy individuals, a mild decrease in ABI is seen immediately after physical exercise of the leg due to increased left ventricular pressure and vasodilation in the exercising muscles [17]. However, a drop of ⬎ 15% following exercise may indicate endothelial dysfunction [38]. Accordingly, in a cohort study of more than 3000 patients a decrease in eABI between 6 and 24% with normal values of ABI at rest was associated with a 1.6-fold increase in risk of overall mortality [19]. In the present study, 14% of patients had a postexercise drop in ABI of ⬎ 15%. Nevertheless an examination of this subgroup did not show any significant difference in age, lipid profiles, FRS or cIMT, compared to the cases that did not exhibit a drop in ABI following exercise. We found no correlation between cIMT and ABI. However, cIMT, in contrast to ABI, correlated with lipid profile, systolic blood pressure, age and the FRS, but not with HIV parameters other than pretreatment HIV viral load. These results indicate that cIMT may be a more useful screening tool in an HIV-infected population, as supported by other studies [39]. On the other hand, it could be argued that since the cIMT was tightly correlated with FRS, cIMT does not give much additional information. The levels of cIMT in the present study seemed in concordance with what has been found by others [40].
This study aimed to investigate the prevalence of PAD in an unselected group of HIV-infected individuals and to evaluate the potential value of a simple examination modality as a screening method. In spite of the acknowledged increased risk of cardiovascular disease in HIV-infected patients, our results did not show higher prevalence of PAD, compared to the general population. The lower prevalence in our cohort, as compared with some of the other studies in HIV-infected patients, may be explained by the rather low proportion of smokers, diabetics and normal CD4 cell counts and low viraemia. Also, this present study was carried out in a setting where the focus on CVD risk among HIV-infected patients is higher than before, and the ART regimens may have become less toxic with regard to the cardiovascular system [6]. Previous studies of PAD, defined as low ABI, have shown various results, both among HIVinfected subjects and in the population in general. Despite the simplicity of the measurement, different examination techniques exist (using Doppler vs oscillometric sphygmanometer, synchronic measurement of blood pressure vs ankle before arm, using highest vs lowest pressure for index, etc.). Further, heterogeneity of cohorts regarding age, sex, smoking habits or other cardiovascular risk factors, as well as the number investigated, contribute to the complexity of evaluating the modality. The American College of Cardiology Foundation and American Heart Association stated in their guideline for assessment of CVD risk in asymptomatic adults that measurement of ABI is reasonable in asymptomatic adults at intermediate risk (10–20% risk of cardiovascular disease over 10 years), yet acknowledging the conflicting evidence from studies [41]. The HIV-infected population is complex and heterogeneous, and consensus on how to screen for cardiovascular co-morbidities is still to be reached [42]. Whether our results are true negative, hereby excluding PAD and increased cardiovascular risk in these patients, or if they rather imply that ABI is not the modality to choose is unclear. However, the finding of a low prevalence of PAD would be in line with our own studies in the same type of HIV population using other modalities [14,43]. Nevertheless, it can be concluded that in a well-treated, unselected HIV population, measurement of ABI for screening purposes seems without obvious value. This study was limited by the relatively low number of patients, and the fact that only four patients had an ABI ⱕ 0.9 made assessment of risk factors difficult. We used a simple and validated technique for blood pressure measurement with an oscillometric sphygmanometer and pedal plantar flexions
HIV and peripheral arterial disease instead of the treadmill test for simplicity, which could lead to difficulties in comparison with other studies using different modalities. Declaration of interest: A.M.L. is a board member of Abbott and Bristol-Myers Squibb, and has received research funding and/or honoraria from Abbott, Bristol-Myers Squibb, Gilead, Tibotec and Glaxo Smith Kline. The remaining authors have no conflicts of interest.
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asymptomatic subjects in the general population. J Vasc Surg 2003;38:1323–30. Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FGR. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). Eur J Vasc Endovasc Surg 2007;33:S1–75. Mangili A, Polak JF, Quach LA, Gerrior J, Wanke CA. Markers of atherosclerosis and inflammation and mortality in patients with HIV infection. Atherosclerosis 2011;214: 468–73. Hsue PY, Ordovas K, Lee T, Reddy G, Gotway M, Schnell A, et al. Carotid intima-media thickness among human immunodeficiency virus-infected patients without coronary calcium. Am J Cardiol 2012;109:742–7. Greenland P, Alpert JS, Beller GA, Benjamin EJ, Budoff MJ, Fayad ZA, et al. 2010 ACCF/AHA Guideline for Assessment of Cardiovascular Risk in Asymptomatic Adults: A Report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the American Society of Echocardiography, American Society of Nuclear Cardiology, Society of Atherosclerosis Imaging and Prevention, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, and Society for Cardiovascular Magnetic Resonance. J Am Coll Cardiol 2010;56:e50–103. D’Agostino RB. Cardiovascular risk estimation in 2012: lessons learned and applicability to the HIV population. J Infect Dis 2012;205:S362–7. Kristoffersen U, Lebech A, Gerstoft J, Hesse B, Petersen C, Gutte H, et al. Right and left cardiac function in HIVinfected patients investigated using radionuclide ventriculography and brain natriuretic peptide: a 5-year follow-up study. HIV Med 2008;9:180–6.
ISSN: 2374-4235 (Print) 2374-4243 (Online) Journal homepage: http://www.tandfonline.com/loi/infd20
Low prevalence of peripheral arterial disease in a cross-sectional study of Danish HIV-infected patients Andreas Knudsen, Catarina Anna Evelina Malmberg, Andreas Kjær & AnneMette Lebech To cite this article: Andreas Knudsen, Catarina Anna Evelina Malmberg, Andreas Kjær & AnneMette Lebech (2015) Low prevalence of peripheral arterial disease in a cross-sectional study of Danish HIV-infected patients, Infectious Diseases, 47:11, 776-782 To link to this article: http://dx.doi.org/10.3109/23744235.2015.1061204
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Infectious Diseases, 2015; 47: 776–782
ORIGINAL ARTICLE
Low prevalence of peripheral arterial disease in a cross-sectional study of Danish HIV-infected patients
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ANDREAS KNUDSEN1,2*, CATARINA ANNA EVELINA MALMBERG1,2*, ANDREAS KJÆR2 & ANNE-METTE LEBECH1 From the 1Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre and 2Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark
Abstract Background: Patients infected with human immunodeficiency virus (HIV) appear to be at increased risk of cardiovascular disease (CVD). The ankle-brachial index (ABI) is a well-established screening tool for peripheral arterial disease (PAD) and future cardiovascular events in the general population. However, controversies exist on the prevalence of PAD among HIV-infected patients. In this study we aimed to measure the prevalence of PAD among HIV-infected patients and compare the ABI with carotid intima-media thickness (cIMT) and other known CVD risk predictors. Methods: We prospectively included HIV-infected patients from an outpatient clinic at the Department of Infectious Diseases, Hvidovre University Hospital, Denmark. We assessed the ABI pre- and post-exercise with a threshold for PAD defined as ABI ⱕ 0.9. All patients had cIMT measured at the far wall of the distal common carotid artery. Results: Of 102 patients included (mean age 52 years, 75% male, 94% receiving antiretroviral therapy (ART), 33% active smokers), 1 had a pre-exercise ABI ⱕ 0.9 and in addition 3 patients had a post-exercise ABI ⱕ 0.9. We found a poor correlation between ABI and traditional CVD risk factors other than body mass index. In contrast, a strong correlation was found between cIMT and traditional risk factors. Values of post-exercise ABI and cIMT were not correlated. The current ART did not influence ABI values. Conclusions: We found a low prevalence of PAD in HIV-infected patients. ABI did not correlate with CVD risk factors or cIMT. Based on these results ABI does not seem valuable as a screening tool for CVD among HIV-infected patients.
Keywords: HIV infection; peripheral arterial disease; atherosclerosis; carotid intima-media thickness
Introduction In countries with free access to antiretroviral treatment (ART), infection with human immunodeficiency virus (HIV) has become a chronic, manageable disease with a life expectancy approaching that of the general population [1]. However, non-AIDS co-morbidities are now of growing concern. In particular, cardiovascular diseases (CVD) seem to be overrepresented in the HIV-infected population [2], with the most striking finding being a 50% increased risk of myocardial infarction beyond that explained by traditional risk factors [3]. Possible explanations for this increased risk include ART [4] and chronic inflammation [5]. However, recent studies report
decreasing rates of cardiovascular events among optimally treated HIV-infected patients with high CD4 cell counts and full viral suppression during the last few years [6–8]. Many studies have investigated the peripheral endothelial function and early atherosclerosis in HIV-infected patients by different modalities including flow-mediated dilation [9], arterial stiffness [10] and carotid intima-media thickness (cIMT) [11,12]. The general findings were an overall tendency towards impaired endothelial function and signs of early atherosclerosis due to both traditional risk factors [12] and HIV-related immunodeficiency [10], and possibly certain ART regimens, most notably
*These authors contributed equally to the manuscript. Correspondence: Andreas Knudsen PhD, Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Kettegaard Allé 30, DK-2650 Hvidovre, Denmark. Tel: ⫹ 45 38626061. Fax: ⫹ 45 36474979. E-mail: [email protected]. © 2015 Informa UK Ltd. This is an open-access article distributed under the terms of the CC-BY-NC-ND 3.0 License which permits users to download and share the article for non-commercial purposes, so long as the article is reproduced in the whole without changes, and provided the original source is credited. (Received 4 February 2015 ; accepted 1 June 2015) ISSN 2374-4235 print/ISSN 2374-4243 online © 2015 Informa Healthcare DOI: 10.3109/23744235.2015.1061204
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HIV and peripheral arterial disease abacavir (ABC) [9] and the early protease inhibitors (PIs) [4]. But also here recent studies suggest that optimally treated patients may not be as prone to vascular changes as previously described [13,14]. A simple method to assess atherosclerosis is the ankle-brachial index (ABI), which is the ratio of systolic arterial pressure measured at the ankle to that measured at the brachial artery. This has been well validated in the general population, initially as an indicator of peripheral arterial disease (PAD) [15], and later as a predictor of cardiovascular events in asymptomatic patients [16]. The sensitivity of the ABI has been shown to increase when measured after mild exercise [17]. Traditionally, an ABI ⱕ 0.9 is taken as an indicator of PAD and increased risk of CVD [18], but studies have shown that even modest reductions in post-exercise ABI with a normal pre-exercise ABI are associated with increased risk of death [19]. In contrast to the general population, studies of ABI in HIV patients have been conflicting [20–22]. We therefore wanted to establish the prevalence of PAD in an unselected group of HIV-infected patients and assess the rationale of using ABI as a screening method for CVD risk in this population. To do so, we compared ABI with other known CVD risk predictors, including the Framingham risk score (FRS) and cIMT.
Materials and Methods Study design The study was a prospective cross-sectional study. A total of 102 patients were consecutively recruited during routine visits to the outpatient clinic at the Department of Infectious Diseases, Hvidovre University Hospital between October 2013 and May 2014. The clinic has an HIV-infected patient population of approximately 1500, which constitutes ≈30% of the Danish HIV-infected population. Inclusion criteria were (i) HIV infection and (ii) age ⬎ 18 years. Exclusion criteria were (i) inability to perform plantar flexion, (ii) immeasurable cIMT or (iii) alcohol or drug abuse hampering the ability to adhere to the protocol. All included patients were given oral and written information, and written informed consent was obtained from them all. The Danish National Committee on Biomedical Research Ethics approved the study (H-2-2011-042). Cardiovascular risk factors and Edinburgh claudication questionnaire The patients’ demographic and clinical characteristics were obtained by interviewing and examining medical
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records. The data included: age, gender, height, weight, smoking habits, alcohol use, renal disease, hepatitis, known diabetes or CVD and family history of CVD. Cardiac risk factors were used to calculate the 10-year risk of developing coronary heart disease (CHD) according to the FRS [23]. Patients’ use of medication specified as statins, antihypertensive or other cardiovascular medication, antidiabetic agents and ART were registered. All patients answered the Edinburgh claudication questionnaire to note symptoms related to peripheral vascular disease [24].
Pre- and post-exercise ABI measurement Patients rested comfortably on a bed in a dark room for 5 min, after which blood pressure was measured at the right and left ankle at the posterior tibial artery, followed by measurements at the right and left arm at the brachial artery. All patients had palpable peripheral pulses. The blood pressure was measured with a semiautomated cuff-oscillometric sphygmomanometer (A&D Co. Ltd, Saitama, Japan) with cuff size adapted to the circumference of the extremity [25]. Thereafter, the patient was asked to perform 50 consecutive repetitions of active ankle plantar flexion while standing with fully extended knees. Patients were allowed fingertip support against a wall to assist with balance. The exercises were carried out under supervision [26]. Immediately after the exercise, the patient lay down and the blood pressure measurement was repeated in the same manner as previously. The ABI was calculated by dividing the highest pressure recorded at the ankles with the highest systolic pressure of the arms. In accordance with the American Heart Association guidelines, the threshold for peripheral vascular disease diagnosed by ABI measurements was defined as ⱕ 0.9 [27]. Patients with ABI ⱕ 0.9 were referred to the Department of Clinical Physiology, Hvidovre University Hospital, for further clinical work-up.
Carotid intima-media thickness cIMT was measured bilaterally at the far wall of the distal common carotid artery caudally of the sinus caroticus covering 10 mm using a Sonosite M-Turbo (Sonosite Inc., Bothell, WA, USA) with a 13.6 MHz linear transducer and automated software (SonoCalc IMT 5.0; Sonosite Inc.). The measurement was performed in one projection in a longitudinal view with both the near and far wall visible. An increased cIMT was defined as an average thickness of ⬎ 900 μm. All patients had measurable cIMT. Average measurements ⬎ 900 μm or visible plaques resulted in referral to the Department of Clinical Physiology for further evaluation.
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Biochemical and immunological analyses and ART Levels of lipids, glucose, creatinine, HIV viral load and CD4 cell counts were extracted from analyses performed on blood samples from the routine visit, where patients were included in the study. Data on viral load and CD4 cell counts before treatment were taken from patients’ medical records and represent HIV RNA zenith and CD4 cell count nadir. ART represents the current treatment regimen at time of examination.
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Statistics Values are presented as mean ⫾ SEM unless otherwise specified. Correlation analyses were performed using Spearman’s rho. Intergroup differences were assessed by unpaired t test or ANOVA when analyzing more than two groups. A p value of ⬍ 0.05 was considered significant. All statistical analyses were made using SPSS22 (IBM, Armonk, NY, USA).
Results Baseline characteristics of all the patients are shown in Table I. A total of 94% of patients received ART at time of the study. The HIV parameters of the patients on ART at time of investigation showed that 93% of the patients had CD4 cell counts ⬎ 400 (106/L) and viral load below 40 (copies/ml). In all, 28% of the patients had been diagnosed with hypertension, and 7% had been diagnosed with other type of CVD (unstable angina, n ⫽ 1; ischaemic heart disease, n ⫽ 1; minor stroke, n ⫽ 1; myocardial infarction, n ⫽ 1; and coronary bypass graft surgery, n ⫽ 3). Also, 50% of the patients had elevated total cholesterol above 5 mmol/L, 12% had high density lipoprotein (HDL) values ⬍ 0.9 mmol/L and 2% had high values of low density lipoprotein (LDL) ⬎ 5 mmol/L. Sixty-three percent of patients had a low FRS (⬍ 10%), 18% had an intermediate FRS (⬎ 10 and ⬍ 20%) and 19% had a high FRS (⬎ 20%). Thirty-nine percent of patients had a systolic blood pressure of 140 mmHg or more on the day of the examination. Carotid intima-media thickness The results showed that 15% of patients had a high mean value of cIMT (⬎ 900 μm). Eight patients had minor, non-obstructive plaques on one or both sides of the common carotid artery or the bifurcation, three of which had cIMTvalues ⬍ 900 μm.
Table I. Baseline characteristics of patients in the study (n ⫽ 102). Parametersa
Value
Male/female Age (years) BMI (kg/m2) Smoking: active, former, never Systolic blood pressure (mmHg) Blood glucose (mmol/L) Total cholesterol (mmol/L) HDL (mmol/L) LDL (mmol/L) Diabetes Hypertension CVD other Positive Edinburgh questionnaire Framingham risk score (CHD 10 years) Intima media thickness (μm) CD4 cell count, median (range) HIV RNA, median (range) Duration of HIV infection (years) ⱖ 2 NRTIs ⫹ 1 NNRTI ⱖ 2 NRTIs ⫹ ⱖ 1 PI ⱖ 2 NRTIs ⫹ 1 II PI monotherapy PIs ⫹ 1 II 3 NRTIs Other No ART
77 (75%)/25 (25%) 52 ⫾ 1 26 ⫾ 0.5 33%, 25%, 42% 156 ⫾ 2 5.7 ⫾ 0.1 5.2 ⫾ 0.1 1.3 ⫾ 0.4 3.0 ⫾ 0.1 7% 28% 7% 7% 9.5 ⫾ 0.9 750 ⫾ 13 644 (57–1540) 19 (19–131 100) 12.5 ⫾ 0.6 53%b 23%b 9%b 4%b 3%b 2%b 6%b 6%
ART, antiretroviral therapy; BMI, body mass index; CHD, coronary heart disease; CVD, cardiovascular disease; HDL, high density lipoprotein; II, integrase inhibitor; LDL, low density lipoprotein; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor. aValues are presented as mean ⫾ SEM, unless otherwise indicated. bPercentage of patients receiving ART.
Ankle-brachial index and Edinburgh questionnaire One patient had an ABI ⱕ 0.9 both pre- and post-exercise and one patient had an ABI ⱕ 0.9 preexercise, but had normal ABI post-exercise. An additional three patients had ABI ⱕ 0.9 only after exercise. These four patients are described in Table II. A decrease in ABI from pre- to post-exercise ⱖ 15% was found in 14% of patients. Three patients had Table II. Characteristics of the four patients with post-exercise ABI of ⱕ 0.9. Patient
Sex
Age (years)
Risk factors
eABI
FRS
IMT (μm)
1 2 3 4
F M F M
38 72 40 52
Smoker Smoker, UAP Smoker Smoker, HT
0.83 0.75 0.84 0.89
0.3 26 1 21
494 906 583 988
eABI, post-exercise ankle-brachial index; F, female; FRS, Framingham risk score; HT, hypertension; IMT, intima-media thickness; M, male; UAP, unstable angina pectoris.
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pre-exercise ABI ⱖ 1.3 and three had post-exercise ABI (eABI) ⬎ 1.3. Six of the patients had a positive Edinburgh claudication questionnaire, but only one of these had eABI ⱕ 0.9.
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Correlation between post-exercise ABI and traditional cardiovascular risk factors We found a tendency towards a correlation between eABI and FRS (ρ ⫽ 0.2; p ⫽ 0.07), whereas none was found between eABI and lipids, blood pressure, or HIV parameters. There was a significant, positive correlation between age and eABI (ρ ⫽ 0.2, p ⫽ 0.03) and eABI and BMI (ρ ⫽ 0.2; p ⫽ 0.03). The smokers tended to have lower values of eABI, as shown in Figure 1. We found no correlation between eABI and cIMT (Figure 2). cIMT values were highly correlated with traditional risk factors and HIV viral load before treatment, but none of the other HIV parameters, as presented in Table III. A comparison of the 14% of patients who experienced a drop in ABI ⱖ 15% post-exercise with the patients who did not, revealed no difference in age, BMI, total cholesterol, LDL, HDL, FRS or cIMT (data not shown). ART had no obvious influence on eABI, since the groups did not differ significantly (PI ⫹ 1.08 ⫾ 0.03 vs PI– 1.10 ⫾ 0.01; p ⫽ 0.35; and ABC⫹ ⫽ 1.1 ⫾ 0.02 vs ABC– 1.08 ⫾ 0.01; p ⫽ 0.24).
Discussion In this study of 102 HIV-infected patients we found a low prevalence of PAD as determined by reduced
Figure 2. Scatterplot of the carotid intima-media thickness (cIMT) values versus post-exercise ankle-brachial index (ABI) values showing no correlation.
pre- or post-exercise ABI (ⱕ 0.9). Further, the ABI values did not correlate with traditional CVD risk factors other than BMI. In contrast, cIMT was significantly correlated with both CVD risk factors and pre-ART HIV viral load. Previous studies of PAD among HIV-infected patients have reported prevalences ranging from 2–6% [20,21,28–31] to values ⬎ 10% [22,32]. The prevalence of asymptomatic PAD in the general population has been estimated to be between 2 and 4% in two large studies from the USA [33,34], but somewhat higher (7–10%) in a Danish study [35]. The study cohort consisted of consecutive patients with HIV infection as the only inclusion criterion; they were generally well treated, with normal CD4 cell counts and viral load, and baseline characteristics were representative of the population in general [35]. We hypothesized that values of Table III. Correlation between cardiovascular risk factors and post-exercise ABI and intima-media thickness.
Figure 1. Post-exercise values of ankle-brachial index (ABI) according to smoking status. Analysis of variance showed a tendency towards lower values across the groups (p ⫽ 0.06).
Correlation analysis
Post-exercise ABI
FRS Total cholesterol HDL LDL IMT Systolic BP BMI Age CD4 HIV RNA
0.2, p ⫽ 0.07 NS NS NS NS NS 0.2b 0.2b NS NS
Intima-media thickness 0.6a 0.2b ⫺0.3b 0.2b – 0.4a NS 0.6a NS NS
Values are Spearman’s ρ: ap value ⬍ 0.005, bp value ⬍ 0.05. ABI, ankle-brachial index; BMI, body mass index; BP, blood pressure; CVD, cardiovascular disease; FRS, Framingham risk score; HDL, high density lipoprotein; IMT, intima-media thickness; LDL, low density lipoprotein; NS, not significant.
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ABI would reflect the amount of cardiac risk factors [18]. However, the only risk factor that the 4% of patients with an eABI ⱕ 0.9 had in common was smoking. Smoking is an acknowledged risk factor for PAD [36], but in this study we found only a tendency towards a difference in mean eABI between the current, former smokers and never smokers (p ⫽ 0.06). This was probably due to the low occurrence of ABI ⱕ 0.9 in our patient group. The Edinburgh claudication questionnaire did not predict low ABI well in this study, since only one of the positive responders proved to have an eABI ⱕ 0.9. In comparison, other studies in HIVinfected patients found around 50% of the positive responders to have low ABI [22,32]. The post-exercise measurement was correlated to BMI (ρ ⫽ 0.2; p ⫽ 0.03) and marginally correlated to FRS (ρ ⫽ 0.2; p ⫽ 0.07), but further correlations between eABI and lipids, blood pressure, or HIV infection parameters were absent. However, we did find eABI to be positively correlated to age (ρ ⫽ 0.22; p ⫽ 0.03). Normally, an aging population displays decreasing values of ABI [18,37], and our values in the older patients may be artificially high due to an increased arterial stiffening found in HIV-infected patients [10]. In healthy individuals, a mild decrease in ABI is seen immediately after physical exercise of the leg due to increased left ventricular pressure and vasodilation in the exercising muscles [17]. However, a drop of ⬎ 15% following exercise may indicate endothelial dysfunction [38]. Accordingly, in a cohort study of more than 3000 patients a decrease in eABI between 6 and 24% with normal values of ABI at rest was associated with a 1.6-fold increase in risk of overall mortality [19]. In the present study, 14% of patients had a postexercise drop in ABI of ⬎ 15%. Nevertheless an examination of this subgroup did not show any significant difference in age, lipid profiles, FRS or cIMT, compared to the cases that did not exhibit a drop in ABI following exercise. We found no correlation between cIMT and ABI. However, cIMT, in contrast to ABI, correlated with lipid profile, systolic blood pressure, age and the FRS, but not with HIV parameters other than pretreatment HIV viral load. These results indicate that cIMT may be a more useful screening tool in an HIV-infected population, as supported by other studies [39]. On the other hand, it could be argued that since the cIMT was tightly correlated with FRS, cIMT does not give much additional information. The levels of cIMT in the present study seemed in concordance with what has been found by others [40].
This study aimed to investigate the prevalence of PAD in an unselected group of HIV-infected individuals and to evaluate the potential value of a simple examination modality as a screening method. In spite of the acknowledged increased risk of cardiovascular disease in HIV-infected patients, our results did not show higher prevalence of PAD, compared to the general population. The lower prevalence in our cohort, as compared with some of the other studies in HIV-infected patients, may be explained by the rather low proportion of smokers, diabetics and normal CD4 cell counts and low viraemia. Also, this present study was carried out in a setting where the focus on CVD risk among HIV-infected patients is higher than before, and the ART regimens may have become less toxic with regard to the cardiovascular system [6]. Previous studies of PAD, defined as low ABI, have shown various results, both among HIVinfected subjects and in the population in general. Despite the simplicity of the measurement, different examination techniques exist (using Doppler vs oscillometric sphygmanometer, synchronic measurement of blood pressure vs ankle before arm, using highest vs lowest pressure for index, etc.). Further, heterogeneity of cohorts regarding age, sex, smoking habits or other cardiovascular risk factors, as well as the number investigated, contribute to the complexity of evaluating the modality. The American College of Cardiology Foundation and American Heart Association stated in their guideline for assessment of CVD risk in asymptomatic adults that measurement of ABI is reasonable in asymptomatic adults at intermediate risk (10–20% risk of cardiovascular disease over 10 years), yet acknowledging the conflicting evidence from studies [41]. The HIV-infected population is complex and heterogeneous, and consensus on how to screen for cardiovascular co-morbidities is still to be reached [42]. Whether our results are true negative, hereby excluding PAD and increased cardiovascular risk in these patients, or if they rather imply that ABI is not the modality to choose is unclear. However, the finding of a low prevalence of PAD would be in line with our own studies in the same type of HIV population using other modalities [14,43]. Nevertheless, it can be concluded that in a well-treated, unselected HIV population, measurement of ABI for screening purposes seems without obvious value. This study was limited by the relatively low number of patients, and the fact that only four patients had an ABI ⱕ 0.9 made assessment of risk factors difficult. We used a simple and validated technique for blood pressure measurement with an oscillometric sphygmanometer and pedal plantar flexions
HIV and peripheral arterial disease instead of the treadmill test for simplicity, which could lead to difficulties in comparison with other studies using different modalities. Declaration of interest: A.M.L. is a board member of Abbott and Bristol-Myers Squibb, and has received research funding and/or honoraria from Abbott, Bristol-Myers Squibb, Gilead, Tibotec and Glaxo Smith Kline. The remaining authors have no conflicts of interest.
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