|Year : 2018 | Volume
| Issue : 2 | Page : 362-367
Carotid intima-media thickness, flow-mediated dilatation and proteinuria in patients of human immunodeficiency virus-positive patients: A case–control study
Aarti Sharma1, Nikhil Gupta2, Dinesh Srivastava3
1 Department of Rheumatology, King George Medical University, Lucknow, Uttar Pradesh, India
2 Department of Rheumatology, Christian Medical College, Vellore, Tamil Nadu, India
3 Department of Internal Medicine, Max Super Specialty Hospital, New Delhi, India
|Date of Web Publication||11-Jul-2018|
Dr. Nikhil Gupta
Department of Rheumatology, Christian Medical College, Vellore, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Introduction: Endothelium-dysfunction (ED) is a surrogate marker of coronary atherosclerotic disease. Carotid intima-media thickness (CIMT), flow-mediated dilatation (FMD), and proteinuria are surrogate markers of ED. Few studies have shown that patients with HIV have impaired endothelial function and are thus at risk of accelerated atherosclerosis. Materials and Methods: The present study assessed ED in HIV patients by various biophysical parameters as brachial artery FMD, CIMT, and proteinuria. A total of 43 HIV-infected patients were compared with 25 healthy controls who were healthy. Results: Mean age of patients with HIV was 33.84 ± 5.61 years while that of healthy controls was 31.48 ± 5.40 years. Male to female ratio among cases was 24:19 while among controls was 17:8. Mean CIMT was significantly higher among cases than control (0.513 ± 0.079, 0.452 ± 0.050 mm, respectively, P = 0.001). Percentage change in FMD was significantly lower among cases than control (3.27 ± 2.01, 6.96 ± 1.28, respectively, P = 0.001). Urine protein grading was significantly different between cases and controls (P = 0.007), with stable HIV cases having significantly higher urine protein grading compared to healthy controls. However, no correlation was seen between CIMT, FMD, and proteinuria overall among cases and controls. Conclusions: HIV-infected patients have significant impairment of endothelial function, in the form of increased CIMT, impaired FMD, and more proteinuria as compared to healthy controls.
Keywords: Carotid intima-media thickness, endothelial dysfunction, flow-mediated dilatation, HIV, subclinical atherosclerosis
|How to cite this article:|
Sharma A, Gupta N, Srivastava D. Carotid intima-media thickness, flow-mediated dilatation and proteinuria in patients of human immunodeficiency virus-positive patients: A case–control study. J Family Med Prim Care 2018;7:362-7
|How to cite this URL:|
Sharma A, Gupta N, Srivastava D. Carotid intima-media thickness, flow-mediated dilatation and proteinuria in patients of human immunodeficiency virus-positive patients: A case–control study. J Family Med Prim Care [serial online] 2018 [cited 2019 May 21];7:362-7. Available from: http://www.jfmpc.com/text.asp?2018/7/2/362/236421
| Introduction|| |
HIV-infected patients are at higher risk for cardiovascular events. Thus, we need to identify the patients at risk at the earliest using easily obtainable, noninvasive, and inexpensive markers. Endothelial dysfunction (ED) is an early step that leads to progression of atherosclerosis. Proteinuria is another marker which predicts future cardiovascular events.
The development of systemic ED has been suggested as the link between the presence of proteinuria and development of cardiovascular disease. Not only HIV, its therapies have also been associated with ED. Endothelial function can be assessed by flow-mediated dilatation (FMD). Carotid intima-media thickness (CIMT) is a measure of the extent of early arterial wall changes. Increased carotid IMT is a strong predictor of acute coronary events. Thus, we conducted a study to look at the endothelial cell dysfunction in stable HIV patients and compare with healthy controls.
| Materials and Methods|| |
The study population included forty-three consecutive stable HIV patients attending Medical OPD and HIV clinic at a tertiary care hospital at New Delhi.
The aims of our study were:
- To study endothelial cell dysfunction in stable HIV patients as a marker of premature atherosclerosis by FMD, proteinuria, and carotid intima-media thickness
- To study its correlation with healthy controls.
We included stable patients of HIV (confirmed by IGM ELISA).
Patients with age <18 years and >40 years, overweight (body mass index >25 kg/m 2), suffering from preexisting diabetes mellitus or hypertension, receiving highly active antiretroviral therapy, suffering from known renal disease (serum creatinine >1.4 mg/dl or >124 μmol/L), history of cardiovascular and ischemic heart disease, fever (temperature >38.0°C) currently or 2 days before enrolment in the study, suffering from any opportunistic infection, smokers, alcoholics, or other active substance abuse, on drugs such as growth hormone, systemic steroids, ketoconazole, any form of estrogen, progesterone, testosterone, or any anabolic agents within 3 months before enrolment in the study and pregnant women were excluded from the study.
Twenty-five apparently healthy controls were residents and nurses working in the same tertiary care hospital. Exclusion criteria for controls were same as that for the HIV cases.
All the patients and controls in the study group were subjected to detailed history and physical examination. Informed consent was taken from both cases as well as controls. The study protocol has been evaluated and approved by the hospital Ethical Committee.
Following investigations were carried out in all the patients and controls:
- Brachial FMD using 10MHZ linear array transducer
- Common Carotid Ultrasonography-Using 7.5MHZ B-mode ultrasound with high-density lipoprotein 3500 machine, (ATL, USA) equipped with color flow imaging and pulse Doppler and one examiner examined the result of all the patients
- Urine examination-single spot urine sample for proteinuria and cells/casts was obtained.
The data of all patients were entered into Microsoft Excel version 2007. The data analysis was done by the SPSS software for window version 17(IBM Corporation, New York, United States). Quantitative variables were reported as mean ± standard deviation and were compared by Student's t-test or Mann–Whitney test as appropriate. One-way analysis of variance (ANOVA) model was used to compare cases and controls for difference of urine protein grading. Qualitative variables were reported and compared by Chi-square test or by Fischer's exact test as appropriate. P < 0.05 was considered statistically significant. Continuous variables were correlated using Pearson's correlation coefficient.
| Results|| |
Our study included 43 cases and 25 healthy controls. Proteinuria was estimated by dip stick method which is represented in [Table 1]. Baseline characteristics of both cases and controls are shown in [Table 2].
The studied parameters were compared which is shown in [Table 3].
Urine protein was also compared among cases and controls which is shown in [Table 4].
Urine protein grading was significantly different between cases and controls (P = 0.007), with stable HIV cases having significantly higher urine protein grading compared to healthy controls (one-way ANOVA). In urine microscopy, cells and casts were absent both in cases and controls.
The association between the parameters was calculated which is shown in [Table 5].
|Table 5: Association between various studied parameters overall in cases and controls|
Click here to view
| Discussion|| |
In this study, we studied forty-three stable HIV patients and twenty-five apparently healthy controls and looked for any significant difference between stable HIV patients and controls with respect to CIMT, FMD, and proteinuria and examined the relationship between CIMT, FMD, and proteinuria and their use as a marker of ED for premature atherosclerosis.
In our study, we found higher baseline mean CIMT in HIV-positive patients (0.513 ± 0.079 mm), as compared to controls (0.452 ± 0.050 mm) with a significant difference (P = 0.001). [Table 6] summarizes previous major studies on CIMT in HIV patients.
|Table 6: Summary of previous major studies on carotid intima media thickness in human immunodeficiency virus patients|
Click here to view
In our study, we excluded the patients on HAART to prevent its effect on CIMT.
We also found that in stable HIV patients have increased in brachial artery diameter in response to passive hyperemia which was significantly lower as compared to healthy controls (3.27 ± 2.01 mm vs. 6.96 ± 1.28 mm, P < 0.001). Furthermore, significantly lower HIV cases had percent FMD ≥4.5% as compared to controls (23.3% vs. 100%, P < 0.001). [Table 7] summarizes previous major studies of FMD in HIV patients.
|Table 7: Summary of previous major studies on flow-mediated dilatation in human immunodeficiency virus patients|
Click here to view
Our finding of unequal percentage FMD in HIV patients and non-HIV participants is in agreement with previous studies that found decreased FMD in HIV patients compared to HIV-uninfected controls , but in contrast to other studies , that found equal FMD in HIV patients and non-HIV participants. Various explanations have been proposed for conflicting results regarding brachial FMD in the literature. These include heterogeneity in patient populations being studied, different measurement protocols or inadequate sample sizes.
We also found significant difference in urine protein grading between stable HIV cases and healthy controls, with overall urine protein grading significantly higher in HIV cases compared to healthy controls (P = 0.007). [Table 8] summarizes the previous major studies on proteinuria in HIV patients.
|Table 8: Summary of previous major studies on proteinuria in human immunodeficiency virus patients|
Click here to view
The high prevalence of proteinuria in this cohort of HIV-infected patients in our study is similar to earlier reports , from HIV-infected children and adults. The implication of this observation is that markers of kidney damage such as proteinuria should be searched for in HIV-infected patients with advanced clinical and or immunological stage of HIV disease.
We also found a weak inverse relationship between carotid IMT and brachial percent FMD but not significant (r = −0.197, P = 0.107), when data were combined both for HIV cases and healthy controls. There is only one previous study by Odueyungbo et al. (257 HIV patients), that has validated this correlation in HIV patients with borderline significance (r = −0.126, P = 0.043).
We did not find any significant correlation between percentage FMD and proteinuria, overall in HIV cases and healthy controls (P = 0.177). After an extensive review of literature, we could find only one pilot study of its kind to study the relation between FMD and proteinuria in stable HIV patients. This study by Gupta et al. of 34 stable HIV patients (28 nonproteinuric and 6 proteinuric), also could not establish any significant correlation between proteinuria and FMD.
We did not find any significant correlation between CIMT and proteinuria (P = 0.764), overall in HIV cases and healthy controls and also, separately for HIV cases (P = 0.178). To the best of our knowledge, this is the first study of its kind to study the association between CIMT and proteinuria.
Although HIV infection appears to be associated with substantial impairment of endothelial function, the degree to which this impairment translates into increased risk for cardiovascular disease in persons with HIV infection is still largely unknown. Large prospective, well-controlled studies are required to demonstrate that impaired endothelial functions translate into increased cardiovascular events and premature death in stable HIV patients.
Several limitations of our study need attention. First, the sample size of our study was small, limiting our ability to detect potentially clinically important associations. Second, proteinuria was determined by a semi-quantitative measure of urine protein concentration (dipstick), which is inferior to quantitative measures such as protein-to-creatinine ratio from a random or 24-h sample. Third, other potential confounders that were not accounted for include diet, physical activity, duration of HIV infection, and CD4 count.
| Conclusions|| |
Indian stable HIV patients have increased ED, as evidenced by increased carotid intima-media thickness, impaired FMD, and higher proteinuria. This subclinical ED would probably translate into premature atherogenesis and increased vascular events in these patients. However, the correlation between these various surrogates of endothelial cell function was poor in Indian stable HIV patients.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
James JS. Atherosclerosis risk increased with HIV; Treatment effects unclear. AIDS Treat News 2004;26:4-5.
Currie G, Delles C. Proteinuria and its relation to cardiovascular disease. Int J Nephrol Renovasc Dis 2013;7:13-24.
Solages A, Vita JA, Thornton DJ, Murray J, Heeren T, Craven DE, et al.
Endothelial function in HIV-infected persons. Clin Infect Dis 2006;42:1325-32.
Mary-Krause M, Cotte L, Simon A, Partisani M, Costagliola D; Clinical Epidemiology Group from the French Hospital Database, et al.
Increased risk of myocardial infarction with duration of protease inhibitor therapy in HIV-infected men. AIDS 2003;17:2479-86.
Stein JH, Korcarz CE, Hurst RT, Lonn E, Kendall CB, Mohler ER, et al.
Use of carotid ultrasound to identify subclinical vascular disease and evaluate cardiovascular disease risk: A consensus statement from the American Society of Echocardiography Carotid Intima-media Thickness Task Force. Endorsed by the society for vascular medicine. J Am Soc Echocardiogr 2008;21:93-111.
George JM, Bhat R, Pai KM, S A, Jeganathan J. The carotid intima media thickness: A predictor of the clincal coronary events. J Clin Diagn Res 2013;7:1082-5.
Kaplan RC, Kingsley LA, Gange SJ, Benning L, Jacobson LP, Lazar J, et al.
Low CD4+ T-cell count as a major atherosclerosis risk factor in HIV-infected women and men. AIDS 2008;22:1615-24.
Lorenz MW, Stephan C, Harmjanz A, Staszewski S, Buehler A, Bickel M, et al.
Both long-term HIV infection and highly active antiretroviral therapy are independent risk factors for early carotid atherosclerosis. Atherosclerosis 2008;196:720-6.
Currier JS, Kendall MA, Henry WK, Alston-Smith B, Torriani FJ, Tebas P, et al.
Progression of carotid artery intima-media thickening in HIV-infected and uninfected adults. AIDS 2007;21:1137-45.
de Saint Martin L, Vandhuick O, Guillo P, Bellein V, Bressollette L, Roudaut N, et al.
Premature atherosclerosis in HIV positive patients and cumulated time of exposure to antiretroviral therapy (SHIVA study). Atherosclerosis 2006;185:361-7.
Hsue PY, Hunt PW, Sinclair E, Bredt B, Franklin A, Killian M, et al.
Increased carotid intima-media thickness in HIV patients is associated with increased cytomegalovirus-specific T-cell responses. AIDS 2006;20:2275-83.
Jericó C, Knobel H, Calvo N, Sorli ML, Guelar A, Gimeno-Bayón JL, et al.
Subclinical carotid atherosclerosis in HIV-infected patients: Role of combination antiretroviral therapy. Stroke 2006;37:812-7.
Maggi P, Perilli F, Lillo A, Gargiulo M, Ferraro S, Grisorio B, et al.
Rapid progression of carotid lesions in HAART-treated HIV-1 patients. Atherosclerosis 2007;192:407-12.
Mangili A, Gerrior J, Tang AM, O'Leary DH, Polak JK, Schaefer EJ, et al.
Risk of cardiovascular disease in a cohort of HIV-infected adults: A study using carotid intima-media thickness and coronary artery calcium score. Clin Infect Dis 2006;43:1482-9.
Currier JS, Kendall MA, Zackin R, Henry WK, Alston-Smith B, Torriani FJ, et al.
Carotid artery intima-media thickness and HIV infection: Traditional risk factors overshadow impact of protease inhibitor exposure. AIDS 2005;19:927-33.
Hsue PY, Lo JC, Franklin A, Bolger AF, Martin JN, Deeks SG, et al.
Progression of atherosclerosis as assessed by carotid intima-media thickness in patients with HIV infection. Circulation 2004;109:1603-8.
Depairon M, Chessex S, Sudre P, Rodondi N, Doser N, Chave JP, et al.
Premature atherosclerosis in HIV-infected individuals – Focus on protease inhibitor therapy. AIDS 2001;15:329-34.
Maggi P, Serio G, Epifani G, Fiorentino G, Saracino A, Fico C, et al.
Premature lesions of the carotid vessels in HIV-1-infected patients treated with protease inhibitors. AIDS 2000;14:F123-8.
Blanco JJ, García IS, Cerezo JG, de Rivera JM, Anaya PM, Raya PG, et al.
Endothelial function in HIV-infected patients with low or mild cardiovascular risk. J Antimicrob Chemother 2006;58:133-9.
Nolan D, Watts GF, Herrmann SE, French MA, John M, Mallal S, et al.
Endothelial function in HIV-infected patients receiving protease inhibitor therapy: Does immune competence affect cardiovascular risk? QJM 2003;96:825-32.
Stein JH, Klein MA, Bellehumeur JL, McBride PE, Wiebe DA, Otvos JD, et al.
Use of human immunodeficiency virus-1 protease inhibitors is associated with atherogenic lipoprotein changes and endothelial dysfunction. Circulation 2001;104:257-62.
van Wijk JP, de Koning EJ, Cabezas MC, Joven J, op't Roodt J, Rabelink TJ, et al.
Functional and structural markers of atherosclerosis in human immunodeficiency virus-infected patients. J Am Coll Cardiol 2006;47:1117-23.
Chaparro AI, Mitchell CD, Abitbol CL, Wilkinson JD, Baldarrago G, Lopez E, et al.
Proteinuria in children infected with the human immunodeficiency virus. J Pediatr 2008;152:844-9.
Szczech LA, Gange SJ, van der Horst C, Bartlett JA, Young M, Cohen MH, et al.
Predictors of proteinuria and renal failure among women with HIV infection. Kidney Int 2002;61:195-202.
Esezobor CI, Iroha E, Onifade E, Akinsulie AO, Temiye EO, Ezeaka C, et al.
Prevalence of proteinuria among HIV-infected children attending a tertiary hospital in Lagos, Nigeria. J Trop Pediatr 2010;56:187-90.
Eke FU, Anochie IC, Okpere AN, Ugboma H. Proteinuria in HIV positive children – A pilot study. Pediatr Nephrol 2007;22:1456.
Emem CP, Arogundade F, Sanusi A, Adelusola K, Wokoma F, Akinsola A, et al.
Renal disease in HIV-seropositive patients in nigeria: An assessment of prevalence, clinical features and risk factors. Nephrol Dial Transplant 2008;23:741-6.
Agaba EI, Agaba PA, Sirisena ND, Anteyi EA, Idoko JA. Renal disease in the acquired immunodeficiency syndrome in North central Nigeria. Niger J Med 2003;12:120-5.
Odueyungbo A, Smieja M, Thabane L, Smaill F, Gough K, Gill J, et al.
Comparison of brachial and carotid artery ultrasound for assessing extent of subclinical atherosclerosis in HIV: A prospective cohort study. AIDS Res Ther 2009;6:11.
Gupta SK, Mather KJ, Agarwal R, Saha CK, Considine RV, Dubé MP, et al.
Proteinuria and endothelial dysfunction in stable HIV-infected patients. A pilot study. J Acquir Immune Defic Syndr 2007;45:596-8.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]