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The prevalence of computer tomography defined coronary stenosis is similar in HIV-positive and HIV-negative patients.
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HIV-positive patients present higher rates of non-calcific coronary plaques.
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The prevalence of non-calcific coronary plaques in is higher in HIV-positive patients with low CD4+ T lymphocytes.
Abstract
Introduction
Asymptomatic patients with human immunodeficiency virus (HIV) infection are at increased risk of vascular disease. Whether asymptomatic HIV patients have increased prevalence or structural differences in coronary artery plaques is not clear.
Methods
Pubmed, Cochrane and Google Scholar were searched for articles evaluating asymptomatic HIV patients evaluated with coronary computed tomography. The prevalence of coronary stenosis (defined as >30% and >50%), of calcified coronary plaques (CCP) viewed as more ‘stable’ plaques, and of non-calcified coronary plaques (NCP) viewed as more ‘vulnerable’ plaques were the end points of interest.
Results
9 studies with 1229 HIV patients and 1029 controls were included. No significant differences were detected about baseline cardiovascular risk profile. The prevalence of significant coronary stenosis >30% or >50% did not differ between HIV+ and HIV- patients (42% [
Differences between HIV-infected and uninfected adults in the contributions of smoking, diabetes and hypertension to acute coronary syndrome: two parallel case-control studies.
] and 46% [35–52] with an Odds Ratio [OR] of 1.38 [0.86–2.20] for >30% stenosis) and (15% [9–21] and 14% [7–22] with an OR of 1.11 [0.81–1.52]), respectively. The prevalence of calcified coronary plaques (CCP) (31% [24–32] and 21% [14–30] with an OR of 1.17 [0.63–2.16]) also did not differ among HIV+ and HIV- patients. On the contrary rates of NCP were >3-fold higher in HIV-positive patients [58% (48–60) and 17% (14–27) with an OR of 3.26 (1–30-8.18)], with an inverse relationship with CD4 cell count at meta-regression (Beta −0.20 [-0.35-0.18], p 0.04).
Conclusion
Asymptomatic HIV patients present a similar burden of coronary stenosis and calcified coronary artery plaques but significantly higher rates of non-calcific coronary plaques at computed tomography. The association between HIV infection, reduced CD4 cell counts and higher prevalence on non-calcific coronary artery plaques may shed light into the pathogenesis in HIV-associated coronary artery disease, stressing the importance of primary prevention in this population.
]. Physicians managing these patients are shifting towards a more global assessment of clinical conditions, with a particular attention of development of both clinical and subclinical cardiovascular disease [
HIV patients, actually, are exposed for many years to the continuous interaction between traditional risk factors, coronary HIV infection, immune-mediated response and the still debated effect of HAART [
In acute coronary syndrome (ACS) settings, this peculiar pathological pattern has led to a higher risk of coronary adverse events; several challenges have been identified in those patients, such as drug to drug interaction with new antiaggregants or statins and compliance to medications [
Percutaneous coronary intervention and surgical revascularization in HIV Database (PHD) Study investigators Prognostic indicators for recurrent thrombotic events in HIV-infected patients with acute coronary syndromes: use of registry data from 12 sites in Europe, South Africa and the United States.
Acute coronary syndromes in human immunodeficiency virus patients: a meta-analysis investigating adverse event rates and the role of antiretroviral therapy.
Percutaneous coronary intervention and surgical revascularization in HIV Database (PHD) Study investigators Prognostic indicators for recurrent thrombotic events in HIV-infected patients with acute coronary syndromes: use of registry data from 12 sites in Europe, South Africa and the United States.
]. An increased use of coronary computed tomography (CCT) has been reported, both to measure coronary artery calcium (CAC) and to evaluate the prevalence and features of coronary plaques, in order to accurately address pharmacological and interventional strategies [
Coronary computed tomographic angiography for detection of coronary artery disease in patients presenting to the emergency department with chest pain: a meta-analysis of randomized clinical trials.
Eur. Heart J. Cardiovasc Imaging.2013 Aug; 14: 782-789
Prognostic value of aortic and mitral valve calcium detected by contrast cardiac computed tomography angiography in patients with suspicion of coronary artery disease.
] but the results are not consistent. Consequently we performed a systematic review to understand the prevalence and the peculiarities of coronary plaques in asymptomatic HIV-positive patients.
2. Methods
The Cochrane Collaboration and Meta-analysis Of Observational Studies in Epidemiology (MOOSE) [
Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of observational Studies in epidemiology (MOOSE) group.
] with Mesh strategy: ((coronary computed tomography) OR (CCT)) AND (hiv OR aids OR (human AND immunodeficiency AND virus)).
Two independent reviewers (F.DA, E.C.) first screened retrieved citations at the title and/or abstract level, with divergences resolved after consensus. If potentially pertinent, they were then appraised as complete reports according to the following explicit selection criteria. Studies were included if (i) investigating with CCT asymptomatic HIV and non HIV patients (ii) with more than 90% of patients treated with HAART. Exclusion criteria was (i) absence of non HIV controls.
2.2 Data extraction
Two unblinded independent reviewers (G.B.-Z, F.DA, and E.C.) abstracted the following data on pre-specified forms: authors, journal, year of publication, location of the study group, baseline features, type and timing of antiretroviral therapy, and protocols of CCT. The prevalence of coronary stenosis (more than 30% and more than 50%), of calcified coronary (CCP), of non-calcified coronary plaques (NCP) and of Coronary Artery Calcification Score (CAC) more than 0 were the end points of interest.
2.3 Internal validity and quality appraisal
Unblinded independent reviewers (G.B.-Z, F.DA, and E.C.) evaluated quality of included studies on pre-specified forms. Modifying the MOOSE items to take into account the specific features of included studies [
Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of observational Studies in epidemiology (MOOSE) group.
], we separately abstracted and appraised study design, setting, data source, as well as risk of analytical, selection, adjudication, detection, and attrition bias (expressed as low, moderate, or high risk of bias, as well as incomplete reporting leading to inability to ascertain the underlying risk of bias). For the quality assessment of the selected studies we used the Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Nonrandomized Studies in Meta-Analysis [
Continuous variables are reported as mean (standard deviation) or median (range). Categorical variables are expressed as n/N (%). Statistical pooling was performed according to a random-effect model with generic inverse-variance weighting, computing risk estimates with 95% confidence intervals, using RevMan 5 (The Cochrane Collaboration, The Nordic Cochrane Centre, and Copenhagen, Denmark). Meta-regression analysis for the impact of traditional risk factors and HIV features on the primary end point was performed with random effect with Comprehensive Meta-Analysis after computation of the event rate. All confidence intervals were of 95%). Standard hypothesis testing was set at the two-tailed 0.05 level.
3. Results
217 studies were first screened at abstract level, and after evaluation 9 studies with 1229 HIV patients and 1029 controls were included [
Increased coronary artery calcium score and noncalcified plaque among HIV-infected men: relationship to metabolic syndrome and cardiac risk parameters.
J. Acquir Immune Defic. Syndr.2010 Dec; 55: 495-499
Baseline features of the included patients are reported in Table 1. HIV patients were more frequently of male gender, with higher rates of diabetes mellitus and of hypertension in the included studies, but without significant differences.
Concerning immunovirological variables these patients had been on HAART for 8.3 (8–9) years, with a CD4+ T lymphocyte cell count of 529/mm3 (525–571) and a CD4+ nadir of 201 cells/mm3 (181–257). 52% (51–53) have been exposed to Protease Inhibitors (PI), 94% (81–96) to nonnucleoside reverse-transcriptase inhibitors (NNRT) and 46% (43–47) to nucleoside reverse-transcriptase inhibitors (NRTIs) (Table 2).
Table 2HIV status.
Median or %
First quartile
Third quartile
Cd4 cell count (mm3)
529
525
571
Cd4 nadir cell count (mm3)
202
181
257
Length of HAART (years)
8.3
8
9
Patients exposed to protease inhibitors (PI) (%)
52
51
53
Patients exposed to nonnucleoside reverse-transcriptase inhibitors (NNRT) (%)
94
81
96
Patients exposed to nucleoside reverse-transcriptase inhibitors (NRT) (%)
], they were included after a positive ergometric test. Protocols and definitions of CCT were consistent among all studies (Table A, Appendix web only).
Prevalence of significant coronary stenosis (>30%) did not differ between HIV+ and HIV- patients [42% (37–44) and 46% (35–52) with an Odds Ratio (OR) of 1.38 (0.86–2.20)]. Similarly prevalence of coronary stenosis above 50% (15% 9–21 and 14% 7–22 with an OR of 1.11 [0.81–1.52]), of calcific coronary plaques (31% 24–32 and 21% 14–30 with an OR of 1.17 [0.63–2.16] and of CAC above zero (43% [39–48] and 46% [26–56] with an OR of 0.88 [0.43–1,79] did not differ among HIV+ and HIV- patients (see Fig. 2, Fig. 3). On the contrary rates of NCP were significantly higher in HIV-positive patients [58% (48–60) and 17% (14–27) with an OR of 3.26 (1.30–8.18)] (Fig. 4).
Fig. 2Incidence of CCT findings in HIV and control patients.
At meta-regression analysis for coronary stenosis above 30% active smoking habit increased the risk (Beta 0.02 0.01–0.03, p < 0.001) in HIV+, Immunologic status and HAART therapy showed a neutral effect. Moreover, CD4 cell counts was inversely related to the risk of non-calcific plaque (the higher CD4 cell counts the lower the prevalence, Beta −0.20 -0.35–0.18 p 0.04). (see Table 3, Table 4, Fig. 5).
Table 3Meta-regression analysis on traditional cardiovascular risk factors and HIV status on finding of coronary stenosis (more than 30%).
Fig. 5Meta regression analysis for HIV + patients (smoking habits), and HIV- (age) on coronary stenosis more than 30% and on non calcific plaque (Cd4+).
At funnel plot analysis, low selection bias was noted (Fig. A).
4. Discussion
This is the first paper reporting a pooled analysis of data about CCT scan in asymptomatic HIV patients. The main findings are: 1) HIV-infected patients present higher rates of NCP compared to similar cohorts of HIV-negative subjects 2) NCP prevalence and degree were positively associated with worse immunovirological parameters, suggesting that disease stage contributes to cardiovascular instability.
NCP represent an early stage of atherosclerosis, resulting to be more prone to rupture and thrombus formation compared than calcified ones, potentially leading to ACS. These observations were already reported in series of patients evaluated by CCT as well in ACS patients undergoing angiography followed by grayscale and radiofrequency intravascular ultrasonography (IVUS) and were also consistent with pathological studies reporting that plaque more prone to rupture show a thin cap fibro atheroma and necrotic core with an overlying thin fibrous cap [
Previous CCT studies reported a higher prevalence of NCP in intermediate-risk asymptomatic patients, especially in those with significantly higher level of C-reactive protein, cholesterol (total and low-density lipoprotein) as well as a trend for a higher prevalence of diabetes mellitus [
Prevalence of noncalcified coronary plaques by 64-slice computed tomography in patients with an intermediate risk for significant coronary artery disease.
]. Our analysis includes a young population (median age of 47 years) with a low prevalence of diabetes and a moderate prevalence of hyperlipidemia (11% and 27% respectively). Despite these characteristics, the prevalence of NCP was 3-fold higher compared with similar Framingham-based score non-HIV population (58% vs. 17%) and comparable to the one reported in recent study [
We reported a CAC score value higher than zero in less than half of subjects. Even if CAC score of zero was associated with very low risk of cardiac events, NCP plaque cannot be detected on non-contrast cardiac scans, used to measure CAC levels. Previous studies utilizing CCT to estimate the extent of coronary artery disease in HIV patients assessed only CAC by scoring without explore directly the lumen caliber or plaques burden [
Coronary artery calcification, atherogenic lipid changes, and increased erythrocyte volume in black injection drug users infected with human immunodeficiency virus-1 treated with protease inhibitors.
]. Although the CAC scoring is a well defined marker for atherosclerotic lesions and cardiac event risk in non-HIV population, it may not provide a reliable valuation of early atherosclerosis in young HIV patients in whom calcifications are absent: our finding demonstrate that a significant proportion of patients with coronary atherosclerosis may be missed using only calcium score criterion. Thus we stressed the additional value of adopting CCT over CAC scoring alone for the assessment of coronary tree in young HIV-positive patients; since CCP probably reflects advanced stable atherosclerosis while identifying NCP seem crucial in this group of patients.
Additionally we reported a significant correlation between low CD4 cell counts and risk of NCP. The association between CD4 cell count and cardiovascular disease has already been previously reported and it may be related to immune-dysfunction (immune activation and immune senescence) or to the prevalence of other infection potentially affecting endothelial cells (cytomegalovirus, HHV-8, and others) [
]: our findings strengthen these observations supporting the hypothesis of a systemic inflammatory dysregulation in HIV-positive patients.
The only other variable that showed a positive interaction on the risk of coronary stenosis was active smoking status, accordingly to the higher risk of smoker-related comorbidities previously reported in HIV-infected than uninfected patient. Notably, these subgroup are actually an attractive target for a “multi-disease” screening since that recent studies are currently investigating the role of CT for lung cancer prevention in HIV-positive smokers even if with sparse results [
Differences between HIV-infected and uninfected adults in the contributions of smoking, diabetes and hypertension to acute coronary syndrome: two parallel case-control studies.
Clinical implications of present study may be of interest for physicians, cardiologists, infective disease specialists and general practitioners. Plaque characteristics observed using CCT underline the vulnerable atherosclerotic pattern of HIV-positive subjects, suggesting the need of aggressive primary prevention programs in this specific population. These data highlight the importance of addressing modifiable cardiovascular risk factors to optimize long-term health in the setting of HIV infection comorbidities. Although not confirmed in randomized controlled trial, statins use may be crucial, for their effect on plaques stability. A parallel focus on smoking cessation is important, considering the interaction on the risk of coronary stenosis demonstrated from several studies. Furthermore several data report the underuse of aspirin in primary prevention [
] in high-risk HIV-positive patients despite heightened awareness regarding elevated cardiovascular risk, although the absence of randomized controlled trials may explain such conduct.
Finally even if a CCT based approach for primary prevention has never been suggested to improve prognosis, these results may advise HIV physicians to evaluate and to focus on plaque characteristics in order to select appropriate primary prevention strategies
4.1 Limitations
Our study shares several limitations. Unfortunately it was not possible to report about long-term follow-up or hard clinical events in this population. Moreover we do not have detailed data about HAART regimen and almost all patients are male making it impossible to appraise specific differences. Third, we reported incidence of coronary stenosis more than 30% considering our aim to focus on plaques’ features independently of the degree of stenosis. Finally, the potential benefit by CCT needs to be weighted against its safety related to radiation exposure in asymptomatic young patients. Moreover as demonstrated in Table B, most of the included studies were of high quality, with an accurate definition of control population.
5. Conclusion
In this comprehensive meta-analysis, NCP was more prevalent and extensive in asymptomatic HIV-infected patients, especially in presence of lower CD4 cell counts. This finding provides new details on the differences in atherosclerotic process in HIV-infected patients, stressing the importance of primary prevention in this population. On the other hand the use of CCT may be considered in the future, if supported by larger prospective studies, as a complementary tool to evaluate high risk patients, both for traditional cardiovascular risk factors as well for severity of HIV infection.
Appendix.
Table ACCT's protocols.
Slice
Analysis
Non-calcified plaque
Post, 14
64 slice in 3 centers 320-row in 1 center
modified 15-segment model of the American Heart Association
any discernible structure that could be clearly assignable to the vessel wall, with a CT density less than the contrast enhanced coronary lumen but greater than the surrounding connective tissue, and identified in at least 2 independent planes.
D'Abramo, 13
64 slice
modified 15-segment model of the American Heart Association
–
Hwang, 13
64 slice in
modified 15-segment model of the American Heart Association
any discernible structure that could be clearly assignable to the vessel wall, with a CT density less than the contrast enhanced coronary lumen but greater than the surrounding connective tissue, and identified in at least 2 independent planes.
Zanni, 13
64 slice
modified 15-segment model of the American Heart Association
mean minimal attenuation less than 40 Hounsfield Units
Duarte, 12
64 slice
modified 15-segment model of the American Heart Association
any discernible structure that could be clearly assignable to the vessel wall, with a CT density less than the contrast enhanced coronary lumen but greater than the surrounding connective tissue, and identified in at least 2 independent planes.
Pereyra, 12
–
–
–
Burdo, 11
64 slice
modified 15-segment model of the American Heart Association
any discernible structure that could be clearly assignable to the vessel wall, with a CT density less than the contrast enhanced coronary lumen but greater than the surrounding connective tissue, and identified in at least 2 independent planes.
Fitch, 10
64 slice
modified 15-segment model of the American Heart Association
any discernible structure that could be clearly assignable to the vessel wall, with a CT density less than the contrast enhanced coronary lumen but greater than the surrounding connective tissue, and identified in at least 2 independent planes.
Lo, 10
64 slice
modified 15-segment model of the American Heart Association
any discernible structure that could be clearly assignable to the vessel wall, with a CT density less than the contrast enhanced coronary lumen but greater than the surrounding connective tissue, and identified in at least 2 independent planes.
Robinson, 10
64 slice
modified 15-segment model of the American Heart Association
any discernible structure that could be clearly assignable to the vessel wall, with a CT density less than the contrast enhanced coronary lumen but greater than the surrounding connective tissue, and identified in at least 2 independent planes.
Selection: – Adequate case definition: 9/10 – Representativeness of the cases: 9/10 – Selection of controls: 9/10 community Controls; 1/10 hospital controls – Definition of controls: 9/10 no History of disease
Comparability: – Study controls for cardiovascular risk factors: 9/10 – Study controls for cardiologist indications: 1/10
Percutaneous coronary intervention and surgical revascularization in HIV Database (PHD) Study investigators Prognostic indicators for recurrent thrombotic events in HIV-infected patients with acute coronary syndromes: use of registry data from 12 sites in Europe, South Africa and the United States.
Acute coronary syndromes in human immunodeficiency virus patients: a meta-analysis investigating adverse event rates and the role of antiretroviral therapy.
Coronary computed tomographic angiography for detection of coronary artery disease in patients presenting to the emergency department with chest pain: a meta-analysis of randomized clinical trials.
Eur. Heart J. Cardiovasc Imaging.2013 Aug; 14: 782-789
Prognostic value of aortic and mitral valve calcium detected by contrast cardiac computed tomography angiography in patients with suspicion of coronary artery disease.
Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of observational Studies in epidemiology (MOOSE) group.
Increased coronary artery calcium score and noncalcified plaque among HIV-infected men: relationship to metabolic syndrome and cardiac risk parameters.
J. Acquir Immune Defic. Syndr.2010 Dec; 55: 495-499
Prevalence of noncalcified coronary plaques by 64-slice computed tomography in patients with an intermediate risk for significant coronary artery disease.
Coronary artery calcification, atherogenic lipid changes, and increased erythrocyte volume in black injection drug users infected with human immunodeficiency virus-1 treated with protease inhibitors.
Differences between HIV-infected and uninfected adults in the contributions of smoking, diabetes and hypertension to acute coronary syndrome: two parallel case-control studies.
Since the advent of highly active anti-retroviral therapy (HAART), the prevalence of infectious complications in HIV-infected patients has dropped dramatically [1]. While up to 1995 these complications were directly responsible for more than 80% of the deaths, this rate has dropped to less than 20% in the recent cohorts [1]. Not only are HIV-infected individuals living longer and with better quality of life, but their causes of death are progressively resembling those of the non-HIV population. [1] Current data suggests that cardiovascular (CV) death is only second to cancer as the cause of death in this population [2].
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