Detection of Subclinical Coronary Artery Lesions by Framingham Risk Score,Peripheral Artery Atheromatosis and Coronary Artery Calcium Score: A Pilot Study in Asymptomatic Individuals Living with HIV

Abstract

The incidence of acute coronary events is increased among people living with HIV (PLWH), but there is no risk estimation score, nor a surrogate biomarker able to predict subclinical coronary artery disease (sCAD). We assessed the performance of: (i) Framingham risk score (FRMs), (ii) peripheral (carotid and femoral) artery atheromatosis, and (iii) coronary artery calcium (CACs) score, to detect the presence of sCAD, in PLWH. In a cohort of PLWH free of cardiovascular disease (CVD), we measured sCAD and CACs by computed tomography, calculated FRMs, and assessed carotid/femoral plaques by ultrasound. In 56 participants (age: 49 ± 10 years, men: 88%, FRMs: 7.2 ± 6.9; mean number of carotid/femoral plaques: 1.4 ± 1.5; CACs >0 present in 59%, median CACs 0.9 [IQR 0–22]): (i) minimal sCAD (stenosis 1%–24%; present in 30%) and mild sCAD (25%–49%, 25%) were effectively detected by FRMs, number of plaques, and CACs [area under the curve (AUC) of CACs was better than that of both FRM and plaques, p < .05]; (ii) moderate sCAD (stenosis 50%–69%; present in 8.9%) was detected by number of plaques and CACs, but similar AUC (0.969 vs. 0.867, respectively, p = NS); and (iii) severe sCAD (70%–99%, present in only 3 [5.4%]) was detected only by CACs. A high prevalence of sCAD in asymptomatic PLWH free of CVD was detected; CACs is a highly efficient biomarker to detect all grades of sCAD, however, the number of carotid/femoral plaques combined is also a very promising—lower cost and radiation free—surrogate biomarker. Future, larger studies are needed to verify these results.

Introduction

The advent of antiretroviral therapy (ART) has significantly prolonged the disease progression-free survival of people living with HIV (PLWH) over the past decades.^1,2 PLWH without other significant comorbidities, who started ART early in the course of the infection, can expect a life expectancy approaching that of the general population.³ Consequently, cardiovascular disease (CVD) has emerged as one of the prevailing causes of death in this population.^1

–4 Even virally suppressed PLWH have 50%–75% higher risk of acute coronary syndrome compared with the general population after rigorous adjustment for multiple traditional risk factors.^5,6 The mechanisms underlying the appearance of accelerated coronary artery disease (CAD) in PLWH has been shown to be related to increased platelet reactivity, procoagulant state, residual systemic inflammation despite viral suppression, ART exposure, and excess of the traditional cardiovascular risk factors.⁷

In the general population, presence of subclinical CAD (sCAD), defined as the presence of any coronary plaque, and detected by coronary computed tomography angiography (CCTA) is associated with higher incidence of CVD events.⁸ The degree of coronary artery stenoses (obstructive vs. nonobstructive [either as 1%–49% or 1%–69% luminal stenosis] vs. no lesions) and the number of diseased vessels in CCTA are closely correlated with CVD outcomes and all-cause mortality, and better stratify risk of CVD compared with coronary artery calcium (CACs) score in young adults.⁹ Several studies have also demonstrated an association between HIV infection and the presence of sCAD, as assessed by CCTA.⁷ Given the limitations pertaining to the wide use of CCTA (cost, availability, radiation exposure), several risk scores and noninvasively measured vascular biomarkers have been used to reclassify patients with regard to their risk of sCAD.^10,11 One of the most commonly used risk scores is the Framingham risk score (FRMs), which considers six well-established risk factors of CAD, namely age, gender, total cholesterol, high-density lipoprotein cholesterol, smoking, and systolic blood pressure. However, such studies in PLWH are for the time being lacking.

Multiple scores have been developed to predict the risk of incident CVD. However, these scores are based on large unselected general populations, and their reproducibility and prognostic value in subpopulations with special characteristics, such as PLWH, is limited.^12,13 Interestingly, the best performing score for prediction of prevalence and incidence of peripheral artery disease in PLWH, at least in Greek patients, seems to be the FRMs.¹⁴

Coronary artery imaging modalities have gained significant popularity lately to better understand the pathophysiology of CAD and provide improved risk assessment beyond traditional risk factors in this specific population.¹⁵ In this respect, the utility of CACs, using noncontrast computed tomography (CT), to stratify patients at risk for future CVD events has been well studied and established in the general population.¹⁶ A CACs >100 has also been shown to have prognostic value in PLWH.¹⁷ Given, although that CACs have limited ability to detect noncalcified plaques, which seem to be the prevailing type of atheromatic plaques in PLWH,¹⁸ CACs may not be the optimal index of risk stratification for future CVD events among these individuals. On the other hand, the less-expensive, readily available, and radiation-free ultrasound imaging of peripheral arteries has well established the increased incidence of subclinical peripheral arterial atheromatosis (carotid and/or femoral) in PLWH,^{14,19

–23} and might be used as a surrogate biomarker of coronary lesions even at the subclinical level.

The aim of the present cross-sectional pilot study was to assess the performance of: (i) FRMs, (ii) presence of peripheral artery atheromatosis, namely the presence of carotid and/or femoral plaques assessed by ultrasound, and (iii) CACs, to identify the presence of sCAD as assessed by CCTA, in a cohort of asymptomatic, free of established CVD, PLWH.

Materials and Methods

The Ethics Review Board of our institution (Laiko General Hospital of Athens) approved this study (Protocol No. 12/19-1-2018), which conforms to the principles outlined in the Declaration of Helsinki and all its participants granted an informed consent.

Study population

Consecutive consenting PLWH with at least one cardiovascular risk factor who were followed at the outpatient Clinic of the Infectious Diseases Unit from January 2017 to July 2018 of our department were recruited. Exclusion criteria were: (i) age <18 years, (ii) history of diabetes and/or presence of established CVD, (iii) active injection drug use, (iv) coinfection with hepatitis B or C. Hepatitis/HIV coinfection has been shown to increase the risk of CVD, so selection of a population of HIV mono-infected individuals was included.

Study design

All study participants underwent baseline CCTA and vascular assessment and completed medical structured questionnaires on their demographic, clinical, and medical history characteristics.

Study procedures and data collection

Demographic characteristics, detailed medical history, including classical CVD risk factors such as smoking, arterial hypertension and dyslipidemia, clinical characteristics, and drug regimen and doses were recorded at baseline. The patients underwent thorough physical and laboratory examination, including height and body weight measurements with calculation of body mass index, blood pressure and heart rate measurements, and levels of serum glucose, creatinine, and lipid measurements. Additionally, CD4 count, HIV viral load, receipt of antiretroviral medications and duration of therapy with each agent, nadir CD4 count, and disease duration were also recorded. The Framingham score equation for 10-year coronary heart disease events was used as the FRMs in the present analysis.

Noncontrast CT and CCTA

Acquisition and analysis of CCTA images were performed with a Siemens Somatom Definition AS 128+. The data acquisition protocol consisted of two parts. First, a noncontrast scan was performed for calculation of the CACs. Second, a scan was performed for evaluation of the coronary arteries with contrast and standard retrospective gating. On average, 96 ± 14 mL of iodinated contrast medium (400 mg iodine/mL) was then injected at a flow rate of 6 mL/s, followed by 30 mL of saline at 5 mL/s. Sublingual nitrates were used in all patients. Detector collimation was 128 × 0.6 mm, with a gantry rotation of 0.5 s and pitch of 0.6. Images were reconstructed using IR algorithms SAFIRE 3. Also, a tube voltage of 80–120 kV with 85–254 mAs was used. The arterial segments of interest were reconstructed in end systole, end diastole, and 40% and 70% of the R–R interval. The coronary CCTAs were analyzed in a core laboratory by the same observer. The recently proposed Society of Cardiovascular Computed Tomography grading scale for stenosis severity was used to assess the degree of luminal diameter stenosis (19): 0% = no visible stenosis; 1%–24% = minimal stenosis; 25%–49% = mild stenosis; 50%–69% = moderate stenosis; 70%–99% = severe stenosis; and 100% = occlusion. A stenosis >50% of the left main coronary artery was considered severe.¹⁹

Peripheral atheromatosis by ultrasound

All participants underwent vascular examination performed by the same trained operator. Ultrasonography imaging with LOGIQ V5 Expert (General Electric Healthcare, Little Chalfont, United Kingdom) was also utilized to assess the presence of atheromatic plaques at eight overall arterial sites, that is, the internal carotid artery, the common carotid artery, the carotid sinus, and the femoral arteries (right and left). A plaque was defined as a bulging to the lumen intima-medial thickness (IMT) greater than 1.5 mm or local increase of the IMT of more than 50% compared with the adjacent vessel wall, according to international guidelines.²⁴

Statistical analyses

Statistical analyses were performed with Superior Performance Software System, version 21.0 (IBM, Armonk, NY) and Medcalc, version 19.5.3. The Kolmogorov–Smirnov goodness-of-fit test was used to assess distribution of each variable. Continuous variables, which were normally distributed, are presented as mean ± standard deviation, whereas non-normally distributed variables are presented as median [25th–75th percentile]. Categorical variables are presented as counts (percentages). For evaluation of the diagnostic utility of each parameter to detect the presence of sCAD in the study population, receiver operating characteristic (ROC) curves were applied. Results are expressed as area under the curve (AUC) with 95% confidence intervals (CI). The AUCs of the different parameters tested were compared with the Delong method.²⁵ All p values were two-sided and a value <.05 was considered statistically significant for all analyses.

Results

Fifty-six consecutive patients were enrolled between January 2017 and July 2018. Mean age of the participants was 49 ± 10 years, 88% were male, 57% active smokers, whereas mean HIV duration was 8.9 ± 6.9 years. Mean FRMs was 7.2 ± 6.9. Baseline characteristics of study cohort are depicted in Table 1.

Table 1.

Baseline Characteristics of Study Participants (n = 56)

Age, years	49 ± 10 [40–55]
Male sex	49 (88)
Body mass index, kg/m²	27 ± 5 [24–29]
Waist circumference, cm	98 ± 14 [89–105]
Family history of coronary artery disease	8 (14)
Smoking
No	15 (27)
Active	32 (57)
Former	9 (16)
Smoking, pack-years	23 ± 13 [10–34]
History of hypertension	9 (16)
History of dyslipidemia	15 (27)
Systolic arterial pressure, mmHg	119 ± 19 [105–123]
Diastolic arterial pressure, mmHg	70 ± 7 [65–77]
Heart rate, bpm	71 ± 10 [64–78]
Glucose, mg/dL	95 ± 14 [85–100]
Total cholesterol, mg/dL	184 ± 42 [155–213]
Low-density lipoprotein, mg/dL	111 ± 34 [81–131]
High-density lipoprotein, mg/dL	44 ± 12 [35–49]
Triglycerides, mg/dL	152 ± 78 [93–189]
Creatinine, mg/dL	0.9 ± 0.2 [0.80–1.00]
HIV duration, years	8.9 ± 6.9 [4.5–12.2]
Nadir CD4 count	300 ± 205 [115–405]
CD4 count	841 ± 400 [543–1,131]
Antiretroviral therapy	48 (86)

Data are presented as mean ± standard deviation [25th–75th percentile] or counts (%).

Coronary CT angiography

CACs >0 was present in 33/56 (59%) patients and CACs >100 in 8/56 (14%). Median CAC score was 0.9 [IQR 0–22]. sCAD, defined as the presence of at least one minimal coronary artery stenosis was present in 17/56 (30%) of patients. Among these, 4 (23.5%) patients had at least one noncalcified plaque, whereas 10 (58.8%) only calcified plaques and 3 (17.6%) both calcified and mixed type of plaques. The exact prevalence of sCAD and the other findings of CCTA are depicted in detail in Table 2. Mean left ventricular ejection fraction and mass were 66% ± 7% and 124 ± 41 g, respectively; an ejection fraction lower than 40% was not detected in any individual.

Table 2.

Results of Vascular Ultrasound, Noncontract Computed Tomography, and Contract Coronary Computed Tomography Angiography in People Living with HIV, All Free of Symptomatic Cardiovascular Disease (Coronary and Peripheral)

Peripheral subclinical atheromatosis by ultrasound
Mean number of carotid plaques	0.9 ± 1.3
Carotid artery atheromatosis (at least 1 out of 8 evaluated site), n (%)	21 (40)
Mean number of femoral plaques	0.5 ± 0.5
Femoral artery atheromatosis (at least 1 out of 2 evaluated sites), n (%)	26 (49)
Mean number of peripheral atheromatosis (carotid and femoral plaques)	1.4 ± 1.5
Peripheral atheromatosis (carotid or femoral plaques), n (%)	34 (59)
Noncontrast computed tomography
Median CAC scores	0.9 [0–22]
CAC score >0, n (%)	33 (59)
CAC score >100, n (%)	8 (14)
Coronary artery and heart assessment by contrast computed tomography angiography
Mean number of coronary lesions	3.6 ± 4.5
Any coronary plaque, n (%)	17 (30)
Calcified coronary plaques, n (% among individuals with a coronary plaque)	10 (59)
Mean number of coronary stenosis	2.0 ± 3.3
At least minimal coronary stenosis (CAD-RAD ≥1), n (%)	17 (30)
At least mild coronary stenosis (CAD-RAD ≥2), n (%)	14 (25)
At least moderate coronary stenosis (CAD-RAD ≥3), n (%)	5 (8.9)
Severe coronary stenosis (CAD-RAD ≥4), n (%)	3 (5.4)
Left ventricular ejection fraction	66 ± 7.0
Left ventricular mass, g/1.73 m²	124 ± 41

CACs, coronary artery calcium; CAD-RAD, coronary artery disease–reporting and data system.

Prevalence of carotid and femoral artery atheromatosis was 38% and 46%, respectively (Table 2). The mean number of peripheral atheromatic plaques was 1.4 ± 1.5 plaques. No participant had overt peripheral arterial disease, as documented by an abnormal ankle–brachial index (<0.9).

Ability of noninvasive indices to identify abnormal CAC score and presence of sCAD

The performance of the various FRMs, CACs, and total number of peripheral (carotid and femoral) plaques to detect the presence of sCAD is depicted in Table 3. Minimal and mild sCAD could be reliably detected by all three indices. The CACs had the highest AUC compared with FRMs (p = .006 and p = .03 for minimal and mild sCAD, respectively), as well as to the total number of peripheral plaques (p = .002 for both minimal and mild sCAD). Moderate sCAD could not be reliably detected by FRMs; on the contrary, both CACs (sensitivity of 100% and a specificity of 93% when a cutoff of CAC >50 was used) and the number of peripheral plaques (sensitivity of 75% and a specificity of 86% when a cutoff >3 plaques was used), reliably detected moderate sCAD. Most importantly, the ROC curves of the two indices did not differ significantly regarding moderate sCAD detection (p = .10). Notably, the presence of severe sCAD (Table 3) could be detected only by the CACs. When a cutoff of CAC >50 was used a sensitivity of 100% and a specificity of 93% was reported.

Table 3.

Performance of Framingham 10-Year Coronary Heart Disease Score (Framingham Risk Score), Peripheral Atheromatosis (Combined Total Number of Carotid and Femoral Plaques Combined) and Coronary Artery Calcium Score to Detect the Presence of Subclinical Coronary Artery Disease Presence

	AUC (95% CI)	p
At least minimal sCAD, n = 17
FRMs	0.821 (0.709–0.932)	<.001
Total number of peripheral plaques	0.765 (0.625–0.905)	.002
CACs	0.977 (0.001–1.000)	<.001^a
At least mild sCAD, n = 14
FRMs	0.826 (0.715–0.937)	<.001
Total number of peripheral plaques	0.765 (0.625–0.905)	.002
CACs	0.952 (0.900–1.000)	<.001^b
At least moderate sCAD, n = 5
FRMs	0.720 (0.536–0.904)	.107
Total number of peripheral plaques	0.837 (0.637–1.000)	.026
CACs	0.969 (0.001–1.000)	.001^c
Severe sCAD, n = 3
FRMs	0.718 (0.429–1.000)	.208
Total number of peripheral plaques	0.797 (0.549–1.000)	.087
CACs	0.962 (0.001–1.000)	.007

Figures in bold are statistically significant.

p < .05 for the difference of “CACs” AUC and the AUC of both “FRMs” and “Total number of peripheral plaques,” as compared with the Delong method.²⁵

Nonsignificant difference between the AUC of “CAC” and “Total number of peripheral plaques,” as compared with the Delong method.²⁵

AUC, area under the curve; CI, confidence interval; FRM, Framingham risk score; sCAD, subclinical coronary artery disease.

With regard to noncalcified stenoses, neither FRMs (AUC: 0.667; 95% CI: 0.372–0.962, p = .332), nor CACs (AUC: 0.731; 95% CI: 0.436–1.000, p = .174), or the number of peripheral plaques (AUC: 0.771; 95% CI: 0.538–1.000, p = .115) could reliably detect their presence.

Discussion

In the present pilot study we tested the performance of: (i) a widely used CVD risk score designed for the general population, that is, the FRMs, (ii) an easy-to-apply and low-cost noninvasive biomarker, that is, the combined number of atheromatic plaques detected by ultrasound at the level of the carotid and femoral bed, and (iii) the CACs as measured by CT, to detect the presence of different grades of sCAD and the presence of noncalcified coronary stenoses, as assessed by CCTA, in PLWH. There are five main findings of this study. First, sCAD is present in almost one out of three asymptomatic PLWH. Second, the FRMs performed reasonably well in identifying only the presence of minimal and mild sCAD, but failed to predict the presence of moderate or severe sCAD. Third, peripheral atheromatosis (carotid and femoral plaques combined), detected the presence of minimal, mild, and moderate sCAD with a clinically meaningful accuracy (sensitivity of 75% and a specificity of 86% when a cutoff >3 plaques was used). Fourth, the CACs showed an excellent diagnostic accuracy for detecting sCAD, irrespectively of the grade of the stenosis; the optimal CAC's cutoff level was 50, which provided impressive sensitivity (100%) and specificity (93%). Finally, in contrast to previous publications,⁷ in our cohort the unstable and noncalcified plaques were not the most prevalent type leading to stenosis and none of the tested parameters could reliably predict their presence, although this may be possibly related to small number of prevalent cases.

This is a single-center, single-operator study that attempts to stratify PLWH as per their risk of sCAD presence assessed by CCTA, using a readily available prediction score, a noninvasive vascular biomarker, and CACs. In this regard, our study is unique in the literature. Recent data suggest that PLWH have a high burden of sCAD, which in turn is followed by a higher incidence of acute coronary syndromes during follow-up compared with HIV-negative individuals.²⁶ Indeed, our cohort suggests that almost one out of three asymptomatic and free of established CVD individuals with HIV have at least minimal sCAD. Therefore, timely detection of sCAD in this specific patient population may have important therapeutic implications.

The current European AIDS Clinical Society guidelines recommend that the CVD risk stratification should be performed at least every 2 years in PLWH and that national scores should be preferred when available.²⁷ Nonetheless, we have recently shown that—at least in the Greek population—the FRMs score outperforms all the other scores, including the HIV-specific D:A:D score, and the Greek population-specific ESC 10-year Heart Score in detecting the presence and progression of subclinical vascular disease in PLWH.¹⁴ A single study, performed a decade ago, demonstrated that there was a significant, although unadjusted for confounders, association between FRMs and sCAD burden in men living with HIV,²⁸ a finding which is corroborated by our study.

Although it was beyond the scope of our study to test the concordance of FRMs and CACs, we found that CACs could detect the presence of sCAD of all grades (from mild up to severe) with the highest accuracy compared with the other tested parameters. Interestingly, the best cutoff for risk stratification was 50, which provided impressive sensitivity (100%) and specificity (93%), contrary to the frequently used cutoffs of 0 or 100. The use of CACs has been recently suggested to better stratify CVD risk and guide therapeutic decisions in asymptomatic PLWH.²⁹ However, CACs can be calculated using noncontrast chest CT, which is accompanied by significant cost, it exposes the examinees to excessive radiation,³⁰ and it is at present rarely indicated for sCAD detection and risk assessment in asymptomatic individuals with stable coronary heart disease.³¹ However, it could be reasonably used to identify high-risk patients—based on other parameters—who would benefit from further investigations, including CCTA.

Given the cost and radiation-related limitations of CACs, other noninvasive, low-cost modalities, able to stratify CAD risk in PLWH are needed to identify the subset of PLWH who would most benefit from further work-up, enabling targeted use of CACs and CCTA and optimizing health care resources and cost utilization. In this direction, vascular ultrasound has the potential to play a pivotal role. Our study reinforces this notion; the total number of peripheral (carotid and femoral) atheromatic plaques (with optimal cutoff of the number of three plaques) could detect the presence of almost all grades of sCAD (excluding severe stenosis, most likely due to the very small number of three events in the present cohort) with clinically significant accuracy, superior to the one provided by FRMs and in some case statistically similar to CACs. Consequently, a stepped and combined approach of FRMs, peripheral artery ultrasound and CACs might be tested in future studies and used to optimally risk stratify asymptomatic PLWH and forward them for further diagnostic and/or therapeutic modalities.

Noncalcified stenoses were least prevalent in the participants of our study, contrary to previous reports on PLHW.¹⁸ None of the tested parameters could reliably detect the presence of noncalcified plaques, finding which could be attributable to the small number of noncalcified stenoses, which were found in our population. It certainly also reflects an intrinsic limitation of the CAC score in detecting noncalcified lesions, as previously suggested.¹⁸ Accordingly, the use of a novel density/volume calcium score seems to better predicts sCAD in PLWH.³²

Limitations

This is a single-center pilot study, with relatively small-scale population and a nonrandomized design, which does not allow deduction of definite or causal relationships. Therefore, generalization of the results should be applied with caution before confirmation is available from larger population analyses. Moreover, due to the small sample size and the limited number of participants with severe stenosis (n = 3), the corresponding results for FRMs and vascular ultrasound (peripheral atheromatosis) may be unreliable. Therefore, it is of paramount significance that larger studies are performed to confirm or refute our findings.

In conclusion, the present pilot study demonstrated that asymptomatic PLWH with no history of CVD has a high prevalence of sCAD, particularly calcified. In order of increasing predictive value, FRM-CHD-10y, the presence of peripheral (carotid and femoral) artery atheromatosis, and the CAC score >50 can be used to stratify the risk of these patients regarding the presence of sCAD and can guide therapeutic decision making. However, given the abovementioned limitations of CAC score and the herein predictive superiority of peripheral atheromatosis ultrasound over the FRM-CHD-10y score, it seems plausible to suggest vascular ultrasonography as the optimal, low cost, and widely available method to detect PLWH at risk for sCAD. Given the limited number of participants, especially ones with severe coronary stenoses, future, larger studies are needed to validate our findings.

Footnotes

Authors' Contributions

C.J.K., G.M., A.A., and I.K.: analysis and interpretation of data and drafting of the article.

M.G., A.K., and A.Z.: analysis and interpretation of data and critical revision of the article for important intellectual content.

S.S., N.V.S., and A.D.P.: conception and design and critical revision of the article for important intellectual content.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

References

Lewden

, May

, Rosenthal

, et al.: Changes in causes of death among adults infected by HIV between 2000 and 2005: The “Mortalite 2000 and 2005” surveys (ANRS EN19 and Mortavic). J Acquir Immune Defic Syndr, 2008; 48:590–598.

Palella

Jr. , Baker

, Moorman

, et al.: Mortality in the highly active antiretroviral therapy era: Changing causes of death and disease in the HIV outpatient study. J Acquir Immune Defic Syndr, 2006; 43:27–34.

Samji

, Cescon

, Hogg

, et al.: Closing the gap: Increases in life expectancy among treated HIV-positive individuals in the United States and Canada. PLoS One, 2013; 8:e81355.

Smith

, Ryom

, Weber

, et al.: Trends in underlying causes of death in people with HIV from 1999 to 2011 (D:A:D): A multicohort collaboration. Lancet, 2014; 384:241–248.

Triant

, Lee

, Hadigan

, Grinspoon

: Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease. J Clin Endocrinol Metab, 2007; 92:2506–2512.

Freiberg

, Chang

, Kuller

, et al.: HIV infection and the risk of acute myocardial infarction. JAMA Intern Med, 2013; 173:614–622.

Bonou

, Kapelios

, Athanasiadi

, Mavrogeni

, Psichogiou

, Barbetseas

: Subclinical cardiovascular disease imaging in people living with HIV. Vasc Med, 2021. [Epub ahead of print]; DOI: 10.1177/1358863X20978702.

Hadamitzky

, Täubert

, Deseive

, et al.: Prognostic value of coronary computed tomography angiography during 5 years of follow-up in patients with suspected coronary artery disease. Eur Heart J, 2013; 34:3277–3285.

Min

, Dunning

, Lin

, et al.: Age- and sex-related differences in all-cause mortality risk based on coronary computed tomography angiography findings results from the International Multicenter CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry) of 23,854 patients without known coronary artery disease. J Am Coll Cardiol, 2011; 58:849–860.

10.

Schneer

, Bachar

, Atar

, Koronowski

, Dicker

: Evaluation of Framingham and systematic coronary risk evaluation scores by coronary computed tomographic angiography in asymptomatic adults. Am J Cardiol, 2013; 111:700–704.

11.

Guaricci

, Arcadi

, Brunetti

, et al.: Carotid intima media thickness and coronary atherosclerosis linkage in symptomatic intermediate risk patients evaluated by coronary computed tomography angiography. Int J Cardiol, 2014; 176:988–993.

12.

D'Agostino

, Sr.: Cardiovascular risk estimation in 2012: Lessons learned and applicability to the HIV population. J Infect Dis, 2012 Jun;205(Suppl 3):S362–S367.

13.

Triant

, Perez

, Regan

, et al.: Cardiovascular risk prediction functions underestimate risk in HIV infection. Circulation, 2018; 137:2203–2214.

14.

Kapelios

, Argyris

, Protogerou

, et al.: Progression of subclinical vascular damage in people living with HIV is not predicted by current cardiovascular risk scores: A prospective 3-year study. J Acquir Immune Defic Syndr, 2020; 83:504–512.

15.

Stein

, Currier

, Hsue

: Arterial disease in patients with human immunodeficiency virus infection: What has imaging taught us?. JACC Cardiovasc Imaging, 2014; 7:515–525.

16.

Raggi

, Callister

, Cooil

, et al.: Identification of patients at increased risk of first unheralded acute myocardial infarction by electron-beam computed tomography. Circulation, 2000; 101:850–855.

17.

Raggi

, Zona

, Scaglioni

, et al.: Epicardial adipose tissue and coronary artery calcium predict incident myocardial infarction and death in HIV-infected patients. J Cardiovasc Comput Tomogr, 2015; 9:553–558.

18.

Choi

, Choi

, Rivera

, et al.: Coronary computed tomography angiography as a screening tool for the detection of occult coronary artery disease in asymptomatic individuals. J Am Coll Cardiol, 2008; 52:357–365.

19.

Cury

, Abbara

, Achenbach

, et al.: CAD-RADS(TM) coronary artery disease—Reporting and data system. An expert consensus document of the Society of Cardiovascular Computed Tomography (SCCT), the American College of Radiology (ACR) and the North American Society for Cardiovascular Imaging (NASCI). Endorsed by the American College of Cardiology. J Cardiovasc Comput Tomogr, 2016; 10:269–281.

20.

Psichogiou

, Kapelios

, Konstantonis

, et al.: Prevalence, incidence, and contributors of subclinical atheromatosis, arteriosclerosis, and arterial hypertrophy in HIV-infected individuals: A single-center, 3-year prospective study. Angiology, 2019; 70:448–457.

21.

Protogerou

, Fransen

, Zampeli

, et al.: The additive value of femoral ultrasound for subclinical atherosclerosis assessment in a single center cohort of 962 adults, including high risk patients with rheumatoid arthritis, human immunodeficiency virus infection and type 2 diabetes mellitus. PLoS One, 2015; 10:e0132307.

22.

Phan

BAP

, Weigel

, Ma

, et al.: Utility of 2013 American College of Cardiology/American Heart Association Cholesterol Guidelines in HIV-infected adults with carotid atherosclerosis. Circ Cardiovasc Imaging, 2017; 10:e005995.

23.

Subramanya

, McKay

, Brusca

, et al.: Inflammatory biomarkers and subclinical carotid atherosclerosis in HIV-infected and HIV-uninfected men in the Multicenter AIDS Cohort Study. PLoS One, 2019; 14:e0214735.

24.

Roman

, Naqvi

, Gardin

, Gerhard-Herman

, Jaff

, Mohler

: American society of echocardiography report. Clinical application of noninvasive vascular ultrasound in cardiovascular risk stratification: A report from the American Society of Echocardiography and the Society for Vascular Medicine and Biology. Vasc Med, 2006; 11:201–211.

25.

DeLong

, DeLong

, Clarke-Pearson

: Comparing the areas under two or more correlated receiver operating characteristic curves: A nonparametric approach. Biometrics, 1988; 44:837–845.

26.

Nadel

, O’ Dwyer

, Emmanuel

, et al.: High-risk coronary plaque, invasive coronary procedures, and cardiac events among HIV-positive individuals and matched controls. J Cardiovasc Comput Tomogr, 2016; 10:391–397.

27.

Ryom

, Boesecke

, Bracchi

, et al.: Highlights of the 2017 European AIDS Clinical Society (EACS) Guidelines for the treatment of adult HIV-positive persons version 9.0. HIV Med, 2018; 19:309–315.

28.

, Abbara

, Shturman

, et al.: Increased prevalence of subclinical coronary atherosclerosis detected by coronary computed tomography angiography in HIV-infected men. AIDS, 2010; 24:243–253.

29.

Pereira

, Mazzitelli

, Milinkovic

, et al.: Use of coronary artery calcium scoring to improve cardiovascular risk stratification and guide decisions to start statin therapy in people living with HIV. J Acquir Immune Defic Syndr, 2020; 85:98–105.

30.

Min

, Shaw

, Berman

: The present state of coronary computed tomography angiography a process in evolution. J Am Coll Cardiol, 2010; 55:957–965.

31.

Wolk

, Bailey

, Doherty

, et al.: ACCF/AHA/ASE/ASNC/HFSA/HRS/SCAI/SCCT/SCMR/STS 2013 multimodality appropriate use criteria for the detection and risk assessment of stable ischemic heart disease: A report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, American Heart Association, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance, and Society of Thoracic Surgeons. J Am Coll Cardiol, 2014; 63:380–406.

32.

Nakanishi

, Delaney

, Post

, et al.: A novel density-volume calcium score by non-contrast CT predicts coronary plaque burden on coronary CT angiography: Results from the MACS (Multicenter AIDS cohort study). J Cardiovasc Comput Tomogr, 2020; 14:266–271.