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Coronary artery disease (CAD) is a common comorbidity in people with human immunodeficiency virus (HIV) (PWH) and impaired coronary endothelial function (CEF) plays a central role in the pathogenesis of CAD. Age-related impaired CEF among PWH, however, is not well characterized. We investigated the association between CEF and age in males and females with and without HIV using 3-T magnetic resonance imaging (MRI). We measured the changes in coronary cross-sectional area (CSA) and coronary blood flow during isometric handgrip exercise (IHE), an established endothelial-dependent stressor with smaller increases in CSA and coronary blood flow indicative of impaired CEF. We included 106 PWH and 82 individuals without HIV. Differences in demographic and clinical characteristics between PWH and individuals without HIV were explored using Pearson's χ 2 test for categorical variables and Welch's t test for continuous variables. Linear regression models were used to examine the association between CEF and age. CEF was significantly lower in PWH as compared with individuals without HIV. Coronary endothelial dysfunction was also present at younger ages in PWH than in the individuals without HIV and there were significant differences in CEF between the PWH and individuals without HIV across age groups. Among the individuals without HIV, the percent changes in CSA were inversely related to age in unadjusted and adjusted models. There was no significant association between CEF and age in PWH. To the best of our knowledge, this is the first study to examine the relationship between age and CEF in PWH, and our results suggest that factors other than age significantly impair CEF in PWH across the life span. NEW & NOTEWORTHY This is the first study to examine the relationship between age and coronary endothelial function (CEF) in people with human immunodeficiency virus (HIV) (PWH). CEF was assessed using magnetic resonance imaging (MRI) in people with and without HIV. Although age and CEF were significantly inversely related in individuals without HIV, there was no association between age and CEF in PWH.

Background: People with HIV (PWH) are at an increased risk of cardiovascular disease, partially believed to be related to chronically elevated systemic inflammation. Abnormal systemic endothelial function (SEF) and coronary endothelial function (CEF) develop early in atherogenesis and predict adverse events. It is unknown whether abnormal CEF is related to systemic inflammation in PWH., Methods: In this substudy of a prior randomized controlled trial in PWH without prior clinical coronary artery disease suppressed on antiretroviral therapy with CEF as a primary end point (N = 82), we investigated the associations between baseline serum markers of inflammation and adhesion and baseline CEF, assessed by noninvasive MRI measures of percentage changes in coronary blood flow and cross-sectional area during isometric handgrip exercise, and SEF using brachial ultrasound for flow-mediated dilation. We also evaluated whether baseline marker levels were associated with CEF after 8 weeks in the placebo group (N = 40)., Results: CEF measures were abnormal at baseline, based on trial entry criteria. A higher value of CEF was directly associated with levels of interleukin 10, whereas CEF at baseline was inversely associated with E-selectin. Worse CEF at 8 weeks was directly associated with baseline tumor necrosis factor alpha, intercellular adhesion molecule 1, C-reactive protein, interferon gamma and sICAM-3. SEF at baseline or 8 weeks was not associated with any baseline markers., Conclusion: Coronary but not systemic endothelial dysfunction was significantly associated with select markers of inflammation and adhesion in PWH. Furthermore, CEF but not SEF at 8 weeks was associated with baseline levels of inflammation. Our findings suggest that abnormal CEF and systemic markers of inflammation are linked in PWH., Competing Interests: The authors declare that no financial conflicts of interest exist., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: People living with HIV (PWH) experience an increased burden of coronary artery disease (CAD) believed to be related, in part, to an interplay of chronically increased inflammation and traditional risk factors. Recent trials suggest cardiovascular benefits of the anti-inflammatory, colchicine, in HIV-seronegative CAD patients. However, the impact of colchicine on impaired vascular health, as measured by coronary endothelial function (CEF), an independent contributor to CAD, has not been studied in PWH. We tested the hypothesis that colchicine improves vascular health in PWH., Design: This was a randomized, placebo-controlled, double-blinded trial in 81 PWH to test whether low-dose colchicine (0.6 mg daily) improves CEF over 8-24 weeks., Methods: Coronary and systemic endothelial function and serum inflammatory markers were measured at baseline, and at 8 and 24 weeks. The primary endpoint was CEF, measured as the change in coronary blood flow from rest to that during an isometric handgrip exercise, an endothelial-dependent stressor, measured with non-invasive MRI at 8 weeks., Results: Colchicine was well tolerated and not associated with increased adverse events. However, there were no significant improvements in coronary or systemic endothelial function or reductions in serum inflammatory markers at 8 or 24 weeks with colchicine as compared to placebo., Conclusions: In PWH with no history of CAD, low-dose colchicine was well tolerated but did not improve impaired coronary endothelial function, a predictor of cardiovascular events. These findings suggest that this anti-inflammatory approach using colchicine in PWH does not improve vascular health, the central, early driver of coronary atherosclerosis., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background PCSK9 (proprotein convertase subtilisin/kexin type 9) is well recognized for its important role in cholesterol metabolism. Elevated levels are associated with increased cardiovascular risk and inhibition with PCSK9 antibodies (PCSK9i) lowers cardiovascular events in patients with coronary artery disease. PCSK9 levels are also elevated in people living with HIV (PLWH) and those with dyslipidemia. Because increased PCSK9 in PLWH is associated with impaired coronary endothelial function, a barometer of coronary vascular health, we tested the hypothesis that PCSK9i improves impaired coronary endothelial function in dyslipidemia without coronary artery disease and in PLWH with nearly optimal/above goal low-density lipoprotein cholesterol levels. Methods and Results We performed a single-center study in 19 PLWH and 11 with dyslipidemia to evaluate the effects of the PCSK9i evolocumab on coronary endothelial function using cine 3T MRI to noninvasively measure coronary endothelial function, assessed as the changes in coronary cross-sectional area and coronary blood flow from rest to that during isometric handgrip exercise, a known endothelial-dependent vasodilator. Before evolocumab, there was a decrease or no coronary vasodilation and no increase in coronary blood flow (the normal responses) to isometric handgrip exercise in either group. Following 6 weeks of evolocumab, 480 mg q4 weeks, the % cross-sectional area changes from rest to isometric handgrip exercise were +5.6±5.5% and +4.5±3.1% in the PLWH and dyslipidemia groups, respectively, both P <0.01 versus baseline. Improved cross-sectional area was paralleled by a significant coronary blood flow improvement in both groups. Conclusions To our knowledge, these data represent the first evidence that PCSK9 inhibition improves coronary artery health in PLWH and people with dyslipidemia. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03500302.

Background and Aims: Coronary artery disease (CAD) is now an important cause of premature death in people with HIV but the causes of accelerated CAD are poorly understood. Epicardial adipose tissue (EAT) is metabolically-active and thought to contribute to CAD development. We tested the hypothesis that abnormal coronary endothelial function (CEF), an early marker and mediator of atherosclerosis, is related to the amount of local pericoronary EAT in HIV., Methods: We studied 36 participants with HIV and no CAD (HIV+ CAD-), 15 participants with HIV and known CAD (HIV+ CAD+), and 14 age-matched, healthy participants without HIV (HIV-CAD-). To measure CEF, coronary MRI was performed before and during isometric handgrip exercise (IHE), an endothelial-dependent stressor. EAT was measured with MRI at the same imaging plane as CEF., Results: CEF was significantly depressed, as measured by IHE-induced % coronary cross sectional area (CSA) change, in HIV+ CAD- and HIV+ CAD+ as compared to HIV-CAD-participants (p<0.0001). EAT thickness was significantly greater in HIV+ CAD- and HIV+ CAD+ participants as compared to HIV-CAD-participants (p=0.001). There was a significant inverse relationship between CEF and local EAT thickness and area (R = -0.48 and R = -0.51 respectively, p<0.0001 for both) among participants with HIV even after adjustment for cardiovascular risk factors. In participants with multiple CEF measures, CEF was lower in segments with higher EAT, other factors being equivalent., Conclusions: There is a significant relationship between increased metabolically-active EAT and depressed local CEF in people with HIV, consistent with the hypothesis that increased epicardial fat contributes to accelerated CAD in persons with HIV., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background HIV + people are at increased risk of coronary artery disease, but the responsible mechanisms are incompletely understood. Proprotein convertase subtilisin/kexin type 9 ( PCSK 9) is traditionally recognized for its importance in cholesterol metabolism; however, recent data suggest an additional, low-density lipoprotein receptor-independent adverse effect on endothelial cell inflammation and function. We tested the hypotheses that PCSK 9 levels are increased and that abnormal coronary endothelial function is related to PCSK 9 serum levels in HIV + individuals. Methods and Results Forty-eight HIV + participants receiving antiretroviral therapy with suppressed viral replication, without coronary artery disease, and 15 age- and low-density lipoprotein cholesterol-matched healthy HIV- subjects underwent magnetic resonance imaging to measure coronary endothelial function, quantified as percentage change in coronary artery cross-sectional area during isometric handgrip exercise, an endothelial-dependent stressor; and blood was obtained for serum PCSK 9 and systemic vascular biomarkers. Data are presented as mean±SD. Mean serum PCSK 9 was 65% higher in the HIV + subjects (302±146 ng/ mL ) than in the HIV - controls (183±52 ng/ mL , P<0.0001). Coronary endothelial function was significantly reduced in the HIV + versus HIV - subjects (percentage change in coronary artery cross-sectional area, 2.9±9.6% versus 11.1±3.7%; P<0.0001) and inversely related to PCSK 9 ( R=-0.51, P<0.0001). Markers of endothelial activation and injury, P-selectin and thrombomodulin, were also significantly increased in the HIV + subjects; and P-selectin was directly correlated with serum PCSK 9 ( R=0.31, P=0.0144). Conclusions Serum PCSK 9 levels are increased in treated HIV + individuals and are associated with abnormal coronary endothelial function, an established measure of vascular health.

Background: The xanthine oxidase (XO) system is a significant source of vascular oxidative stress, which is believed to impair endothelial function, an important contributor to atherosclerotic disease. We tested whether febuxostat, a potent XO inhibitor, improves coronary endothelial function (CEF) in patients with stable coronary artery disease (CAD) in a single-center, randomized, placebo-controlled, double-blind crossover trial., Methods: CEF was measured using noninvasive magnetic resonance imaging (MRI) assessment of changes in 30 patients with stable CAD and baseline impaired CEF. Patients received either febuxostat or placebo for 6 weeks and then were crossed over to the alternative for an additional 6 weeks. MRI-detected changes in coronary flow and in coronary cross-sectional area from rest to isometric handgrip exercise, a known endothelial-dependent stressor, were measured at the end of each 6 week period., Results: Mean serum urate levels were lower at the end of the 6-week febuxostat period (2.9±0.8mg/dL) than at the end of the 6-week placebo period (5.9±0.04, P<.001). However, there were no significant differences in any of the CEF parameters measured at the end of the febuxostat and placebo periods., Conclusions: In summary, although XO inhibition with febuxostat was well tolerated and lowered serum urate, it did not improve the primary end point of the study, CEF measured using MRI after 6 weeks of treatment. In conclusion, these findings suggest that short-term inhibition of XO does not significantly improve impaired CEF in patients with stable CAD., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Coronary endothelial function (CEF) in patients with coronary artery disease (CAD) varies among coronary segments in a given patient. Because both coronary vessel wall eccentricity and coronary endothelial dysfunction are predictors of adverse outcomes, we hypothesized that local coronary endothelial dysfunction is associated with local coronary artery eccentricity., Methods: We used 3 T coronary CMR to measure CEF as changes in coronary cross-sectional area (CSA) and coronary blood flow (CBF) during isometric handgrip exercise (IHE), a known endothelial-dependent stressor, in 29 patients with known CAD and 16 healthy subjects. Black-blood MRI quantified mean coronary wall thickness (CWT) and coronary eccentricity index (EI) and CEF was determined in the same segments., Results: IHE-induced changes in CSA and CBF in healthy subjects (10.6 ± 6.6% and 38.3 ± 29%, respectively) were greater than in CAD patients 1.3 ± 7.7% and 6.5 ± 19.6%, respectively, p < 0.001 vs. healthy for both measures), as expected. Mean CWT and EI in healthy subjects (1.1 ± 0.3 mm 1.9 ± 0.5, respectively) were less than those in CAD patients (1.6 ± 0.4 mm, p < 0.0001; and 2.6 ± 0.6, p = 0.006 vs. healthy). In CAD patients, we observed a significant inverse relationship between stress-induced %CSA change and both EI (r = -0.60, p = 0.0002), and CWT (r = -0.54, p = 0.001). Coronary EI was independently and significantly related to %CSA change with IHE even after controlling for mean CWT (adjusted r = -0.69, p = 0.0001). For every unit increase in EI, coronary CSA during IHE is expected to change by -6.7 ± 9.4% (95% confidence interval: -10.3 to -3.0, p = 0.001)., Conclusion: There is a significant inverse and independent relationship between coronary endothelial macrovascular function and the degree of local coronary wall eccentricity in CAD patients. Thus anatomic and physiologic indicators of high-risk coronary vascular pathology are closely related. The noninvasive identification of coronary eccentricity and its relationship with underlying coronary endothelial function, a marker of vascular health, may be useful in identifying high-risk patients and culprit lesions.

Background: Normal endothelial function is a measure of vascular health and dysfunction is a predictor of coronary events. Nitric oxide-mediated coronary artery endothelial function, as assessed by vasomotor reactivity during isometric handgrip exercise (IHE), was recently quantified noninvasively with magnetic resonance imaging (MRI). Because the internal mammary artery (IMA) is often visualized during coronary MRI, we propose the strategy of simultaneously assessing systemic and coronary endothelial function noninvasively by MRI during IHE., Methods and Results: Changes in cross-sectional area and blood flow in the right coronary artery and the IMA in 25 patients with coronary artery disease and 26 healthy subjects during IHE were assessed using 3T MRI. In 8 healthy subjects, a nitric oxide synthase inhibitor was infused to evaluate the role of nitric oxide in the IMA-IHE response. Interobserver IMA-IHE reproducibility was good for cross-sectional area (R=0.91) and blood flow (R=0.91). In healthy subjects, cross-sectional area and blood flow of the IMA increased during IHE, and these responses were significantly attenuated by monomethyl-l-arginine (P<0.01 versus placebo). In patients with coronary artery disease, the right coronary artery did not dilate with IHE, and dilation of the IMA was less than that of the healthy subjects (P=0.01). The blood flow responses of both the right coronary artery and IMA to IHE were also significantly reduced in patients with coronary artery disease., Conclusions: MRI-detected IMA responses to IHE primarily reflect nitric oxide-dependent endothelial function and are reproducible and reduced in patients with coronary artery disease. Endothelial function in both coronary and systemic (IMA) arteries can now be measured noninvasively with the same imaging technique and promises novel insights into systemic and local factors affecting vascular health., (© 2016 American Heart Association, Inc.)

Endothelial cell release of nitric oxide (NO) is a defining characteristic of nondiseased arteries, and abnormal endothelial NO release is both a marker of early atherosclerosis and a predictor of its progression and future events. Healthy coronaries respond to endothelial-dependent stressors with vasodilatation and increased coronary blood flow (CBF), but those with endothelial dysfunction respond with paradoxical vasoconstriction and reduced CBF. Recently, coronary MRI and isometric handgrip exercise (IHE) were reported to noninvasively quantify coronary endothelial function (CEF). However, it is not known whether the coronary response to IHE is actually mediated by NO and/or whether it is reproducible over weeks. To determine the contribution of NO, we studied the coronary response to IHE before and during infusion of N(G)-monomethyl-l-arginine (l-NMMA, 0.3 mg·kg(-1)·min(-1)), a NO-synthase inhibitor, in healthy volunteers. For reproducibility, we performed two MRI-IHE studies ~8 wk apart in healthy subjects and patients with coronary artery disease (CAD). Changes from rest to IHE in coronary cross-sectional area (%CSA) and diastolic CBF (%CBF) were quantified. l-NMMA completely blocked normal coronary vasodilation during IHE [%CSA, 12.9 ± 2.5 (mean ± SE, placebo) vs. -0.3 ± 1.6% (l-NMMA); P < 0.001] and significantly blunted the increase in flow [%CBF, 47.7 ± 6.4 (placebo) vs. 10.6 ± 4.6% (l-NMMA); P < 0.001]. MRI-IHE measures obtained weeks apart strongly correlated for CSA (P < 0.0001) and CBF (P < 0.01). In conclusion, the normal human coronary vasoactive response to IHE is primarily mediated by NO. This noninvasive, reproducible MRI-IHE exam of NO-mediated CEF promises to be useful for studying CAD pathogenesis in low-risk populations and for evaluating translational strategies designed to alter CAD in patients.

Background: Transient balanced steady-state free-precession (bSSFP) has shown substantial promise for noninvasive assessment of coronary arteries but its utilization at 3.0 T and above has been hampered by susceptibility to field inhomogeneities that degrade image quality. The purpose of this work was to refine, implement, and test a robust, practical single-breathhold bSSFP coronary MRA sequence at 3.0 T and to test the reproducibility of the technique., Methods: A 3D, volume-targeted, high-resolution bSSFP sequence was implemented. Localized image-based shimming was performed to minimize inhomogeneities of both the static magnetic field and the radio frequency excitation field. Fifteen healthy volunteers and three patients with coronary artery disease underwent examination with the bSSFP sequence (scan time = 20.5 ± 2.0 seconds), and acquisitions were repeated in nine subjects. The images were quantitatively analyzed using a semi-automated software tool, and the repeatability and reproducibility of measurements were determined using regression analysis and intra-class correlation coefficient (ICC), in a blinded manner., Results: The 3D bSSFP sequence provided uniform, high-quality depiction of coronary arteries (n = 20). The average visible vessel length of 100.5 ± 6.3 mm and sharpness of 55 ± 2% compared favorably with earlier reported navigator-gated bSSFP and gradient echo sequences at 3.0 T. Length measurements demonstrated a highly statistically significant degree of inter-observer (r = 0.994, ICC = 0.993), intra-observer (r = 0.894, ICC = 0.896), and inter-scan concordance (r = 0.980, ICC = 0.974). Furthermore, ICC values demonstrated excellent intra-observer, inter-observer, and inter-scan agreement for vessel diameter measurements (ICC = 0.987, 0.976, and 0.961, respectively), and vessel sharpness values (ICC = 0.989, 0.938, and 0.904, respectively)., Conclusions: The 3D bSSFP acquisition, using a state-of-the-art MR scanner equipped with recently available technologies such as multi-transmit, 32-channel cardiac coil, and localized B0 and B1+ shimming, allows accelerated and reproducible multi-segment assessment of the major coronary arteries at 3.0 T in a single breathhold. This rapid sequence may be especially useful for functional imaging of the coronaries where the acquisition time is limited by the stress duration and in cases where low navigator-gating efficiency prohibits acquisition of a free breathing scan in a reasonable time period.

Objectives: Our objective is to test the hypothesis that coronary endothelial function (CorEndoFx) does not change with repeated isometric handgrip (IHG) stress in CAD patients or healthy subjects., Background: Coronary responses to endothelial-dependent stressors are important measures of vascular risk that can change in response to environmental stimuli or pharmacologic interventions. The evaluation of the effect of an acute intervention on endothelial response is only valid if the measurement does not change significantly in the short term under normal conditions. Using 3.0 Tesla (T) MRI, we non-invasively compared two coronary artery endothelial function measurements separated by a ten minute interval in healthy subjects and patients with coronary artery disease (CAD)., Methods: Twenty healthy adult subjects and 12 CAD patients were studied on a commercial 3.0 T whole-body MR imaging system. Coronary cross-sectional area (CSA), peak diastolic coronary flow velocity (PDFV) and blood-flow were quantified before and during continuous IHG stress, an endothelial-dependent stressor. The IHG exercise with imaging was repeated after a 10 minute recovery period., Results: In healthy adults, coronary artery CSA changes and blood-flow increases did not differ between the first and second stresses (mean % change ±SEM, first vs. second stress CSA: 14.8%±3.3% vs. 17.8%±3.6%, p = 0.24; PDFV: 27.5%±4.9% vs. 24.2%±4.5%, p = 0.54; blood-flow: 44.3%±8.3 vs. 44.8%±8.1, p = 0.84). The coronary vasoreactive responses in the CAD patients also did not differ between the first and second stresses (mean % change ±SEM, first stress vs. second stress: CSA: -6.4%±2.0% vs. -5.0%±2.4%, p = 0.22; PDFV: -4.0%±4.6% vs. -4.2%±5.3%, p = 0.83; blood-flow: -9.7%±5.1% vs. -8.7%±6.3%, p = 0.38)., Conclusion: MRI measures of CorEndoFx are unchanged during repeated isometric handgrip exercise tests in CAD patients and healthy adults. These findings demonstrate the repeatability of noninvasive 3T MRI assessment of CorEndoFx and support its use in future studies designed to determine the effects of acute interventions on coronary vasoreactivity.

Background: Coronary endothelial function is abnormal in patients with established coronary artery disease and was recently shown by MRI to relate to the severity of luminal stenosis. Recent advances in MRI now allow the noninvasive assessment of both anatomic and functional (endothelial function) changes that previously required invasive studies. We tested the hypothesis that abnormal coronary endothelial function is related to measures of early atherosclerosis such as increased coronary wall thickness., Methods and Results: Seventeen arteries in 14 healthy adults and 17 arteries in 14 patients with nonobstructive coronary artery disease were studied. To measure endothelial function, coronary MRI was performed before and during isometric handgrip exercise, an endothelial-dependent stressor, and changes in coronary cross-sectional area and flow were measured. Black blood imaging was performed to quantify coronary wall thickness and indices of arterial remodeling. The mean stress-induced change in cross-sectional area was significantly higher in healthy adults (13.5%±12.8%, mean±SD, n=17) than in those with mildly diseased arteries (-2.2%±6.8%, P<0.0001, n=17). Mean coronary wall thickness was lower in healthy subjects (0.9±0.2 mm) than in patients with coronary artery disease (1.4±0.3 mm, P<0.0001). In contrast to healthy subjects, stress-induced changes in cross-sectional area, a measure of coronary endothelial function, correlated inversely with coronary wall thickness in patients with coronary artery disease (r=-0.73, P=0.0008)., Conclusions: There is an inverse relationship between coronary endothelial function and local coronary wall thickness in patients with coronary artery disease but not in healthy adults. These findings demonstrate that local endothelial-dependent functional changes are related to the extent of early anatomic atherosclerosis in mildly diseased arteries. This combined MRI approach enables the anatomic and functional investigation of early coronary disease.

Coronary vessel distensibility is reduced with atherosclerosis and normal aging, but direct measurements have historically required invasive measurements at cardiac catheterization. Therefore, we sought to assess coronary artery distensibility noninvasively using 3.0 Telsa coronary magnetic resonance imaging (MRI) and to test the hypothesis that this noninvasive technique can detect differences in coronary distensibility between healthy subjects and those with coronary artery disease (CAD). A total of 38 healthy, adult subjects (23 men, mean age 31 ± 10 years) and 21 patients with CAD, diagnosed using x-ray angiography (11 men, mean age 57 ± 6 years) were studied using a commercial whole-body MRI system. In each subject, the proximal segment of a coronary artery was imaged for the cross-sectional area measurements using cine spiral MRI. The distensibility (mm Hg(-1) × 10(3)) was determined as (end-systolic lumen area - end-diastolic lumen area)/(pulse pressure × end-diastolic lumen area). The pulse pressure was calculated as the difference between the systolic and diastolic brachial blood pressure. A total of 34 healthy subjects and 19 patients had adequate image quality for coronary area measurements. Coronary artery distensibility was significantly greater in the healthy subjects than in those with CAD (mean ± SD 2.4 ± 1.7 mm Hg(-1) × 10(3) vs 1.1 ± 1.1 mm Hg(-1) × 10(3), respectively, p = 0.007; median 2.2 vs 0.9 mm Hg(-1) × 10(3)). In a subgroup of 10 patients with CAD, we found a significant correlation between the coronary artery distensibility measurements assessed using MRI and x-ray coronary angiography (R = 0.65, p = 0.003). In a group of 10 healthy subjects, the repeated distensibility measurements demonstrated a significant correlation (R = 0.80, p = 0.006). In conclusion, 3.0-Tesla MRI, a reproducible noninvasive method to assess human coronary artery vessel wall distensibility, is able to detect significant differences in distensibility between healthy subjects and those with CAD., (Copyright © 2011 Elsevier Inc. All rights reserved.)