Background

Carotid and coronary atherosclerosis are critical determinants of cardiovascular risk, yet their interrelationship in middle-aged populations is incompletely understood. This study assessed carotid plaque composition, risk-factor associations, coronary disease, and sex differences in a subclinical cohort.

Methods

Within the Swedish CArdioPulmonary bioImage Study (SCAPIS), 533 asymptomatic individuals aged 50–64 years with carotid plaque ≥2.7 mm on ultrasound underwent 3 T multi-contrast carotid cardiovascular magnetic resonance (CMR) and coronary computed tomography angiography. Carotid plaque characteristics were determined manually using established criteria on multi-contrast weighted carotid CMR. Bayesian regression models evaluated associations between cardiovascular risk factors and coronary atherosclerosis.

Results

Lipid rich necrotic core (LRNC) was present in 60% and intraplaque hemorrhage (IPH) in 5.4%; calcification occurred in 48.6%. Maximum carotid wall thickness was 1.8 (1.6-2.0) mm, and mean lumen area 31.3 (26.7-36.1) mm². Coronary atherosclerosis was present in 63.6% of participants, with ≥50% stenosis in 12.9%, and coronary artery calcium score >400 in 12.8%. Men (N=367) had larger carotid lumen area, mean wall area, and maximum wall thickness (all p < 0.001) than women (N=166), differences that persisted after body-surface-area adjustment (all p < 0.01). LRNC was present in 66% of men compared to 47% of women (p < 0.001). LRNC presence was not associated with coronary atherosclerosis, whereas IPH was associated with coronary involvement.

Conclusion

In middle-aged individuals, distinct cardiovascular risk factors were positively linked to presence and volume of LRNC and calcified plaques. The substantial prevalence of high-risk plaque features, particularly LRNC and especially in men, highlights a significant subclinical carotid disease burden.

Lay summary

This study used state-of-the-art magnetic resonance imaging to characterize atherosclerotic plaques in the carotid arteries in middle-aged individuals without clinical cardiovascular disease, offering the following insight into early, subclinical atherosclerosis:

Lipid rich necrotic core (LRNC), a marker of high-risk plaques, was present in 60% of participants with carotid plaques, suggesting a substantial burden of potentially vulnerable atherosclerosis even in asymptomatic individuals.Carotid plaque features such as increased wall thickness, calcification, and presence of LRNC were variably associated with cardiovascular risk factors and plaques with increased wall area, wall thickness, and calcium showed correlations with coronary artery calcium and plaque burden on CT, indicating systemic atherosclerotic involvement.

Objectives 

Coronary computed tomography angiography is the primary modality for noninvasive assessment of coronary artery disease. Photon-counting computed tomography (PCCT) offers superior spatial resolution and spectral imaging for detailed characterization of atherosclerotic plaques. This study aimed to evaluate the impact of virtual monoenergetic imaging (VMI) energy levels and reconstruction kernels on segmentation-based measurement of plaque volume in individuals with coronary atherosclerosis using PCCT.

Materials and Methods 

Fifty study participants underwent coronary computed tomography angiography with ultra-high-resolution PCCT. Both polyenergetic, 120 kVp (T3D) images and spectral images at varying VMI energy levels were reconstructed using different kernels. Plaque volumes were measured using semiautomated attenuation-based segmentation, adjusting segmentation thresholds for each VMI energy level. In addition, absolute plaque volume measurements were conducted using a coronary phantom simulating different plaque types.

Results 

Using a sharper kernel (Bv64 vs Bv48) significantly increased noncalcified plaque volume measurements (P < 0.005) in study participants, whereas a 0.2-mm slice thickness reduced calcified plaque volumes compared with 0.4 mm (P < 0.005). VMI energy level had no impact on measured volumes. Phantom measurements confirmed significant variability in measured volumes of calcified and noncalcified plaques depending on reconstruction method, as well as a minor effect of VMI level.

Conclusions 

In PCCT, the reconstruction kernel predominantly affects noncalcified coronary plaque quantification, whereas slice thickness mainly impacts calcified plaque volumes. In study participants, measured plaque volumes were not affected by VMI energy level when energy-specific segmentation thresholds were used, although a minor effect of VMI was observed in the phantom model.

The pro-inflammatory and regulatory roles of T lymphocytes in atherosclerosis are well established but less is known about natural killer (NK) cells and natural killer T (NKT)-like cells. The effects of cardiovascular risk management on the phenotypes of these cells are unknown. To assess changes in NK cell and lymphocyte phenotypes and circulating inflammatory proteins in response to cardiovascular risk management in patients with carotid atherosclerosis. Fifty patients were included in a prospective clinical study. Measurements were at baseline and after 12 months of cardiovascular risk management. Circulating NK, NKT-like and T lymphocyte subpopulations were phenotyped by multi-colour flow cytometry. Proximity extension assay was performed for 176 plasma proteins associated with inflammation and cardiovascular disease. At 12 months there were significant reductions in LDL (P=0.001) and blood pressure (P=0.028). NK cells responded with a reduction in pro-inflammatory (NKG2C(+)) cells (P=0.0003), an increase in anti-inflammatory (NKG2A(+)) cells (P=0.032), and a reduction in terminally differentiated (CD57(+)) NK cells. NKT-like cells showed a similar decrease in terminally differentiated subpopulations (P=0.000002). Subpopulations of T helper cells exhibited a significant reduction in central memory (P=1.09x10(-8)) and a significant increase in CD4(+) naive- (P=0.0008) and effector memory T cells (P=0.006). The protein analysis indicated that cardiovascular risk management affects proteins involved in the inflammatory NF-kappa B pathway. The consistent decrease in senescent phenotypes of NK, NKT-like and CD4(+) cells with a concomitant increase in more naive, phenotypes suggests a change towards a less pro-inflammatory lymphocyte profile in response to cardiovascular risk management.Trial registry name: CARotid MRI of Atherosclerosis (CARMA). ClinicalTrials.gov identifier NCT04835571 (08/04/2021). https://www.clinicaltrials.gov/study/NCT04835571.

Atherosclerosis causes more deaths than any other disease worldwide, and the cause of death is most commonly a rupture of a vulnerable atherosclerotic plaque, resulting in a thrombotic event in the heart or brain. The major risk factors for plaque progression are well known, but all the mechanisms that drive atherosclerotic plaques towards catastrophic events are not yet fully elucidated.   

This thesis revolves around the atherosclerotic plaque; how plaques can be analysed using cardiovascular magnetic resonance imaging and the study of biological responses to cardiovascular risk management. In Study I we interrogated the quality of cardiovascular risk management in patients diagnosed with high-grade carotid stenosis and found that cardiovascular risk management was deficient in all aspects, despite the very high risk for events in these patients. Thus, we designed the next two studies to address the unmet clinical need for improved cardiovascular risk management in patients with carotid atherosclerosis while at the same time asking mechanistic questions about the effect of this approach on lymphocyte phenotypes (Study II) and on plaque composition (Study III).  

In Study II, the effect of cardiovascular risk management on Natural Killer cell, Natural Killer T cell and T lymphocyte subpopulations were studied in patients with carotid atherosclerosis. Our results show a polarisation away from a senescent phenotype towards more naïve i.e., juvenile cell types suggesting a transition towards a possibly less pro-inflammatory lymphocyte profile.   

In Study III, we applied a newly developed quantitative Dixon MRI technique to the quantification of lipid rich necrotic core and hemorrhage inside atherosclerotic plaques. Employing this technique, we explored the relationships between these high-risk plaque compositional features and circulating lipoproteins as they changed over time in response to cardiovascular risk management. In the current study there was no evidence for such a linear relationship.  

To further study the associations between inflammation and quantitative plaque measurements we explored in Study IV the relationship between inflammation in atherosclerotic plaques as measured by 18F-FDG uptake and features of high-risk plaque as measured by quantitative Dixon MRI.   

To facilitate the use of carotid MRI in larger cohorts we developed in Study V a technique for the segmentation of the carotid artery using supervised machine learning.   

Taken together these studies describe the importance of cardiovascular risk management, the complexity of atherosclerotic plaque biology and they propose new strategies for quantitative plaque imaging.   

Background Lipid-rich necrotic core (LRNC) and intraplaque hemorrhage (IPH) are morphological features of high-risk atherosclerotic plaques. However, their relationship to circulating lipoproteins is unclear. Purpose To study associations between changes in lipoproteins vs. changes in LRNC (represented by fat fraction [FF]) and IPH (represented by R2*). Study Type Prospective. Subjects Fifty-two patients with carotid plaques, 33 males (63.5%), mean age 72 (+/- 5). Field Strength/Sequence Four-point fast gradient Dixon magnetic resonance imaging (MRI) was used to quantify FF and R2* (to measure IPH) inside plaques and in vessel wall. Turbo-spin echo was used for T-1 weighted sequences to guide manual segmentation. Assessment Carotid MRI and serum lipid levels were assessed at baseline and at 1-year follow-up. For patients, lipid-lowering therapy was customized to reduce low-density lipoprotein (LDL) levels below 1.8 mmol/L. Segmentation was performed with one set of regions of interest for the plaque and one for the vessel wall at the location of the plaque. Thereby MRI data for FF, R2*, and volumes in plaque- and vessel-wall segmentations could be obtained from baseline and follow-up, as well as changes over the study year. Statistical Tests Pearson correlation coefficient for correlations. Paired samples t-test for changes over time. Significance at P &lt; 0.05, 95% confidence interval. Results LDL decreased significantly (2.19-1.88 mmol/L, Z - 2.9), without correlation to changes in plaque composition, nor to the significant reduction in vessel-wall volume (-106.3 mm(3)). Plaque composition remained unchanged, FF +8.5% (P = 0.366) and R2* +3.5% (P = 0.304). Compared to plaque segmentations, R2* was significantly lower in the vessel-wall segmentations both at baseline (-9.3%) and at follow-up (-9.1%). Data Conclusion The absence of correlations between changes in lipoproteins and changes in plaque composition indicates more complex relationships between these parameters than previously anticipated. The significant differences in both R2* and volume dynamics comparing plaque segmentations and vessel-wall segmentations suggest differences in their pathobiology of atherosclerosis. Level of Evidence 1 Technical Efficacy Stage 4

Background MRI can be used to generate fat fraction (FF) and R2* data, which have been previously shown to characterize the plaque compositional features lipid-rich necrotic core (LRNC) and intraplaque hemorrhage (IPH) in the carotid arteries (CAs). Previously, these data were extracted from CA plaques using time-consuming manual analyses. Purpose To design and demonstrate a method for segmenting the CA and extracting data describing the composition of the vessel wall. Study Type Prospective. Subjects 31 subjects from the Swedish CArdioPulmonary bioImage Study (SCAPIS). Field Strength/Sequences T-1-weighted (T1W) quadruple inversion recovery, contrast-enhanced MR angiography (CE-MRA), and 4-point Dixon data were acquired at 3T. Assessment The vessel lumen of the CA was automatically segmented using support vector machines (SVM) with CE-MRA data, and the vessel wall region was subsequently delineated. Automatically generated segmentations were quantitatively measured and three observers visually compared the segmentations to manual segmentations performed on T(1)w images. Dixon data were used to generate FF and R2* maps. Both manually and automatically generated segmentations of the CA and vessel wall were used to extract compositional data. Statistical Tests Two-tailedt-tests were used to examine differences between results generated using manual and automated analyses, and among different configurations of the automated method. Interobserver agreement was assessed with Fleiss kappa. Results Automated segmentation of the CA using SVM had a Dice score of 0.89 +/- 0.02 and true-positive ratio 0.93 +/- 0.03 when compared against ground truth, and median qualitative score of 4/5 when assessed visually by multiple observers. Vessel wall regions of 0.5 and 1 mm yielded compositional information similar to that gained from manual analyses. Using the 0.5 mm vessel wall region, the mean difference was 0.1 +/- 2.5% considering FF and 1.1 +/- 5.7[1/s] for R2*. Level of Evidence 1. Technical Efficacy Stage 1. J. Magn. Reson. Imaging 2020;52:710-719.

BACKGROUND: Patients with high-grade (≥70%) carotid artery stenosis (CAS) rank in the highest risk category for future cardiovascular (CV) events, but the quality of cardiovascular risk management in this patient group is unknown.

DESIGN: Cross-sectional retrospective study.

METHODS: Data were collected for all patients diagnosed with high-grade CAS in Östergötland county, Sweden between 1 January 2009 and 31 July 2012 regarding the quality of cardiovascular risk management, co-morbidity and outcomes during the 2-year follow-up period after a diagnosis of CAS with a carotid ultrasound scan. Patients were included regardless of whether they underwent carotid endarterectomy (CEA).

RESULTS: A total of 393 patients with CAS were included in the study; 133 (33.8%) underwent CEA and 260 (66.2%) were assigned to a conservative management (CM) group. In both groups of patients the prescription of platelet inhibitors, statins and antihypertensive drugs increased significantly (p < 0.001) after diagnosis. However treatment targets were not met in the majority of patients and the low-density lipoprotein level was on target in only 13.5% of patients. During follow-up, low-density lipoprotein levels were not measured in 19.8% of patients who underwent CEA and 44.2% of patients in the CM group (p < 0.001); HbA1c was not measured in 24.4% of patients with diabetes in the CEA group and in 18.8% of patients in the CM group (p = 0.560). There was no documentation of counselling on diet, exercise, smoking cessation or adherence to medication. The combined clinical event rate (all-cause mortality, cardiovascular mortality and non-fatal cardiovascular events) was high in both groups (CEA 36.8% and CM 36.9%; p = 1.00) with no difference in the occurrence of ipsilateral ischaemic stroke.

CONCLUSIONS: The clinical event rate was high in patients with high-grade CAS and the management of cardiovascular risk was deficient in all aspects.