Characteristics of carotid atherosclerotic plaques of chronic lipid apheresis patients as assessed by In Vivo High-Resolution CMR - a comparative analysis

A total of 48 patients were enrolled in this prospective cross sectional, monocentric observational study, which has been approved by the local institutional ethics committee. In the chronic lipid apheresis group we examined 32 arteries of 16 patients who had been treated by chronic lipid apheresis for more than 5 years (7 patients by heparin mediated plasma precipitation in acidic milieu (HELP ©), 7 patients by temperature optimized double-filtration plasmapheresis (Lipidfiltration ©), 2 patients by polyacrylat full blood adsorption (DALI ©)). Indication for chronic lipid apheresis was severe therapy refractory hypercholesterolemia (N=13) or isolated Lp(a) hyperlipoproteinemia with progressive vascular disease (N=3). Lipid apheresis treatment had been performed in intervals between 3 and 14 days. In the control group we included 32 consecutive patients matched for the degree of vascular stenosis, who had recently suffered an ischemic stroke. Of these patients only the asymptomatic artery contralateral to the ischemic stroke was included. The majority of patients from the lipid apheresis group (9 out of 16, 56%) and control group (20 out of 32, 63%) received lipid lowering medication at the time of examination. Manifest coronary artery disease and cardiovascular risk factors including serum lipid levels, arterial hypertension, active or past nicotine abuse, diabetes mellitus, family history of coronary artery disease and body mass index (BMI) were recorded. Values for LDL and Lp (a) for the lipid apheresis group are given as mean levels calculated as proposed by Kroon et al. [25]. Other serum lipid levels for the lipid apheresis group are given as average of measurements before and after apheresis therapy. Serum lipid levels for the control group were measured at the time of the CMR examination performed at time of admission due to acute ischemic stroke.

All subjects underwent a carotid black-blood high resolution CMR at 3.0-Tesla on a Siemens Verio Scanner (Siemens AG, Erlangen, Germany) using surface coils (Machnet, Elde, Netherlands) and a previously published multi-sequence protocol [26] (time-of-flight MR angiography (TOF), axial fat suppressed pre- and post- contrast black-blood T1-, PD- and T2- weighted sequences; best in-plane resolution 0.5 × 0.5 mm²). Parallel imaging based on the generalized autocalibrating partially parallel acquisition (GRAPPA) algorithm was used for all sequences with a parallel acquisition technique (PAT) acceleration factor of 2. Total imaging time was 17:43 minutes. Gadobutrol (Gadovist®, Bayer Schering, Leverkusen, Germany) of 0.1 mmol/kg (0.1 ml/kg) was given at a rate of 3 ml/s. Post-contrast T1w imaging was performed approximately 5 minutes after intravenous injection of the contrast agent. Each scan covered 30 mm (2 mm slice thickness × 15 matched images across the 5 sequences).

An image-quality rating (4-point scale, 1 = non-diagnostic, 2 = poor, 3 = good, 4 = excellent) was assigned to all MR images. MR data were then independently reviewed by two experienced radiologists (T.S. and J.G.) who where blinded regarding the clinical status of the patient. In case of discrepancy, a consensus decision was made. Atherosclerotic plaques in the carotid arteries were recorded and classified according to the modified criteria of the American Heart Association [27]. For definition of a complicated AHA-LT6 plaque, at least one of the following three criteria was required: fibrous cap rupture, intraplaque hemorrhage, juxtaluminal hemorrhage/mural thrombus. Area measurements of the lumen, outer wall, and tissue components were obtained using a custom-designed image analysis tool CASCADE (University of Washington, Seattle, USA). Tissue components (lipid-rich necrotic core, calcification, hemorrhage) were identified based on previously published criteria [20]. The “total vessel area” included the lumen and wall areas. The normalized wall index (NWI) was calculated by dividing the wall area by the total vessel area.

For statistical comparison of the patients with and without lipid apheresis therapy, the Mann–Whitney test with correction for ties was used for variables describing frequencies of plaque features, which had skewed distribution. For continuous variables, the Student unpaired t-test with equal or unequal variances (as appropriate) was used. To compare clinical demographics between both groups, Fisher’s exact test was used for categorical variables, and the unpaired t-test was used for continuous variables. Categorical variables are presented as absolute and relative frequencies, while continuous variables are presented as mean and standard deviation. Tissue components were calculated as percentages of the vessel wall. Analyses were carried out in SPSS for Windows (version 14.0, IBM, Chicago, IL). A p-value of <0.05 was considered as statistically significant.

Patients in the lipid apheresis group were younger (63.5 vs. 73.9 years, p<0.05) and had a higher prevalence of hypercholesterolemia (100% vs. 53%), coronary artery disease and/or family history of coronary artery disease (100% vs. 34%) (all p-values <0.05). Total cholesterol (148.8 vs. 200.8 mg/dl) and LDL (94.7 vs. 128.3 mg/dl) - averaged as described above - were significantly lower in the lipid apheresis group than in the control group (p<0.001). Consequently, LDL/HDL was also lower in the lipid apheresis group (2.0 vs. 2.8; p<0.01). No further statistically significant differences in clinical data were found [Table 1].

Although this study shows significant differences in plaque morphology and lesion type distribution between the two groups, the number of patients in this study is relatively small, and a larger study performed in multiple centers is necessary to confirm these preliminary findings. Furthermore, the cross-sectional design of the study allows by definition only a snapshot of plaque burden and composition at one single time point and no definite conclusions can be drawn on the evolution of plaque composition over time. Only CMR examinations with at least average image quality were considered for the review, resulting in exclusion of two arteries from analysis. However, this exclusion rate is lower than in previously published studies [28, 29] and should not have hampered the results. These results were based on a single imaging modality: CMR. Information gathered from other well-known imaging techniques, notably measurements of calcifications from computed tomography, might further illuminate the differences. However, CMR is generally considered best suited to identify and quantify atherosclerotic plaque components in the carotid arteries, shows good correlation with histology for quantitative measurements, and does not use ionizing radiation. Given these advantages and the comparative complexity of a multi-modality study, sole use of CMR was the logical choice for this study.