Imaging of inflamed carotid artery atherosclerotic plaques with the use of 99mTc-HYNIC-IL-2 scintigraphy in end-stage renal disease patients

Marta Opalinska 0 2 3 Tomasz Stompor 0 2 3 Dorota Pach 0 2 3 Renata Mikolajczak 0 2 3 Danuta Fedak 0 2 3 Marcin Krzanowski 0 2 3 Tomasz Rakowski 0 2 3 Anna Sowa-Staszczak 0 2 3 Boguslaw Glowa 0 2 3 Piotr Garnuszek 0 2 3 Micha Maurin 0 2 3 Urszula Karczmarczyk 0 2 3 Wadysaw Sulowicz 0 2 3 Alicja Hubalewska-Dydejczyk 0 2 3 0 T. Stompor Department of Nephrology, Hypertensiology and Internal Medicine, Faculty of Medicine, University of Warmia and Mazury in Olsztyn , Olsztyn, Poland 1 ) Nuclear Medicine Unit, Department of Endocrinology, Jagiellonian University Medical School , ul. Kopernika 17, 31-501 Cracow, Poland 2 T. Rakowski 2nd Department of Cardiology, Institute of Cardiology, Jagiellonian University Medical School , Cracow, Poland 3 D. Fedak Clinical Biochemistry, Jagiellonian University Medical School , Cracow, Poland Purpose Identification of vulnerable plaques remains crucial for better cardiovascular risk assessment. At least 20% of inflammatory cells within unstable (vulnerable) plaques comprise T lymphocytes, which contain receptors for interleukin-2 - (IL-2); those receptors can be identified by scintigraphy with radiolabelled IL-2.The aim of this study was to identify the inflamed (vulnerable) plaques by scintigraphy using IL-2 labelled with 99mTc in the selected, high cardiovascular risk group of end-stage renal disease (ESRD) patients. Methods A total of 28 patients (18 men, 10 women, aged 55.29.6 years, 17 on peritoneal dialysis, 11 on haemodialysis) underwent common carotid artery (CCA) scintigraphy with the use of 99mTc-hydrazinonicotinamide (HYNIC)-IL-2. In all cases, ultrasound examination of the CCA was performed and levels of selected proinflammatory factors, atherogenic markers and calcium-phosphate balance parameters were measured. Finally, the target to non-target (T/nT) ratio of IL-2 uptake in atherosclerotic plaques with intima-media thickness (IMT), classic cardiovascular risk factors and concentrations of the measured factors were compared. Results Increased 99mTc-HYNIC-IL-2 uptake in atherosclerot ic plaques in 38/41 (91%) cases was detected. The median T/nT ratio of focal 99mTc-HYNIC-IL-2 uptake in atherosclerotic plaques was 2.35 (range 1.233.63). The mean IMT value on the side of plaques assessed by scintigraphy was 0.79 0.18 mm (median 0.8, range 0.51.275). Correlations between T/nT ratio and homocysteine (R 0 0.22, p 0 0.037), apolipoprotein B (apoB) (R 0 0.31, p 0 0.008), apoB to apoA-I ratio (R 0 0.29, p 0 0.012) and triglyceride concentration (R 0 0.26, p 0 0.021) were detected. A lower T/nT ratio in patients with better parameters of nutritional status (haemoglobin, albumin, adiponectin) in comparison with patients with worse nutritional parameters (3.200.5 vs 2.160.68, p0 0.025) was revealed as well as a difference between values of T/nT ratio in groups of patients with values of apoB, soluble CD40 ligand and asymmetric dimethylarginine above and below median (3.18 0.52 vs 2.160.68, p0 0.031). No statistically significant association was found between T/nT ratio and mean value of either IMT or classic cardiovascular risk factors. Conclusion Scintigraphy with the use of 99mTc-HYNIC-IL-2 can be a tool for inflamed atherosclerotic (vulnerable) plaque visualization within CCA in ESRD patients. Quantitative results of carotid artery scintigraphy with 99mTc-HYNIC-IL-2 correlate with serum concentration of selected cardiovascular risk markers. Routinely used methods for quantification of short-term cardiovascular risk are considered inefficient. Most of the available methods are based on insight into the arterial lumen, namely assessment of atherosclerotic plaque size, its degree of calcification or intima-media complex thickness measurements. These methods may, however, be imprecise in identifying vulnerable patients with plaques at the highest risk of rupture. Providing such information would seem to be very important since it may potentially result not only in more sensitive selection of patients for invasive procedures, but also for choosing candidates best suited to aggressive conservative treatment (leading to stabilization of vulnerable plaques). This kind of information may potentially be obtained with scintigraphy using deliberately chosen tracers. Among a variety of candidates, the most promising substances are those involved in regulation of the inflammatory process. Interleukin-2 (IL-2) was identified in 1975 as a growth factor for T lymphocytes and is now considered one of the most important modulators of the inflammatory response. IL-2 is produced mainly by the CD4+ lymphocyte subpopulation, and its biological activity is attained after binding to specific receptors located, among other target cells, on these lymphocytes [1]. IL-2 induces autoproliferation of helper T cells and cytotoxic lymphocytes as well as B lymphocytes, NK (natural killer) and memory cells [2]. IL-2 secretion by activated lymphocytes also stimulates other immunomodulating cytokines, such as interferon gamma (IFN-) or tumour necrosis factor beta (TNF-), which in turn interact with cells from the monocyte/macrophage lineage, endothelial layer and fibroblasts leading to fibrous cap thickening and plaque vulnerability. IL-2 radiolabelled with 99mTc or 123I has previously been proven a useful tracer in imaging of the lymphocytic tissue infiltration in patients with autoimmune disorders [35] or lymphocyte infiltration into atherosclerotic plaques in patients with symptomatic atherosclerosis [6, 7]. In certain populations, including patients with end-stage renal disease (ESRD), cardiovascular disease is more common and more accelerated than in the general population. This makes the ESRD group a valuable model for advanced and rapidly progressing atherosclerosis, useful for clinical studies. The increased cardiovascular mortality in ESRD patients is based mainly on a chronic inflammatory process (the malnutrition-inflammation-atherosclerosis syndrome) as well as chronic anaemia, bone and mineral disorders, hypertension and uraemia with derangement of the biochemical milieu with accumulation of several cardiotoxic and atherogenic substances. Most of these abnormalities mentioned are poorly corrected with dialysis [8]. Serum concentrations of a wide range of inflammatory agents that promote atherosclerosis or indicate severity of endothelial impairment are used to evaluate the cardiovascular risk in ESRD patients [9, 10] as well as in the general population [1114]. Simultaneous assessments of several agents enable better cardiovascular risk estimation because none of them is sufficient as a single risk indicator. The aim of the study was to identify the inflamed (vulnerable) atherosclerotic plaques within common carotid arteries (CCA) using 99mTc-labelled IL-2 scintigraphy in a selected group of ESRD patients who are at high cardiovascular risk. Materials and methods A total of 28 patients (10 women, 18 men, aged 55.29.6 years) were included in (...truncated)