Introduction: Carotid atherosclerotic intraplaque hemorrhage (IPH) predicts stroke. Patients with a history of stroke are treated with antiplatelet agents to prevent secondary cardiovascular... Show moreIntroduction: Carotid atherosclerotic intraplaque hemorrhage (IPH) predicts stroke. Patients with a history of stroke are treated with antiplatelet agents to prevent secondary cardiovascular events. A positive association between previous antiplatelet use and IPH was reported in a cross-sectional analysis. We investigated the changes in IPH over 2 years in patients who recently started versus those with continued antiplatelet use. Methods: In the Plaque at Risk (PARISK) study, symptomatic patients with <70% ipsilateral carotid stenosis underwent carotid plaque magnetic resonance imaging (MRI) at the baseline and after 2 years to determine IPH presence and volume. Participants were categorized into new users (starting antiplatelet therapy following the index event) and continued users (previous use of antiplatelet therapy before the index event). The association between previous antiplatelet therapy and the presence of IPH at baseline MRI was investigated using multivariable logistic regression analysis. The IPH volume change over a period of 2 years, defined as the difference in volume between follow-up and baseline, was investigated in each group with a Wilcoxon signed-rank test. The IPH volume change was categorized as progression, regression, or no change. Using multivariable logistic regression, we investigated the association between new antiplatelet use and (1) newly developed ipsilateral or contralateral IPH and (2) IPH volume progression. Results: A total of 108 patients underwent carotid MRI at the baseline and follow-up. At the baseline, previous antiplatelet therapy was associated with any IPH (OR = 5.6, 95% CI: 1.3–23.1; p = 0.02). Ipsilateral IPH volume did not change significantly during the 2 years in patients who continued receiving antiplatelet agents (86.4 mm3 [18.2–235.9] vs. 59.3 mm3 [11.4–260.3]; p = 0.6) nor in the new antiplatelet users (n = 31) (61.5 mm3 [0.0–166.9] vs. 27.7 mm3 [9.5–106.4]; p = 0.4). Similar results of a nonsignificant change in contralateral IPH volume during those 2 years were observed in both groups (p > 0.05). No significant associations were found between new antiplatelet use and newly developed IPH at 2 years (odds ratio [OR] = 1.0, 95% CI: 0.1–7.4) or the progression of IPH (ipsilateral: OR = 2.4, 95% CI: 0.3–19.1; contralateral: OR = 0.3, 95% CI: 0.01–8.5). Conclusion: Although the baseline association between IPH and previous antiplatelet therapy was confirmed in this larger cohort, the new onset of antiplatelet therapy after transient ischemic attack/stroke was not associated with the newly developed IPH or progression of IPH volume over the subsequent 2 years. Show less
Kassem, M.; Kam, S.S. de; Velzen, T.J. van; Geest, R. van der; Wagner, B.; Sokolska, M.; ... ; Kooi, M.E. 2023
Purpose: Carotid intraplaque hemorrhage (IPH) on MRI predicts stroke. Magnetization-prepared rapid acquisition gradient (MP-RAGE) is widely used to detect IPH. CE-MRA is used routinely to assess... Show morePurpose: Carotid intraplaque hemorrhage (IPH) on MRI predicts stroke. Magnetization-prepared rapid acquisition gradient (MP-RAGE) is widely used to detect IPH. CE-MRA is used routinely to assess stenosis. Initial studies indicated that IPH can be identified on mask images of CE-MRA, while Time-of-Flight (TOF) images were reported to have high specificity but lower sensitivity. We investigated the diagnostic accuracy of detecting IPH on mask images of CE-MRA and TOF. Methods: Thirty-six patients with >= 50% stenosis enrolled in the ongoing 2nd European Carotid Surgery Trial underwent carotid MRI. A 5-point quality score was used. Inter-observer agreement between two independent readers was determined. The sensitivity and specificity of IPH detection on mask MRA and TOF were calculated with MP-RAGE as a reference standard. Results: Of the 36 patients included in the current analysis, 66/72 carotid arteries could be scored. The interobserver agreements for identifying IPH on MP-RAGE, mask, and TOF were outstanding (K: 0.93, 0.96, and 0.85). The image quality of mask (1.42 +/- 0.66) and TOF (2.42 +/- 0.66) was significantly lower than MP-RAGE (3.47 +/- 0.61). When T1w images were used to delineate the outer carotid wall, very high specificities (>95%) of IPH detection on mask and TOF images were found, while the sensitivity was high for mask images (>81%) and poor for TOF (50–60%). Without these images, the specificity was still high (>97%), while the sensitivity reduced to 62–71%. Conclusion: Despite the lower image quality, routinely acquired mask images from CE-MRA, but not TOF, can be used as an alternative to MP-RAGE images to visualize IPH. Show less
Chemaly, M.; Marlevi, D.; Iglesias, M.J.; Lengquist, M.; Kronqvist, M.; Bos, D.; ... ; Hedin, U. 2023
Background: Intraplaque hemorrhage (IPH) is a hallmark of atherosclerotic plaque instability. Biliverdin reductase B (BLVRB) is enriched in plasma and plaques from patients with symptomatic carotid... Show moreBackground: Intraplaque hemorrhage (IPH) is a hallmark of atherosclerotic plaque instability. Biliverdin reductase B (BLVRB) is enriched in plasma and plaques from patients with symptomatic carotid atherosclerosis and functionally associated with IPH. Objective: We explored the biomarker potential of plasma BLVRB through (1) its correlation with IPH in carotid plaques assessed by magnetic resonance imaging (MRI), and with recurrent ischemic stroke, and (2) its use for monitoring pharmacotherapy targeting IPH in a preclinical setting. Methods: Plasma BLVRB levels were measured in patients with symptomatic carotid atherosclerosis from the PARISK study (n = 177, 5 year follow-up) with and without IPH as indicated by MRI. Plasma BLVRB levels were also measured in a mouse vein graft model of IPH at baseline and following antiangiogenic therapy targeting vascular endothelial growth factor receptor 2 (VEGFR-2). Results: Plasma BLVRB levels were significantly higher in patients with IPH (737.32 & PLUSMN; 693.21 vs. 520.94 & PLUSMN; 499.43 mean fluorescent intensity (MFI), p = 0.033), but had no association with baseline clinical and biological parameters. Plasma BLVRB levels were also significantly higher in patients who developed recurrent ischemic stroke (1099.34 & PLUSMN; 928.49 vs. 582.07 & PLUSMN; 545.34 MFI, HR = 1.600, CI [1.092-2.344]; p = 0.016). Plasma BLVRB levels were significantly reduced following prevention of IPH by anti-VEGFR-2 therapy in mouse vein grafts (1189 & PLUSMN; 258.73 vs. 1752 & PLUSMN; 366.84 MFI; p = 0.004). Conclusions: Plasma BLVRB was associated with IPH and increased risk of recurrent ischemic stroke in patients with symptomatic low- to moderate-grade carotid stenosis, indicating the capacity to monitor the efficacy of IPH-preventive pharmacotherapy in an animal model. Together, these results suggest the utility of plasma BLVRB as a biomarker for atherosclerotic plaque instability. Show less
Aims/hypothesisObesity is a major risk factor for type 2 diabetes. However, body composition differs between women and men. In this study we investigate the association between diabetes status and... Show moreAims/hypothesisObesity is a major risk factor for type 2 diabetes. However, body composition differs between women and men. In this study we investigate the association between diabetes status and body composition and whether this association is moderated by sex.MethodsIn a population-based cohort study (n=7639; age 40–75 years, 50% women, 25% type 2 diabetes), we estimated the sex-specific associations, and differences therein, of prediabetes (i.e. impaired fasting glucose and/or impaired glucose tolerance) and type 2 diabetes (reference: normal glucose metabolism [NGM]) with dual-energy x-ray absorptiometry (DEXA)- and MRI-derived measures of body composition and with hip circumference. Sex differences were analysed using adjusted regression models with interaction terms of sex-by-diabetes status.ResultsCompared with their NGM counterparts, both women and men with prediabetes and type 2 diabetes had more fat and lean mass and a greater hip circumference. The differences in subcutaneous adipose tissue, hip circumference and total and peripheral lean mass between type 2 diabetes and NGM were greater in women than men (women minus men [W–M] mean difference [95% CI]: 15.0 cm2 [1.5, 28.5], 3.2 cm [2.2, 4.1], 690 g [8, 1372] and 443 g [142, 744], respectively). The difference in visceral adipose tissue between type 2 diabetes and NGM was greater in men than women (W–M mean difference [95% CI]: −14.8 cm2 [−26.4, −3.1]). There was no sex difference in the percentage of liver fat between type 2 diabetes and NGM. The differences in measures of body composition between prediabetes and NGM were generally in the same direction, but were not significantly different between women and men.Conclusions/interpretationThis study indicates that there are sex differences in body composition associated with type 2 diabetes. The pathophysiological significance of these sex-associated differences requires further study. Show less
Aims (Ultra) Small superparamagnetic iron oxide nanoparticles, (U)SPIO, are widely used as magnetic resonance imaging contrast media and assumed to be safe for clinical applications in... Show moreAims (Ultra) Small superparamagnetic iron oxide nanoparticles, (U)SPIO, are widely used as magnetic resonance imaging contrast media and assumed to be safe for clinical applications in cardiovascular disease. As safety tests largely relied on normolipidaemic models, not fully representative of the clinical setting, we investigated the impact of (U)SPIOs on disease-relevant endpoints in hyperlipidaemic models of atherosclerosis. Methods and results RAW264.7 foam cells, exposed in vitro to ferumoxide (dextran-coated SPIO), ferumoxtran (dextran-coated USPIO), or ferumoxytol [carboxymethyl (CM) dextran-coated USPIO] (all 1 mg Fe/mL) showed increased apoptosis and reactive oxygen species accumulation for ferumoxide and ferumoxtran, whereas ferumoxytol was tolerated well. Pro-apoptotic (TUNEL+) and pro-oxidant activity of ferumoxide (0.3 mg Fe/kg) and ferumoxtran (1 mg Fe/kg) were confirmed in plaque, spleen, and liver of hyperlipidaemic ApoE(-/-) (n = 9/group) and LDLR-/- (n = 9-16/group) mice that had received single IV injections compared with saline-treated controls. Again, ferumoxytol treatment (1 mg Fe/kg) failed to induce apoptosis or oxidative stress in these tissues. Concomitant antioxidant treatment (EUK-8/EUK-134) largely prevented these effects in vitro (-68%, P < 0.05) and in plaques from LDLR-/- mice (-60%, P < 0.001, n = 8/group). Repeated ferumoxtran injections of LDLR-/- mice with pre-existing atherosclerosis enhanced plaque inflammation and apoptosis but did not alter plaque size. Strikingly, carotid artery plaques of endarterectomy patients who received ferumoxtran (2.6 mg Fe/kg) before surgery (n = 9) also showed five-fold increased apoptosis (18.2 vs. 3.7%, respectively; P = 0.004) compared with controls who did not receive ferumoxtran. Mechanistically, neither coating nor particle size seemed accountable for the observed cytotoxicity of ferumoxide and ferumoxtran. Conclusions Ferumoxide and ferumoxtran, but not ferumoxytol, induced apoptosis of lipid-laden macrophages in human and murine atherosclerosis, potentially impacting disease progression in patients with advanced atherosclerosis. Show less
PURPOSE: Currently, a multi-contrast protocol, including a combination of five MR-sequences is used as reference standard for morphologic imaging and quantitative measurements of the carotid artery... Show morePURPOSE: Currently, a multi-contrast protocol, including a combination of five MR-sequences is used as reference standard for morphologic imaging and quantitative measurements of the carotid artery vessel wall. The purpose of this study is to investigate the scan-rescan reproducibility together with intra- and inter-observer reproducibility of each of the five MR-sequences. METHODS: Twenty healthy volunteers (55% male, mean age=26 years) underwent repeated MR-examinations (3T-Philips-MRI) of the left carotid artery vessel wall with five sequences; T1-TFE, T2-TSE, PD-TSE, T1-TSE and 3D TOF. A standard phased-array coil with two flexible elements of 14cm×17cm was used to obtain nine transverse imaging sections of the left carotid artery with identical in-plane resolution (0.46mm×0.46mm). Reproducibility analysis was performed in 3 slices of the common carotid artery for all sequences. RESULTS: For, scan-rescan reproducibility, intra class correlation coefficients (ICC) were excellent for all sequences and ranged from 0.79 to 0.95. The intra-observer ICC ranged from 0.89 to 0.98 and the inter-observer ICC ranged from 0.84 to 0.96, for both lumen and vessel wall assessment. CONCLUSIONS: By high field MR imaging, vessel wall and lumen area of the carotid artery can be assessed with excellent scan-rescan, intra- and inter-observer reproducibility for all five sequences. Show less
Schrauwen-Hinderling, V.B.; Meex, R.C.R.; Hesselink, M.K.C.; Weijer, T. van de; Leiner, T.; Schar, M.; ... ; Kooi, M.E. 2011
Background: Increased cardiac lipid content has been associated with diabetic cardiomyopathy. We recently showed that cardiac lipid content is reduced after 12 weeks of physical activity training... Show moreBackground: Increased cardiac lipid content has been associated with diabetic cardiomyopathy. We recently showed that cardiac lipid content is reduced after 12 weeks of physical activity training in healthy overweight subjects. The beneficial effect of exercise training on cardiovascular risk is well established and the decrease in cardiac lipid content with exercise training in healthy overweight subjects was accompanied by improved ejection fraction. It is yet unclear whether diabetic patients respond similarly to physical activity training and whether a lowered lipid content in the heart is necessary for improvements in cardiac function. Here, we investigated whether exercise training is able to lower cardiac lipid content and improve cardiac function in type 2 diabetic patients. Methods: Eleven overweight-to-obese male patients with type 2 diabetes mellitus (age: 58.4 +/- 0.9 years, BMI: 29.9 +/- 0.01 kg/m(2)) followed a 12-week training program (combination endurance/strength training, three sessions/week). Before and after training, maximal whole body oxygen uptake (VO2max) and insulin sensitivity (by hyperinsulinemic, euglycemic clamp) was determined. Systolic function was determined under resting conditions by CINE-MRI and cardiac lipid content in the septum of the heart by Proton Magnetic Resonance Spectroscopy. Results: VO2max increased (from 27.1 +/- 1.5 to 30.1 +/- 1.6 ml/min/kg, p = 0.001) and insulin sensitivity improved upon training (insulin stimulated glucose disposal (delta Rd of glucose) improved from 5.8 +/- 1.9 to 10.3 +/- 2.0 mu mol/kg/min, p = 0.02. Left-ventricular ejection fraction improved after training (from 50.5 +/- 2.0 to 55.6 +/- 1.5%, p = 0.01) as well as cardiac index and cardiac output. Unexpectedly, cardiac lipid content in the septum remained unchanged (from 0.80 +/- 0.22% to 0.95 +/- 0.21%, p = 0.15). Conclusions: Twelve weeks of progressive endurance/strength training was effective in improving VO(2)max, insulin sensitivity and cardiac function in patients with type 2 diabetes mellitus. However, cardiac lipid content remained unchanged. These data suggest that a decrease in cardiac lipid content in type 2 diabetic patients is not a prerequisite for improvements in cardiac function. Show less
Bilet, L.; Weijer, T. van de; Hesselink, M.K.C.; Glatz, J.F.C.; Lamb, H.J.; Wildberger, J.; ... ; Schrauwen-Hinderling, V.B. 2011
Cardiac lipid accumulation is associated with decreased cardiac function and energy status (PCr/ATP). It has been suggested that elevated plasma fatty acid (FA) concentrations are responsible for... Show moreCardiac lipid accumulation is associated with decreased cardiac function and energy status (PCr/ATP). It has been suggested that elevated plasma fatty acid (FA) concentrations are responsible for the cardiac lipid accumulation. Therefore, the aim of the present study was to investigate if elevating plasma FA concentrations by exercise results in an increased cardiac lipid content, and if this influences cardiac function and energy status. Eleven male subjects (age 25.4 +/- A 1.1 years, BMI 23.6 +/- A 0.8 kg/m(2)) performed a 2-h cycling protocol, once while staying fasted and once while ingesting glucose, to create a state of high versus low plasma FA concentrations, respectively. Cardiac lipid content was measured by proton magnetic resonance spectroscopy (H-1-MRS) at baseline, directly after exercise and again 4 h post-exercise, together with systolic function (by multi-slice cine-MRI) and cardiac energy status (by P-31-MRS). Plasma FA concentrations were increased threefold during exercise and ninefold during recovery in the fasted state compared with the glucose-fed state (p < 0.01). Cardiac lipid content was elevated at the end of the fasted test day (from 0.26 +/- A 0.04 to 0.44 +/- A 0.04%, p = 0.003), while it did not change with glucose supplementation (from 0.32 +/- A 0.03 to 0.26 +/- A 0.05%, p = 0.272). Furthermore, PCr/ATP was decreased by 32% in the high plasma FA state compared with the low FA state (n = 6, p = 0.014). However, in the high FA state, the ejection fraction 4 h post-exercise was higher compared with the low FA state (63 +/- A 2 vs. 59 +/- A 2%, p = 0.018). Elevated plasma FA concentrations, induced by exercise in the fasted state, lead to increased cardiac lipid content, but do not acutely hamper systolic function. Although the lower cardiac energy status is in line with a lipotoxic action of cardiac lipid content, a causal relationship cannot be proven. Show less
Objective: To investigate the natural course of carotid plaque progression in transient ischemic attack/stroke patients by using serial multisequence magnetic resonance imaging (MRI). Materials and... Show moreObjective: To investigate the natural course of carotid plaque progression in transient ischemic attack/stroke patients by using serial multisequence magnetic resonance imaging (MRI). Materials and Methods: Forty transient ischemic attack/stroke patients with ipsilateral <70% carotid stenosis underwent MRI of the plaque ipsilateral to the symptomatic side at baseline and after 1 year. The MRI protocol consisted of T1-weighted turbo field-echo, time-of-flight, T2-weighted turbo spin-echo (TSE), and pre- and postgadopentetate dimeglumine-enhanced T1-weighted TSE images. For each plaque, carotid lumen volume, wall volume, total vessel volume (=carotid lumen volume + wall volume), the presence of a lipid-rich necrotic core (LRNC), fibrous cap (FC) status, and the presence of intraplaque hemorrhage (IPH) were assessed at both time points. Results: Over a 1-year period, mean carotid lumen volume decreased with 4.8% +/- 2.0% (+/- standard error) (P = 0.013). Mean wall volume increased with 11.2% +/- 2.2% (P < 0.001). Total vessel volume did not significantly change (P = 0.147). At baseline, there were 18 plaques with a LRNC, which also had a LRNC at 1-year follow-up. No plaque without a LRNC at baseline developed a LRNC during the follow-up period. All plaques with a LRNC had a thin and/or ruptured FC at both time points. Twelve patients had IPH both at baseline and at follow-up. In one patient, IPH disappeared, whereas in another patient, new IPH appeared at follow-up. The presence of IPH and a LRNC with a thin and/or ruptured FC were not significantly associated with plaque progression (P > 0.05). Conclusions: In symptomatic patients with an ipsilateral carotid plaque causing <70% stenosis, we found evidence for inward plaque remodeling over a 1-year period. Overall, the presence/absence of IPH, a LRNC, and FC status did not change over 1 year. Show less
Bilet, L.; Weijer, T. van de; Hesselink, M.K.C.; Glatz, J.; Lamb, H.; Schar, M.; ... ; Schrauwen-Hinderling, V. 2010
