High-field magnetic resonance microscopy of aortic plaques in a mouse model of atherosclerosis.

OBJECTIVES: Pre-clinical models of human atherosclerosis are extensively used; however, traditional histological methods do not allow for a holistic view of vascular lesions. We describe an ex-vivo, high-resolution MRI method that allows the 3 dimensional imaging of the vessel for aortic plaque visualization and quantification. MATERIALS AND METHODS: Aortas from apolipoprotein-E-deficient (apoE-/-) mice fed an atherogenic diet (group 1) or a control diet (group 2) were subjected to 14 T MR imaging using a 3D gradient echo sequence. The obtained data sets were reconstructed (Matlab), segmented, and analyzed (Avizo). The aortas were further sectioned and subjected to traditional histological analysis (Oil-Red O and hematoxylin staining) for comparison. RESULTS: A resolution up to 15 × 10x10 µm3 revealed that plaque burden (mm3) was significantly (p < 0.05) higher in group 1 (0.41 ± 0.25, n = 4) than in group 2 (0.01 ± 0.01, n = 3). The achieved resolution provided similar detail on the plaque and the vessel wall morphology compared with histology. Digital image segmentation of the aorta's lumen, plaque, and wall offered three-dimensional visualizations of the entire, intact aortas. DISCUSSION: 14 T MR microscopy provided histology-like details of pathologically relevant vascular lesions. This work may provide the path research needs to take to enable plaque characterization in clinical applications.

Early Life Determinants of Vascular Structure in Fetuses, Infants, Children, and Adolescents: A Systematic Review and Meta-Analysis.

OBJECTIVE: To investigate the association between early life exposures during the first 1000 days (conception to age 24 months) and aortic intima-media thickness (aIMT), an early indicator of cardiovascular disease (CVD) risk, in youths. STUDY DESIGN: The MEDLINE, Embase, Scopus, CINAHL, and Allied and Complementary Medicine databases were searched from inception to July 2021. Eligibility criteria included observational controlled studies in youths aged <20 years with risk factors/exposures during the first 1000 days and aIMT measurements (unadjusted mean ± SD). Outcome data were pooled using a random-effects meta-analysis. Meta-regression was used to investigate confounders. RESULTS: A total of 8657 articles were identified, of which 34 were included in our meta-analysis. The age of participants ranged from 22.9 weeks gestation in utero to 10.9 years. In the meta-analysis (n = 1220 cases, n = 1997 controls), the following factors were associated with greater aIMT: small for gestational age (SGA) status (14 studies, mean difference, 0.082 mm; 95% CI, 0.051-0.112; P < .001; I2 = 97%), intrauterine growth restriction (6 studies; mean difference, 0.198 mm, 95% CI, 0.088-0.309; P < .001; I2 = 97%), preeclampsia (2 studies; mean difference, 0.038 mm; 95% CI, 0.024-0.051; P < .001; I2 = 38%), and large for gestational age (LGA) status (3 studies; mean difference, 0.089 mm; 95% CI, 0.043-0.0136; P < .001; I2 = 93%). In meta-regression, older age (P < .001), higher prevalence of maternal smoking (P = .04), and SGA (P < .001) were associated with greater difference in aIMT in preterm participants compared with controls. Limitations included the high heterogeneity present in most meta-analyses and the scope of our meta-regression. CONCLUSIONS: Adverse early life exposures are associated with greater aIMT in youths, consistent with an increased risk for CVD later in life. Further research is needed to determine whether intervention and preventive strategies deliver clinical benefits to improve future cardiovascular health.

The effect of vitamin K1 on arterial calcification activity in subjects with diabetes mellitus: a post hoc analysis of a double-blind, randomized, placebo-controlled trial.

BACKGROUND: Coronary and aortic artery calcifications are generally slow to develop, and their burden predicts cardiovascular disease events. In patients with diabetes mellitus, arterial calcification is accelerated and calcification activity can be detected using 18F-sodium fluoride positron emission tomography (18F-NaF PET). OBJECTIVES: We aimed to determine whether vitamin K1 supplementation inhibits arterial calcification activity in individuals with diabetes mellitus. METHODS: This was a post hoc analysis of the ViKCoVaC (effect of Vitamin-K1 and Colchicine on Vascular Calcification activity in subjects with Diabetes Mellitus) double-blind randomized controlled trial conducted in Perth, Western Australia. Individuals with diabetes mellitus and established coronary calcification (coronary calcium score > 10), but without clinical coronary artery disease, underwent baseline 18F-NaF PET imaging, followed by oral vitamin K1 supplementation (10 mg/d) or placebo for 3 mo, after which 18F-NaF PET imaging was repeated. We tested whether individuals randomly assigned to vitamin K1 supplementation had reduced development of new 18F-NaF PET positive lesions within the coronary arteries and aorta. RESULTS: In total, 149 individuals completed baseline and follow-up imaging studies. Vitamin K1 supplementation independently decreased the odds of developing new 18F-NaF PET positive lesions in the coronary arteries (OR: 0.35; 95% CI: 0.16, 0.78; P = 0.010), aorta (OR: 0.27; 95% CI: 0.08, 0.94; P = 0.040), and in both aortic and coronary arteries (OR: 0.28; 95% CI: 0.13, 0.63; P = 0.002). CONCLUSIONS: In individuals with diabetes mellitus, supplementation with 10 mg vitamin K1/d may prevent the development of newly calcifying lesions within the aorta and the coronary arteries as detected using 18F-NaF PET. Further long-term studies are needed to test this hypothesis.This trial was registered at anzctr.org.au as ACTRN12616000024448.

Do biologic therapies reduce aortic inflammation in rheumatoid arthritis patients?

OBJECTIVES: Rheumatoid arthritis (RA) patients have an increased risk of cardiovascular disease (CVD). In the present study, we evaluated the inflammatory activity of the ascending aorta in RA patients who received biological treatment. METHODS: We assessed the aortic wall inflammation of RA patients using 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography before and after 6 months of biologic therapies. We also compared the inflammatory activity at the aortic wall in RA patients with remission or low disease activity (RLDA) and those with moderate or high disease activity (MHDA). The aortic uptake was measured by the standardized uptake value (SUV) and the target-to-background ratio (TBR). RESULTS: A total of 64 patients were included in the analysis (mean age, 58.4 ± 13.8 years old; female, 77%). The Disease Activity Score for 28 joints (DAS28) erythrocyte sedimentation rate (ESR) had significantly decreased after 6 months: from 5.0 ± 1.2 to 3.3 ± 1.2 (p < 0.001). The FDG uptake in the ascending aorta changed from baseline to 6 months, showing a maximum SUV (SUVmax) of 1.83 ± 0.34 to 1.90 ± 0.34 (p = 0.059) and TBR of 1.71 ± 0.23 to 1.75 ± 0.24 (p = 0.222). The SUVmax and TBR after 6 months were significantly higher in the RLDA group than in the MHDA group (2.05 ± 0.32 vs. 1.79 ± 0.33 (p = 0.002) and 1.89 ± 0.33 vs. 1.65 ± 0.20 (p = 0.001), respectively). The percentage of monocytes also significantly increased from baseline to 6 months: from 5.9 ± 1.6 to 6.9 ± 2.6 (p = 0.032). CONCLUSION: The inflammation activity at the ascending aorta in RA patients did not change significantly after 6 months of biological treatment. RA patients with a low disease activity or in clinical remission after 6 months of biological treatment still had an increased inflammatory activity at the aortic wall.

Formation of low-voltage zones on the anterior left atrial wall due to mechanical compression by the ascending aorta.

BACKGROUND: Although low-voltage zones (LVZs) in the left atrium (LA) are considered arrhythmogenic substrates in some patients with atrial fibrillation (AF), the pathophysiologic factors responsible for LVZ formations remain unclear. OBJECTIVE: To elucidate the anatomical relationship between the LA and ascending aorta responsible for anterior LA wall remodeling. METHODS: We assessed the relationship between existence of LVZs on the anterior LA wall and the three-dimensional computed tomography image measurements in 102 patients who underwent AF ablation. RESULTS: Twenty-nine patients (28%) had LVZs grearer than 1.0 cm2 on the LA wall in the LA-ascending aorta contact area (LVZ group); no LVZs were seen in the other 73 patients (no-LVZ group). The LVZ group (vs. no-LVZ group) had a smaller aorta-LA angle (21.0 ± 7.7° vs. 24.9 ± 7.1°, p = .015), greater aorta-left-ventricle (LV) angle (131.3 ± 8.8° vs. 126.0 ± 7.9°; p = .005), greater diameter of the noncoronary cusp (NCC; 20.4 ± 2.2 vs. 19.3 ± 2.5 mm; p = .036), thinner LA wall-thickness adjacent to the NCC (2.3 ± 0.7 vs. 2.8 ± 0.8 mm; p = .006), and greater cardiothoracic ratio (percentage of the area in the thoracic area, 40.1 ± 7.1% vs. 35.4 ± 5.7%, p < .001). The aorta-LA angle correlated positively with the patients' body mass index (BMI), and the aorta-LV angle correlated negatively with the body weight and BMI. CONCLUSION: Deviation of the ascending aorta's course and distention of the NCC appear to be related to the development of LA anterior wall LVZs in the LA-ascending aorta contact area. Mechanical pressure exerted by extracardiac structures on the LA along with the limited thoracic space may contribute to the development of LVZs associated with AF.

Mapping and Ablation of Arrhythmias from Uncommon Sites (Aortic Cusp, Pulmonary Artery, and Left Ventricular Summit).

Despite advances in our understanding of the relevant anatomy and mapping and catheter ablation techniques of idiopathic outflow tract ventricular arrhythmias, challenging sites for catheter ablation remain the aortic cusps, pulmonary artery, and notably the left ventricular summit. A systematic approach should be used to direct mapping efforts efficiently between endocardial, coronary venous, and epicardial sites. Foci at the left ventricular summit, particularly intraseptal and at the inaccessible epicardial region, remain difficult to reach and when percutaneous techniques fail, surgical ablation remains an option but with risk of late coronary artery stenosis.

A Novel Technique for the Treatment of Type 2 Endoleak After Endovascular Aortic Repair: Sac Embolization with Balloon Occlusion of the Aorta (SEBOA).

PURPOSE: We presented a new method of sac embolization using n-butyl-cyanoacrylate (NBCA) with balloon occlusion of the aorta (SEBOA) that can facilitate decreasing flow rate of the involved branches with the goal of type 2 endoleak resolution after endovascular aortic repair (EVAR). TECHNIQUE: This technique is demonstrated in six patients who required type 2 endoleak treatment including previous technical failure. A transarterial approach was performed in four patients and transabdominal direct puncture in two. Technical success was defined as complete embolization of both involved branches and sac on postoperative CT. Sacography under balloon occlusion of the aorta demonstrated decreased flow rate of the all involved branches in all patients. SEBOA was performed using 25 or 33% of NBCA diluted with lipiodol. Technical success was obtained in 3 of 6 patients, and one major complication was observed with adhesion of NBCA to the microcatheter resulting in foreign body retention. CONCLUSION: SEBOA may help solve the difficulty of type 2 endoleak treatment after EVAR as decreased flow rate of the involved branches under balloon occlusion of the aorta was achieved in all patients. However, protocols regarding concentration of NBCA or using other embolic materials are needed to improve the success rate.

Site-specific chelation therapy with EDTA-loaded albumin nanoparticles reverses arterial calcification in a rat model of chronic kidney disease.

Medial arterial calcification (MAC) is a common outcome in diabetes and chronic kidney disease (CKD). It occurs as linear mineral deposits along the degraded elastin lamellae and is responsible for increased aortic stiffness and subsequent cardiovascular events. Current treatments for calcification, particularly in CKD, are predominantly focused on regulating the mineral disturbance and other risk factors. Ethylene diamine tetraacetic acid (EDTA), a chelating agent, can resorb mineral deposits, but the systemic delivery of EDTA may cause side effects such as hypocalcemia and bone resorption. We have developed elastin antibody conjugated albumin nanoparticles that target only degraded elastin in vasculature while sparing healthy tissues. In this study, we tested a targeted nanoparticle-based EDTA chelation therapy to reverse CKD-associated MAC. Renal failure was induced in Sprague-Dawley rats by a high adenine diet supplemented by high P and Ca for 28 days that led to MAC. Intravenous delivery of DiR dye-loaded nanoparticles confirmed targeting to vascular degraded elastin and calcification sites within 24 hours. Next, EDTA-loaded albumin nanoparticles conjugated with an anti-elastin antibody were intravenously injected twice a week for two weeks. The targeted nanoparticles delivered EDTA at the site of vascular calcification and reversed mineral deposits without any untoward effects. Systemic EDTA injections or blank nanoparticles were ineffective in reversing MAC. Reversal of calcification seems to be stable as it did not return after the treatment was stopped for an additional four weeks. Targeted EDTA chelation therapy successfully reversed calcification in this adenine rat model of CKD. We consider that targeted NP therapy will provide an attractive option to reverse calcification and has a high potential for clinical translation.

Discriminatory Value of the Ascending Aorta Diameter in Suspected Acute Type A Aortic Dissection.

OBJECTIVE: The objective was to determine if ascending aorta (AscAo) diameters measured by noncontrast computed tomography (CT) allow for meaningful discrimination between patients with and without type A aortic dissection (TAAD), ideally with 100% sensitivity. METHODS: This study was a retrospective analysis of cases of TAAD, as well as controls, undergoing evaluation for TAAD with CT aortography, presenting to 21 emergency departments within an integrated health system between 2007 and 2015. AscAo diameters were determined using axial noncontrast CT images at the level of the right main pulmonary artery by two readers. AscAo diameters were additionally normalized for age, sex, and body surface area (assessed by a Z-score, which is the number of standard deviations between the observed and expected AscAo diameters). Overall model discrimination was assessed using the area under the receiver operating characteristic curve (AUC). Comparative discrimination was assessed using both the change in AUC (∆AUC) and the continuous net reclassification index (NRI). RESULTS: A total of 230 cases of TAAD and 325 controls were included in the study. The median ages for cases and controls were 65 and 62 years, and the median AscAo diameters were 50 and 35 mm, respectively. The raw and normalized AscAo diameters demonstrated similarly excellent discrimination (AUCs of 0.96 vs. 0.97, respectively; ∆AUC = 0.01, p = 0.09) and an NRI of 0.30 (95% confidence interval [CI] = 0.13-0.47), both indicating small incremental improvements in classification with the use of the normalized AscAo measures. A raw AscAo diameter of 34 mm and a normalized Z-score of 1.84 both yielded 100% sensitivity for TAAD, with respective specificities of 35% (95% CI = 29.6%-40.2%) and 67% (95% CI = 61.7%-72.2%). CONCLUSIONS: Nearly all patients with TAAD appear to have enlarged AscAo diameters as measured by noncontrast CT, whereas most patients with suspected but absent TAAD have relatively normal AscAo diameters. Both raw and normalized AscAo measures provided relatively comparable discriminatory value. If validated, these data may be useful in adjudicating risk among patients with suspected TAAD in whom a criterion standard test is unavailable, nondiagnostic, or contraindicated.

Folic acid delays development of atherosclerosis in low-density lipoprotein receptor-deficient mice.

Many studies support the cardioprotective effects of folic acid (FA). We aimed to evaluate the utility of FA supplementation in preventing the development of atherosclerotic in low-density lipoprotein receptor-deficient (LDLR-/-) mice and to elucidate the molecular processes underlying this effect. LDLR-/- mice were randomly distributed into four groups: control group, HF group, HF + FA group and the HF + RAPA group. vascular smooth muscle cells (VSMCs) were divided into the following four groups: control group, PDGF group, PDGF + FA group and PDGF + FA + RAPA group. Blood lipid levels, oxidative stress and inflammatory cytokines were measured. Atherosclerosis severity was evaluated with oil red O staining. Haematoxylin and eosin (H&E) staining was used to assess atherosclerosis progression. Immunohistochemical staining was performed with antismooth muscle α-actin (α-SMA) antibodies and anti-osteopontin (OPN) antibodies that demonstrate VSMC dedifferentiation. The protein expression of α-SMA, OPN and mechanistic target of rapamycin (mTOR)/p70S6K signalling was detected by Western blot analysis. FA and rapamycin reduced serum levels of total cholesterol, triacylglycerol, LDL, inhibiting oxidative stress and the inflammatory response. Oil red O and H&E staining demonstrated that FA and rapamycin inhibited atherosclerosis. FA and rapamycin treatment inhibited VSMC dedifferentiation in vitro and in vivo, and FA and rapamycin attenuated the mTOR/p70S6K signalling pathway. Our findings suggest that FA attenuates atherosclerosis development and inhibits VSMC dedifferentiation in high-fat-fed LDLR-/- mice by reduced lipid levels and inhibiting oxidative stress and the inflammatory response through mTOR/p70S6K signalling pathway.

Association Between Skin and Aortic Vascular Inflammation in Patients With Psoriasis: A Case-Cohort Study Using Positron Emission Tomography/Computed Tomography.

Importance: Inflammation is critical in the development of atherosclerosis. Psoriasis is a chronic inflammatory skin disease that is associated with increased vascular inflammation by 18fluorodeoxyglucose positron emission tomography/computed tomography in vivo and future cardiovascular events. It provides a human model to understand the effect of treating inflammation in a target organ (eg, the skin) on vascular diseases. Objective: To investigate the association between change in skin disease severity and change in vascular inflammation at 1 year and to characterize the impact of 1 year of anti-tumor necrosis factor therapy on vascular inflammation. Design, Setting, and Participants: In this prospective cohort study, 220 participants from outpatient practices were recruited at the US National Institutes of Health. A total of 115 consecutively recruited patients with psoriasis were followed up at 1 year. The study was conducted from January 1, 2013, through October 31, 2016, with data analyzed in November 2016. Exposure: Skin inflammation measured as Psoriasis Area and Severity Index (PASI) score. Main Outcomes and Measures: Vascular inflammation assessed as target-to-background ratio by 18fluorodeoxyglucose positron emission tomography/computed tomography. Results: Among the 115 patients, the mean (SD) age at 1-year follow-up was 50.8 (12.8) years and 68 were men (59%). The cohort had a low cardiovascular risk by Framingham risk score and mild-to-moderate psoriasis, with a median PASI score of 5.2 (interquartile range, 3.0-8.9). At follow-up, the total cohort had a median improvement in PASI score of 33%, with use of topical therapy (60%), biological therapy (66%, mostly anti-tumor necrosis factor) and phototherapy (15%) (P < .001). Moreover, improvement in PASI score was associated with improvement in target-to-background ratio of 6%, mainly driven by those with higher responses in PASI score (P < .001). This association persisted beyond traditional risk factors (ß = 0.19; 95% CI, 0.012-0.375; P = .03) and was the strongest in those initiated with anti-tumor necrosis factor therapy (ß = 0.79; 95% CI, 0.269-1.311; P = .03). Conclusions and Relevance: Improvement in psoriasis skin disease severity was associated with improvement in aortic vascular inflammation by 18fluorodeoxyglucose positron emission tomography/computed tomography, with greater improvement in aortic vascular inflammation observed in those who had higher than 75% reduction in skin disease severity. These findings suggest that controlling remote target organ inflammation (eg, in the skin) may improve vascular diseases; however, randomized clinical trials are needed to confirm these findings.

Aortic Calcification Progression in Heterozygote Familial Hypercholesterolemia.

BACKGROUND: Patients with homozygous and heterozygous familial hypercholesterolemia (HeFH) develop severe aortic calcifications in an age- and gene dosage-dependent manner. The purpose of this study was to determine the rate of progression of aortic calcification in patients with HeFH. METHODS: We performed thoracoabdominal computed tomography scans and quantified aortic calcium (AoCa) score in 16 HeFH patients, all with the null low-density lipoprotein (LDL) receptor DEL15Kb mutation. Patients (12 men, 4 women) were rescanned an average of 8.2 ± 0.8 years after the first scan. RESULTS: Mean LDL cholesterol (LDL-C) during treatment was 2.53 mmol/L; all patients were receiving high-dose statin/ezetimibe; 5 of 16 were receiving evolocumab. Baseline LDL-C was 7.6 ± 1.3 mmol/L. Aortic calcifications increased in all patients in an exponential fashion with respect to age. Age was the strongest correlate of AoCa score. Cholesterol, LDL-C, or age × cholesterol did not correlate with AoCa score or its progression. Control patients (n = 31; 8 male, 23 female; mean age 61 ± 11 years) who underwent virtual colonoscopy were rescanned over the same period and showed an abdominal AoCa score of 1472 ± 2489 compared with 7916 ± 7060 Agatston U (P < 0.001) in patients with HeFH during treatment (mean age, 60 ± 14 years). The rate of progression was 159 vs 312 Agatston U/y in control participants vs those with HeFH. CONCLUSIONS: HeFH patients exhibit accelerated aortic calcification that increases exponentially with age. LDL-C at baseline or during treatment seems to have little effect on the rate of progression of AoCa score. Strategies to prevent aortic calcifications with statins have not met with clinical success and novel approaches are required; statins might also contribute to the process of arterial calcification.

Impact of aortic encroachment to left atrium on non-pulmonary vein triggers of atrial fibrillation.

BACKGROUND: Aortic dilatation was frequently observed in patients with atrial fibrillation (AF) and non-pulmonary vein (PV) triggers are important for mapping and ablation of AF. We hypothesized that the aortic encroachment area over left atrium (LA) could contribute to the local substrate characteristics. METHODS: We studied 32 consecutive patients of AF (age=57.34±8.07, male=30), including 26 paroxysmal and 6 persistent AFs. Anatomic relationship between LA and aorta, and electrophysiological characteristics of the encroachment areas were investigated. IRB approval was taken. RESULTS: The LA bipolar voltage (mean 0.49±0.26mV) was lower at aortic encroached area compared to global LA (mean 1.52±0.48mV) and it was statistically significant (p<0.001). There was a linear correlation between the voltages of LA and distance from the aorta to the aortic encroachment area of LA (p<0.001, R=0.616). Non-PV triggers were observed in 34.37% (n=11) of total patients. The initiation of AF in aortic encroached area was seen in 45.45% (n=5) of non-PV trigger and 15.62% of total patients. All the patients were followed up for 6months and 4 (14.81%) out of 27 patients without trigger at aortic encroached site of LA and 1 (20%) out of 5 patients with trigger at aortic encroached site of LA had recurrence of AF. CONCLUSION: The aorta contributed to low voltages on its encroachment area over the anterior wall of LA. Non-pulmonary vein triggers originating from the aortic encroachment area were found in 15.62% of total patients. Careful evaluation of the anatomical relationship between LA and aorta is important during AF ablation for a better long term outcome.

A pilot trial to examine the effect of high-dose niacin on arterial wall inflammation using fluorodeoxyglucose positron emission tomography.

RATIONALE AND OBJECTIVES: Although studies have reported direct inhibition of inflammatory pathways with niacin, the effect of niacin on arterial wall inflammation remains unknown. We examined the effect of niacin on arterial (18)F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT). MATERIALS AND METHODS: Nine statin-treated patients with coronary disease were randomized to niacin 6000 mg/day or placebo. FDG-PET/CT and lipids were assessed at baseline and at 12 weeks. FDG was quantified in the aorta, right carotid artery, and left carotid artery as the target-to-background ratio (TBR) and target-to-background difference (TBD). RESULTS: Eight patients completed the study. No significant changes in FDG measured by aortic, left carotid, or right carotid TBR or TBD were seen in either group. Compared to baseline, niacin-treated subjects exhibited a significant 29% reduction in low-density lipoprotein cholesterol (LDL-C; 95% confidence interval [CI], -50% to 8%; P = .01) and a nonsignificant 29% reduction in LDL particle number (LDL-P; 95% CI, -58% to 0.2%; P = .07). A nonsignificant 11% increase in HDL-C (95% CI, -15% to 37%; P = .30) and 8% decrease in HDL-P (95% CI, -44% to 28%; P = .51) were observed with niacin treatment. In a pooled analysis, changes in LDL-P were positively correlated with FDG uptake in the aorta (TBR r = 0.66, P = .08; TBD r = 0.75, P = .03), left carotid (TBR r = 0.65, P = .08; TBD r = 0.74, P = .03), and right carotid (TBR r = 0.54, P = .17; TBD r = 0.61, P = .11). CONCLUSIONS: In this pilot study, adding niacin to statin therapy did not affect arterial wall inflammation measured by FDG-PET/CT. However, an association between changes in arterial FDG uptake and LDL-P was observed. Larger studies are needed to definitively examine the effect of niacin on arterial wall inflammation.

Vascular function and risk factors in children with epilepsy: associations with sodium valproate and carbamazepine.

AIM: To investigate biochemical cardiovascular risk factors and vascular endothelial function and structure in children with epilepsy on antiepileptic drugs (AEDs), particularly sodium valproate (VPA) and carbamazepine (CBZ). BACKGROUND: Individuals with epilepsy have increased risk factors for vascular disease, particularly lipid abnormalities and elevated total plasma homocyst(e)ine (tHcy). AED induced B-vitamin deficiencies have been suggested to contribute to this risk. Vitamin B supplementation has consequently been recommended for children on AEDs. Early vascular endothelial dysfunction and atherosclerosis are detectable by measuring flow-mediated dilation (FMD) and intima-media thickness (IMT). METHODS: Thirty children with epilepsy on AEDs (13.3±2.3 years, 14 male) and 30 controls (13.9±2.9 years, 14 male) were recruited. Fasting tHcy, folate, pyridoxal-5-phosphate (PLP), vitamin B12, glucose and lipids were measured. Vascular function and structure were assessed using FMD (brachial artery) and IMT (carotid/aortic arteries). RESULTS: No differences were found between children with epilepsy and controls for tHcy, folate, PLP, lipids, FMD, carotid or aortic IMT. Vitamin B12 levels were elevated and glucose reduced in children treated with VPA. Elevated total cholesterol, cholesterol/HDL ratio and triglycerides occurred in children treated with CBZ. Aortic IMT correlated with weight (r=0.75, p<0.001), BMI (r=0.54, p=0.01), and HDL cholesterol (r=-0.58, p=0.006). CONCLUSION: We found no early changes in vascular function or structure in children on valproate or carbamazepine. We were also unable to confirm previous reports of tHcy abnormalities in this group. This may be due to higher B-vitamin intake, which compensates for loss of vitamins induced by this AED therapy. Vitamin supplementation in children with epilepsy on valproate and carbamazepine is not required in populations with adequate dietary intake of B vitamins.

Development of a dual-modal tissue diagnostic system combining time-resolved fluorescence spectroscopy and ultrasonic backscatter microscopy.

We report a tissue diagnostic system which combines two complementary techniques of time-resolved laser-induced fluorescence spectroscopy (TR-LIFS) and ultrasonic backscatter microscopy (UBM). TR-LIFS evaluates the biochemical composition of tissue, while UBM provides tissue microanatomy and enables localization of the region of diagnostic interest. The TR-LIFS component consists of an optical fiber-based time-domain apparatus including a spectrometer, gated multichannel plate photomultiplier, and fast digitizer. It records the fluorescence with high sensitivity (nM concentration range) and time resolution as low as 300 ps. The UBM system consists of a transducer, pulser, receiving circuit, and positioning stage. The transducer used here is 45 MHz, unfocused, with axial and lateral resolutions 38 and 200 microm. Validation of the hybrid system and ultrasonic and spectroscopic data coregistration were conducted both in vitro (tissue phantom) and ex vivo (atherosclerotic tissue specimens of human aorta). Standard histopathological analysis of tissue samples was used to validate the UBM-TRLIFS data. Current results have demonstrated that spatially correlated UBM and TR-LIFS data provide complementary characterization of both morphology (necrotic core and calcium deposits) and biochemistry (collagen, elastin, and lipid features) of the atherosclerotic plaques at the same location. Thus, a combination of fluorescence spectroscopy with ultrasound imaging would allow for better identification of features associated with tissue pathologies. Current design and performance of the hybrid system suggests potential applications in clinical diagnosis of atherosclerotic plaque.

Effect of long-term homocysteine reduction with B vitamins on arterial wall inflammation assessed by fluorodeoxyglucose positron emission tomography: a randomised double-blind, placebo-controlled trial.

BACKGROUND: Homocysteine may promote atherosclerosis by exacerbating inflammatory processes within the arterial wall. B-vitamin supplements reduce total plasma homocysteine concentrations (tHcy), but it is not known whether the treatment also reduces arterial wall inflammation. We used (18)F-fluorodeoxygluose positron emission tomography ((18)F-FDG PET) to investigate whether long-term homocysteine-lowering treatment alters arterial wall inflammation in patients with a history of ischemic stroke. METHODS: 30 stroke patients were randomly assigned to B-vitamin therapy (folic acid 2 mg, vitamin B(6) 25 mg and vitamin B(12) 0.5 mg) or placebo in a double-blind clinical trial. After a mean treatment period of 4.0 +/- 0.7 years, all subjects had tHcy, carotid intima-medial thickness (CIMT) and flow-mediated dilation (FMD) of the brachial artery measured and underwent an (18)F-FDG PET scan. Standardised uptake values (SUV) were measured at six sites in the carotid, femoral and aortic arteries. Areas of locally increased tracer uptake in the arterial wall ('hot spots') were also identified and counted. RESULTS: Long-term B-vitamin treatment significantly reduced tHcy compared with placebo (8.4 micromol/l, 95% confidence interval, CI, 7.2-9.6 vs. 11.6 micromol/l, 95% CI 10.0-13.4, p = 0.002). The treatment did not affect mean arterial SUV (2.0 +/- 0.3 vitamins vs. 2.1 +/- 0.3 placebo, p = 0.65) or the number of hot spots (n = 1.1 +/- 1.0 vitamins vs. n = 1.2 +/- 1.0 placebo, p = 0.65). There was no significant correlation between mean arterial SUV and CIMT or FMD. CONCLUSIONS: These results suggest that a long-term Hcy reduction with B vitamins does not affect arterial wall inflammation assessed by (18)F-FDG PET.

Cardiovascular involvement in patients with beta-thalassemia major without cardiac iron overload.

BACKGROUND: Cardiovascular complications are common in beta-thalassemia major (beta-TM), mainly attributed to increased cardiac iron depositions. Early cardiovascular involvement in patients without cardiac symptoms and without cardiac iron overload has not been adequately investigated. METHODS: Twenty six patients (11 males) with beta-TM, on chelation therapy, age 23+/-4 years without cardiac iron overload (measured by magnetic resonance imaging), and 30 age and gender matched healthy controls were included in the study. Carotid-femoral and carotid-radial pulse wave velocity (PWVc-f and PWVc-r) and augmentation index (AI) were measured by SphygmoCor device; carotid intima-media thickness; left ventricular (LV) dimensions and function; left atrial (LA) volume and function were assessed by echocardiography. RESULTS: Patients with beta-TM had higher PWVc-f (8.4+/-1.4 vs 7.2+/-1.1 m/s, p=0.002) and augmentation index (21.7+/-10.9 vs 14.7+/-9.7%, p=0.04) indicating decreased aortic elastic properties; greater LV mass index (72.0+/-13.3 vs 63.8+/-11.5 g/m(2), p=0.04) and greater LA volumes. Multivariate logistic regression analysis revealed that higher PWVc-f was independently associated with higher LV mass [OR 1.74 95%CI (1.09-2.88), p=0.026]; and greater LA dimensions [OR 1.68 95%CI (1.04-2.72), p=0.035]. CONCLUSIONS: In the absence of cardiac iron overload, asymptomatic patients with beta-TM demonstrated aortic stiffening associated with increased LV mass and LA enlargement. These alterations may represent signs of early cardiovascular involvement.