Mária Tünde Magyar

Early-Onset Carotid Atherosclerosis Is Associated With Increased Intima-Media Thickness and Elevated Serum Levels of Inflammatory Markers

Background and Purpose— Several factors have been held responsible for the development of atherosclerosis. To avoid the masking effect of age, we evaluated correlates of carotid atherosclerosis in patients <55 years of age. Methods— Plasma lipids, oxidative resistance of low-density lipoprotein, homocysteine, inflammatory markers, plasma viscosity, and red cell deformability were measured in fasting blood samples of 100 subjects: 45 patients with >30% stenosis of the internal carotid artery, 20 patients with carotid occlusion, and 35 control subjects. Stenosis and intima-media thickness (IMT) of the carotid artery were evaluated by duplex ultrasound. Results— White blood cell (WBC) count, plasma fibrinogen, C-reactive protein (CRP), and lipoprotein(a) levels were significantly higher in patients than in control subjects, and patients had increased IMT (P <0.01 for all comparisons). There was a tendency for higher homocysteine levels in patients. Smokers had higher WBC, fibrinogen, and CRP levels. After the effect of smoking was controlled for, WBC count, natural logarithmic transform of homocysteine, and online-measured IMT remained significantly higher in patients than in control subjects. WBC, fibrinogen, and CRP levels were highest in the highest IMT quartile (P =0.012, P =0.007, and P =0.036, respectively). Conclusions— Inflammatory markers and homocysteine have a more important role than lipid factors in early-onset carotid atherosclerosis. We cannot recommend the measurement of low-density lipoprotein peroxidation as a routine screening test to identify high-risk patients for early-onset carotid atherosclerosis. The confounding effect of smoking on inflammatory markers should be considered in studies on atherosclerosis.

Should Soluble CD40 Ligand Be Measured From Serum or Plasma Samples

To the Editor: We were surprised to read the article by Blake et al1 on the relationship of soluble CD40 ligand (sCD40L) and lipid accumulation in carotid atheroma. We recently reported an association between inflammatory markers and early onset carotid atherosclerosis.2 Of the patients noted in that report, we had plasma samples from EDTA-anticoagulated blood, stored frozen for 1 to 3 years. Although the product information and manual of the Bender MedSystem’s ELISA kit clearly states that plasma preparations are not suitable for the essay,3 we decided to run a test on some of these plasma samples for sCD40L. We also used duplicate plasma samples, together with fresh serum and plasma of 5 healthy subjects obtained less than 4 hours before the ELISA test, in the same ELISA plate. We were not surprised but were disappointed, as no activity could be detected either in the frozen plasma samples of patients or in the fresh or recalcified plasma samples of the healthy subjects. The method and the plate worked properly, as sCD40L activity was measured with small variation between duplicates in all of the serum samples (7.0±1.5 ng/mL, mean±SD). We had to conclude and admit that, as stated in the product information, EDTA-anticoagulated plasma samples—either frozen or freshly collected—are not appropriate for the test. After this failure, we came …

Increased levels of platelet activation markers are positively associated with carotid wall thickness and other atherosclerotic risk factors in obese patients

The role of platelets in the development of atherosclerosis and obesity-related prothrombotic state is still under investigation. In this cross-sectional cohort study, we measured the levels of different platelet activation markers and evaluated their relationship with carotid intima-media thickness (IMT) along with other atherosclerotic risk factors in obese patients with or without atherosclerotic co-morbidities. We enrolled 154 obese patients, including 98 with either hypertension, type 2 diabetes mellitus or dyslipidaemia, 56 without these co-morbidities and 62 age- and sex-matched healthy controls. Platelet P-selectin expression and the number of platelet-derived microparticles (PMPs) were measured by flow cytometry; soluble P-selectin levels were analysed by ELISA and Thr715Pro P-selectin polymorphism was determined by PCR-RFLP. Carotid IMT was examined by ultrasonography. The levels of platelet activation parameters were significantly elevated in all obese subjects with increased carotid IMT compared to healthy controls. There was no effect of Thr715Pro genotype on soluble P-selectin levels in obese individuals contrary to normal subjects. Significant and positive association was revealed between carotid IMT and platelet P-selectin (p<0.0001), soluble P-selectin (p=0.039) and PMP (p=0.0001) levels. After adjusting for multiple variables, independent association was found between soluble P-selectin and fibrinogen (p=0.007), PMP levels and body mass index (p<0.0001) as well as platelet P-selectin and carotid IMT (p=0.012) plus plasminogen activator inhibitor-1 (p=0.009). In conclusion, P-selectin and PMP levels showed positive associations with abnormal carotid IMT and other risk factors in obesity suggesting a critical role of enhanced platelet reactivity in atherosclerotic wall alteration.

Anxiety, depression and autonomic nervous system dysfunction in hypertension

OBJECTIVES This study examined the relationship between autonomic nervous system dysfunction, anxiety and depression in untreated hypertension. PATIENTS AND METHODS 86 newly diagnosed hypertensive patients and 98 healthy volunteers were included in the study. The psychological parameters were assessed with Spielberger State-Trait Anxiety Inventory and Beck Depression Inventory by a skilled psychologist. Autonomic parameters were examined during tilt table examination (10min lying position, 10min passive tilt). Heart rate variability (HRV) was calculated by autoregressive methods. Baroreflex sensitivity (BRS) was calculated by non-invasive sequence method from the recorded beat to beat blood pressure values and RR intervals. RESULTS Significantly higher state (42.6±9.3 vs. 39.6±10.7 p=0.05) and trait (40.1±8.9 vs. 35.1±8.6, p<0.0001) anxiety scores were found in the hypertension group. There was no statistically significant difference in the depression level. LF-RRI (Low Frequency-RR interval) of HRV in passive tilt (377.3±430.6 vs. 494.1±547, p=0.049) and mean BRS slope (11.4±5.5 vs. 13.2±6.4, p=0.07) in lying position were lower in hypertensives. Trait anxiety score correlates significantly with sympatho/vagal balance (LF/HF-RRI) in passive tilt position (Spearman R=-0.286, p=0.01). CONCLUSIONS Anxiety could play a more important role than depression in the development of hypertension. Altered autonomic control of the heart could be one of the pathophysiological links between hypertension and psychological factors.

Association between human paraoxonase 1 activity and intima-media thickness in subjects under 55 years of age with carotid artery disease.

Background: Human serum paraoxonase (PON1) protects lipoproteins against oxidation by hydrolyzing lipid peroxides in oxidized low-density lipoprotein (oxLDL); therefore, it may protect against atherosclerosis. PON1 activity and polymorphisms have been inconsistently associated with carotid artery disease. The goal of this study was to clarify the role of PON1 activity and phenotype on carotid artery disease and its correlation with some inflammatory and immune markers in subjects under 55 years with early-onset carotid atherosclerosis. Methods: Sixty patients with occlusive carotid artery disease and 30 healthy controls were enrolled. Intima-media thickness (IMT) was measured by high-resolution ultrasound of both common carotid arteries. Anti-oxLDL antibody levels were determined by ELISA. Results: In the whole study population we found a negative correlation between PON1 activity and IMT (r = –0.27, p = 0.011), and between salt-stimulated PON1 activity and IMT (r = –0.24, p = 0.02). Both PON1 activity and salt-stimulated PON1 activity negatively correlated with anti-oxLDL levels (r = –0.28, p = 0.008; r = –0.26, p = 0.01). PON1 activity was lower in patients compared to controls; however, the difference was not significant.PON1 phenotype distribution of patients and controls did not differ significantly. Conclusion: The importance of PON1 activity as a predictive risk factor for early-onset occlusive carotid artery disease should be assessed in future studies.

Cortical Spreading Edema in Persistent Visual Migraine Aura

We present imaging evidence of the spreading of cortical edema with reversibly restricted water diffusion from the left occipital to the temporoparietal cortex in persistent visual migraine aura in a 58‐year‐old man. The right‐sided visual field defect lasting for 15 days was associated with discoupling of glucose metabolism and blood flow and the decreased apparent diffusion coefficient also suggested cytotoxic edema. At 8 weeks no signs were present, and magnetic resonance imaging became normal; therefore, long‐lasting restricted cortical water diffusion, even if coupled with hypometabolism and edema, can be reversible in persistent visual migraine aura.

Endothelial cell markers reflecting endothelial cell dysfunction in patients with mixed connective tissue disease

IntroductionThe aim of the present study was to investigate the association between cardiovascular risk factors and endothelial dysfunction in patients with mixed connective tissue disease (MCTD) and to determine which biomarkers are associated with atherosclerotic complications, such as cardiovascular disease.MethodsFifty MCTD patients and 38 healthy age-matched and sex-matched controls were enrolled in this study. In order to describe endothelial dysfunction, we assessed flow-mediated dilation (FMD), nitrate-mediated dilation (NMD) and carotid artery intima-media thickness (IMT). We investigated FMD of the brachial artery after reactive hyperemia and NMD after sublingual nitroglycerin administration, while the IMT of the common carotid artery was determined by ultrasound. Anti-U1 ribonucleoprotein (anti-U1RNP) antibodies, anti-cardiolipin (anti-CL) antibodies, anti-endothelial cell antibody (AECA) and endothelial cell markers, such as soluble thrombomodulin (TM) and von Willebrand factor antigen (vWFAg), were assessed.ResultsThe endothelium-dependent vasodilation (FMD) was significantly impaired in patients with MCTD, as compared with controls (%FMD: 4.7 ± 4.2% vs. 8.7 ± 5.0%; P < 0.001), while the percentage NMD did not differ (%NMD: 14.3 ± 6.6% vs. 17.1 ± 6.7%; P = 0.073). Mean carotid IMT values were higher in patients than in controls (IMT: MCTD, 0.64 ± 0.13 mm vs. controls, 0.53 ± 0.14 mm; P < 0.001). FMD negatively correlated with disease duration, the levels of apolipoprotein A1, the paraoxonase-1 activity, and systolic blood pressure in MCTD patients. The percentage FMD was significantly lower in MCTD patients with cardiovascular diseases (CVD), than in those without CVD (%FMD: 3.5 ± 2.9 vs. 5.8 ± 4.8, P < 0.0002), while percentage NMD did not differ between patients with and without CVDs. Serum levels of autoantibodies (anti-U1RNP, AECA and anti-CL) were significantly higher in MCTD patients and differed between MCTD patients with and without CVD. Endothelial cell markers such as soluble TM (12.2 ± 8.1 ng/ml vs. 3.2 ± 1.3 ng/ml; P < 0.001) and vWFAg (224.1 ± 115% vs. 89.4 ± 27.1%, P < 0.001) were the highest in MCTD patients with CVD.ConclusionsFMD is a reliable sensitive marker of endothelial cell dysfunction in MCTD. Beside the traditional risk factors, anti-U1RNP, AECA and anti-CL antibodies may be important not only in the pathogenesis of MCTD but in the induction of endothelial cell activation, and may play crucial roles in the development of early atherosclerosis in MCTD.

Serum asymmetric dimethylarginine negatively correlates with intima-media thickness in early-onset atherosclerosis.

Background: Asymmetric dimethylarginine (ADMA) assumes a significant role in atherosclerosis by inhibiting the endothelial nitric oxide synthase (eNOS). Moreover, ADMA inhibits the inducible NOS (iNOS), the isoform that triggers atherosclerosis via peroxynitrite formation. Therefore, we investigated whether ADMA is a risk or protective factor in the atherosclerotic process. Intima-media thickness (IMT) of the common carotid artery, a surrogate for vascular diseases, was chosen as the outcome variable of interest. Methods: Sixty patients younger than 55 years having at least 30% stenosis of the internal carotid artery and 30 age- and gender-matched controls were recruited at a community-based neurosonological laboratory. We investigated relatively young patients to circumvent the confounding effect age has in the development of atherosclerosis. Results: The IMT showed a negative correlation with ADMA upon analysis of the pooled data (Spearman correlation coefficient –0.300, p = 0.0041) and the atherosclerotic stratum (Spearman correlation coefficient –0.323, p = 0.012). A multiple linear regression model containing all determinant factors of IMT previously identified by simple regression was used to further quantify the relationship between IMT and ADMA. The negative association between IMT and ADMA remained statistically significant (β: –0.510, CI: –0.894, –0.127; p = 0.010), furthermore it was even stronger in the atherosclerotic stratum (β: –0.67, CI: –1.16, –0.18; p = 0.008). Conclusions: A minimal increase in ADMA concentration may be protective by inhibiting iNOS but not eNOS in states where iNOS is induced, e.g. inflammation accompanying atherosclerosis.

Miller Fisher syndrome--a presenting clinical manifestation of lung cancer in a previously apparently healthy individual.

Sirs: A 54 year-old white male complained of clumsiness of the right upper extremity, diplopia and unsteadiness of gait starting about 6 days before admission. The history was negative except for smoking an average of 2 packs of cigarettes per day in the preceding 40 years. On admission he had right sided complete oculomotor nerve lesion, severe bilateral lower motoneuron facial palsy (Fig. 1A and 1B), absent Achilles reflexes, diminished other deep tendon reflexes and severe gait ataxia. The patient did not have objective sensory loss, major paresis or signs of upper motor neuron lesion. Except for an elevated erythrocyte sedimentation rate (46 mm/hour) and a borderline serum glucose level the routine blood tests were normal. The cerebrospinal fluid (CSF) had an extremely elevated protein content (3.115 g/L) associated with some pleocytosis (256 cells per microliters). The CSF cells were lymphocytes (20 %), macrophages (48 %, a few of them signet-ring cells), monocytes (12 %), and 20 % of the cells were intensely stained, atypical giant cells with large round marginal nuclei. These cells were PAS positive and were also cytokeratin positive with CK7 immunocytochemistry (Fig. 2A). Nerve conduction studies revealed mild axonal sensorimotor neuropathy. On computed tomography contrast enhancement was seen in the right Sylvian fissure (Fig. 2B). MRI detected several small (< 10 mm) contrast enhancing lesions mostly in the cerebral cortex (Fig. 2C, arrows), and in some other CSF-adjacent regions (cerebellar surface, basal ganglia adjacent to the lateral ventricle, periaqueductal gray matter) as well. Chest CT identified a small tumor in the right lung (Fig. 2D). The tumor was removed and appeared to be a carcinoma with adenomatous structure staining with PAS. With immunohistochemical examination the tumor cells were CK7 positive, CK20 negative, exhibited nuclear positivity with TTF-1, and about 5 % of the cells had nuclear positivity with Mib-1. A histological diagnosis of grade 3 bronchial adenocarcinoma was established. Miller Fisher described a syndrome of ophthalmoplegia, ataxia and areflexia as a variant of the Guillain-Barré syndrome [2]. In a series of 50 cases [4] facial palsy was present in about one third of the cases. Although a cerebrospinal fluid (CSF) cell count over 50/μl is rare in Guillain-Barré syndrome, it has been reported in several cases [6]. Axonal, predominantly, sensory neuropathy was found in 5 of 6 patients with Miller Fisher syndrome (MFS) [9]. Therefore, from the clinical signs the diagnosis of MFS could have been considered for our case. In leptomeningeal carcinomatosis the incidence of clinical signs at presentation were 11 % for oculomotor lesion, 11 % for facial nerve involvement and 15–15 % for cerebellar signs and polyradiculopathy [1]. Therefore the probability of the coincidence of the individual signs of MFS is low. There are only 4 published cases where the syndrome was associated with malignant diseases. Leptomeningeal infiltration was described by Guarino et al. [3] in 2 cases. One of them developed the syndrome 6 months after gastrectomy for cancer and the other patient 4 years after thyroidectomy for cancer and 2 years after the diagnosis of acute LETTER TO THE EDITORS

The effect of sleep apnea on QT interval, QT dispersion, and arrhythmias.

QT interval (QT) and QT dispersion (QTd) are electrocardiograph (ECG) parameters for the evaluation of myocardial repolarization. The inhomogeneity of ventricular repolarization is associated with ventricular arrhythmias. An increased QT, QTd, and increased incidence of nocturnal cardiac rhythm disturbances have been described in patients with obstructive sleep apnea (OSA), while other investigators did not find a relationship between ventricular arrhythmias and OSA.