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Fabry disease is a rare X-linked lysosomal disorder. Alpha-galactosidase A deficiency caused by mutation leads to accumulation of glycosphingolipids predominantly in endothelial cells, leading to impairment of vascular wall morphology and function. We assessed vascular wall hypertrophy (carotid artery intima-media thickness, cIMT), endothelial function (brachial artery flow-mediated dilation, FMD), presence of atherosclerotic plaques in the carotid and femoral arteries, and levels of endothelial adhesion and inflammatory biomarkers in 33 Fabry patients compared with 66 healthy matched controls. Fabry patients had thicker cIMT (0.07 ± 0.02 vs 0.06 ± 0.02 cm; P = .021), as well as dilated common carotid arteries (0.80 ± 0.12 vs 0.70 ± 0.06 cm; P < .001), and aortic annulus than controls (3.07 ± 0.48 vs 2.7 ± 0.48 cm; P = .001). Flow-mediated dilation was reduced (4.48 ± 8.80 vs 10.67 ± 8.72%; P = .001) and atherosclerotic plaques were less present in Fabry patients (9.10% vs 43.94%; P < .001). Vascular cell adhesion molecule-1, interleukin-6, tumor necrosis factor α, and high-sensitivity CRP were significantly higher and E-selectin lower in Fabry patients. Our results suggest that a complex vascular phenotype is present in Fabry patients. This represents a challenge for further research that could have important clinical applications.

Background and Aim. Our previous study showed that the empagliflozin-metformin combination significantly improved arterial function; i.e., it improved endothelial function (measured by flow-mediated dilation and reactive hyperaemia index) and reduced arterial stiffness (measured as pulse wave velocity and local carotid artery stiffness) in adults with type 1 diabetes. In the present study, we explored the underlying mechanism by investigating the antioxidative and anti-inflammatory properties of the empagliflozin-metformin combination (compared to the individual drugs or placebo) and its association with improving arterial function. Methods. 40 individuals with type 1 diabetes (average age of 44.7 ± 2.5 years) were randomized into four groups: (1) control (placebo), (2) empagliflozin 25 mg daily, (3) metformin 2000 mg daily, and (4) empagliflozin-metformin combination (25 mg and 2000 mg daily, respectively). At inclusion and after 12 weeks of treatment, the blood samples were collected, and the oxidative stress (total antioxidative status (TAS), superoxide dismutase (SOD), glutathione peroxidase (GPx), uric acid, advanced oxidation protein products (AOPP), advanced glycosylation end products ((AGE) and isoprostane), and inflammation (C-reactive protein (CRP) and interleukin-6 (IL-6)) parameters were determined. Results. The empagliflozin-metformin combination increased levels of the antioxidants (TAS, SOD, and GPx up to 1.1-fold; P < 0.01 ), decreased the levels of prooxidants (AOPP and isoprostanes up to 1.2-fold, P < 0.01 ; AGE up to 1.5-fold, P < 0.01 ), and decreased inflammatory parameters (up to 1.5-fold, CRP P < 0.01 ; IL-6 P < 0.001 ). Antioxidative action was associated with the improvement in arterial function (obtained in the previous study) in the empagliflozin-metformin combination group. Conclusion. Empagliflozin-metformin combination has strong antioxidative and anti-inflammatory capacity, in adults with type 1 diabetes that is greater than that for the individual drugs. Its antioxidative activity at least partially explains the improvement in arterial function. Therefore, it appears that the combination provides the most powerful vascular protection.

Idarucizumab reverses the anticoagulant dabigatran; it is recommended during intravenous thrombolysis treatment of dabigatran-treated patients with acute ischemic stroke (AIS) and in dabigatran-treated patients with intracranial hemorrhage (ICH).Outcomes of consecutive idarucizumab/dabigatran-treated patients with intravenous thrombolysis-treated AIS (n = 22) were compared with consecutive similar intravenous thrombolysis-treated patients with AIS who were not anticoagulated (n = 182) [primary aim]; idarucizumab/dabigatran-treated patients with ICH (n = 13) were compared with patients with ICH who received the anticoagulants rivaroxaban or apixaban (n = 24) [secondary aim]. Efficacy was estimated by National Institutes of Health Stroke Scale score changes between admission and discharge and by the modified Rankin score after 3 months; safety was assessed by symptomatic ICH and mortality.Basal neurological impairment was similar in both idarucizumab/dabigatran-treated and control groups of patients with AIS and ICH. The idarucizumab/dabigatran-treated patients with AIS with subsequent intravenous thrombolysis showed a mean National Institutes of Health Stroke Scale improvement of 84% vs 68% in the control group (p0.05). A favorable outcome (modified Rankin score ≤ 2 after 3 months) was achieved significantly more frequently than in the control group (86% vs 57%; p0.05). The complication rate was similar in both groups. In patients with ICH, a positive functional outcome (modified Rankin score ≤ 3 after 3 months) was achieved more often in the idarucizumab/dabigatran-treated group than in the control group (70% vs 42%; p = 0.109). The complication rate was similar.Idarucizumab use in dabigatran-treated patients with AIS resulted in significantly more efficacious intravenous thrombolysis treatment and a non-significantly better outcome in dabigatran-treated patients with ICH compared with controls. There was no difference regarding complications.

The results of randomised clinical trials (RCTs) on direct oral anticoagulants (DOACs) for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF) can mostly be applied to primary prevention in relatively young patients, since only a minority of patients included in these trials were receiving DOACs for secondary prevention. The real-life secondary prevention subgroup, comprising mostly elderly and high-risk patients, remains a point of interest where further exploration is needed. Our objective was to explore the effectiveness and safety of DOACs for secondary prevention in the real-life conditions.In a six-year (2012-2018) period all consecutive patients with a history of transient ischaemic attack (TIA) or stroke, recorded NVAF and prescription of DOAC, were included in this single-centre registry. Choice of the DOAC and dose was based on the discretion of the attending clinician. Data regarding recurrent stroke/TIA or other embolic events, intracranial haemorrhage, other major bleeding, adherence and potential changes of therapy were collected and analysed.During the study period, 566 patients were prescribed a DOAC for secondary stroke prevention, and follow-up data were available for 510 patients, with an average observational time of 2.6 years. The mean age of patients was 77.9 ± 8.7 years. The mean CHAOur real-life data study suggests that secondary stroke prevention with DOACs is as effective and safe as primary prevention, both in standard and reduced doses, in a typical group of patients who are older than patients included in RCTs.

Successful revascularization therapy is of paramount importance in patients suffering acute ischemic stroke (AIS). However, there is currently only limited evidence on revascularization outcomes for patients suffering AIS while treated with direct oral anticoagulants (DOACs). The aim of our study was to determine the efficacy and safety of intravenous thrombolysis (IVT) and mechanical reperfusion (MeR) in AIS patients taking DOACs, and compare them to randomized clinical trials (RCTs), which included patients without DOAC treatment. In an observational cohort study, we analyzed clinical and radiological outcomes following AIS for all consecutive patients on DOAC therapy treated by IVT or MeR, between 2013 and 2019, at the University Medical Center Ljubljana. Patients in the IVT group were on dabigatran treatment and have received idarucizumab as a reversal agent prior to IVT. Patients in the MeR group had a large vessel occlusion. The primary outcome of the study was efficiency, defined as significant improvement after recanalization (National Institutes of Health Stroke Scale (NIHSS) score improvement of ≥8 points after 24 h and modified Rankin Scale (mRS) ≤2 after 3 months) and safety, defined as occurrence of symptomatic intracerebral hemorrhage (SICH) and mortality. Fifty-one DOAC-treated patients with AIS were included. Nineteen dabigatran-treated patients received IVT after reversal by idarucizumab. Thirty-two patients with a large vessel occlusion (12 on dabigatran, 12 on rivaroxaban, and 8 on apixaban) received MeR. Median NIHSS at admission was 9 in the IVT group and 17 in the MeR group. A significant clinical improvement, 24 h after revascularization (median improvement of NIHSS ≥8), occurred in 84% of patients treated with IVT and 25% of patients treated with MeR. A favorable functional outcome after 3 months (modified Rankin Scale (mRS) ≤2) occurred in 84 % of patients treated with IVT and 44% of patients treated with MeR. SICH occurred in one patient (5%) in the IVT group, and in two patients (6%) in the MeR group. In summary, in our observational study of DOAC-treated AIS patients, the level of IVT efficiency was substantially better than in the RCTs. At the same time, the results of MeR treatment were on the same level as in non-DOAC AIS patients included in the RCTs. The observed safety of IVT and MeR treatment was similar to the RCTs. We propose that thrombi in patients on dabigatran may have increased susceptibility to IVT, thereby allowing for better clinical results.

BACKGROUND We tested the concept of improving arterial wall characteristics by treatment with a very low-dose combination of fluvastatin and valsartan (low-flu/val) in stable, post-myocardial infarction (MI) patients. MATERIAL AND METHODS We enrolled 36 post-MI middle-aged males in the treatment (n=20) or control (n=16) group receiving low-flu/val (10 mg/20 mg) or placebo, respectively. The parameters of endothelial function (flow-mediated dilatation (FMD), reactive hyperemia index), and arterial stiffness (carotid-femoral pulse wave velocity (cf-PWV), local carotid PWV, and beta stiffness coefficient) were measured before and after 30 days of therapy, and 10 weeks later. RESULTS Treatment with low-flu/val improved FMD from 3.1±1.3% to 4.8±1.5% (p

Introduction: The lifespan of patients with Fabry disease (FD) is shorter than that seen in the general population. Leukocyte telomere length (LTL) and telomerase activity (TA) are potential markers of biologic aging. The aim of the current study was to determine the LTL and TA in FD patients and to assess the correlation between LTL and TA and renal involvement. Methods: We included 33 FD patients and 66 healthy matched controls. LTL and TA were measured using a quantitative PCR assay and gene expression assay. FD patients were stratified by renal function (estimated glomerular filtration rate [eGFR] higher or lower than 60 mL/min/1.73 m2) and proteinuria (urine protein creatinine ratio higher or lower than 0.5 g/g). Results: LTL was significantly shorter (0.69 vs. 0.73, p = 0.015) and TA significantly higher (1.55 vs. 1.19, p = 0.047) in FD patients compared to controls. Males with FD had significantly shorter LTL (p = 0.020) and lower, but non-significant, TA compared to male controls (p = 0.333). Female FD patients had similar LTL (p = 0.285) but significantly higher TA compared to female controls (p = 0.005). LTL was not influenced by eGFR, but TA was significantly lower in the low eGFR group (p = 0.003). Conclusions: FD patients have significantly shorter LTL, but significantly higher TA compared to healthy controls. Increased TA activity in FD patients could be the compensation mechanism to prevent LTL decrease (and accelerated ageing), which seems to be exhausted at the advanced stage of renal disease.

The incidence of aging-related disorders may be decreased through strategies influencing the expression of longevity genes. Although numerous approaches have been suggested, no effective, safe, and easily applicable approach is yet available. Efficacy of low-dose fluvastatin and valsartan, separately or in combination, on the expression of the longevity genes in middle-aged males, was assessed. Stored blood samples from 130 apparently healthy middle-aged males treated with fluvastatin (10 mg daily), valsartan (20 mg daily), fluvastatin-valsartan combination (10 and 20 mg, respectively), and placebo (control) were analyzed. They were taken before and after 30 days of treatment and, additionally, five months after treatment discontinuation. The expression of the following longevity genes was assessed: SIRT1, PRKAA, KLOTHO, NFE2L2, mTOR, and NF-κB. Treatment with fluvastatin and valsartan in combination significantly increased the expression of SIRT1 (1.8-fold; p < 0.0001), PRKAA (1.5-fold; p = 0.262) and KLOTHO (1.7-fold; p < 0.0001), but not NFE2L2, mTOR and NF-κB. Both fluvastatin and valsartan alone significantly, but to a lesser extent, increased the expression of SIRT1, and did not influence the expression of other genes. Five months after treatment discontinuation, genes expression decreased to the basal levels. In addition, analysis with previously obtained results revealed significant correlation between SIRT1 and both increased telomerase activity and improved arterial wall characteristics. We showed that low-dose fluvastatin and valsartan, separately and in combination, substantially increase expression of SIRT1, PRKAA, and KLOTHO genes, which may be attributed to their so far unreported pleiotropic beneficial effects. This approach could be used for prevention of ageing (and longevity genes)–related disorders.

Background Deteriorated arterial function and high incidence of cardiovascular events characterise diabetes mellitus. Metformin and recent antidiabetic drugs, SGLT2 inhibitors, reduce cardiovascular events. We explored the possible effects of empagliflozin’s effect on top of metformin treatment on endothelial function and arterial stiffness parameters in type 1 diabetes mellitus (T1DM) patients. Methods Forty T1DM patients were randomised into three treatment groups: (1) empagliflozin (25 mg daily), (2) metformin (2000 mg daily) and (3) empagliflozin/metformin (25 mg daily and 2000 mg daily, respectively). The fourth group received placebo. Arterial function was assessed at inclusion and after 12 weeks treatment by: endothelial function [brachial artery flow-mediated dilation (FMD), reactive hyperaemia index (RHI)], arterial stiffness [pulse wave velocity (PWV) and common carotid artery stiffness (β-stiffness)]. For statistical analysis one-way analysis of variance with Bonferroni post-test was used. Results Empagliflozin on top of metformin treatment significantly improved endothelial function as did metformin after 12 weeks of treatment: FMD [2.6-fold (P Conclusion Empagliflozin on top of metformin treatment significantly improved arterial stiffness compared to metformin in T1DM patients. Endothelial function was similarly improved in all treatment groups. Empagliflozin seems to possess a specific capacity to decrease arterial stiffness, which could support its cardioprotective effects observed in large clinical studies. Trial registration Clinical trial registration: NCT03639545

Background The largest population that suffers from cardiovascular events are subjects at moderate cardiovascular risk. However, no effective and safe preventive treatment is available for this population. We investigated whether their arterial wall phenotype could be turned to a lower risk direction by low-dose fluvastatin/valsartan combination (low-flu/val). Methods Twenty males at moderate cardiovascular risk (as classified by SCORE) were blindly randomized into the intervention group (N.=10, low-flu/val: 10 mg/20 mg) or control group (N.=10, placebo). At inclusion and after 30 days of treatment, brachial flow-mediated dilatation (FMD), β-stiffness coefficient, carotid pulse wave velocity (c-PWV), carotid-femoral PWV, Reactive Hyperemia Index, high-sensitivity C-reactive protein (hs-CRP), interleukin 6, vascular cell adhesion molecule 1, total antioxidant status and expression of several protective genes (SIRT1, mTOR, NF-κB1, NFE2L2, PRKAA1) were followed. Results Treatment resulted in improved FMD (from 3% to 4.2%, P=0.008), c-PWV (from 6.7 to 6.2 m/s, P=0.006), hs-CRP (from 5.39 to 3.35 mg/L, P=0.041) and SIRT1 expression (3.34-fold difference, P=0.047). No other vascular, inflammation and genetic parameters changed. The hs-CRP values after intervention correlated significantly with SIRT1 expression. The improved FMD persisted even 10 weeks after treatment discontinuation. The obtained changes were not followed by changes of lipids or blood pressure. Overall, the results revealed improvement in three different, although interrelated preventive arterial wall characteristics. Conclusions This pilot study revealed that intervention with low-flu/val importantly shifts the arterial wall phenotype in a lower risk direction. This improvement could be interpolated into clinical benefits that remain to be further studied.

Background: Rapid inactivation of dabigatran by its specific inhibitor idarucizamab allows intravenous thrombolysis (IVT) in patients suffering ischemic stroke while being treated with dabigatran. Only limited data of this approach is available and numerous questions regarding efficacy/safety remain to be answered. Herein, we present the findings from the Slovenian national cohort study. Methods: Retrospective analysis of all stroke patients treated with idarucizumab and IVT (n = 11) in the period from July 2016 to February 2018 from Slovenian region were analyzed. Results: The indication for dabigatran treatment in all 11 cases was nonvalvular atrial fibrillation. Importantly, 6 out of 11 cases were classified as severe ischemic strokes (National Institutes of Health Stroke Scale; NIHSS ≥ 10) with a median NIHSS 13. At admission, prolonged activated partial thromboplastin time was present in 9 patients indicating therapeutic anticoagulation activity. The average door-to-needle time was 156 minutes. After 3 months, 9 patients had a modified Rankin Score of less than or equal to 2 and 7 patients had mRS less than 1 whereas, 2 patients died due to symptomatic intracranial hemorrhage (sICH); 1 due to spontaneous sICH, and the other due to a large ischemic stroke with hemorrhagic transformation. No thrombotic complications were observed. Conclusions: Our data show that IVT after idarucizumab administration is a safe and effective method of treatment in ischemic stroke patients on dabigatran. We recorded a higher proportion of patients with favorable outcome as well as with sICH compared to the randomized controlled studies which could suggest a higher sensitivity of thrombi to IVT in dabigatran treated patients.

BACKGROUND Chronic venous disorders (CVD) is estimated to affect 30% to 50% of women and 10% to 30% of men. The most widely prescribed treatment for CVD worldwide is micronized purified flavonoid fraction 500 mg (MPFF). The aim of this clinical trial was to develop a new once daily 1000-mg oral suspension of MPFF. METHODS In an international, randomized, double-blind, parallel-group study, symptomatic individuals classified CEAP C0s to C4s were randomized in either treatment arm and treated for 8 weeks. Lower limb symptoms (discomfort, pain and heaviness) were assessed using Visual Analog Scales (VAS), and quality of life (QoL) was measured with the CIVIQ-20 Questionnaire. RESULTS A total of 1139 patients were included in the study. Both MPFF treatment regimens were well tolerated and associated with a significant reduction in lower limb symptoms. A non-inferiority of MPFF 1000-mg oral suspension once daily compared to MPFF 500-mg tablet twice daily (P

Increased life expectancy of human immunodeficiency virus (HIV)-infected patients appears to be coupled with increased incidence of cardiovascular disease (CVD).The aim of our study was to determine the presence of early atherosclerosis among Slovenian HIV-infected patients below the age of 55 years.A total of 86 HIV-infected male patients below the age of 55 years participated in our study. Ankle-brachial index (ABI) was measured using a handheld Doppler ultrasonic probe and a blood pressure cuff. Carotid intima-media thickness (CIMT) was assessed by the B-mode high-resolution ultrasound technique. Low ABI, CIMT 0.8 mm or presence of carotid plaques were considered markers of early atherosclerosis.Average CIMT was lowest among treatment-naïve patients (0.65 mm); 10 (38.4 %) had CIMT 0.8 mm, and carotid plaques were detected in 1 (3.8 %). Average CIMT among treated patients was 0.71 mm; 30 (50.0 %) had CIMT 0.8 mm, and plaques were detected in 11 (18.3 %). Low ABI (≤ 0.90) was found in five patients (5.8 %) without symptoms of peripheral artery disease; two were treatment-naïve, and three received antiretroviral therapy. Early atherosclerosis was found in 43 (50.0 %) patients; 10 (38.4 %) were in treatment-naïve and 33 (55.0 %) in the treated group.Increased prevalence of early atherosclerosis among Slovenian HIV-infected patients below the age of 55 years has been demonstrated. Screening for early atherosclerosis should be implemented in the evaluation of young HIV-infected patients because a more aggressive treatment approach, aimed to delay the progression of atherosclerosis, may be warranted especially when carotid plaques are detected. We have shown that although ABI contributes to CVD risk assessment, CIMT assessment remains the more sensitive method.

High-sensitivity C-reactive protein (hsCRP) is an important biomarker of risk for coronary heart disease morbidity and mortality. We investigated the influence of short-term cardiac rehabilitation (CR) after acute myocardial infarction (AMI) on values of hsCRP and classical risk factors, including metabolic syndrome.hsCRP and classical risk factors were measured before and after completed 2-week CR program in 30 men after AMI. The comparison group comprised 30 age-balanced healthy men, with no risk factors for coronary heart disease.As expected, in comparison to healthy individuals, patients had higher values of hsCRP; furthermore, smokers had significantly higher hsCRP values than nonsmokers. Patients had more expressed markers of metabolic syndrome and due to pharmacological therapy lower blood pressure, total cholesterol and low-density lipoprotein cholesterol (LDL-C). After CR was completed, a significant drop in hsCRP (P=0.006) and improvement of metabolic syndrome parameters (lower body mass index, blood pressure, LDL-C, triglycerides) was observed in nonsmokers, whereas no such changes occurred in smokers.Our study revealed that hsCRP and metabolic syndrome parameters can be substantially reduced by a 2-week CR program; however, this effect is present only in nonsmokers. Thus, all patients entering the CR program after AMI should be advised to quit smoking before entering the program to achieve optimal benefits.

Background Statin use is frequently associated with muscle-related symptoms. Coenzyme Q10 supplementation has yielded conflicting results in decreasing statin myopathy. Herein, we tested whether coenzyme Q10 supplementation could decrease statin-associated muscular pain in a specific group of patients with mild-to-moderate muscle symptoms. Material/Methods Fifty patients treated with statins and reporting muscle pain were recruited. The Q10 group (n=25) received coenzyme Q10 supplementation over a period of 30 days (50 mg twice daily), and the control group (n=25) received placebo. The Brief Pain Inventory (BPI) questionnaire was used and blood testing was performed at inclusion in the study and after 30 days of supplementation. Results The intensity of muscle pain, measured as the Pain Severity Score (PSS), in the Q10 group was reduced from 3.9±0.4 to 2.9±0.4 (P

PURPOSE: Oxidative stress is an important nonclassical risk factor for myocardial infarction (MI), and thus, it seems extremely important to recognize factors that effectively reduce it. The aim of our study was to explore possible influences of short-term cardiac rehabilitation (CR) of only 2 weeks in duration on oxidative stress in men after MI. METHODS: Male patients (N = 21; aged 41-88 years, median 56 years), 6 to 8 weeks after acute MI, were included in our observational study using a pretest/posttest design. We investigated markers of oxidative stress and antioxidant enzymes before and after CR of only 2 weeks in duration and influence of smoking status on these differences. RESULTS: We found significant decrease in isoprostanes in urine in nonsmokers (n = 9) (P = .036) but not in smokers (n = 12) (not significant) during CR. After CR, nonsmokers had lower isoprostanes in urine (P = .039), lower non-transferrin-bound iron (P = .020), and higher erythrocyte catalase (P = .023) than smokers. Of classical risk factors, only low-density lipoprotein cholesterol was lower in nonsmokers before (P = .041) and after CR (P = .015) than in smokers. No other significant differences were seen at the beginning or at the end of CR. CONCLUSIONS: To our knowledge, the results of our study indicate for the first time that short-term CR of only 2 weeks in duration already has a positive effect on reduction of oxidative stress in the body. However, this positive effect is seen only in nonsmokers and not in smokers.

Patients with type 2 diabetes are at increased cardiovascular risk. The aim was to explore whether the impaired arterial wall characteristics typical of these patients could be improved by the unique beneficial effects of a very low-dose combination of fluvastatin and valsartan (low-flu/val).Forty middle-aged males (50.4±6.1years) with type 2 diabetes were recruited to a double-blind, randomized study. Patients (N=20) received low-flu/val (10/20mg) or placebo (N=20) over 30days in addition to their regular therapy. Brachial artery flow mediated dilation (FMD), common carotid artery pulse wave velocity (PWV) and β-stiffness were assessed before and after treatment, and 3 and 6months after treatment discontinuation. The treatment was then repeated.Arterial wall characteristics significantly improved. After 30days of intervention, FMD increased from 2.4±0.3 to 4.2±0.3 (p0.001), PWV decreased from 6.4±0.1 to 5.8±0.2 (p0.001) and β stiffness decreased from 7.8±0.4 to 6.7±0.4 (p0.001). Lipids and arterial pressure did not change. After treatment discontinuation, the beneficial effects decreased over the following months. The repetition of treatment completely regained the initial benefits. No changes were observed in the placebo group.Low-flu/val added on-top of optimal therapy substantially improves arterial wall characteristics in patients with type 2 diabetes.

BACKGROUND Patients with peripheral arterial disease (PAD) are at very high risk for cardiovascular events. How do patients with PAD differ from age- and sex-matched controls in survival, major ischemic events and revascularization procedures when both groups were managed according to the European guidelines on cardiovascular disease prevention? METHODS Patients with PAD (N.=742) and 713 age and sex-matched control subjects without PAD, both groups aged 65±9 years at inclusion, were managed for 5 years according to the European guidelines on cardiovascular disease prevention and evaluated yearly for occurrence of death, non-fatal major ischemic events and revascularization procedures (minor events). RESULTS In the PAD group, the 5-year survival was 84.7% (CI 82.1-87.3%) vs. 93.3% (CI 91.5-95.2%) in the control group, P

Ageing progressively diminishes arterial functions, even in the absence of traditional risk factors. Our aim was to explore whether age-related arterial changes in middle-aged males could be reversed using short-term, low-dose fluvastatin/valsartan combination intervention.Forty apparently healthy, middle-aged males (43.3 ± 5.8 years) were recruited in a double-blind, randomised intervention. Individuals received either 10mg fluvastatin/20mg valsartan daily or placebo over 30 days. The brachial artery flow mediated dilation (FMD), pulse wave velocity (PWV) and common carotid artery β-stiffness were assessed at baseline and after 30 days, and again 5-10 months after therapy discontinuation.Arterial function variables significantly improved after 30 days of intervention; FMD improved by 167.7% (P0.001), PWV by 10.9% (P0.05) and β-stiffness by 18.8% (P0.01), whereas no changes were obtained in the placebo group. The favourable outcomes in the intervention group were accompanied by a significant decrease of high sensitivity-C reactive protein levels (1.8-fold; P0.05). In contrast, lipids and blood pressure remained unchanged. Surprisingly, the beneficial arterial effects were still present to a substantial degree 7 months after completing intervention (remaining % of initial improvement: FMD 82.1%, PWV 69.5% and β-stiffness 68.5%), but declined substantially after 10 months.Our results indicate that age-related arterial changes, at least in middle-aged males, can be reversed. Short-term treatment with a low-dose fluvastatin/valsartan combination resulted in a large and long lasting improvement of arterial function.

Early arterial wall changes are already present in the apparently healthy, middle-aged population and continuously progress with age. The aim of our study was to investigate whether 30 days low-dose fluvastatin treatment could improve and reverse these arterial changes that are primarily associated with ageing, in otherwise healthy middle-aged males.In a double blind, randomized study, 50 middle-aged males received either placebo or fluvastatin (10mg) for 30 days. Brachial artery flow-mediated dilation (FMD), pulse wave velocity (PWV) and β-stiffness of the common carotid artery were measured on the 1st, 14th and 30th day of the study using an Aloka instrument by integrated eTracking.In 77% of subjects, impaired endothelial function was revealed at inclusion in the study. All the parameters were improved already after 14 days, and after 30 days of treatment FMD improved by 91.5 ± 15.6%, while PWV and β-stiffness improved by 6.2 ± 1.1% and 10.7 ± 1.5%, respectively (all P0.001). After therapy discontinuation, the beneficial effects progressively decreased, but were still detectable after 5 months. During the study the lipid profile remained unchanged, thus the beneficial effects obtained were attributed to the pleiotropic effects of fluvastatin.We found that subtherapeutic low-dose fluvastatin (10mg daily; 30 days) considerably improves and reverses early functional and morphological arterial wall impairments that are present in apparently healthy, middle-aged males. It might be supposed that such a new and original approach could be valuable in cardiovascular prevention.

BACKGROUND AND AIM: Raised levels of inflammation markers are associated with worse prognosis in patients with coronary artery disease. It is generally believed, although it has never been proven, that inflammation markers are released from (un)stable plaques in coronary arteries. We investigated this issue by directly comparing levels of inflammation markers in coronary and systemic blood. PATIENTS AND METHODS: Patients with acute coronary syndrome (N = 11), stable angina pectoris (N = 10) and controls with noncoronary origin of chest pain (N = 9) were included in the study. Intracoronary blood samples were taken at the culprit lesion in the coronary artery in patients with acute coronary syndrome and from any coronary artery in the other two groups, together with systemic blood samples from the femoral vein and artery. Levels of high-sensitivity C reactive protein (hsCRP), interleukin 6, interleukin 8, interleukin 10, soluble receptor for interleukin 2 (tR IL-2) and myeloperoxidase were measured in all samples. RESULTS: We found significantly elevated levels of hsCRP and interleukin 10 in patients with acute coronary syndrome compared with patients with stable angina and the control patients. Notably, we did not find any difference between intracoronary and systemic levels of any inflammatory marker in patients with acute coronary syndrome. Furthermore, no difference between intracoronary and systemic levels of markers was present in patients with stable angina or in the control group. CONCLUSIONS: We observed that excess circulating inflammation markers, being characteristic of unstable coronary artery disease, are released from noncoronary sources. Thus, it may be speculated that systemic inflammation precedes local inflammation at the plaques, thereby transforming coronary disease from a stable to an unstable form.

BACKGROUND: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is increasingly used in the diagnosis and prognostic assessment of heart failure; however, the possible influence of atrial fibrillation on BNP is still a matter of controversy. We assessed the influence of atrial fibrillation on NT-proBNP levels in outpatients with signs and symptoms of heart failure. METHODS: Consecutive outpatients (n = 306) referred to a university hospital heart-failure clinic for evaluation of signs and symptoms of heart failure underwent clinical and echocardiographic assessment and had their NT-proBNP levels determined in a sandwich chemiluminescent immunoassay with two antibodies on an Elecsys analyzer. The influence of atrial fibrillation on NT-proBNP levels was assessed using a non-parsimonious linear regression model with propensity score adjustments to balance for possible confounders. RESULTS: Atrial fibrillation was associated with increased NT-proBNP levels in patients with (median concentration 1944 vs. 1390 pg/ml) and without (1093 vs. 172 pg/ml) underlying structural disease (P < 0.001). In a linear regression model with a propensity score, atrial fibrillation emerged as an independent determinant of NT-proBNP levels (P = 0.023), even after allowing for possible confounders (left ventricular ejection fraction and end-diastolic diameter, left atrial diameter, mitral insufficiency, age, sex, NYHA class or heart rate). CONCLUSIONS: Atrial fibrillation is an independent determinant of increased NT-proBNP levels. This association should be taken into account when NT-proBNP levels are used in the diagnosis of heart failure in patients with atrial fibrillation.

Heart failure is characterized by activation of the immune system which is strongly associated with disease severity and outcome. We sought to compare the prognostic impact of two established inflammatory markers - interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hsCRP) - in patients with chronic heart failure. In stable, optimally managed outpatients with chronic heart failure, baseline levels of hsCRP and IL-6 were determined. Clinical follow-up was obtained and the rate of events (heart failure related deaths or hospitalizations) were recorded. We included 201 patients (32.7% female, NYHA class II [66.2%] or III [33.8%], mean age 70 years). During a median follow up of 614 (367-761) days, 64 (30.9%) patients experienced an event; those with an event had higher levels of hsCRP (median 2.93 [interquartile range 2.36-8.92] vs 2.23 [1.32-5.77] mmol/l) and IL-6 (7.8 [4.7-10.3] vs 4.3 [2.6-7.9] pg/ml). However, on Cox multivariate analysis, IL-6 but not hsCRP emerged as an independent predictor of prognosis (hazard ratio HR(adjusted) 2.74, 95% confidence interval 1.17-6.43; P = 0.020). Our findings suggest that IL-6 is a better prognostic predictor than hsCRP in patients with chronic stable heart failure.

SummaryHeart failure is characterised by activation of haemostasis. We sought to explore the prognostic impact of deranged haemostasis in chronic heart failure. In stable, optimally managed outpatients with chronic heart failure, baseline levels of prothrombin fragment F1+2, D-dimer, and tPA and PAI-1 antigens were determined. Clinical follow-up was obtained and the rate of events (heart failure related deaths or hospitalisations) was recorded. We included 195 patients [32.3% female, NYHA class II (66.2%) or III (33.8%), mean age 71 years]. During a median follow up of 693 (interquartile range [IQR] 574–788) days, 63 (30.9%) patients experienced an event; those with an event had higher levels of tPA antigen (median 11.8 [IQR 8.7–14.0] vs. 9.4 [7.9–12.1] µg/l; p=0.033) and D-dimer (938 [485–1269] vs. 620 [37–1076] µg/l; p=0.018). However, on Cox multivariate analysis, only tPA levels above optimal cut-off value of 10.2 µg/l (but not D-dimer) emerged as an independent predictor of prognosis (HRadjusted 2.695, 95% confidence interval 1.233–5.363; p=0.017). Our findings suggest that elevated tPA antigen levels are an independent prognostic predictor in patients with chronic stable heart failure.

Recent data have shown that statins can help prevent atrial fibrillation (AF). We hypothesized that statins vary in their ability to prevent AF after successful electrical cardioversion (EC).Sixty-five patients (29 receiving atorvastatin and 36 receiving simvastatin) who had undergone successful EC for persistent AF were included in the study. They received statins at least one month before EC, and continued the treatment through 2 years of follow-up. The statins they received were selected independently by their attending physicians. In the follow-up period, AF reoccurred in 11 (38.0%) patients of the atorvastatin group and in 24 (66.7%) patients of the simvastatin group. Using a logistic regression model, the unadjusted odds ratio (OR) of having an AF recurrence for patients on atorvastatin versus those on simvastatin was 0.31 (95% CI 0.11-0.85, P = 0.02). After adjustment for other potentially confounding variables (age, sex, hypertension, diabetes, ischemic heart disease, echocardiographic characteristics, and therapy), treatment with atorvastatin retained its significance for maintaining sinus rhythm in a multivariate model (OR 0.20, CI 0.04 to 0.98, P < 0.05).Our study suggests that atorvastatin and simvastatin exert different effects on the AF recurrence rate after successful EC. Larger prospective randomized trials are needed to definitively evaluate the role of different statins in patients with AF, especially on AF recurrence after EC.

The impact of heart failure with preserved left ventricular ejection fraction (LVEF) on activated hemostasis is still unclear. We sought to compare the activation of hemostasis in patients with heart failure with preserved LVEF, with impaired LVEF, and in healthy controls. Biomarkers of coagulation and fibrinolysis (D-dimer, tPA and PAI-1) were determined in outpatients with chronic stable (NYHA I-III), optimally managed heart failure with preserved LVEF (n = 46) and with impaired LVEF (n = 52), and in healthy age- and gender-matched controls (n = 14). In comparison to healthy controls, patients with heart failure and preserved LVEF had increased median D-dimer levels (606 [330-1222] microg/L versus 174 [86-249] microg/L; P < 0.001), and median PAI-1 (20 [15.3-33.1] microg versus 6.2[3.4-8.9] microg/L; P < 0.001) and tPA antigen concentrations (9.6 [8.1-13.3] versus 3.6 [2.2-5.0] microg/L; P < 0.001). However, unlike tPA and PAI antigens, D-dimer levels in preserved LVEF did not reach values as high as in impaired LVEF (917 [454-1185] microg/L; P = 0.013). Moreover, in patients with impaired LVEF, but not in those with preserved LVEF, age and NT-proBNP emerged as independent predictors of log-transformed D-dimer levels. Heart failure with preserved LVEF is associated with a procoagulant state as determined by increased levels of D-dimer, tPA and PAI-1 antigens. D-dimer levels are significantly higher in patients with impaired LVEF, while tPA and PAI-1 levels are increased regardless of LVEF.

BacKGroUnD The pleiotropic effects of statins on the endothelial function are well recognized. However, the effect of statins might not be equally pronounced in the cerebral and systemic circulation. We compared cerebral and systemic endothelial function by l-arginine cerebrovascular reactivity and flow-mediated dilatation (FMD), respectively, in patients with arterial hypertension (AH) and healthy controls before and after atorvastatin treatment. metHoDS l-arginine reactivity and FMD were measured in patients with AH (29 patients, aged 61.1 ± 6.2 years) and 21 healthy controls. The mean arterial velocity (v m ) in both middle cerebral arteries was measured by transcranial Doppler sonography before, during, and after a 30-min intravenous infusion of l-arginine. FMD of the brachial artery after hyperemia was determined. The measurements were repeated after 3 months of treatment with atorvastatin. reSUL t S l-arginine reactivity and FMD were decreased in patients with AH (12.5 ± 8.7%; 2.7 ± 5.0 %) compared with controls (21.3 ± 10.9%; 8.5 ± 5.9%) (P < 0.01). After atorvastatin treatment, l-arginine reactivity and FMD improved in patients with AH (19.5 ± 10.6%; 4.6 ± 4.1%) compared with the controls (20.2 ± 10.2%; 9.7 ± 3.9%). The use of statin restored the cerebral circulation reactivity, while there was little change in the systemic circulation measured by FMD. concLUSIon The decreased l-arginine reactivity and FMD were found to improve after atorvastatin treatment in patients with AH, but the results suggest that statin therapy improved cerebral more than systemic endothelial function.

The factors contributing to platelet dysfunction in hemodialysis patients are still not completely known. We explored whether the fibrinolytic system influences platelet function in hemodialysis patients. We measured standard fibrinolytic parameters and markers of fibrinolysis/coagulation activation, and correlated them to platelet aggregation in 15 hemodialysis patients. Fifteen healthy age-matched volunteers served as controls. Hemodialysis patients had significantly decreased levels of plasminogen (0.76 [0.64-0.86] vs. 0.98 [0.87-1.08] rel, P < 0.001), and increased levels of fibrinogen (4.6 [3.9-5.5] vs. 4.0 [3.4-4.6] g/L, P < 0.05), whereas tissue-type plasminogen activator antigen and plasminogen activator inhibitor (PAI)-1 antigen and PAI activity were comparable to controls. Furthermore, elevated levels of markers of fibrinolysis/coagulation were found in hemodialysis patients: D-dimer (280 [170-460] vs. 135 [120-150] ng/mL, P < 0.01), prothrombin fragments 1 + 2 (1.7 [1.4-1.9] vs. 1.1 [1.0-1.2] nmol/L, P < 0.001), and thrombin-antithrombin complexes (5.2 [4.2-17.7] vs. 0 [0-4.2]microg/L, P < 0.01). The aggregation of platelets (induced by adenosine diphosphate) was slightly impaired in patients compared to controls (72 [43-79] vs. 83 [73-88]%, P = 0.08). Analysis showed that platelet aggregation positively correlated with plasminogen levels (r = 0.48, P < 0.01). No correlation with other fibrinolytic parameters or markers of activation was found. In hemodialysis patients platelet (dys)function appears to be associated with both the fibrinolytic and coagulation systems. We found that platelet aggregation significantly correlates with plasma plasminogen levels. This relation, which has not been hitherto described, seems to be causal and clinically important. Further exploration of this may help us to better understand the mechanisms of platelet dysfunction in hemodialysis patients.

To investigate whether a chronic pro-thrombotic tendency, which may contribute to a high rate of atherothrombotic disease, is present in patients treated for continuous peritoneal dialysis (CAPD), and, if so, what its pattern is. We investigated this issue by jointly exploring all the systems involved, the coagulation and fibrinolytic systems and platelets.Markers of coagulation activation, markers of fibrinolysis activation, and standard fibrinolytic parameters and platelet aggregation induced by different agents were measured in 15 patients treated by CAPD and in 15 matched, healthy controls. All CAPD patients received erythropoietin, were in the stable condition, and did not have acute disease or malignancy.CAPD patients had substantially (p0.001) increased levels of prothrombin fragments F1+2, disclosing a low-grade activation of the coagulation system. D-dimer was also significantly (p0.05) increased, whereas the levels of t-PA antigen and activity, PAI antigen and activity, and plasminogen were comparable to controls, suggesting that slight secondary (and not primary) activation of fibrinolysis due to coagulation activation took place. Patients had significantly (p0.05) elevated levels of fibrinogen. A study of platelet aggregation (induced by adenosine diphosphate, collagen, and epinephrine) did not show platelet hyperactivity in patients.We found that a pro-thrombotic tendency is present in the plasma of CAPD patients. The main reason for a pro-thrombotic state is chronic low-grade activation of the coagulation system and elevated levels of fibrinogen. The fibrinolytic system and platelets seemingly do not contribute to this pro-thrombotic tendency.

Recently, L-arginine reactivity has been used for evaluation of cerebral endothelial impairment. However, the diagnostic potential of the method is still unknown. The aim of the study was to establish the sensitivity and specificity of L-arginine reactivity and compare this method with flow-mediated dilation (FMD) and intima-media thickness (IMT). L-arginine reactivity, FMD and IMT were determined in patients with arterial hypertension (AH) and presumed endothelial impairment (41 patients, aged 60.9 ± 7.4 y) and 21 age- and gender-matched healthy controls. The relative increase in the mean arterial velocity after a 30-min i.v. infusion of L-arginine (dv m(L-arg) ) was ascertained by TCD. FMD of the brachial artery after hyperaemia and IMT of the common carotid artery on both sides were determined. The diagnostic value of the methods was assessed using receiver-operating-characteristic (ROC) analysis. In patients with AH, dv m(L-arg) , FMD and IMT were diminished (11.5% ± 8.9%; 3.8% ± 4.8%; 0.82 ± 0.16 mm) compared with the healthy controls (20.5% ± 9.9%; 7.9% ± 6.0%;0.64 ± 0.15 mm) ( p ≤ 0.01). The optimal cut-point for L-arginine reactivity of 0.22 yielded a 40% sensitivity and 93% specificity, which was comparable to the other two methods. For all three methods, the area under the ROC curves differed significantly from 0.5 (0.694; p = 0.013 for dv m(L-arg) , 0.784; p ≤ 0.01 for FMD, 0.827; p ≤ 0.01 for IMT). Cerebrovascular reactivity to L-arginine is a valuable method for determination of cerebral endothelial function. The diagnostic value of the three methods is comparable. (E-mail: janja.pretnar@kclj.si )

Antiphospholipid autoantibodies particularly antibodies against beta2-glycoprotein I (anti-beta2GPI) are casually associated with thromboses in patients with autoimmune diseases. However, their exact prevalence and role in the pathogenesis of thromboses in the absence of autoimmune disease is still inconclusive. They might be particularly important when other risk factors of thrombosis are absent. We investigated antiphospholipid antibodies in 68 young women (aged45yr at onset of the event, without autoimmune disease and with an otherwise low risk of thrombosis) in the stable period following myocardial infarction (MI), lacunar cerebral infarction (LACI) or deep vein thrombosis (DVT) and in 37 healthy age-matched controls. Patients had increased IgM anti-beta2GPI compared to controls (36.0, 11.5-49.5 vs. 17.50, 3.50-30.0 arbitrary units (AU), p0.001), whereas no difference was obtained in other measured antibodies (anticardiolipin and antiphosphatidylserine (aPS) antibodies of IgG and IgM). IgM anti-beta2GPI positively correlated with some markers of increased coagulation potential and negatively with BMI (r=-039, p0.005) and other parameters of the metabolic syndrome. In conclusion, we found that levels of IgM anti-beta2GPI are increased in young women suffering arterial or venous thromboses in the absence of other known autoimmune diseases and also in the absence of pronounced classical risk factors. We found that IgM anti-beta2GPI positively correlated with some markers of increased coagulation potential and negatively with parameters of the metabolic syndrome. Thus, it appears that elevated levels of IgM anti-beta2GPI are linked to thrombotic disorders in young women (without autoimmune disease) particularly when classical risk factors or the metabolic syndrome are absent.

The relationships between cerebral and systemic endothelial (dys)function and between cerebral (dys)function and intima-media thickness (IMT) of carotid arteries in patients and healthy volunteers have not yet been clarified. In order to explore these issues, the authors performed a post hoc correlation analysis of cerebrovascular reactivity to L-arginine, a marker of cerebral endothelial function; flow-mediated dilatation (FMD), a marker of systemic endothelial function; and IMT of the carotid arteries, a marker of the extent of atherosclerosis. Correlations were analyzed in a heterogeneous group consisting of 20 patients with lacunar infarctions (LIs) and extensively impaired endothelial function, 21 patients with similar risk factors (SRs), but without LIs, and 21 healthy controls. Cerebrovascular reactivity to L-arginine was determined by the transcranial Doppler method (TCD), FMD by ultrasound measurements of the brachial artery after hyperemia, and IMT by measurement of the common carotid arteries. Analysis of correlations in the group of 62 subjects revealed that L-arginine reactivity, which was diminished in LI and SR patients, did not correlate with FMD, which was also diminished in both LI and SR patients (Rho = 0.10 with p = 0.458). On the contrary, a significant negative correlation was found between L-arginine reactivity and IMT (Rho = -0.30 with p = 0.015). In conclusion, our study investigating relations between cerebral and systemic endothelial dysfunction showed that cerebral endothelial function, determined by L-arginine reactivity, correlates well with the degree of atherosclerosis determined by IMT but does not correlate with FMD, suggesting that cerebral and systemic endothelial function may not be closely associated.

Background In spite of high prevalence and clinical relevance of leukoaraiosis (LA), its pathophysiology is still incompletely understood. Theories of ischaemic genesis and a leaky blood–brain barrier are contradictory yet could share a common denominator–endothelial dysfunction (cerebral, systemic or both), which has not been studied thoroughly in LA. Methods Thirty patients with LA (58 years (SD 7)) and 30 gender- and age-matched controls without LA (55 years (SD 6)) were recruited. The vascular risk factors (VRF) were identical in both groups. Cerebral endothelial function was determined by cerebrovascular reactivity to L-arginine (CVR). Systemic endothelial function was determined by flow-mediated dilatation (FMD) of the brachial artery after hyperaemia. All participants underwent a brain MRI to search for radiological signs of LA that was classified according to the Fazekas score. Linear regression was used to explore the correlation between CVR and FMD in patients with LA. A 95 % confidence interval was used. For any statistical test used in the study, p ≤ 0.050 was regarded as statistically significant. Results We found a marked and significant decrease in both CVR (9.6 % (SD 3.2) vs. 15.8 % (SD 6.1), p

Previously, we have shown that slightly to moderately aged arteries in middle-aged males can be rejuvenated functionally by sub-therapeutic, low-dose fluvastatin and valsartan treatment. Here, we explore whether this treatment could also increase telomerase activity. We hypothesized that telomerase activity might be associated with (1) an improvement of arterial wall properties and (2) a reduction of inflammatory/oxidative stress parameters (both observed in our previous studies).The stored blood samples from 130 apparently healthy middle-aged males treated with fluvastatin (10 mg daily), valsartan (20 mg daily), fluvastatin and valsartan combination (10 and 20 mg), respectively, and placebo (control), were analyzed. The samples were taken before and after treatment lasting 30 days, and 5 months after treatment discontinuation. Telomerase activity was measured in blood leukocytes by a TaqMan Gene Expression Assay.Low-dose fluvastatin or valsartan increased telomerase activity (106.9% and 59.5% respectively; both p 0.05, vs. control), whereas their combination was even more effective (an increase of 228.0%; p 0.001, vs. control). No change was noted in the control group. Importantly, increased telomerase activity obtained in the combination group significantly correlated with arterial function, measured by flow-mediated dilation (FMD) (r = 0.79; p 0.001) and C-reactive protein concentration (r = -0.54; p = 0.02) and total anti-oxidative status (r = 0.50; p = 0.03).We found that a low-dose combination of fluvastatin and valsartan substantially increased telomerase activity, which significantly correlated with an improvement of endothelial function and a decrease of inflammation/oxidative stress. These findings could lead to a new innovative approach to arterial rejuvenation.

It is known that overweight induces fibrinolysis impairment. Since this association has not been completely explored in patients with venous thromboembolism (VTE), we aimed to investigate its presence in young women with VTE and, if present, to determine its extent and the factors that influence it. Thirty women aged 23-49 years in the stable period after VTE were included [19 overweight (body mass indexor = 25) and 11 normal weight]; 52 healthy women (27 overweight and 25 normal weight) served as controls. The euglobulin clot lysis time (ECLT), plasminogen, D-dimer, tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) antigen and activity, lipids, fasting plasma glucose, insulin, fibrinogen, interleukin-6 and sedimentation rate were compared between the groups. Overweight patients had more impaired fibrinolysis (delayed ECLT, higher PAI-1 and t-PA antigen) than overweight controls (and normal weight patients). There was no difference in levels of insulin, glucose, fibrinogen and interleukin-6, whereas the sedimentation rate was significantly elevated in overweight patients compared with overweight controls [16 (8-31) versus 8 (5-12), P0.05]. The sedimentation rate in overweight patients significantly correlated with body mass index, ECLT, t-PA and PAI-1 antigen, but not with fibrinogen or interleukin-6. We found that overweight VTE patients have more prominent fibrinolysis impairment than predictable from parameters of metabolic syndrome and that is associated with an elevated sedimentation rate. This association could represent a new thrombotic risk profile in overweight women.

Background: The estimation of coronary risk based on consideration of classical risk factors is insufficient in young patients with myocardial infarction who have low expressions of classical risk factors. Endothelial dysfunction (ED) and markers of vascular inflammation may be more appropriate for risk estimation. The relations among ED and inflammation markers in such patients have not yet been explored. Patients and Methods: Twenty-one patients (on average 44 years old) in the stable phase after myocardial infarction, with low expressions of risk factors, were included in the study. The control group consisted of 25 healthy age-matched males. ED was estimated by ultrasound measurement of the endothelium-dependent dilatation of the brachial artery. The following inflammation markers were measured: hsCRP, interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), ICAM-1, VCAM-1, selectin-P and selectin-E. Results: Patients had a significantly reduced level of endothelium-dependent vasodilatation (5.6 ± 3.5 vs. 8.8 ± 6.5%, p < 0.05), and an increased level of IL-6 (3.2 [1.5–8.4] vs. 1.4 [0.9–2.3] ng/ml; p < 0.01). All other inflammation markers were comparable to controls. We found a significant negative correlation between ED and the levels of IL-6 (r = –0.54, p = 0.012). Conclusion: It appears that IL-6 is the most valuable circulating marker of ED, and consequently a useful marker of coronary risk.

Background: Endothelial dysfunction and inflammation, in particular their lack of improvement after risk reduction, might better reflect advanced atherosclerosis than just the presence of risk factors. The aim of this study was to compare endothelial function and inflammatory parameters in high-risk patients who had no history of myocardial infarction and in patients in a stable phase after myocardial infarction. Methods: We compared endothelial function of the brachial artery, measured using high-resolution ultrasound, in 45 patients with hyperlipidaemia (Group 1), and in 45 patients in a stable period after myocardial infarction (Group 2). Forty-five healthy individuals served as a control group (Group 3). Results: Compared to patients with treated hyperlipidaemia, patients after myocardial infarction had lower values of total and LDL cholesterol (p = 0.015; 0.005) and homocysteine (p < 0.005), but marginally higher IL-6 levels (p = 0.1). Other measurements were comparable. However, flow-mediated dilation of the brachial artery was significantly diminished in patients after myocardial infarction (10.6 ± 3.0; 5.9 ± 4.0; 14.0 ± 1.9% for Groups 1–3; ANOVA p = 0.0001; respectively). Conclusions: We found that patients with previous myocardial infarction have substantially lower endothelial function and increased some inflammatory parameters than patients with a similar level of atherosclerotic risk profile but without clinically evident coronary artery disease.

It is assumed that endothelial dysfunction due to arterial hypertension could be improved or even normalized by antihypertensive treatment. The present study was designed to explore that assumption in patients with essential hypertension treated with an angiotensin-converting enzyme (ACE) inhibitor-enalapril. Twenty-eight patients (mean age: 55.1 years) who fulfilled the following criteria were included: essential arterial hypertension present for more than 2 years, monotherapy with enalapril for at least 1 year, adequate treatment (blood pressure in the last year

We describe a 45-year-old female with polycythemia vera and Leiden factor V mutation, who suffered the subacute form of Budd-Chiari syndrome and was treated with anticoagulants and diuretics. Surprisingly, after 3 months clinical signs of Budd-Chiari syndrome resolved; venography disclosed the resolution of thrombosis in the vena cava inferior and hepatic veins. This was associated with considerable increase of endogenous fibrinolytic activity, documented by a substantial change in the euglobulin clot lysis time, and a decrease of plasminogen activator inhibitor antigen and activity. During the disease the patient followed a diet and significantly reduced her body weight. Putting all data together it could be speculated that weight reduction (along with anticoagulants) considerably activated endogenous fibrinolysis, resulting in spontaneous resolution of Budd-Chiari syndrome. The validity of this explanation should be explored in a larger clinical study.

SummaryIt is known that anaemia in haemodialysis patients could contribute to haemostasis impairment. However, the precise relation between the degree of anaemia and the degree of haemostasis impairment is not known, nor the optimal level of hematocrit above which anaemia no longer disturbs haemostasis. Our study addresses these clinically relevant questions by employing in vitro closure time test, a new method in which the process of platelet adhesion and aggregation following vascular injury is simulated in vitro in samples of whole blood. We studied 63 haemodialysis patients, with 30 age-matched, healthy controls. Results show that patients with hematocrit below 0.32 (N=28) had significantly impaired primary haemostasis, in contrast to patients with hematocrit above 0.32 (N=35), as measured by both types of closure time test. A significant negative association was found between hematocrit values and closure time (CEPI cartridges: rho=–0.41, p

Local fibrinolytic activity in leg veins has not been completely explored. Since the blood in the right atrium is a mixture of venous blood supplied from the whole body, the fibrinolytic activity in the right atrium may be used as a reference value to which local values can be compared in order to identify local hyperfibrinolysis or hypofibrinolysis. We compared fibrinolytic parameters [tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor (PAI-1), euglobulin clot lysis time] measured in the femoral vein with those in the right atrium. The blood samples were obtained during right heart catheterization of 51 patients. No differences in t-PA antigen [9.6 ng/ml (6.6-11.9 ng/ml) versus 8.1 ng/ml (6.7-11.3 ng/ml)] [median (interquartile range)] and PAI-1 antigen [9.3 ng/ml (7.1-16.0 ng/ml) versus 8.4 ng/ml (5.5-14.3 ng/ml)] levels were found, whereas t-PA activity was significantly higher [183 IU/ml (39-1097 IU/ml) versus 92 IU/ml (5-680 IU/ml), P < 0.05], PAI-1 activity significantly lower [7.2 IU/ml (5.1-10.2 IU/ml) versus 7.9 IU/ml (5.8-10.3 IU/ml), P < 0.05], and the euglobulin clot lysis time was significantly shorter [6.2 1000/min (4.8-10.0 1000/min) versus 5.5 1000/min (4.1-9.1 1000/min), P < 0.05] in the femoral vein compared with the right atrium. In conclusion, our results show that local fibrinolytic activity in the femoral vein is higher than in the right atrium, and thus demonstrate that increased local fibrinolysis is present in leg veins.

The lung vasculature bed has a unique fibrinolytic potential, which has not yet been completely elucidated. We investigated the effect of blood passage through the pulmonary circulation on the values of fibrinolytic parameters in plasma. Forty-seven patients (16 women, 31 men, mean age 54 years, range 21–67 years) who had undergone elective cardiac catheterization were included in the study. The blood samples were taken simultaneously from the right atrium and the left ventricle. The following fibrinolytic parameters were measured: tissue-type plasminogen (t-PA) antigen and activity, plasminogen activator inhibitor-1 (PAI-1) antigen and activity, and euglobulin clot lysis time (ECLT). No difference was found between the samples obtained from the right atrium and the left ventricle with respect to t-PA antigen: 8.1 (6.7–11.3) vs 8.4 (5.9–11.0) ng/ml; t-PA activity: 92 (5–680) vs 62 (32–696) IU/ml; PAI-1 antigen: 8.4 (5.5–14.3) vs 8.7 (6.2–13.1) ng/ml; and ECLT: 5.5 (4.1–9.1) vs 5.6 (4.1–8.5) 1 000/min. In contrast, PAI activity decreased significantly: 7.9 (5.8–10.3) vs 7.4 (6.0–10.4) IU/ml, P ≪ 0.01. Patients with and without pulmonary hypertension did not differ in any of measured parameters, either in the right atrium or in the left ventricle. These results show that under basal conditions fibrinolytic activity which is not attributed to t-PA is elevated in lung vasculature. Further, basal fibrinolytic activity in the lungs is not influenced by pulmonary hypertension.

The platelet aggregation and skin bleeding time (SBT) tests currently used for assessment of hemostasis impairment in dialysis patients have important disadvantages. The authors explored the utility of a novel in vitro closure time test (PFA-100, platelet function analyzer) in which the process of platelet adhesion and aggregation after vascular injury is simulated in vitro in dialysis patients.Thirty-four long-term dialysis patients were included in the study with 30 healthy volunteers as the control group. In vitro closure time was compared with results from the platelet aggregation and SBT tests.In vitro closure time identified more patients and fewer controls with hemostasis impairment. In the patient group, 60%, 40%, and 20%, and in the control group, 0%, 10% and 3% of persons were found to have hemostasis impairment as determined by in vitro closure time, platelet aggregation, and SBT, respectively. In addition, values for patients and controls were significantly different for in vitro closure time (P0.05) but not for platelet aggregation or SBT. Thus, closure time appears to be more sensitive and specific than the other 2 tests. No correlation was found between the 3 tests, either in patients or in controls. However, a high correlation (r = 0.73; P0.0001) was found between the 2 types of in vitro closure time test (collagen/epinephrine [CEPI] and collagen/adenosine diphosphate [CADP]) in patients and controls.These results indicate that in vitro closure time can be a useful test for detecting platelet-related primary hemostasis defects in dialysis patients.

Background. In a pilot, non-randomized trial we tested the efficacy of tranexamic acid (TXA), a potent fibrinolytic inhibitor, as adjunctive therapy in standard treatment of major upper gastrointestinal bleeding in dialysis patients. Methods. Twenty consecutive patients (12 male, eight female; 63"8 years) with 36 episodes of major upper gastrointestinal bleeding were included in the study. In 16 episodes of bleeding TXA was used (in a dosage of 20 mg intravenously, followed for the next 4 weeks by 10 mgukgu48 h orally), whereas in 20 other cases of bleeding, TXA was not used. The decision to use TXA was left to the attending physician’s clinical judgement, resulting in all the more severe cases of bleeding being treated with TXA. Results. Treatment including TXA was shown to be beneficial (relative to cases not treated with TXA) in terms of decreasing the rate of early re-bleeding (in the first week, 0 vs 6, P-0.05), the rate of early and late re-bleeding (in the first month, 1 vs 8, P-0.05), the rate of repeated endoscopic procedures (in the first month, 1 vs 8, P-0.05) and the number of blood transfusions needed (in the first month, 1.4"1.3 vs 2.6"1.5 units, P-0.05). Conclusions. The results of this pilot study suggest that TXA can be beneficial in the treatment of major upper gastrointestinal bleeding in dialysis patients. This remains to be definitely confirmed in a randomized study.

The possible existence of distinctive, vascular bed specific alterations of coagulation and fibrinolytic parameters associated with three different types of thrombosis was investigated in young women (n = 68

Impaired fibrinolysis and elevated lipoprotein(a) (Lp[a]) are possible nonclassic risk factors for myocardial infarction (MI) at young age. The fibrinolytic system in young women with MI has not been evaluated yet and the role of Lp(a) is still controversial. The authors determined fibrinolytic parameters and Lp(a) in premenopausal women (mean age 42 ±3 years, n = 22) 0.5 to 6 (mean 3.5) years after MI, who were all without severe classic risk factors and had an otherwise low risk for MI. Elevated levels of tissue type plasminogen activator (t-PA) (p < 0.05) were measured in comparison to 52 age-matched controls; no difference was found in plas minogen activator inhibitor, plasminogen, fibrinogen, euglobulin clotting time and D-dimers. Significantly more MI patients had Lp(a) levels greater than 300 mg/L compared to controls (36% vs 13.5%, p < 0.05). The combination of elevated Lp(a), mild hyperlipidemia, and nonsevere smoking was found in 62.5% of MI patients who had elevated levels of Lp(a), in 23% of all women with MI, and in none of the controls. Elevated t-PA is probably only a marker of increased risk of MI, whereas elevated Lp(a) probably has a causative role. A combination of elevated Lp(a), hyperlipidemia, and nonsevere smoking seems to be a high-risk profile, rela tively common in young women with MI.

Introduction: Antiretroviral therapy in HIV-infected patients appears to be associated with increased incidence of cardiovascular disease (CVD).The aim of our study was to investigate the differences in markers of inflammation, endothelial dysfunction and prothrombotic state between treated and untreated HIV-infected patients with or without subclinical atherosclerosis. Methods: Eighty-six Slovenian HIV-infected male patients below the age of 55 participated in our study. Levels of high-sensitivity C- reactive protein (hsCRP), vascular cell adhesion molecule 1 (VCAM-1) and plasminogen activator inhibitor 1 (PAI-1) were measured. The presence of subclinical atherosclerosis was determined by measuring carotid intima-media thickness. Results: The level of hsCRP was significantly increased in HIV-infected patients; it was higher in treated than untreated patients. VCAM-1 was significantly increased; it was higher in untreated than treated patients. PAI-1 was significantly increased; there were no differences between untreated and treated patients. Patients with subclinical atherosclerosis had elevated hsCRP; levels of VCAM-1 and PAI-1 were not significantly different. Conclusion: Signs of systemic and vascular inflammation persist in both untreated and treated HIV infected patients. None of the studied markers contributed to improved assessment of subclinical atherosclerosis. The usefulness of such markers in routine clinical evaluation of CVD risk in HIV infected patients remains unclear.

Background The role of vascular endothelial growth factor (VEGF) in patients in the stable phase after myocardial infarction (MI) has not yet been explored. Therefore, we compared the values of VEGF in post-MI patients with those obtained in healthy controls. Furthermore, we investigated whether the values of VEGF correlate to either inflammation markers or the atherosclerotic burden. Methods 41 male patients (on average 44 years old) in the stable phase after MI (on average 20.5 months after MI) were recruited, while 25 healthy age-matched males served as controls. Plasma levels of VEGF and several markers of inflammation were measured by standard procedures. The atherosclerotic burden was determined by the angiographic severity of coronary atherosclerosis, endothelial dysfunction (measured by ultrasound measurement of the flow mediated dilation of the brachial artery), the intima-media thickness of the common carotid artery and the ankle-brachial pressure index. Results VEGF values were significantly elevated in post-MI patients compared to the controls (53.8 ± 42.7 pg/ml vs. 36.3 ± 8.9 pg/ml, p = 0.014). The elevated VEGF values significantly correlated to the (increased) values of the inflammatory molecules interleukin 6 and 8 (r = 0.37, p = 0.017; and r = 0.45, p = 0.003; respectively). In contrast, no correlation was found between VEGF and the parameters of the atherosclerotic burden, although FMD and IMT were significantly impaired in patients. Conclusions We found that plasma levels of VEGF are increased in the stable phase after MI and correlate with inflammation cytokines, but not with the atherosclerotic burden. Thus, this suggests that increased levels of VEGF are a part of ongoing inflammatory activity. Since VEGF in these patients stimulates neovascularization of inflamed plaques and induces their destabilization, the VEGF level can have an important negative prognostic value. Clearly, further studies are needed to clarify the role of VEGF as a prognostic marker.

We describe a successful treatment of a severe, persistent bleeding from both kidneys in a patient with autosomal dominant polycystic kidney disease (ADPKD) with tranexamic acid (TXA), a potent antifibrinolytic agent. The bleeding could not be controlled by intensive conservative treatment, it became life-threatening and urgent bilateral nephrectomy was intended. Since local and systemic hyperfibrinolysis play a role in bleeding in ADPKD patients, we tried TXA treatment. In fact, the massive bleeding promptly stopped, and haematuria gradually ceased. Removal of both kidneys was prevented. After 5 days both ureters became obstructed by blood clots, but placing J-catheters in each pyelon successfully solved this complication. Our case shows that it is reasonable to try antifibrinolytic treatment with TXA in such devastating uncontrolled bleeding.

PURPOSE: We have previously shown that a "short-term, low-dose" treatment approach with statins, angiotensin receptor blockers, and especially their low-dose combination, is effective in improving arterial wall properties in apparently healthy middle-age men. This study was performed to expand investigation of its effects on inflammation and oxidative stress. METHODS: The study was performed supplementary to 3 previous studies, overall 65 treated participants (25 received fluvastatin 10 mg, 20 valsartan 20 mg, 20 their combination) and 65 participants placebo. The stored blood samples (collected at inclusion and after 30 days of treatment) were used to measure high-sensitivity CRP, interleukin-6, vascular cell adhesion molecule-1, total antioxidant status, glutathione peroxidase, and selenium concentration. RESULTS: A low-dose combination decreased inflammation parameters (high-sensitivity CRP: from 1.2 +/- 0.1 to 0.7 +/- 0.1 mg/L; P < .001; vascular cell adhesion molecule-1: from 523 +/- 21 to 482 +/- 12 pg/mL; P < .05; while interleukin-6 did not reach the level of significance). It also increased antioxidant defenses, as measured by total antioxidant status and glutathione peroxidase (from 1.4 +/- 0.04 to 1.5 +/- 0.04 mmol/L; P < .01, and from 1.2 +/- 0.06 to 1.4 +/- 0.06 [mu]kat/g hemoglobin; P < .05, respectively), accompanied by decreased selenium levels. Low-dose valsartan was separately less effective than the combination. No changes were observed in the control groups. CONCLUSIONS: Low-dose combination of fluvastatin and valsartan and, to a lesser extent low-dose valsartan alone, produced important anti-inflammatory and anti-oxidative effects. These results confirm and extend the potential of the "short-term, low-dose" preventive strategy.