Low α2-Plasmin Inhibitor Antigen Levels on Admission Are Associated With More Severe Stroke and Unfavorable Outcomes in Acute Ischemic Stroke Patients Treated With Intravenous Thrombolysis.

Background: Intravenous administration of recombinant tissue plasminogen activator (rt-PA) fails to succeed in a subset of acute ischemic stroke (AIS) patients, while in approximately 6-8% of cases intracerebral hemorrhage (ICH) occurs as side effect. Objective: Here, we aimed to investigate α2-plasmin inhibitor (α2-PI) levels during thrombolysis and to find out whether they predict therapy outcomes in AIS patients. Patients/Methods: In this prospective, observational study, blood samples of 421 AIS patients, all undergoing i.v. thrombolysis by rt-PA within 4.5 h of their symptom onset, were taken before and 24 h after thrombolysis. In a subset of patients (n = 131), blood was also obtained immediately post-lysis. α2-PI activity and antigen levels were measured by chromogenic assay and an in-house ELISA detecting all forms of α2-PI. α2-PI Arg6Trp polymorphism was identified in all patients. Stroke severity was determined by NIHSS on admission and day 7. Therapy-associated ICH was classified according to ECASSII. Long-term outcomes were defined at 3 months post-event by the modified Rankin Scale (mRS). Results: Median α2-PI activity and antigen levels showed a significant drop immediately post-lysis and increased to subnormal levels at 24 h post-event. Admission α2-PI levels showed a significant negative stepwise association with stroke severity. Patients with favorable long-term outcomes (mRS 0-1) had significantly higher admission α2-PI antigen levels (median:61.6 [IQR:55.9-70.5] mg/L) as compared to patients with poor outcomes (mRS 2-5: median:59.7 [IQR:54.5-69.1] and mRS 6: median:56.0 [IQR:48.5-61.0] mg/L, p < 0.001). In a Kaplan-Meier survival analysis, patients with an α2-PI antigen in the highest quartile on admission showed significantly better long-term survival as compared to those with α2-PI antigen in the lowest quartile (HR: 4.54; 95%CI:1.92-10.8, p < 0.001); however, in a multivariate analysis, a low admission α2-PI antigen did not prove to be an independent risk factor of poor long-term outcomes. In patients with therapy-related ICH (n = 34), admission α2-PI antigen levels were significantly, but only marginally, lower as compared to those without hemorrhage. Conclusions: Low α2-PI antigen levels on admission were associated with more severe strokes and poor long-term outcomes in this cohort. Our results suggest that in case of more severe strokes, α2-PI may be involved in the limited efficacy of rt-PA thrombolysis.

Influence of angiotensin-converting enzyme inhibition on reversibility of alterations in arterial wall and cognitive performance associated with early hypertension: A follow-up study.

The importance of optimal blood pressure control for preventing or reducing the impairment of vascular and cognitive functions is well known. However, the reversibility of early alterations in vascular and cognitive functions through antihypertensive agents is under-investigated. In this study, we evaluated the influence of 3 months of angiotensin-converting enzyme (ACE) inhibition treatment on the morphological and functional arterial wall and cognitive performance changes in 30 newly diagnosed primary hypertensive patients.Common carotid intima-media thickness (IMT) and brachial artery flow-mediated dilatation (FMD) were detected by ultrasonography. Arterial stiffness indicated by augmentation index (AIx) and pulse wave velocity (PWV) was assessed by arteriography. Cognitive functions were assessed by neuropsychological examination.The executive function overall score was significantly higher at 3-month follow-up than at baseline (median, 0.233 (IQR, 0.447) vs -0.038 (0.936); P = .001). Three-month ACE inhibition did not produce significant improvement in IMT, FMD, AIx and PWV values. Significant negative associations were revealed between IMT and complex attention (r = -0.598, P = .0008), executive function (r = -0.617, P = .0005), and immediate memory (r = -0.420, P = .026) overall scores at follow-up. AIx had significant negative correlations with complex attention (r = -0.568, P = .001), executive function (r = -0.374, P = .046), and immediate memory (r = -0.507, P = .005). PWV correlated significantly and negatively with complex attention (r = -0.490, P = .007).Timely and effective antihypertensive therapy with ACE inhibitors has significant beneficial effects on cognitive performance in as few as 3 months. Early ACE inhibition may have an important role in the reversal of initial impairments of cognitive function associated with hypertension-induced vascular alterations.

Hypertension-induced subclinical vascular and cognitive changes are reversible-An observational cohort study.

Beside the well-known complications of poorly controlled, long-standing hypertension, milder abnormalities induced by early-stage hypertension have also been described. In our study, the authors examined the reversibility of changes induced by early-stage hypertension. The authors performed laboratory testing, ambulatory blood pressure monitoring, carotid intima-media thickness (IMT) measurement, evaluation of stiffness parameters, assessment of various cardiac and cerebral hemodynamic parameters during head-up tilt table (HUTT) testing, and neuropsychological examinations in 49 recently diagnosed hypertensive patients. Following baseline assessment, antihypertensive therapy was commenced. After one year of therapy, lower IMT values were found. Pulse wave velocity showed a borderline significant decrease. During HUTT, several hemodynamic parameters improved. The patients performed better on neuropsychological testing and reached significantly lower scores on questionnaires evaluating anxiety. The present study shows that early vascular changes and altered cognitive function observed in newly diagnosed hypertensive patients may improve with promptly initiated antihypertensive management.

Low factor XIII levels after intravenous thrombolysis predict short-term mortality in ischemic stroke patients.

In this observational study we investigated whether levels of factor XIII (FXIII) and its major polymorphisms affect the outcome of thrombolysis by recombinant tissue plasminogen activator (rtPA) in acute ischemic stroke (AIS) patients. Study cohort included 132 consecutive AIS patients undergoing i.v. thrombolysis within 4.5 h of symptom onset. Blood samples taken on admission, immediately after and 24 h after therapy were analyzed for FXIII activity and antigen levels. FXIII-A p.Val34Leu, p.Tyr204Phe, FXIII-B p.His95Arg and intron K(IVS11 + 144) polymorphisms were genotyped. Neurological deficit was assessed using the National Institutes of Health Stroke Scale. Intracranial hemorrhage was classified according to ECASSII criteria. Long-term functional outcome was defined at 3 months post-event by the modified Rankin scale. FXIII levels showed a gradual decrease immediately after thrombolysis and 24 h later, which was not related to therapy-associated bleeding. In a multiple logistic regression model, a FXIII level in the lowest quartile 24 h post-lysis proved to be an independent predictor of mortality by 14 days post-event (OR:4.95, 95% CI:1.31-18.68, p < 0.05). No association was found between the investigated FXIII polymorphisms and therapeutic outcomes. In conclusion, our findings indicate that FXIII levels 24 h after thrombolysis might help to identify patients at increased risk for short-term mortality.

Elevated Factor VIII and von Willebrand Factor Levels Predict Unfavorable Outcome in Stroke Patients Treated with Intravenous Thrombolysis.

INTRODUCTION: Plasma factor VIII (FVIII) and von Willebrand factor (VWF) levels have been associated with the rate and severity of arterial thrombus formation and have been linked to outcomes following thrombolytic therapy in acute myocardial infarction patients. Here, we aimed to investigate FVIII and VWF levels during the course of thrombolysis in acute ischemic stroke (AIS) patients and to find out whether they predict long-term outcomes. MATERIALS AND METHODS: Study population included 131 consecutive AIS patients (median age: 69 years, 60.3% men) who underwent i.v. thrombolysis with recombinant tissue plasminogen activator (rt-PA). Blood samples were taken on admission, 1 and 24 h after rt-PA administration to measure FVIII activity and VWF antigen levels. Neurological deficit of patients was determined according to the National Institutes of Health Stroke Scale (NIHSS). ASPECT scores were assessed using computer tomography images taken before and 24 h after thrombolysis. Intracranial hemorrhage was classified according to the European Cooperative Acute Stroke Study (ECASS) II criteria. Long-term functional outcome was determined at 90 days after the event by the modified Rankin scale (mRS). RESULTS: VWF levels on admission were significantly elevated in case of more severe AIS [median and IQR values: NIHSS <6:189.6% (151.9-233.2%); NIHSS 6-16: 199.6% (176.4-250.8%); NIHSS >16: 247.8% (199.9-353.8%), p = 0.013]; similar, but non-significant trend was observed for FVIII levels. FVIII and VWF levels correlated well on admission (r = 0.748, p < 0.001) but no significant correlation was found immediately after thrombolysis (r = 0.093, p = 0.299), most probably due to plasmin-mediated FVIII degradation. VWF levels at all investigated occasions and FVIII activity before and 24 h after thrombolysis were associated with worse 24 h post-lysis ASPECT scores. In a binary backward logistic regression analysis including age, gender, high-sensitivity C-reactive protein, active smoking, diabetes, and NIHSS >5 on admission, elevated FVIII and VWF levels after thrombolysis were independently associated with poor functional outcomes (mRS ≥ 3) at 90 days (immediately after thrombolysis: FVIII: OR: 7.10, 95% CI: 1.77-28.38, p = 0.006, VWF: OR: 6.31, 95% CI: 1.83-21.73, p = 0.003; 24 h after thrombolysis: FVIII: OR: 4.67, 95% CI: 1.42-15.38, p = 0.011, VWF: OR: 19.02, 95% CI: 1.94-186.99, p = 0.012). CONCLUSION: Elevated FVIII activity and VWF antigen levels immediately after lysis and at 24 h post-therapy were shown to have independent prognostic values regarding poor functional outcomes at 90 days.

The acute effects of alcohol on cerebral hemodynamic changes induced by the head-up tilt test in healthy subjects.

BACKGROUND: Alcohol is a known triggering factor for orthostatic dysfunction, increasing the risk of neurally-mediated syncope. Since orthostatic tolerance may be affected by both systemic and cerebral hemodynamic changes, our aim was to investigate the acute effects of alcohol on cerebral vasoreactivity measured during the head-up tilt (HUT) test in 20 healthy subjects. METHODS: Mean arterial blood pressure (mBP), heart rate, and flow parameters in both middle cerebral arteries (MCAs) were continuously recorded in the supine and during a 10-minute HUT positions before and after alcohol intake. RESULTS: The HUT test resulted in a more prominent decline of adjusted mBP at the level of MCAs (mBPMCA) and a significantly larger decrease of MCA mean flow velocities (MFVMCA) in the post-alcohol period than before alcohol intake. During the HUT phase, the relative decrease in MFVMCA was significantly smaller than the reduction in mBPMCA before drinking alcohol, while these changes were similar after alcohol ingestion. The cerebrovascular resistance index (CVRi) decreased during the HUT phase in the control period, however, it increased after alcohol intake. CONCLUSION: The similar decrease in mBPMCA and MFVMCA during orthostatic stress after alcohol ingestion together with the increased CVRi indicated the impairment of the compensatory vasodilation of cerebral resistance vessels, i.e. impaired cerebral autoregulation. These findings suggest that alcohol may contribute to impaired orthostatic tolerance not only by a hypotensive response but also by the alteration of cerebral blood flow regulation.

Mannose-Binding Lectin Levels and Carotid Intima-Media Thickness in Type 2 Diabetic Patients.

INTRODUCTION: Mannose-binding lectin (MBL) activates complement system and has been suggested to play a role in vascular complications in diabetics. Carotid intima-media thickness (cIMT) detects subclinical atherosclerosis. We evaluated the association of MBL and IMT in type 2 diabetic (T2DM) patients. METHODS: Serum MBL levels and cIMT were measured in a total of 103 diabetics and in 98 age-matched healthy controls. RESULTS: There was no significant difference in MBL level in T2DM versus controls. As expected, IMT was significantly higher in T2DM patients than in controls (P = 0.001). In T2DM, the lowest cIMT was seen in patients with normal MBL level (500-1000) while cIMT continuously increased with both high MBL and absolute MBL deficiency states. This was especially significant in high MBL versus normal MBL T2DM patients (P = 0.002). According to multiple regression analysis the main predictors of IMT in T2DM are age (P < 0.003), ApoA level (P = 0.023), and the MBL (P = 0.036). CONCLUSIONS: Our results suggest a dual role of MBL as a risk factor for cIMT in T2DM. MBL may also be used as a marker of macrovascular disease, as both low and high levels indicate the susceptibility for atherosclerosis in T2DM.

Elevated LDL-C combined with hypertension worsens subclinical vascular impairment and cognitive function.

Hypertension and dyslipidemia belong to the most prevalent modifiable risk factors for cerebrovascular and cardiovascular diseases. Hereby, we aimed to examine the combined effects of newly diagnosed hypertension and hyperlipidemia on the characteristics of the arterial wall and on cognitive function. We examined 72 hypertensive and 85 apparently healthy individuals. Based on serum lipid levels, four subgroups were created ranging from normotensive-normolipidemic to hypertensive-hyperlipidemic subjects. Carotid intima-media thickness (IMT), arterial stiffness, and cognitive function were assessed. IMT of controls was the lowest, whereas that of patients with both risk factors the highest. Stiffness parameters increased when both risk factors were present, whereas subjects with only one risk factor exhibited intermediate values. Hypertensive patients performed worse when memory, attention, reaction time, and trait anxiety were assessed. Significant worsening of IMT, arterial stiffness, and sum of neuropsychological scores was observed along with increasing mean arterial pressure. Generally, hyperlipidemia combining with hypertension resulted in further worsening of all examined parameters. Subclinical changes of the vascular wall and cognitive performance are already present in recently diagnosed hypertensive patients. Combination of hyperlipidemia and hypertension results in more severe impairments, therefore, early and intensive treatment may be crucial to prevent further deterioration.

[The effect of hypertension and it's therapy on cognitive performance of asymptomatic hypertensive patients]. / A hypertonia és a kezelés hatása tünetmentes hypertoniások kognitív teljesítményére.

The essential hypertension increases the risk of cognitive impairment even in symptom-free patients. Sixty, non-treated hypertensives were investigated (44 +/- 10.5 év) with nine pszichological tests, measuring the reaction time, attention, short and long-term memory, psychomotor speed etc. The results of nine tests were summarized and compared with those of age-matched control persons (n = 98). All hypertensives had normal CT findings. The carotid intima-media-thickness, the arterial stiffness and the velocities in the middle cerebral arteries were also analyzed (with tilting table test). The sum of the results of cognitive tests was significantly worse than that of controls 14.8 +/- 7.1 vs. 27.8 +/- 5.5 p < 0.0001. The results of intima-media thickness and stiffness measurements were also significantly worse compared with controls while the middle cerebral velocities did not differ. After one year antihypertensive therapy not only the improvement of blood pressure, intima-media thickness and stiffness values could be detected but also the score of summarized cognitive tests improved (from 17.4 +/- 6.0 to 31.6 +/- 6.0 p < 0.0001).

Transcranial measurement of cerebral microembolic signals during pulmonary vein isolation: a comparison of two ablation techniques.

BACKGROUND: Pulmonary vein isolation has increasingly been used to cure atrial fibrillation, but concerns have recently been raised that subclinical brain damage may occur because of microembolization during these procedures. We compared the occurrence of bubble formation seen on intracardiac echocardiography and the microembolic signals (MESs) detected by transcranial Doppler on the use of different ablation techniques and anticoagulation strategies. METHODS AND RESULTS: This prospective study included 35 procedures in 34 consecutive patients (age, 52; SD, 12.8 years; female:male 9:25). Pulmonary vein isolation was performed with a cryoballoon and the conventional anticoagulation protocol (activated clotting time >250 s) in 10 procedures (group 1), with a multipolar duty-cycled radiofrequency pulmonary group 2), and with regime a pulmonary vein ablation catheter with an aggressive anticoagulation (activated clotting time >320 s) in 13 procedures (group 3). The mean total numbers of MESs detected during the procedures were 833.7 (SD, 727.4) in group 1, 3142.6 (SD, 1736.4) in group 2, and 2204.6 (SD, 1078.1) in group 3 (P=0.0005). MESs were detected mostly during energy delivery in the pulmonary vein ablation catheter groups, whereas a relatively even distribution of emboli formation was seen during cryoballoon ablations. A significant correlation was found in all groups between the degree of bubble formation on intracardiac echocardiography and the number of MESs (P=0.0000). CONCLUSIONS: Duty-cycled radiofrequency ablation is associated with significantly more MESs, even when more aggressive anticoagulation is applied. With both techniques most of these microemboli are gaseous in nature.

Silent brain infarction--a review of recent observations.

Silent brain infarction is a cerebral ischaemic event evident on brain imaging without any clinical symptom. Silent brain infarction is often detected in apparently healthy, elderly people and in different selected patient groups as well. Lately, several studies were carried out in order to identify the clinical conditions leading to silent brain infarction. A large number of clinical and paraclinical parameters were found to increase silent brain infarction prevalence, and the continuously growing list of risk factors revealed that the majority of them are similar to those related to stroke. Accordingly, some consider silent brain infarction the preclinical stage of clinically overt stroke. This point of view emphasizes the early recognition and management of silent brain infarction-related risk factors, and a great need for comparative studies, which could elicit the most sensitive indicators of the increased silent brain infarction risk, especially the ones that could be cost-effectively screened in the large populations as well.

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.

Cerebro- and cardiovascular reactivity and neuropsychological performance in hypertensive patients.

BACKGROUND: Hypertensive (HT) patients are at higher risk of cognitive decline than normotensive individuals, because high blood pressure is a risk factor for mild cognitive deterioration. In this study cardio- and cerebrovascular reactivity along with cognitive performance was assessed on newly diagnosed HT patients. METHODS: Diagnosis of hypertension was based on international recommendations. None of the patients had diabetes, and all of them had normal cerebral CT scan. Eighty-one patients (43.5±10.2 years, male/female ratio: 42/39) were compared with 94 healthy controls (44±9.4 years, male/female ratio: 50/44). In both groups continuous, non-invasive and simultaneous monitoring of cerebral and cardiac hemodynamical parameters were recorded during head-up tilt table testing (HUTT). Reaction time, attention and memory skills, anxiety and depression rate were determined by neuropsychological tests. RESULTS: During HUTT significant differences were found in certain cardiovascular parameters (blood pressure, total peripheral resistance index, stroke index), but no differences were detected in cerebral blood flow velocity. While there was no significant difference in reaction time between the two groups, tests estimating short-term memory (Digit Span Test) differed significantly. Moreover, sum of standardized test scores was significantly lower, while anxiety level was significantly increased in HT patients compared to controls. CONCLUSION: Decrease in neuropsychological performance along with alterations of cardiovascular parameters is an early manifestation of hypertension. Aim for an early intervention and accurate treatment is crucial for preventing further impairments.

[Antithrombotic therapy in primary and secondary stroke prevention of cardiac patients and in acute stroke]. / Antithromboticus kezelés szívbetegek elsodleges és másodlagos stroke-prevenciójában és akut stroke-ban.

Primary vascular prevention: the prevalence of cardiogenic stroke will increase in the future. All patients with atrial fibrillation but without any ischemic stroke, must undergo a rigorous risk evaluation, which is crucial for pharmacotherapy. Atrial fibrillation is an important risk factor for stroke, therefore patients with atrial fibrillation should be anticoagulated (except those without other risk factors). Even patients over 75 years with atrial fibrillation could be anticoagulated if the INR is properly controlled. The authors review also the role of anticoagulation in patients suffering from myocardial infarction or valve diseases. Acute stroke: The new European stroke guideline does not recommend the use of conventional or fractionated heparin in the first three days of acute stroke, but aspirin therapy is recommended. Long-term anticoagulation is needed only if cardiac source of emboli can be verified, the patient has good compliance, and the risk of hemorrhagic complication is low (INR: 2-3). Otherwise, antiplatelet therapy is recommended. Some authors recommend early anticoagulation in special cases (high risk of embolisation, left atrial/ventricular thrombus, arterial dissection or surgical intervention for a severe arterial stenosis). Caution is needed in patients with large infarct, uncontrolled hypertension and microbleeds on MRI. Secondary prevention: Antiplatelet therapy is recommended for every post-stroke patient, but for those with cardiac source of emboli anticoagulation is recommended.