Clinical Outcomes of Extracranial Carotid Artery-Related Stroke Eligible for Mechanical Reperfusion on Top of Per-Guidelines Thrombolytic Therapy: Analysis from a 6-Month Consecutive Patient Sample in 2 Centers.

BACKGROUND Systemic intravenous thrombolysis and mechanical thrombectomy (MT) are guideline-recommended reperfusion therapies in large-vessel-occlusion ischemic stroke. However, for acute ischemic stroke of extracranial carotid artery origin (AIS-CA) there have been no specific trials, resulting in a data gap. MATERIAL AND METHODS We evaluated referral/treatment pathways, serial imaging, and neurologic 90-day outcomes in consecutive patients, presenting in a real-life series in 2 stroke centers over a period of 6 months, with AIS-CA eligible for emergency mechanical reperfusion (EMR) on top of thrombolysis as per guideline criteria. RESULTS Of 30 EMR-eligible patients (33.3% in-window for thrombolysis and thrombolysed, 73.3% male, age 39-87 years, median Alberta Stroke Program Early Computed Tomography Score (ASPECTS) 10, pre-stroke mRS 0-1 in all, tandem lesions 26.7%), 20 (66.7%) were EMR-referred (60% - endovascular, 6.7% - surgery referrals). Only 40% received EMR, nearly exclusively in stroke centers with carotid artery stenting (CAS) expertise (100% eligible patient acceptance rate, 100% treatment delivery involving CAS±MT with culprit lesion sequestration using micronet-covered stents). The emergency surgery rate was 0%. Baseline clinical and imaging characteristics did not differ between EMR-treated and EMR-untreated patients. Ninety-day neurologic status was profoundly better in EMR-treated patients: mRS 0-2 (91.7% vs 0%; P<0.001); mRS 3-5 (8.3% vs 88.9%; P<0.001), mRS 6 (0% vs 11.1%; P<0.001). CONCLUSIONS In a real-life AIS-CA setting, the referral rate of EMR-eligible patients for EMR was low, and the treatment rate was even lower. AIS-CA revascularization was delivered predominantly in stroke thrombectomy-capable cardioangiology centers, resulting in overwhelmingly superior patient outcome. Large vessel occlusion stroke referral and management pathways should involve centers with proximal-protected CAS expertise. AIS-CA, irrespective of any thrombolysis administration, is a hyperacute cerebral emergency and EMR-eligible patients should be immediately referred for mechanical reperfusion.

Outcomes in acute carotid-related stroke eligible for mechanical reperfusion: SAFEGUARD-STROKE Registry.

BACKGROUND: Carotid-related strokes (CRS) are largely unresponsive to intravenous thrombolysis and are often large and disabling. Little is known about contemporary CRS referral pathways and proportion of eligible patients who receive emergency mechanical reperfusion (EMR). METHODS: Referral pathways, serial imaging, treatment data, and neurologic outcomes were evaluated in consecutive CRS patients presenting over 18 months in catchment area of a major carotid disease referral center with proximal-protected CAS expertise, on-site neurology, and stroke thrombectomy capability (Acute Stroke of CArotid Artery Bifurcation Origin Treated With Use oF the MicronEt-covered CGUARD Stent - SAFEGUARD-STROKE Registry; companion to SAFEGUARD-STROKE Study NCT05195658). RESULTS: Of 101 EMR-eligible patients (31% i.v.-thrombolyzed, 39.5% women, age 39-89 years, 94.1% ASPECTS 9-10, 90.1% pre-stroke mRS 0-1), 57 (56.4%) were EMR-referred. Referrals were either endovascular (Comprehensive Stroke Centre, CSC, 21.0%; Stroke Thrombectomy-Capable CAS Centre, STCC, 70.2%) or to vascular surgery (VS, 1.8%), with >1 referral attempt in 7.0% patients (CSC/VS or VS/CSC or CSC/VS/STCC). Baseline clinical and imaging characteristics were not different between EMR-treated and EMR-untreated patients. EMR was delivered to 42.6% eligible patients (emergency carotid surgery 0%; STCC rejections 0%). On multivariable analysis, non-tandem CRS was a predictor of not getting referred for EMR (OR 0.36; 95%CI 0.14-0.93, P=0.03). Ninety-day neurologic status was profoundly better in EMR-treated patients; mRS 0-2 (83.7% vs. 34.5%); mRS 3-5 (11.6% vs. 53.4%), mRS 6 (4.6% vs. 12.1%); P<0.001 for all. CONCLUSIONS: EMR-treatment substantially improves CRS neurologic outcomes but only a minority of EMR-eligible patients receive EMR. To increase the likelihood of brain-saving treatment, EMR-eligible stroke referral and management pathways, including those for CSC/VS-rejected patients, should involve stroke thrombectomy-capable centres with endovascular carotid treatment expertise.

A multi-center study of the MicroNET-covered stent in consecutive patients with acute carotid-related stroke: SAFEGUARD-STROKE.

Introduction: Acute carotid-related stroke (CRS), with its large thrombo-embolic load and large volume of affected brain tissue, poses significant management challenges. First generation (single-layer) carotid stents fail to insulate the athero-thrombotic material; thus they are often non-optimized (increasing thrombosis risk), yet their use is associated with a significant (20-30%) risk of new cerebral embolism. Aim: To evaluate, in a multi-center multi-specialty investigator-initiated study, outcomes of the MicroNET-covered (cell area ≈ 0.02-0.03 mm2) carotid stent (CGuard, InspireMD) in consecutive CRS patients eligible for emergency recanalization. Treatment, other than study device use, was according to center/operator routine. Material and methods: Seventy-five patients (age 40-89 years, 26.7% women) were enrolled in 7 interventional stroke centers. Results: The median Alberta Stroke Program Early CT Score (ASPECTS) was 9 (6-10). Study stent use was 100% (no other stent types implanted); retrograde strategy predominated (69.2%) in tandem lesions. Technical success was 100%. Post-dilatation balloon diameter was 4.0 to 8.0 mm. 89% of patients achieved final modified Thrombolysis in Cerebral Infarction (mTICI) 2b-c/3. Glycoprotein IIb/IIIa inhibitor use as intraarterial (IA) bolus + intravenous (IV) infusion was an independent predictor of symptomatic intracranial hemorrhage (OR = 13.9, 95% CI: 5.1-84.5, p < 0.001). The mortality rate was 9.4% in-hospital and 12.2% at 90 days. Ninety-day mRS0-2 was 74.3%, mRS3-5 13.5%; stent patency was 93.2%. Heparin-limited-to-flush predicted patency loss on univariate (OR = 14.3, 95% CI: 1.5-53.1, p < 0.007) but not on multivariate analysis. Small-diameter balloon/absent post-dilatation was an independent predictor of stent patency loss (OR = 15.2, 95% CI: 5.7-73.2, p < 0.001). Conclusions: This largest to-date study of the MicroNET-covered stent in consecutive CRS patients demonstrated a high acute angiographic success rate, high 90-day patency and favorable clinical outcomes despite variability in procedural strategies and pharmacotherapy (SAFEGUARD-STROKE NCT05195658).

Imaging modality-dependent carotid stenosis severity variations against intravascular ultrasound as a reference: Carotid Artery intravasculaR Ultrasound Study (CARUS).

PURPOSE: Different non-invasive and invasive imaging modalities are used to determine carotid artery stenosis severity that remains a principal parameter in clinical decision-making. We compared stenosis degree obtained with different modalities against vascular imaging gold standard, intravascular ultrasound, IVUS. METHODS: 300 consecutive patients (age 47-83 years, 192 men, 64% asymptomatic) with carotid artery stenosis of " ≥ 50%" referred for potential revascularization received as per study protocol (i) duplex ultrasound (DUS), (ii) computed tomography angiography (CTA), (iii) intraarterial quantitative angiography (iQA) and (iv) and (iv) IVUS. Correlation of measurements with IVUS (r), proportion of those concordant (within 10%) and proportion of under/overestimated were calculated along with recipient-operating-characteristics (ROC). RESULTS: For IVUS area stenosis (AS) and IVUS minimal lumen area (MLA), there was only a moderate correlation with DUS velocities (peak-systolic, PSV; end-diastolic, EDV; r values of 0.42-0.51, p < 0.001 for all). CTA systematically underestimated both reference area and MLA (80.4% and 92.3% cases) but CTA error was lesser for AS (proportion concordant-57.4%; CTA under/overestimation-12.5%/30.1%). iQA diameter stenosis (DS) was found concordant with IVUS in 41.1% measurements (iQA under/overestimation 7.9%/51.0%). By univariate model, PSV (ROC area-under-the-curve, AUC, 0.77, cutoff 2.6 m/s), EDV (AUC 0.72, cutoff 0.71 m/s) and CTA-DS (AUC 0.83, cutoff 59.6%) were predictors of ≥ 50% DS by IVUS (p < 0.001 for all). Best predictor, however, of ≥ 50% DS by IVUS was stenosis severity evaluation by automated contrast column density measurement on iQA (AUC 0.87, cutoff 68%, p < 0.001). Regarding non-invasive techniques, CTA was the only independent diagnostic modality against IVUS on multivariate model (p = 0.008). CONCLUSION: IVUS validation shows significant imaging modality-dependent variations in carotid stenosis severity determination.

Endovascular carotid revascularization under open-chest extracorporeal circulation combined with cardiac surgery in unstable patients at increased risk of carotid-related stroke: SIMultaneous urgent cardiac surgery and MicroNet-covered stent carotid revascularization in extreme-risk patients-SIMGUARD Study.

BACKGROUND: In patients at urgent need for cardiac surgery coexisting with increased-stroke-risk carotid stenosis, any staged intervention increases the risk of complications from the primarily unaddressed pathology. In this challenging cohort, we assessed safety and feasibility of endovascular carotid revascularization under open-chest extracorporeal circulation (ECC) combined with cardiac surgery (hybrid-room true simultaneous treatment). METHODS: Per-protocol (PP), after general anesthesia induction, chest-opening and ECC stand-by installation, carotid stenting (CAS) was performed (femoral/radial or direct carotid access) with ad-hoc/on-hand switch to ECC cardiac surgery. RESULTS: Over 78 months, 60 patients (70.7±6.9years, 85% male, all American Society of Anesthesiology grade IV) were enrolled. All were at increased carotid-related stroke risk (ipsilateral recent stroke/transient ischemick attack, asymptomatic cerebral infarct, increased-risk lesion morphology, bilateral severe stenosis). Majority of study procedures involved CAS+coronary bypass surgery or CAS+valve replacement±coronary bypass. 45 (75%) patients were PP- and 15 (25%) not-PP (NPP-) managed (context therapy). CAS was 100% neuroprotected (transient flow reversal-64.4%, filters-35.6%) and employed micronet-covered plaque-sequestrating stents with routine post-dilatation optimization/embedding. 4 deaths (6.7%) and 7 strokes (11.7%) occurred by 30-days. Despite CAS+surgery performed on aspirin and unfractionated heparin-only (delayed clopidogrel-loading), no thrombosis occurred in the stented arteries, and 30-days stent patency was 100%. NPP-management significantly increased the risk of death/ipsilateral stroke (OR 38.5; P<0.001) and death/any stroke (OR 12.3; P=0.002) by 30-days. CONCLUSIONS: In cardiac unstable patients at increased carotid-related stroke risk who require urgent cardiac surgery, simultaneous cardiac surgery and CAS with micronet-covered stent lesion sequestration is feasible and safe and shows efficacy in minimizing stroke risk. Larger-scale, multicentric evaluation is warranted. (SIMGUARD NCT04973579).

Misclassification of carotid stenosis severity with area stenosis-based evaluation by computed tomography angiography: impact on erroneous indication to revascularization or patient (lesion) migration to a higher guideline recommendation class as per ESC/ESVS/ESO/SVS and CMS-FDA thresholds.

Intoduction: Despite a growing understanding of the role played by plaque morphology, the degree of carotid lumen reduction remains the principle parameter in decisions on revascularization in symptomatic and asymptomatic patients. Computed tomography angiography (CTA) is a widely used guideline-approved imaging modality, with "percent stenosis" commonly calculated as %area reduction (area stenosis - AS). Aim: We evaluated the impact of the non-linear relationship between diameter stenosis (DS) and AS (area = π • (diameter/2)2, so that in concentric lesions 51%AS is 30%DS and 75%AS is 50%DS) on stenosis severity misclassification using calculation of area reduction. Material and methods: CTA and catheter quantitative angiography (cQA) were performed in 300 consecutive patients referred to a tertiary vascular centre for potential carotid revascularization (age: 47-83 years, 33.7% symptomatic, 36% female; referral stenosis of ≥ "50%"). CTA-AS was determined by agreement of 2 experienced radiologists; cQA-DS (pivotal trials standard reference, NASCET method) was calculated by agreement of 2 corelab analysts. Results: For symptomatic lesion thresholds, CTA-AS-based calculation reclassified 76% of "< 50%" cQA-DS measurements to the "50-69%" group, and 58% of "50-69%" measurements to the "≥ 70%" group. For asymptomatic lesion thresholds, 78% of "< 60%" cQA-DS measurements were reclassified to the "60-79%" group, whereas 42% of "60-79%" cQA measurements crossed to the "≥ 80%" class. Overall, employing CTA-AS instead of cQA-DS enlarged the "60-79%" and "≥ 80%" lesion severity classes 1.6- and 5.8-fold, respectively, whereas the "≥ 70%" class increased 4.15-fold. Conclusions: Replacing the pivotal carotid trials reference standard cQA-DS "%stenosis" measurement with CTA-AS-based "%stenosis" results in a large-scale lesion/patient erroneous gain of an "indication" to revascularization or migration to a higher revascularization indication class. In consequence, unnecessary carotid procedures may be performed in the absence of cQA verification. Until guidelines rectify the "%stenosis" measurement methods with different guideline-approved imaging modalities (and, where needed, re-adjust decision thresholds), CTA-AS measurement should not be used as a basis for carotid revascularization.

Early abciximab use in ST-elevation myocardial infarction treated with primary percutaneous coronary intervention improves long-term outcome. Data from EUROTRANSFER Registry.

BACKGROUND: Primary percutaneous coronary intervention (PCI) is the preferred method of reperfusion in patients with ST elevation myocardial infarction (STEMI). Abciximab is a well established adjunct to primary PCI. The proper timing of abciximab administration in STEMI patients has been investigated in randomised trials, registries and metanalysis, providing conflicting results. METHODS: Consecutive data on STEMI patients, transferred for primary PCI in hospital/ambulance STEMI networks between November 2005 and January 2007, from 15 PCI centres in seven European countries was gathered together for a one-year long-term clinical observation (93% rate of completeness). RESULTS: Data from 1,650 patients was collected in the EUROTRANSFER Registry. Abciximab was administered to 1,086 patients (66%), 727 patients received early (at least 30 minutes prior to first balloon inflation) abciximab (EA), and another 359 patients received late abciximab (LA). One year mortality was 5.8% in the EA group vs 10.3% with LA (p = 0.007). Adjustment for propensity score methods for EA administration did not change the results, still providing a favourable outcome for the EA group (p = 0.004). It was also revealed that only a minority of patients (36%) were treated within the 90-minute recommended time window from first medical contact to PCI (and 60% for the 120-min time delay). CONCLUSIONS: Patients transferred for primary PCI in STEMI hospital networks showed lower rates of death in long-term one-year clinical follow-up when treatment with abciximab was started early.

Early abciximab administration before transfer for primary percutaneous coronary interventions for ST-elevation myocardial infarction reduces 1-year mortality in patients with high-risk profile. Results from EUROTRANSFER registry.

BACKGROUND: There are conflicting data on the clinical benefit from early administration of abciximab from a large randomized trial and a registry. However, both sources suggest that a benefit may depend on the baseline risk profile of the patients. We evaluated the role of early abciximab administration in patients with ST-segment-elevation myocardial infarction (STEMI) referred for primary percutaneous coronary intervention stratified by the STEMI Thrombolysis In Myocardial Infarction (TIMI) risk score. METHODS: A total of 1,650 patients were enrolled into the EUROTRANSFER Registry. One thousand eighty-six patients received abciximab (66%). Abciximab was administered early in 727 patients (EA) and late in 359 patients (LA). We used the TIMI risk score for risk stratification. Patients with scores >or=3 constituted the high-risk group of 616 patients (56.7%), whereas 470 patients formed the low-risk cohort. Factoring in the timing of the abciximab administration resulted in 4 groups of patients who were compared for mortality at 1 year: EA/high-risk (n = 413); LA/high-risk (n = 203); EA/low-risk (n = 314); LA/low-risk (n = 156). Baseline difference was accounted for by means of propensity score. RESULTS: In high-risk patients, 1-year mortality was significantly lower with early abcximab compared to late administration (8.7% vs 15.8%; odds ratio 0.51, CI 0.31-0.85, P = .01). In multivariable Cox regression analysis, both early abciximab administration and patients' risk profile (TIMI score >or=3) were identified as independent predictors of 1-year mortality. CONCLUSIONS: Early abciximab administration before transfer for percutaneous coronary intervention in STEMI shows lower mortality at 1-year follow-up. This effect is confined to patients with higher risk profile as defined by TIMI risk score >or=3.

Inflammatory markers and left ventricular diastolic dysfunction in a family-based population study.

BACKGROUND: Heart failure affects patients with normal left ventricular systolic function (heart failure with preserved ejection fraction [HFPEF]) and those with reduced ejection fraction (HFREF). The treatment of HFPEF remains an unresolved issue. AIM: We sought to determinate the relationship between inflammatory markers and left ventricular diastolic dysfunction (LVDD) in a family-based population study. METHODS: A total of 303 participants from the general population (55% women, median age 49 years and 45% men, median age 40 years) underwent echocardiography and measurement of serum inflammatory markers: C-reactive protein (CRP), myeloperoxidase (MPO), and interleukin 6 (IL-6). RESULTS: Serum IL-6 concentration correlated with peak transmitral late diastolic velocity (A) and pulmonary vein systolic-to-di-astolic velocity (S/D) ratio (p < 0.01). Moreover, a significant correlation between IL-6 concentration and E/A ratio and early diastolic peak velocities of the mitral annulus displacement (E') was observed. The association of IL-6 concentration and peak transmitral early diastolic velocities (E) and the E/E' ratio (p < 0.05) was noted in men. In addition, the CRP concentration was shown to have an effect on E/A ratio in women (p < 0.05). A significant correlation between the CRP concentration and S/D ratio was observed both in women (p < 0.01) and men (p < 0.05). No significant correlation was found between the level of MPO and LVDD parameters. Additionally, only one predictive model was identified; E' was found to be dependent on IL-6, age, and heart rate in men (p < 0.001, R2 = 0.611). CONCLUSIONS: The above results suggest that inflammation may lead to the onset of LVDD, probably via vascular endothelial dysfunction.

[Seasonal variation of hospital morbidity from asthma in Poland]. / Wahania sezonowe chorobowosci szpitalnej z powodu astmy oskrzelowej w Polsce.

The aim of the paper was to describe and compare the seasonal hospital admissions among different subgroups of patients due to bronchial asthma with a special focus on demographic characteristic. Data were collected during the calendar year 2003. Data were gathered for 32,933 patients from 522 hospitals across Poland with confirmed diagnosis of bronchial asthma or status asthmaticus. We noticed a distinct seasonal patterns in the number of hospitalizations due to asthma. Most cases clustered in the beginning and the end of the calendar year. Beside these hospitalization peaks, we observed a less pronounced increase of hospital admissions in spring and through summer months. It was most distinctly pronounced in children. It was also shown that gender of patients did not affect seasonal variability in our study. Emergency admissions to hospitals were less frequent in summer months, whereas elective admissions presented no such distinct pattern. The data revealed differences in seasonality in asthma hospital admissions in various age groups.

Tandemly repeated trinucleotides - comparative analysis.

Characteristics of 64 possible tandem trinucleotide repeats (TSSR) from Homo sapiens (hs), Mus musculus (mm) and Rattus norvegicus (rn) genomes are presented. Comparative analysis of TSSR frequency depending on their repetitiveness and similarity of the TSSR length distributions is shown. Comparative analysis of TSSR sequence motifs and association between type of motif and its length (n) using rho-coefficient method (quantitatively measuring the association between variables in contingency tables) is presented. These analyses were carried out in the context of neurodegenerative diseases based on trinucleotide tandems. The length of these tandems and their relation to other TSSR is estimated. It was found that the higher repetitiveness (n) the lower frequency of trinucleotides tandems. Differences between genomes under consideration, especially in longer than n=9 TSSR were discussed. A significantly higher frequency off A- and T-rich tandems is observed in the human genome (as well as in human mRNA). This observation also applies to mm and rn, although lower abundant in proportion to human genomes was found. The origin of elongation (or shortening) of TSSR seems to be neither frequency nor length dependent. The results of TSSR analysis presented in this work suggest that neurodegenerative disease-related microsatellites do not differ versus the other except the lower frequency versus the other TSSR. CAG occurs with relatively high frequency in human mRNA, although there are other TSSR with higher frequency that do not cause comparable disease disorders. It suggests that the mechanism of TSSR instability is not the only origin of neurodegenerative diseases.

A tabular approach to the sequence-to-structure relation in proteins (tetrapeptide representation) for de novo protein design.

BACKGROUND: Experimental observations classify the protein-folding process as a multi-step event. The backbone conformation has been experimentally recognized as responsible for the early-stage structural forms of a polypeptide. The sequence-to-structure and structure-to-sequence relation is critical for predicting protein structure. A contingency table representing this relation for tetrapeptides in their early-stage is presented. Their correlation seems to be essential in protein-folding simulation. MATERIAL/METHODS: The polypeptide chains of all the proteins in the Protein Data Bank were transformed into their early-stage structural forms. The tetrapeptide was selected as the structural unit. Tetrapetide sequences and structures were expressed by letter codes. The transformation of a contingency table of any size (here: 160,000x2401) to a 2x2 table performed for each non-zero cell of the original table allowed calculation of the rho-coefficient measuring the strength of the relation. RESULTS: High values of the rho-coefficient extracted sequences of strong structural determinability and structures of high sequence selectivity. The web-site program to calculate the rho-coefficient ranking list was constructed to enable applying this method to any problem of contingency table analysis. CONCLUSIONS: The results revealed sequence-to-structure (and vice versa) correlation in early-stage folding. Surprisingly, the irregular structural forms of loops and bends appeared to be highly determined. Comparison of these results with another method based on information entropy revealed high accordance. The method oriented on interpretation of a large contingency table seems very useful especially for large-scale microarray analysis, a very popular technique in the post-genomic era.