Grzegorz Filip

Mechanisms of oxidative stress in human aortic aneurysms — Association with clinical risk factors for atherosclerosis and disease severity

Aortic abdominal aneurysms (AAA) are important causes of cardiovascular morbidity and mortality. Oxidative stress may link multiple mechanisms of AAA including vascular inflammation and increased metalloproteinase activity. However, the mechanisms of vascular free radical production remain unknown. Accordingly, we aimed to determine sources and molecular regulation of vascular superoxide (O2•−) production in human AAA. Methods and results AAA segments and matched non-dilated aortic samples were obtained from 40 subjects undergoing AAA repair. MDA levels (determined by HPLC/MS) were greater in plasma of AAA subjects (n = 16) than in risk factor matched controls (n = 16). Similarly, superoxide production, measured by lucigenin chemiluminescence and dihydroethidium fluorescence, was increased in aneurysmatic segments compared to non-dilated aortic specimens. NADPH oxidases and iNOS are the primary sources of O2•− in AAA. Xanthine oxidase, mitochondrial oxidases and cyclooxygenase inhibition had minor or no effect. Protein kinase C inhibition had no effect on superoxide production in AAA. NADPH oxidase subunit mRNA levels for p22phox, nox2 and nox5 were significantly increased in AAAs while nox4 mRNA expression was lower. Superoxide production was higher in subjects with increased AAA repair risk Vanzetto score and was significantly associated with smoking, hypercholesterolemia and presence of CAD in AAA cohort. Basal superoxide production and NADPH oxidase activity were correlated to aneurysm size. Conclusions Increased expression and activity of NADPH oxidases are important mechanisms underlying oxidative stress in human aortic abdominal aneurysm. Uncoupled iNOS may link oxidative stress to inflammation in AAA. Oxidative stress is related to aneurysm size and major clinical risk factors in AAA patients.

Does diabetes accelerate the progression of aortic stenosis through enhanced inflammatory response within aortic valves

Diabetes predisposes to aortic stenosis (AS). We aimed to investigate if diabetes affects the expression of selected coagulation proteins and inflammatory markers in AS valves. Twenty patients with severe AS and concomitant type 2 diabetes mellitus (DM) and 40 well-matched patients without DM scheduled for valve replacement were recruited. Valvular tissue factor (TF), TF pathway inhibitor (TFPI), prothrombin, C-reactive protein (CRP) expression were evaluated by immunostaining and TF, prothrombin, and CRP transcripts were analyzed by real-time PCR. DM patients had elevated plasma CRP (9.2 [0.74–51.9] mg/l vs. 4.7 [0.59–23.14] mg/l, p = 0.009) and TF (293.06 [192.32–386.12] pg/ml vs. 140 [104.17–177.76] pg/ml, p = 0.003) compared to non-DM patients. In DM group, TF−, TFPI−, and prothrombin expression within valves was not related to demographics, body mass index, and concomitant diseases, whereas increased expression related to DM was found for CRP on both protein (2.87 [0.5–9]% vs. 0.94 [0–4]%, p = 0.01) and transcript levels (1.3 ± 0.61 vs. 0.22 ± 0.43, p = 0.009). CRP-positive areas were positively correlated with mRNA TF (r = 0.84, p = 0.036). Diabetes mellitus is associated with enhanced inflammation within AS valves, measured by CRP expression, which may contribute to faster AS progression.

[OP.2D.04] PERIVASCULAR T REGULATORY CELLS AND ENDOTHELIAL DYSFUNCTION IN HUMAN ATHEROSCLEROSIS.

Objective: Atherosclerosis is an inflammatory disease associated with an imbalance between pro- and anti-inflammatory mechanisms. While ample evidence is available in animal models, less is known about links between local vascular inflammation in human disease. T regulatory cells (Treg) have been implicated in atherosclerosis in mice but links with human vascular inflammation are poorly understood. Accordingly, we aimed to investigate the relationship between T regs in peripheral blood and locally in perivascular adipose tissue (pVAT) with endothelial function as a key mechanism in pathogenesis of vascular disease. Design and method: Treg (CD3+/CD4+/CD25+/FoxP3+) infiltration was studied in pVAT of atherosclerotic coronary artery (CORO), non-atherosclerotic internal mammary artery (IMA), as well as subcutaneous AT and peripheral blood were quantified using flow cytometry from 50 CABG patients (38 M;12F;age 65y+/-1) with typical atherosclerosis risk factor profile. Vascular function was assessed in IMA segments ex vivo by isometric tension studies of vasorelaxations to acetylcholine and ROS production was measured in vascular segments with 5uM lucigenin enhanced chemiluminescence. Results: Treg infiltration was observed in both IMA and CORO, but was significantly higher in IMA pVAT than in pVAT surrounding CORO (13,58 ± 15,6 vs. 4,74 ± 6,2 cells/mg; p < 0,01). Moreover, there was a significant correlation between these two AT depots suggesting systemic pVAT regulation (R = +0,53; p = 0,001). Indeed we observed a significant correlation between number of risk factors for atherosclerosis and Treg content (Rs = +0,33 p = 0,02). Importantly, there was an inverse correlation between Treg content in peripheral blood and Ach-induced vasorelaxations (R = -0,31 p < 0,05). Local T reg infiltration in pVAT was significantly correlated with indices of NO production, as measured by chemiluminescence (R = +0,58 p = 0,007). However, NO produced was scavenged by ROS (measured by ratio of L-NAME enhanced/basal superoxide levels) and Treg infiltration in pVAT did not correlate with IMA endothelial function (R = -0.02 p = 0,92) or total vascular ROS production (R = -0,12 p = 0,53). Conclusions: Atherosclerosis is accompanied by local decrease in T regulatory cell content in atherosclerotic vs. non-atherosclerotic arteries, although their amount is linked with classical risk factors for atherosclerosis. Higher peripheral blood T regs are associated with better endothelial function, although it is not achieved through locally infiltrating Tregs.

A comparison of aortic root measurements by echocardiography and computed tomography

Objectives The aim of the study is to evaluate an optimal way to assess the dimensions of the aortic root and each of the sinuses of Valsalva and examine how a single measurement in 1 plane (echocardiography or 2‐dimensional computed tomography) can underestimate the maximum dimension of the aortic root. Methods Computed tomography and transthoracic echocardiography images of the aortic root and ascending aorta of 112 patients were analyzed. The minimum and maximum aortic root dimensions, the root perimeter, and the total area of all 3 sinuses of Valsalva were measured on a plane perpendicular to the long axis of the aorta using 3‐dimensional multiplanar reconstruction. Moreover, the maximum root dimension was compared with the measurements obtained from the echocardiography and 2‐dimensional computed tomography angiography measurements. Results The difference in the measurements of the minimum and maximum root dimension was 5.4 ± 3.2 mm (range, 0‐21 mm, P < .0001) and was significantly larger in patients with bicuspid aortic valves compared with those with tricuspid valves (6.3 ± 4 mm, range, 0‐21 mm vs 4.9 ± 2.6 mm, range, 0‐15 mm, P = .036). The maximum root dimension measured in 3‐dimensional multiplanar reconstruction (49.1 ± 9.0 mm) differed significantly from the root dimension measured in transthoracic echocardiography in the parasternal long‐axis view (44.8 ± 8.4 mm) and 2‐dimensional computed tomography (axial plane: 45.5 ± 9.0 mm, coronal plane: 46.1 ± 8.8 mm, sagittal plane: 45.1 ± 8.9 mm) (P < .001). Conclusions The difference in the measurements of the minimum and maximum aortic root dimensions is significant and may exceed 20 mm, especially in patients with bicuspid aortic valves. Therefore, aortic root dimensions can be significantly underestimated with the measurement (echocardiography, computed tomography angiography) performed in only 1 plane.

Patient-prosthesis mismatch after minimally invasive aortic valve replacement

1Department of Cardiovascular Surgery and Transplantology, Jagiellonian University and John Paul II Hospital, Krakow, Poland 2Department of Pharmacology, Jagiellonian University, Krakow, Poland 3Department of Physiology, Jagiellonian University, Krakow, Poland 4Department of Cardiac and Vascular Surgery, Medical University of Gdansk, Gdansk, Poland 5CardioVascular Centre Frankfurt, Germany and Swedish Medical Centre Seattle, United States *Grzegorz Filip and Radoslaw Litwinowicz are first authors of this manuscript and have contributed equally to the content of this paper.

Applications of low-cost 3D printing in left atrial appendage closure using epicardial approaches – initial clinical experience

Introduction Left atrial appendage occlusion procedure (LAAO) became an alternative method for stroke prevention in atrial fibrillation (AF) patients with contraindication or intolerance for oral anticoagulation therapy. However, LAA anatomy is complex with several different types of LAA morphology. Therefore matching the correct size of a delivery device to LAA morphology is difficult. In such circumstances, the 3D-printed model of LAA closure may be useful for preoperative planning which increases the efficacy of LAAO procedure. Material and methods We report as a first 2 cases of LAA occlusion procedure using 2 different systems: thoracoscopic AtriClip and the LARIAT device in which a 3D printed LAA model was used in preoperative planning. Results In the first patient, preoperative measurements of 3D LAA model were performed using a dedicated selection guide for AtriClip device were comparable with the intraoperative examination. Left atrial appendage was closed epicardial using 40 mm size AtriClip. In second patients, LAA closure was performed completely percutaneously using LARIAT device. For better visualization of LAA shape on fluoroscopy and TEE examination, intraoperatively sterilized 3D LAA model was used during the procedure. In both cases, intraoperative TEE examination confirmed complete LAA closure with no leak. Conclusions Left atrial appendage 3D model is a useful tool in preoperative planning of a left atrial appendage occlusion using epicardial approaches with thoracoscopic or percutaneous access using LARIAT device. The quality of low-cost 3D printed LAA model is sufficient in planning minimally invasive procedure.

Plasma fibrin clot properties affect blood loss after surgical aortic valve replacement for aortic stenosis

OBJECTIVES Cardiac surgery is associated with elevated bleeding risk. We sought to study whether fibrin clot phenotype influences postoperative blood loss after surgery for aortic stenosis (AS). METHODS We studied 77 isolated AS patients, including 62 who underwent aortic valve replacement and 15 who underwent the Bentall procedure due to post-stenotic aortic dilation. Plasma clot properties, including the tPA-induced clot lysis time (CLT) and clot permeability (Ks), along with fibrinolysis inhibitors, a calibrated automated thrombogram and platelet activation markers, were assessed preoperatively. RESULTS In the whole AS group, the median chest tube output after 12 h was 360 ml (range of 110-2290 ml). Patients with drainage in the top quartile after 12 h (≥600 ml) had lower fibrinogen, shorter CLT, higher Ks, lower plasma plasminogen activator inhibitor-1 antigen, peak thrombin generation and β-thromboglobulin levels than those in the lowest drainage quartile (≤260 ml) with no difference in platelets or von Willebrand factor. A multivariable model that was built after the exclusion of Bentall patients, adjusted for age, sex, body mass index and fibrinogen, showed that high drainage, which was defined as the top quartile after 12 h postaortic valve replacement (≥460 ml), was predicted by β-thromboglobulin [odds ratio (OR) 0.94, 95% confidence interval (CI) 0.90-0.99, P = 0.03], fibrinogen (OR 0.13, 95% CI 0.00-0.47, P = 0.02) and the CLT (OR 0.95, 95% CI 0.91-0.99, P = 0.02). The CLT was inversely related to the number of transfused platelet units (r = -0.27, P = 0.04). CONCLUSIONS Fibrin clot susceptibility to lysis is a modulator of postoperative blood loss after cardiac surgery for AS, which may have practical implications.

Hyperbaric Oxygen Therapy in Treating a Poorly Healing Wound Following Cardiac Surgery in a Patient with Congenital Connective Tissue Defect – Case Report

Abstract We hereby present the case of a female patient with recurrent aortic aneurysms. In order to treat aneurysms of the ascending aorta, aortic arch and aneurysms of the aortic arch branches, the debranching procedure was used. Following the surgery, a deep sternal wound infection occurred characterised by impaired healing. The infection was treated with targeted antibiotic therapy and hyperbaric oxygen therapy.

Use of dressing with human fibrin and thrombin during resection of a right atrial angiosarcoma.

Primary malignant cardiac tumors are rare and are usually detected at an advanced stage of disease. Their location and infiltration often hinder surgical resection. Tissue sarcomas, especially angiosarcomas, are composed of irregular and delicate vascular tissue. The resection of such tumors from the heart is associated with a high risk of life-threatening bleeding that cannot be stopped with traditional surgical methods. We present a case report of the application of a dressing containing human fibrin and thrombin in order to prevent bleeding during the partial resection of advanced cardiac angiosarcoma in a 40-year-old patient.