Grzegorz Grudzień

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.

Impaired fibrinolysis is associated with the severity of aortic stenosis in humans

A role of fibrinolysis in the pathogenesis of aortic valve stenosis (AS) is unknown, although fibrinolytic proteins have been detected in aortic stenotic valves.

Lipoprotein-associated phospholipase A2 is elevated in patients with severe aortic valve stenosis without clinically overt atherosclerosis.

Abstract Background: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an inflammatory mediator involved in atherosclerosis. Since aortic valve stenosis (AVS) is regarded as an atherosclerosis-like inflammatory disease, we sought to investigate whether AVS is associated with elevated Lp-PLA2. Methods: Plasma Lp-PLA2 levels were determined in 48 consecutive patients with severe AVS without atherosclerotic vascular disease and compared with the values obtained in 48 controls matched for age, sex and cardiovascular risk factors. Results: Lp-PLA2 was higher in AVS than in controls (242.3±50.4 vs. 151.9±28.1 ng/mL, p<0.0001). Lp-PLA2 correlated inversely with aortic valve area (AVA) (r=–0.53; p=0.0001) and positively with mean pressure gradient (PG) (r=0.32; p=0.029). In multivariable analysis C-reactive protein (CRP) (OR=1.42; 95% CI 0.95–2.1; p=0.09) and AVA (OR=0.003; 95% CI 0.00004–0.23; p<0.01) were independently associated with Lp-PLA2 above a mean of 242 ng/mL. After adjustment for CRP, AVA was the only independent predictor of Lp-PLA2 in AVS patients (p<0.001). Conclusions: This study is the first to show that AVS is characterized by increased plasma Lp-PLA2 levels associated with the severity of AVS, which suggests active involvement of Lp-PLA2 in the pathogenesis of AVS.

Factor XIII expression within aortic valves and its plasma activity in patients with aortic stenosis: association with severity of disease

Aortic valve stenosis (AS) shares several similarities with atherosclerosis. Factor XIII (FXIII) has been detected within atherosclerotic plaques and may contribute to the development of atherosclerosis via multiple mechanisms. In the current study, we sought to investigate FXIII expression within human stenotic aortic valves and its association with severity of the disease. We prospectively enrolled 91 consecutive patients with AS scheduled for isolated valve replacement. Valvular FXIII subunit A (FXIII-A), fibrin and macrophages expression was evaluated by immunostaining. FXIII-A subunit transcripts and FXIII-A Val34Leu polymorphism was determined by real-time PCR. Plasma FXIII (pFXIII) activity was measured. We demonstrated that the valvular FXIII-A was predominantly expressed on the aortic side of leaflets, colocalized with alternatively activated macrophages (AAM). Areas stained for FXIII-A showed positive correlations with valvular fibrin presence, degree of calcification, pFXIII activity and the severity of AS, reflected by mean and maximum transvalvular gradients (all, p<0.001). The FXIII-A mRNA in the stenotic leaflets was significantly elevated compared to control leaflets. Interestingly, pFXIII activity was also positively correlated with mean (p<0.001) and maximum (p=0.001) transvalvular gradient. The FXIII-A Val34Leu polymorphism did not affect FXIII-A and fibrin expression in AS valves. In conclusion, the study is the first to show abundant expression of FXIII-A at the mRNA and protein levels within human stenotic aortic valves, which is associated with the severity of AS. Our findings might suggest that FXIII in the stenotic valves is presented in AAM and may be involved in the AS progression.

Respiratory System Function in Patients after Aortic Valve Replacement through Right Anterior Minithoracotomy

Background The aim of the study was to analyze respiratory system function after minimally invasive aortic valve replacement through right anterior minithoracotomy (RAT‐AVR). Methods An observational study of 187 patients electively scheduled for RAT‐AVR between January 2010 and December 2013. Pulmonary complications were analyzed and spirometry examinations were performed preoperatively, 1 week, 1 month, and 3 months after surgery. Results Hospital mortality was 1.1%. A double‐lumen intratracheal tube was used in 88.2% and single‐lumen intratracheal tube was used in 11.8% of patients. Pulmonary complications occurred in 10.8% of the patients. Prolonged (>24 hours) mechanical ventilation time was present in five patients (2.7%). The reasons were stroke (n = 1), perioperative myocardial infarction (n = 2), and pneumothorax (n = 2). Right pleural effusion, which occurred in 7.7% (n = 14) of patients, was the most frequent respiratory system complication. One week after surgery, the spirometry parameters decreased in comparison to the preoperative period, then after 3 months statistically significant improvement occurred; however, the spirometry parameters still had not returned to preoperative values. Multivariable median regression analysis shows that the presence of chronic obstructive pulmonary disease and pulmonary complications were associated with lower values of forced expiratory volume in 1 second after surgery. There was no statistically significant difference regarding spirometry values or incidence of pulmonary complications after surgery between patients in whom single‐lung or double‐lung ventilation was applied. Conclusion Pulmonary functional status measured with spirometry parameters was diminished after RAT‐AVR surgery. Single‐lung ventilation did not result in a higher rate of respiratory complications after RAT‐AVR surgery.

Hyperbaric oxygen therapy as additional treatment in deep sternal wound infections – a single center’s experience

Introduction Deep sternal wound infection (DSWI) is one of the most serious complications after cardiac surgery procedures, observed in 5% of patients. Current standard medical therapy for DSWI includes antibiotics, surgical debridement, resuturing or negative pressure wound therapy (NPWT). Unfortunately, in some cases these methods are insufficient, and additional therapeutic options are needed. Aim To assess the effects and usefulness of additional hyperbaric oxygen therapy (HBO2) in patients with DSWI after cardiac surgery procedures. Material and methods A retrospective analysis of 10 patients after cardiac surgery who developed DSWI in the period 2010–2012 was performed. After 3 months of ineffective conventional therapy including targeted antibiotic, surgical sternal debridement and NPWT, patients were qualified for additional HBO2 therapy. A total of 20 sessions of HBO2 therapy were performed, each 92 minutes long. Results After 4 weeks of HBO2 treatment, 7 patients presented complete wound healing with fibrous scar formation. One patient was qualified for the another cycle of HBO2 therapy with 20 additional sessions, and complete wound healing was observed. In 2 cases, after 5 and 19 sessions, HBO2 was interrupted because of improper qualifications. Conclusions The HBO2 as an additional therapy in DSWI was successful in 80% of cases, and no complications were observed. However, due to the small number of published studies with a small number of patients, randomized, clinical trials are needed to assess the clinical results of HBO2 in DSWI after cardiac surgery procedures.

Perioperative Outcomes of Minimally Invasive Aortic Valve Replacement through Right Anterior Minithoracotomy

Background The aim of the study was to analyze perioperative outcomes after minimally invasive aortic valve replacement through right anterior minithoracotomy (RAT-AVR). Patient selection criteria, anesthesia protocol, and surgical technique are presented. Methods A retrospective analysis of 194 patients electively scheduled for RAT-AVR was performed between January 2009 and June 2013. For preoperative planning, computed tomography was performed. Results Among studied patients, there were 48.5% females and 51.5% males with a mean age of 69.9 ± 9.2 years. The predicted mortality calculated with EuroSCORE II was 3.2 ± 0.9%, and observed mortality of RAT-AVR patients was 1.5%. Finally, RAT-AVR surgery was performed on 97.9% of patients (n = 190). Reasons for conversions to median sternotomy were bleeding from aortotomy site (n = 4) and from the right ventricle after epicardial pacing wire placement (n = 1), pleural adhesions (n = 2), and ascending aorta hidden under the sternum (n = 2). The second intercostal space was chosen for surgical access in 97.9% of patients.There were 3.6% reoperations for bleeding: aortotomy place (n = 1), epicardial pacing wire placement (n = 3), right lung tear (n = 2), and intercostal vessels (n = 1). The intensive care unit and hospital length of stays were 1.3 ± 1.2 and 5.7 ± 1.4 days, respectively. Strokes were present in 1.5% of patients. The perioperative complications rate diminished with time, occurring in 44.9% of the patients between 2009 and 2010 and in 15.6% of patients in 2013. Conclusions RAT-AVR can be safely performed without increased morbidity and mortality. Reduced complication rates over time reflect a learning curve.