Paweł Matusik

Targeting NADPH oxidases in vascular pharmacology

Oxidative stress is a molecular dysregulation in reactive oxygen species (ROS) metabolism, which plays a key role in the pathogenesis of atherosclerosis, vascular inflammation and endothelial dysfunction. It is characterized by a loss of nitric oxide (NO) bioavailability. Large clinical trials such as HOPE and HPS have not shown a clinical benefit of antioxidant vitamin C or vitamin E treatment, putting into question the role of oxidative stress in cardiovascular disease. A change in the understanding of the molecular nature of oxidative stress has been driven by the results of these trials. Oxidative stress is no longer perceived as a simple imbalance between the production and scavenging of ROS, but as a dysfunction of enzymes involved in ROS production. NADPH oxidases are at the center of these events, underlying the dysfunction of other oxidases including eNOS uncoupling, xanthine oxidase and mitochondrial dysfunction. Thus NADPH oxidases are important therapeutic targets. Indeed, HMG-CoA reductase inhibitors (statins) as well as drugs interfering with the renin-angiotensin-aldosterone system inhibit NADPH oxidase activation and expression. Angiotensin-converting enzyme (ACE) inhibitors, AT1 receptor antagonists (sartans) and aliskiren, as well as spironolactone or eplerenone, have been discussed. Molecular aspects of NADPH oxidase regulation must be considered, while thinking about novel pharmacological targeting of this family of enzymes consisting of several homologs Nox1, Nox2, Nox3, Nox4 and Nox5 in humans. In order to properly design trials of antioxidant therapies, we must develop reliable techniques for the assessment of local and systemic oxidative stress. Classical antioxidants could be combined with novel oxidase inhibitors. In this review, we discuss NADPH oxidase inhibitors such as VAS2870, VAS3947, GK-136901, S17834 or plumbagin. Therefore, our efforts must focus on generating small molecular weight inhibitors of NADPH oxidases, allowing the selective inhibition of dysfunctional NADPH oxidase homologs. This appears to be the most reasonable approach, potentially much more efficient than non-selective scavenging of all ROS by the administration of antioxidants.

Severe frailty and cognitive impairment are related to higher mortality in 12-month follow-up of nursing home residents.

Frailty syndrome (FS) and cognitive impairment are associated with an increased risk of falls, disability, hospitalization and death. We investigated prognostic meaning of FS and cognitive impairment in persons ≥ 65 years, living in 2 nursing homes. Information about the health status of patients was gathered from history, medical documentation, test assessing FS, according to the Canadian Study of Health and Aging-Clinical Frailty Scale (CSHA-CFS) and the Mini-Mental State Examination (MMSE). The study group included 66 women and 20 men, between 66 and 101 years of age (mean ± S.D.=83.8 ± 8.3 years). The frequency of severe frailty (CSHA-CFS=7) among the elderly living in nursing homes was 34.9%, while severe cognitive impairment (MMSE<18) was present in 55.8%. Residents with severe FS and MMSE<18 consisted 33.7% of examined and 50.0% of those who died during 12-month follow-up, p<0.05. Individuals with severe FS and severe cognitive impairment (n=29) as compared to all other patients, were significantly less probable (59% vs. 79%, p=0.03) to survive one year. Neither frailty, nor dementia, nor severe FS or cognitive impairment when considered separately was associated with higher mortality rate. The risk assessment in severely disabled geriatric patients is best performed with measures of functional and cognitive function considered jointly, but not separately.

Do we know enough about the immune pathogenesis of acute coronary syndromes to improve clinical practice

Morbidities related to atherosclerosis, such as acute coronary syndromes (ACS) including unstable angina and myocardial infarction, remain leading causes of mortality. Unstable plaques are inflamed and infiltrated with macrophages and T lymphocytes. Activated dendritic cells interact with T cells, yielding predominantly Th1 responses involving interferon-gamma (IFN-γ) and tumour necrosis factor-alpha (TNF-α), while the role of interleukin 17 (IL-17) is questionable. The expansion of CD28nullCD4 or CD8 T cells as well as pattern recognition receptors activation (especially Toll-like receptors; TLR2 and TLR4) is characteristic for unstable plaque. Inflammation modifies platelet and fibrin clot characteristics, which are critical for ACS. Understanding of the inflammatory mechanisms of atherothrombosis, bridging inflammation, oxidative stress and immune regulation, will allow for the detection of subjects at risk, through the use of novel biomarkers and imaging techniques including intravascular ultrasound, molecular targeting, magnetic resonance imaging (MRI) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET). Moreover, understanding the specific inflammatory pathways of plaque rupture and atherothrombosis may allow for immunomodulation of ACS. Statins and anti-platelet drugs are anti-inflammatory, but importance of immune events in ACS warrants the introduction of novel, specific treatments directed either on cytokines, TLRs or inflammasomes. While the prime time for the introduction of immunologically inspired diagnostic tests and treatments for atherosclerosis have not come yet, we are closer than ever before to finally being able to benefit from this vast body of experimental and clinical evidence. This paper provides a comprehensive review of the role of the immune system and inflammation in ACS.

Architecture of intraluminal thrombus removed from abdominal aortic aneurysm

Little is known about architecture of intraluminal thrombus (ILT) in abdominal aortic aneurysm (AAA). We present a 74-year-old woman with AAA and high cardiovascular risk. Scanning electron microscopy of ILT removed during surgery showed that its luminal layer is relatively rich in fibrin fibers forming irregular compact structure with low amounts of erythrocytes and platelets, while abluminal portion is composed of densely packed fibrin with caniculi. The structure of ILT may differ largely among AAA patients contrary to previous findings and may reveal large dense fibrin-rich areas deprived of cells, which impair fibrinolysis and stabilize the thrombus size.

Age-related gap in the management of heart failure patients. The National Project of Prevention and Treatment of Cardiovascular Diseases--POLKARD.

BACKGROUND Heart failure (HF) is strongly associated with aging. It affects 10-12% of patients older than 80 years, with five-year overall mortality after first hospitalization for HF being as high as 81%. The main objective of this study was to assess the diagnosis and treatment of HF in hospitalized octogenarians compared to younger subjects. METHODS The survey was performed among a random sample of all Polish hospitals and in all academic centers, as part of the National Project of Prevention and Treatment of Cardiovascular Diseases in Poland -- POLKARD. Using a questionnaire-based method, hospital documentation of the last five patients with diagnosed HF was reviewed. Eventually, in 2005, HF patients of 259 internal medicine and cardiology hospital wards, including 260 very elderly patients, were selected to the study. RESULTS The mean age of the 1,289 studied patients was 69.8 ± 11.4 years (age range: 26-96 years), 57.8% were males, and 80.1% were in NYHA class III or IV. Echocardiography was performed in 41.7% of octogenarians in comparison with 58.7% of those categorized as younger elderly, i.e. 60-79 years, and 75.2% of patients aged below 60 years (p < 0.0001). The most prescribed drugs in very elderly patients were diuretics (86.9%, p = 0.005) and ACE-I (81.9%), while only 61.5% used beta-blockers (p < 0.0001). In stepwise logistic regression analysis, hypertension, history of myocardial infarction and admission to cardiology ward were positively associated with beta-blocker and ACE-I (or ARB) therapy, while older age and pulmonary diseases (COPD or asthma) were related to their non-prescription. CONCLUSIONS Despite significant progress in HF management, there is still a need for an improvement in the medical care of very elderly patients. The major obstacles seem to be advanced age and the presence of coexistent pulmonary diseases. Therefore, the participation of geriatricians and pulmonologists should be recommended in caring for octogenarians with HF.

Systemic T Cells and Monocyte Characteristics in Patients with Denture Stomatitis.

PURPOSE Chronic inflammatory disorders of the oral cavity, such as periodontitis, were recently linked to systemic immune activation. Since fungal oral infections have not yet been studied in this respect, the aim of our study is to determine whether the local inflammation caused by oral fungal infection of the palatal tissue (denture stomatitis-DS) is associated with the systemic inflammatory response. This question is becoming essential as the population ages. MATERIALS AND METHODS Peripheral blood of DS patients (n = 20) and control patients (n = 24) was assessed with flow cytometry to determine lymphocyte and monocyte profiles. Intracellular cytometric analysis was carried out to establish cytokine production by T cells. DS was diagnosed based on clinical symptoms of DS such as swelling and redness of oral mucosa, confirmed by microbiological swabs for fungal colonization with Candida species. The control group was recruited from denture users without clinical and microbiological signs of oral infections. RESULTS Percentages of peripheral lymphocytes, T cells, monocytes, and their subpopulations were similar in both studied groups. The exception was median percentages of CD25+ T cell subsets, which were significantly lower in DS patients than in control subjects. This reduction was observed in both CD4 T cell subset (16.7% and 28.1%; p = 0.0006) and CD8 T cell subset (4.6% and 7.0%; p = 0.007) CONCLUSIONS: While DS and associated local fungal infection do not overtly affect activation of monocytes or lymphocytes, the number of CD 25+ T cells is significantly lower in the DS patients, possibly indicating limited potential for the infection clearance in denture-using aging patients.

Elevated NT-proBNP is associated with unfavorably altered plasma fibrin clot properties in atrial fibrillation

BACKGROUND Dense fibrin clot formation and hypofibrinolysis have been reported in atrial fibrillation (AF). It is unclear which factors affect fibrin clot properties in AF. METHODS AND RESULTS We investigated plasma fibrin clot permeability (Ks), clot lysis time (CLT), endogenous thrombin potential (ETP) as well as other coagulation and fibrinolysis parameters along with N-terminal pro-B-type natriuretic peptide (NT-proBNP) in 160 AF patients (median age, 70.5years). Previous stroke (n=15; 9.4%) was associated with decreased Ks (P=0.04) and longer CLT (P=0.005), together with higher antiplasmin (P=0.03) and lower tissue-type plasminogen activator (P=0.01). Lower Ks (P=0.04) and tendency towards longer CLT (P=0.10) were observed in patients with a left atrium diameter>40mm. Patients with a CHA2DS2-VASc score of 3 or more (82.5%) were characterized by higher thrombin-activatable fibrinolysis inhibitor antigen (P=0.009). Ks was inversely correlated with log NT-proBNP (r=-0.34, P<0.0001), plasminogen activator inhibitor-1 (PAI-1) antigen (r=-0.24, P=0.002) and C-reactive protein (r=-0.18, P=0.02), while CLT was positively correlated with log NT-proBNP (R=0.61, P<0.0001) and ETP (r=0.37, P<0.0001), which were interrelated (r=0.59, P<0.0001). After adjustment for potential confounders, PAI-1 (odds ratio [OR]: 1.14; 95% confidence interval [CI]: 1.02-1.26) was the only independent predictor of low Ks (the lowest quartile,≤6×10-9cm2), while NT-proBNP (OR: 1.21; 95% CI: 1.12-1.31) and PAI-1 (OR: 1.30; 95% CI: 1.12-1.51) both predicted prolonged CLT (the top quartile,≥109min). CONCLUSION In AF patients prothrombotic fibrin clot properties assessed ex vivo are determined by PAI-1 and NT-proBNP and this phenotype is associated with prior ischemic stroke.

Atrioventricular synchrony in the background of ventricular noise and undersensing

The 24‐hr electrocardiogram (ECG) interpretation in patients with double‐chamber pacemakers may be challenging. The difficulty increases if not well‐known pacemaker algorithm and device malfunction coexist. We show atrial synchronization pace (ASP) in a patient with ventricular lead damage. We provide detailed description of electrocardiogram and intracardiac electrogram. ASP may confuse 24‐hr ECG monitoring interpretation, especially in patients with ventricular lead dysfunction.

Analysis of electrical lead failures in patients referred for transvenous lead extraction procedures

We evaluated the influences of selected factors on electrical lead failure (ELF) occurrence in patients referred for transvenous lead extraction (TLE) procedures.

Association of cardiac troponin I with prothrombotic alterations in atrial fibrillation

INTRODUCTION Atrial fibrillation (AF) increases the risk of stroke and systemic thromboembolism. A hypercoagulable state in AF is reflected by elevated von Willebrand factor (vWF), D-dimer, and thrombin generation (TG), as well as increased platelet activation [1]. The usefulness of several biomarkers in stroke and bleeding risk prediction among AF patients, in particular N-terminal pro–B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I (cTnI-hs), has been demonstrated, although practical implications of this strategy are uncertain [2]. We sought to assess the relations of four such markers: cTnI-hs, cystatin C, vWF, and NT-proBNP, with prothrombotic alterations in AF patients.