Jerzy Dropiński

Early antithrombotic and anti-inflammatory effects of simvastatin versus fenofibrate in patients with hypercholesterolemia

The aim of the study was to determine whether a short-term treatment with simvastatin or fenofibrate may result in beneficial anti-inflammatory and antithrombotic effects in patients with high risk of coronary artery disease. In a randomized, double-blind study, we compared markers of inflammation, thrombin formation and platelet activation in patients with LDL cholesterol >130 mg/dl assigned to receive simvastatin (40 mg/d; n=20) or micronised fenofibrate (160 mg/d; n=22) for 28 days. Simvastatin, but not fenofibrate, lowered C-reactive protein (CRP) by 32% on day 3 (p<0.001), while both drugs reduced CRP significantly on day 28. Interleukin-6, soluble CD40 ligand, and monocyte chemoattractant protein-1 levels decreased significantly (by 20 to 50%) in both treatment groups on days 3 and 28. Soluble cell adhesion molecules remained unchanged in both groups. Simvastatin and fenofibrate significantly lowered plasma concentrations of thrombin-antithrombin complexes on days 3 and 28, but not platelet beta-thromboglobulin (betaTG) levels. Soluble P-selectin was lowered only in the simvastatin group. The total amount of thrombin generated at the site of microvascular injury also declined (by about 30%) as early as after 3 days of fenofibrate or simvastatin therapy, whereas beta TG release was reduced only in the simvastatin group on days 3 and 28. All the effects were independent of the changes in lipid profiles. Our results suggest that statins and fibrates can exert antithrombotic and anti-inflammatory effects as early as after 3 days of therapy. However, in contrast to statins, fibrates have no influence on platelet function within one month of therapy.

The additive antiplatelet action of clopidogrel in patients with coronary artery disease treated with aspirin

We searched for additional anti-platelet effects of clopidogrel in coronary artery disease (CAD) patients treated with aspirin. Response to clopidogrel was also stratified according to aspirin resistance. Out of 76 screened aspirin-treated CAD male patients, five were aspirin-resistant based on arachidonic acid (AA) and ADP aggregometry. These five patients and 15 aspirin-sensitive patients entered the proper study. Platelet function was assessed at baseline and after one week of additional clopidogrel treatment using aggregometry, flow cytometry (ADP, TRAP-6) and platelet reactivity index (PRI) based on VASP (vasodilatorstimulated phosphoprotein) expression. We evaluated the same markers in 15 healthy men after aspirin treatment. In healthy subjects aspirin did not affect resting or ADP-induced activated GPIIb/IIIa and P-selectin expression. The P-selectin expression on ADP-activated platelets was increased (p < 0.01) in aspirin treated ASA-resistant CAD patients as compared to ASA-sensitive group or aspirin-treated healthy subjects. Clopidogrel significantly decreased ADP and AA-induced platelet aggregation and overcame aspirin resistance in four of five patients. Expression of ADP-induced activation markers was significantly lowered after clopidogrel in all patients. Out of 20 patients, five did not respond to clopidogrel (<10% inhibition of ADP aggregation), and this group showed no change in expression of ADP-induced activation markers after clopidogrel. Clopidogrel treatment significantly reduced PRI only in the clopidogrel-sensitive group. In conclusion, the addition of clopidogrel to aspirin provides greater inhibition of platelets and can overcome aspirin resistance. Flow cytometric analysis of platelets is useful for monitoring of clopidogrel therapy.

Anti-thrombotic action of clopidogrel and PlA1/A2 polymorphism of ß3 integrin in patients with coronary artery disease not being treated with aspirin

Individual variability in response to clopidogrel is known but its mechanism is poorly understood. We examined the relationship between glycoprotein IIIa polymorphism P1(A1/A2) and anti-thrombotic actions of clopidogrel. Clopidogrel (75 mg/d; 2 weeks) was administered to 48 normolipemic patients with coronary artery disease. Bleeding time, thrombin generation at the site of microvascular injury, platelet function under high shear, using PFA-100 with ADP cartridge, and platelet surface activation markers (P-selectin and fibrinogen binding sites on GPIIb/IIIa complex detected by PAC-1 antibody), were studied both before and after clopidogrel treatment. Both unstimulated and low-dose (0.02 microM and 1 microM) in vitro ADP-stimulated platelets were examined. GP IIIa polymorphism was assessed by polymerase chain reaction and restriction fragment length polymorphism analysis. We identified 32 P1(A1/A1) homozygotes, 15 P1(A1/A2 heterozygotes and one P1(A2/A2) homozygote. Clopidogrel significantly prolonged bleeding time in all subjects, but this effect was greater in P1(A2 carriers (p < 0.01). Furthermore, clopidogrel only depressed thrombin generation at the site of microvascular injury (p < 0.01) in P1(A2) patients and prolonged closure time measured in vitro by PFA-100 (p < 0.05). At baseline spontaneous expression of PAC-1 and P-selectin was higher in P1(A2) subjects as compared to P1(A1) homozygotes (p < 0.05 for both antigens). Clopidogrel lowered the expression of both markers affecting more P1(A2) carriers, so that the difference in binding PAC-1 antibody between platelets from P1(A1) and P1(A2) carriers disappeared, while the difference in P-selectin expression slightly diminished. Anti-thrombotic effects of clopidogrel are more pronounced in CAD patients carrying the P1(A2) allele than in P1(A1) homozygotes.

Influence of leukotriene biosynthesis inhibition on heart rate in patients with atrial fibrillation

Atrialfibrillation (AF) is themost common cardiac arrhythmia. There is an increasing evidence linking systemic and/or local inflammation to AF pathogenesis [1–3]. Leukotrienes (LT) are potent proinflammatory mediators produced via 5-lipoxygenase (5-LO) pathway of arachidonic acid. Both experimental [4,5] and clinical [6,7] data point to their role in cardiac pathology. Our recent results [8] indicate that pharmacological inhibition of LT biosynthesis is associatedwith decrease in the heart rate and enhanced heart rate variability in patients with stable angina pectoris undergoing elective coronary catheterization or angioplasty. This suggested to us that LT biosynthesis inhibition could be of potential interest in patients with AF. We studied49 subjects, recruited from103 consecutive patientswith permanent AF, hospitalized in the Department of Medicine. Exclusion criteria encompassed: age over 80 years, heart failure, asthma, acute or chronic inflammatory diseases, renal or liver insufficiency, hyperthyroidism and pacemaker implantation. The clinical characteristics of the patients are presented in Table 1. Informed written consent was obtained from all patients. The study protocol, that complied with the Helsinki Declaration, was approved by the local Ethics Committee. The participants underwent a single-blind, placebo-controlled study with the inhibitor of 5-lipoxygenase (zileuton; Zyflo, Cornerstone Therapeutics Inc., Cary, NC USA). The study lasted 2 days; placebo was administered on the first day (4×1 tablets/day) and zileuton – in its standard daily dosage (4×600 mg/day) – on the second day. Measurements of the urinary leukotriene E4 , considered to reflect global leukotriene production (uLTE4) (ELISA; Cayman Chemicals, Ann Arbor, MI, USA) were carried out twice; at base and after zileuton treatment. They were expressed as LTE4 pg/mg of creatinine [9]. 24-h, threechannel digital ECG Holter recordings (Aspel, HolCARD 24W, Poland) were performed in all patients on thefirst and the second study day. The mean values of 24-h heart rate (HR), the number of ventricular extrasystoles (VEs), ST-segment depression, as well as episodes of tachycardia, bradycardia and pauses were evaluated. Echocardiography was performed to assess left ventricular ejection fraction and left atrial area. Datawere analyzedusing StatSoft, Inc. STATISTICA software. Theyare presented as mean±SD or median with interquartile range and log transformed when applicable. For comparisons between groups,

Impaired cardiovascular autonomic nervous system function in patients with Churg–Strauss syndrome

Objectives: Although peripheral nervous system involvement in patients with Churg–Strauss syndrome (CSS) has been described, little is known about its autonomic part. Autonomic nervous system (ANS) function can be assessed by studying heart rate variability (HRV) and a decrease in the spectrum of HRV correlates with ANS impairment. Methods: Out of 24 CSS patients we chose 12 (four males, eight females, aged 40 ± 8.3 years) in disease remission and without cardiac involvement. Twelve age- and sex-matched healthy volunteers served as a control group. All underwent 24-h electrocardiogram (ECG) Holter recordings. HRV was calculated from 1-h segments, including: total power (TP), ultra-low frequency (ULF), very low frequency (VLF), low frequency (LF), and high frequency (HF) powers as well as normalized LF (LF%) and HF (HF%) powers and the LF to HF power ratio (LF/HF). Results: The CSS patients showed decreased HRV parameters in the 1-h domains: TP (2038 vs. 3622 ms2, p = 0.001), HF (561 vs. 1574 ms2, p < 0.001), LF (672 vs. 1050 ms2, p < 0.01), and VLF (544 vs. 738 ms2, p = 0.016). However, LF% and LF/HF ratio were markedly higher in CSS patients than in controls (53.4% vs. 39%, p < 0.001 and 1.1 vs. 0.64, p < 0.001), whereas HF% was lower in CSS than in controls (46.6% vs. 61%, p < 0.001). These results were independent of duration of the disease, eosinophil count, corticosteroids, or peripheral nerve involvement in the past. Conclusions: The CSS patients show impaired HRV parameters, indicating parasympathetic ANS dysfunction in addition to peripheral nervous system involvement.

Endothelial dysfunction in patients with eosinophilic granulomatosis with polyangiitis

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare form of vasculitis associated with asthma and eosinophilia. Endothelial dysfunction has been well documented in other types of vasculitis but not in EGPA. Thirty patients (10 men and 20 women) diagnosed with EGPA and remaining in a remission, and 58 controls (24 men and 34 women) matched for age, sex, and body mass index, were enrolled in the study. We assessed each participants for typical risk factors of cardiovascular diseases and measured serum levels of vascular cell adhesion molecule-1 (VCAM-1), interleukin 6 (IL-6), and thrombomodulin. We also measured flow-mediated dilatation (FMD) of the brachial artery and intima-media thickness (IMT) of the common carotid artery using ultrasonography. Patients with EGPA had 20% higher serum level of VCAM-1 (p < 0.001) and 41.9% of thrombomodulin (p < 0.001). They also had 38.8% lower relative increase of FMD (FMD%) (p < 0.001), indicating endothelial dysfunction. These differences remained significant also after adjustment for potential confounders. Laboratory and ultrasonographic parameters of endothelial injury were correlated to the markers of inflammation and impaired kidney function. Determinants of lower FMD% in a simple regression model were pack-years of smoking (β = − 0.3 [95% confidence interval (CI) − 0.5 to − 0.1]), serum level of IL-6 (β = − 0.36 [95% CI − 0.62 to − 0.1]), and thrombomodulin (β = − 0.34 [95% CI − 0.6 to − 0.08]). EGPA patients are characterized by inflammatory endothelial injury that is likely related to the pathogenesis of the disease. Proper immunosuppressive treatment is the best method to prevent atherosclerosis and future cardiovascular events, the patients may also benefit from additional preventive interventions.