Wiesława Piwowarska

Intracoronary infusion of bone marrow-derived selected CD34+CXCR4+ cells and non-selected mononuclear cells in patients with acute STEMI and reduced left ventricular ejection fraction: results of randomized, multicentre Myocardial Regeneration by Intracoronary Infusion of Selected Population of Stem Cells in Acute Myocardial Infarction (REGENT) Trial

AIMS Comparison of intracoronary infusion of bone marrow (BM)-derived unselected mononuclear cells (UNSEL) and selected CD34(+)CXCR4(+) cells (SEL) in patients with acute myocardial infarction (AMI) and reduced <40% left ventricular ejection fraction (LVEF). METHODS AND RESULTS Two hundred patients were randomized to intracoronary infusion of UNSEL (n = 80) or SEL (n = 80) BM cells or to the control (CTRL) group without BM cell treatment. Primary endpoint: change of LVEF and volumes measured by magnetic resonance imaging before and 6 months after the procedure. After 6 months, LVEF increased by 3% (P = 0.01) in patients treated with UNSEL, 3% in patients receiving SEL (P = 0.04) and remained unchanged in CTRL group (P = 0.73). There were no significant differences in absolute changes of LVEF between the groups. Absolute changes of left ventricular end-systolic volume and left ventricular end-diastolic volume were not significantly different in all groups. Significant increase of LVEF was observed only in patients treated with BM cells who had baseline LVEF < median (37%). Baseline LVEF < median and time from the onset of symptoms to primary percutaneous coronary intervention > or = median were predictors of LVEF improvement in patients receiving BM cells. There were no differences in major cardiovascular event (death, re-infarction, stroke, target vessel revascularization) between groups. CONCLUSION In patients with AMI and impaired LVEF, treatment with BM cells does not lead to a significant improvement of LVEF or volumes. There was however a trend in favour of cell therapy in patients with most severely impaired LVEF and longer delay between the symptoms and revascularization.

Effects of Polyunsaturated Omega-3 Fatty Acids on Responsiveness to Dual Antiplatelet Therapy in Patients Undergoing Percutaneous Coronary Intervention: The OMEGA-PCI (OMEGA-3 Fatty Acids After PCI to Modify Responsiveness to Dual Antiplatelet Therapy) Study

OBJECTIVES The purpose of this study was to investigate whether omega-3 polyunsaturated fatty acids (PUFAs) are able to modify platelet responsiveness to dual antiplatelet therapy in stable coronary artery disease patients undergoing percutaneous coronary intervention (PCI). BACKGROUND Although previous studies have suggested antiplatelet properties of omega-3 polyunsaturated fatty acids, it is unknown whether they can enhance platelet inhibition on standard aspirin and clopidogrel treatment. METHODS The OMEGA-PCI (OMEGA-3 Fatty Acids After PCI to Modify Responsiveness to Dual Antiplatelet Therapy) study was an investigator-initiated, prospective, single-center, double-blind, placebo-controlled, randomized study. Patients receiving standard dual antiplatelet therapy (aspirin 75 mg/day and clopidogrel 600 mg loading dose followed by 75 mg/day) were randomly assigned to receive the addition of 1 g of omega-3 ethyl esters (n = 33) or placebo (n = 30) for 1 month. Platelet function was measured serially by light transmission aggregometry (adenosine diphosphate and arachidonic acid [AA] were used as agonists) and assessment of the phosphorylation status of the vasodilator-stimulated phosphoprotein at baseline, 12 h, 3 to 5 days, and 30 days after randomization. RESULTS The P2Y(12) reactivity index was significantly lower, by 22.2%, after 1 month of treatment with omega-3 polyunsaturated fatty acids compared with placebo when used in addition to dual antiplatelet therapy (p = 0.020). Maximal platelet aggregation induced by 5 and 20 micromol/l adenosine diphosphate was lower by 13.3% (p = 0.026) and 9.8% (p = 0.029), respectively, after 1 month of treatment with omega-3 polyunsaturated fatty acids compared with placebo. Platelet aggregation after AA stimulation was low and did not change significantly throughout the study. There were no cases of aspirin resistance during follow-up that was suggestive of good compliance with the medication. CONCLUSIONS The addition of omega-3 ethyl esters to the combination of aspirin and clopidogrel significantly potentiates platelet response to clopidogrel after percutaneous coronary intervention.

Inhibition of Thrombin Generation by Aspirin Is Blunted in Hypercholesterolemia

Recent evidence indicates that aspirin inhibits thrombin generation in clotting blood. We noticed that this effect was less pronounced in patients with hypercholesterolemia. The aim of the study was to prove this observation. The effects of aspirin on thrombin generation were evaluated in (1) 46 healthy volunteers, 2 hours after ingestion of a single, 500-mg dose and (2) 28 survivors of myocardial infarction who took 300 mg aspirin/d for 2 weeks. In both populations, two well-matched subgroups were distinguished, using a serum cholesterol level of 6.2 mmol/L (240 mg/dL) and an LDL cholesterol level of 4.0 mmol/L (155 mg/dL) as borderline. Thrombin generation was monitored ex vivo in blood emerging from a skin microvasculature injury and additionally, in a single-dose study in vitro in recalcified plasma. Aspirin depressed thrombin generation in the group of subjects with serum cholesterol < 6.2 mmol/L and LDL cholesterol < 4.0 mmol/L but not in the group with high blood cholesterol levels. Inhibitory effects of aspirin were more pronounced after the 2-week treatment than after a single dose. There was a significant correlation between total serum cholesterol or LDL cholesterol and total amount of thrombin generated after aspirin treatment. In subjects with high blood cholesterol levels, thrombin generation was not affected by aspirin. Blunting of aspirin action in hypercholesterolemia might be explained by (1) alterations in platelet lipid-protein matrix that render their membrane proteins less accessible for acetylation by aspirin and (2) changes in composition and structure of plasma lipoproteins that diminish the chance of aspirin to interact with prothrombin.

Reduced Thrombin Formation and Altered Fibrin Clot Properties Induced by Polyunsaturated Omega-3 Fatty Acids on Top of Dual Antiplatelet Therapy in Patients Undergoing Percutaneous Coronary Intervention (OMEGA-PCI Clot)

Objective—The goal of this study was to investigate whether omega-3 polyunsaturated fatty acids (n-3 PUFA) are able to alter plasma fibrin clot properties and reduce thrombin formation in stable coronary artery disease patients undergoing percutaneous coronary intervention (PCI). Methods and Results—In an investigator-initiated, prospective, double-blind, placebo-controlled, randomized study, patients undergoing PCI who received standard pharmacotherapy were assigned to the treatment with 1 g/day n-3 PUFA (n=30) or placebo (n=24) for 1 month. Plasma fibrin clot permeability (Ks); lysis time (t50%); prothrombin fragment 1.2; and peak thrombin generation from automated thrombogram, 8-isoprostaglandin F2&agr; (8-iso-PGF2&agr;, an oxidative stress marker), and C-reactive protein were determined at baseline, 3 to 5 days after randomization, and 30 days after randomization. At baseline, both treatment groups did not differ significantly. A 1-month treatment with n-3 PUFA compared with placebo was associated with 15.3% higher Ks, indicating larger pores in the fibrin network (P=0.0005); 14.3% shorter t50%, indicating increased susceptibility to fibrinolysis (P<0.0001); 33.8% lower prothrombin fragment 1.2 (P=0.0013); 13.4% lower peak thrombin generation (P=0.04); and 13.1% lower 8-iso-PGF2&agr; (P=0.009). Treatment with n-3 PUFA had no effect on fibrinogen and C-reactive protein. After 1 month of treatment, fibrinogen (r=−0.53, P<0.0001), treatment assignment (r=0.29, P=0.006) and 8-iso-PGF2&agr; (r=−0.27, P=0.015) were independently associated with clot permeability (P<0.0001, R2=0.66). Conclusion—Adding n-3 PUFA to standard therapy in stable patients undergoing PCI significantly decreases thrombin formation and oxidative stress and favorably alters fibrin clot properties. These findings indicate novel antithrombotic effects induced by n-3 PUFA in humans.

Association between anthropometric obesity measures and coronary artery disease: a cross-sectional survey of 16 657 subjects from 444 Polish cities

Background: Excessive body weight is known to cluster with cardiovascular (CV) risk factors, but it is not clear which anthropometric obesity measure provides best independent predictive value of coronary artery disease (CAD). Methods and results: We explored associations between CAD and four different obesity measures (body mass index (BMI), waist circumference, waist/height and waist/height2) in a cohort of 16 657 subjects (40.4% men; 20.8% CAD patients), recruited by 700 primary care physicians in 444 Polish cities. 42.8% of subjects were classified as overweight, 31.7% as obese and 39.8% had abdominal obesity. In univariate analyses all obesity measures correlated with CAD (p>0.001), but waist/height2 was the strongest discriminator between CAD patients and controls. Age-adjusted and sex-adjusted analyses confirmed a graded increase in CAD risk across distributions of all four obesity measures—1 standard deviation (SD) increase in BMI, waist, waist/height and waist/height2 increased the odds of CAD by 1.23, 1.24, 1.26 and 1.27, respectively (all p<0.001). In models fully adjusted for CV risk factors, waist/height2 remained the strongest obesity correlate of CAD, being the only independent associate of CAD in men. In a fully adjusted BMI—waist circumference stratified model, sarcopenic obesity (waist > median, BMI < median) and simple obesity (waist and BMI > median) were the strongest independent associates of CAD in men (p = 0.008) and women (p>0.001), respectively. Conclusion: This cross-sectional study showed that waist/height2 may potentially offer a slightly higher predictive value of CAD than BMI or waist circumference and revealed an apparent sexual dimorphism in correlations between obesity measures and CAD.

Altered fibrin clot properties in patients with chronic heart failure and sinus rhythm: a novel prothrombotic mechanism

Background Thromboembolic complications occur more frequently in patients with chronic heart failure (CHF) than in the general population. Formation of a compact fibrin clot resistant to lysis has been shown in arterial and venous thrombosis. Objective To investigate fibrin clot properties in patients with CHF. Method Plasma clot permeability, compaction, turbidity and fibrinolysis were assessed in 36 consecutive patients with stable CHF (30M, 6F; aged 64±10 years, left ventricular ejection fraction (LVEF) 34.9±6.7%) and 36 controls matched for age, sex, cardiovascular risk factors and medication. Exclusion criteria were LVEF >40%, anticoagulant therapy, previous thromboembolic events, atrial fibrillation. Results Clots obtained from plasma of patients with CHF had 23% lower clot permeability (p<0.0001), 13% less clot compaction (p<0.001), 15% faster fibrin polymerisation (p<0.0001) and tended to have prolonged fibrinolysis time (p=0.1) compared with controls. C-reactive protein and fibrinogen were associated inversely with clot permeability (R2=0.84, p<0.0001 and R2=0.79, p<0.0001, respectively) and positively with fibrinolysis time (R2=0.88, p<0.0001 and R2=0.80, p<0.0001, respectively) in patients with CHF. Plasma thrombin–antithrombin complex concentrations were inversely correlated with clot permeability (R2=0.88, p<0.0001) and positively with fibrinolysis time (R2=0.91, p<0.0001). Left atrium diameter, but not LVEF, correlated with fibrinolysis time (R2=0.61, p=0.027). Conclusions Patients with CHF with sinus rhythm are characterised by faster formation of compact plasma fibrin clots, which might predispose to thromboembolic complications.

Preoperative Right Ventricular Function in Patients with Organic Mitral Regurgitation

Aims: To assess the right ventricular (RV) function in patients with severe mitral regurgitation (MR); to find a relation between preoperative and postoperative parameters. Methods: RV function was echocardiographically assessed by determining the tricuspid annular plane systolic excursion (TAPSE) and the peak systolic velocity of the lateral tricuspid annulus (Sa) in 45 patients with severe organic MR (53.3% men, age 58 ± 10 years). Mean NYHA class was 2.6 ± 0.4, LVEF was 55.3 ± 12%, RV end‐diastolic diameter was 28.7 ± 4.7, left ventricular end‐systolic diameter (LVESD) was 44.6 ± 12.6 mm, and LV end‐diastolic volume (Simpson) was 160.6 ± 50.3 ml. All patients underwent mitral valve replacement with posterior chordal sparing. Results: Mean preoperative TAPSE and Sa were 19.4 ± 4.3 mm and 10.3 ± 3 cm/sec, respectively. RV dysfunction, defined as TAPSE < 22 mm, had 66.6% of the patients, and Sa < 11 cm/sec was found in 62.2% of the patients preoperatively. Preoperative TAPSE and Sa were significantly correlated (P < 0.00001, r = 0.61). Both TAPSE and Sa were correlated with the RV end‐diastolic diameter (P < 0.01), LVESD (P < 0.05) left ventricular dp/dt (P < 0.05), and LVEF (P < 0.0001). Postoperative LVEF was 50% (P < 0.001), Sa 5.3 ± 2 cm/sec (P < 0.001), and TAPSE 8.7 ± 3.2mm (P < 0.001). Twenty‐one patients (46.6%) reached the study end point of decrease of LVEF by more than 10%. Univariate predictors were age (P = 0.04), male gender (P = 0.01), TAPSE (P = 0.007), and Sa (P = 0.009), while a trend was found for regurgitation fraction (P = 0.058) and LV end‐diastolic volume index (P = 0.09). By multivariate analysis, TAPSE (P = 0.01) and Sa (P = 0.01) were predictive for the study end point. Conclusion: The assessment of the RV function by echocardiography is a simple tool that provides prognostic information in patients with MR. (Echocardiography 2010;27:282‐285)

Common polymorphisms of cyclooxygenase-2 and prostaglandin E2 receptor and increased risk for acute coronary syndrome in coronary artery disease

The arachidonic acid metabolites participate in development of coronary artery disease (CAD) and the plaques instability. We assessed two common genetic polymorphisms: of cyclooxygenase-2 (COX-2) (COX2.8473, rs5275) and prostaglandin EP2 receptor gene (uS5, rs708494) in patients with CAD. Out of 1,368 patients screened by coronary arteriography, two groups fulfilled the entry criteria and were studied: stable coronary disease (sCAD, n = 125) and acute coronary syndromes (ACS, n = 63). They did not differ in the main characteristics. All patients were on aspirin at least seven days prior to the study. In 70 control subjects, the same genotypes were ascertained, expression of cyclooxygenases in peripheral blood monocytes was assessed by flow cytometry, and in-vitro biosynthesis of PGE(2) was measured by mass spectrometry. COX-2 CC homozygotes (variant allele), were more common, while EP2 GG homozygotes (wild-type) were less common in ACS (p = 0.03 and p = 0.017) than in the sCAD group. A combined genotype characterized by the presence of the wild-type COX2.8743T allele and the wild type homozygous EP2uS5 genotype (TT or CT | GG) decreased risk ratio of ACS in CAD patients (relative risk 0.41; 95% confidence interval 0.21-0.81). COX-2 polymorphism in control subjects did not affect the enzyme expression or PGE(2) production by peripheral blood monocytes, but production of PGE(2) increased by 40.1% in the subjects homozygous for EP2 receptor allele uS5A following lipopolysaccharide stimulation. In conclusion, the combined COX-2 (COX2.8473) and the EP2 receptor (uS5) genotypes seem to influence CAD stability, but in peripheral blood monocytes only EP2 receptor modulates PGE(2) production.

Analysis of Circadian Distribution of Premature Ventricular Contractions in Patients After Heart Transplantation

The aim of our study was to analyze circadian distribution of premature ventricular contractions (PVC) and its coupling interval (CI) in patients after orthotopic heart transplantation (HTx). Forty‐two patients (5 females, 37 males) were monitored from 2 weeks to 5 years after HTx; 180 24‐hour Holter ECG studies were performed. All recordings were divided into two groups: group I, within 1 month after HTX; and group II, after 1 month. Patients with more than 250 PVC/24 hours were selected for distribution of PVC and CI evaluation. Conclusions: Ventricular arrhythmias occur frequently in patients after heart transplantation. In patients with high Lown scale arrhythmias low occurrence (< 250/24 hours) of PVC was frequently observed (IVa: 81.8%; IVb: 84.7%). Similar patterns of circadian distribution (CD) of PVC and CD of HR in denervated heart after HTx suggest the influence of circulating catecholamines on their occurrence.

The influence of obesity on progression of coronary arteriosclerosis and clinical course after ST elevation acute myocardial infarction treated with primary coronary interventions

PURPOSE Evaluation of influence of obesity on the coronary atherosclerosis development and clinical outcome in patients with STEMI treated by PCI with BMS implantation. MATERIAL AND METHOD 82 patients (64 men) treated with PCI within 6 hours from 1st STEMI. Three groups of pts were formed according to BMI. Based on coronary angiography number of significant stenoses (NSS), number of stenosed coronary arteries (NSA), and sum of significant stenoses (SSS) were calculated. Echocardiography examination was performed 3 days and 6 months after STEMI. Serial evaluation of TnI, CK, CKMB was performed after admission, and serum BNP was assessed after 2 days, 1 and 6 months after STEMI. RESULTS Obese patients revealed higher values of NSA, NSS and SSS than patients with normal BMI and overweight. There were no differences of BNP, maximal values and AUC of CK, CKMB, TnI and echocardiographic parameters between all groups whereas decrease of BNP during follow-up correlated with BMI. CONCLUSIONS Results of our prospective study indicate that in obese patients, there is a significantly greater number of atherosclerotic lesions in coronary arteries found during PCI, as compared to those with normal body weight or overweight. We proved that overweight and obesity did not result in significantly greater damage to the myocardium and left ventricular dysfunction, both in the acute phase and 6 months after myocardial infarction treated with primary coronary intervention, as compared to those with normal body weight. In addition correlation was found between BNP concentration profile and body mass index in the 6-month follow-up after STEMI treated with PCI and bare metal stent implantation.