Wiesława Tracz

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.

Association of increased carotid intima-media thickness with the extent of coronary artery disease

Objective: To investigate (a) the relation between intima-media thickness (IMT) in carotid arteries and the extent of coronary artery disease (CAD); and (b) whether IMT is predictive of coronary atherosclerosis. The coexistence of severe extracranial atherosclerosis in patients with CAD was also analysed. Methods: Coronary angiography and carotid ultrasound evaluation were performed in 558 consecutive patients (438 men), with a mean (SD) age of 58.8 (9.2) years and suspected CAD. Mean IMT was measured at both carotid arteries and expressed as the mean aggregate value. The relation between IMT and severity of CAD was determined. Results: A significant correlation between mean IMT and advancing CAD (p < 0.0001) was found. Four independent predictors of CAD were found in the discriminant analysis: age (p  =  0.0193), hyperlipidaemia (p < 0.0001), smoking (p  =  0.0032), and IMT (p < 0.0001). A significant increase in IMT was observed among patients with one, two, and three vessel CAD. A log normal distribution of IMT values showed that if mean IMT was over 1.15 mm, patients had a 94% probability of having CAD, with sensitivity of 65% and specificity of 80% in the patients with a high risk of CAD. The number of critically stenosed extracranial arteries increased with advancing CAD. None of the patients with normal coronary arteries had severe stenosis of the extracranial arteries. Severe carotid, vertebral, or subclavian stenosis was found in 16.6% of patients with three vessel CAD. Conclusions: IMT increases with advancing CAD, patients with mean IMT over 1.15 mm have a 94% likelihood of having CAD, and the coexistence of CAD with severe stenosis of aortic arch arteries is relatively high and was found in 16.6% of patients with three vessel CAD.

Hyperglycemia Is Associated With Enhanced Thrombin Formation, Platelet Activation, and Fibrin Clot Resistance to Lysis in Patients With Acute Coronary Syndrome

OBJECTIVE—Acute hyperglycemia on admission for acute coronary syndrome worsens the prognosis in patients with and without known diabetes. Postulated mechanisms of this observation include prothrombotic effects. The aim of this study was to evaluate the effect of elevated glucose levels on blood clotting in acute coronary syndrome patients. RESEARCH DESIGN AND METHODS—We studied 60 acute coronary syndrome patients within the first 12 h after pain onset, including 20 subjects with type 2 diabetes, 20 subjects with no diagnosed diabetes but with glucose levels >7.0 mmol/l, and 20 subjects with glucose levels <7.0 mmol/l. We determined generation of thrombin-antithrombin complexes (TATs) and soluble CD40 ligand (sCD40L), a platelet activation marker, at the site of microvascular injury, together with ex vivo plasma fibrin clot permeability and lysis time. RESULTS—The acute coronary syndrome patients with no prior diabetes but elevated glucose levels had increased maximum rates of formation and total production of TATs (by 42.9%, P < 0.0001, and by 25%, P < 0.0001, respectively) as well as sCD40L release (by 16.2%, P = 0.0011, and by 16.3%, P < 0.0001, respectively) compared with those with normoglycemia, whereas diabetic patients had the highest values of TATs and sCD40L variables (P < 0.0001 for all comparisons). Patients with hyperglycemia, with no previously diagnosed diabetes, had longer clot lysis time (by ∼18%, P < 0.0001) similar to that in diabetic subjects, but not lower clot permeability compared with that in normoglycemic subjects. CONCLUSIONS—Hyperglycemia in acute coronary syndrome is associated with enhanced local thrombin generation and platelet activation, as well as unfavorably altered clot features in patients with and without a previous history of diabetes.

Altered Fibrin Clot Structure/Function in Patients With Cryptogenic Ischemic Stroke

Background and Purpose— We tested the hypothesis that fibrin structure/function is unfavorably altered in patients with cryptogenic ischemic stroke. Methods— Ex vivo plasma fibrin clot permeability, turbidimetry, and efficiency of fibrinolysis were determined in 89 patients with patent foramen ovale (PFO) and a history of first-ever stroke, 58 patients with first-ever stroke and no PFO, and 120 healthy controls. Results— Stroke patients, evaluated 3 to 19 months after the event, and controls did not differ with regard to age, sex, smoking, and fibrinogen. Stroke patients with or without PFO had lower clot permeability (P<0.0001), faster fibrin polymerization (P<0.0001), prolonged clot lysis time (P<0.0001), higher maximum D-dimer levels released from clots (P<0.0001), and maximum rate of D-dimer release (P=0.02) than controls. Time from stroke occurrence showed no association with any clot variables. Scanning electron microscopy of fibrin clots showed increased fiber diameter and density in stroke patients. Clots from stroke patients with PFO were more permeable and showed shorter lysis time compared to those without PFO, and this was related to lower proportion of smokers in the former group. Conclusions— Altered fibrin clot structure and resistance to fibrinolysis are associated with cryptogenic stroke.

Determinants of immediate and long-term results of subclavian and innominate artery angioplasty

Background: Percutaneous angioplasty (PTA) is widely used in the treatment of subclavian/innominate artery obstruction, but factors of long‐term PTA outcome are poorly understood. Our aim was to evaluate the efficiency of PTA on symptom resolution and identify determinants of long‐term outcome. Methods and Results: Seventy‐six lesions were treated in 75 patients (58.7% men) aged 60 ± 8.5 years. PTA was successful in 70 (93.3%) patients, including 58/58 (100%) stenotic lesions and 13/18 (72.2%) occlusions. The mean stenosis grade (QCA) was reduced from 78.9% ± 16.6% to 13.5% ± 10.7% (P < 0.01). A great majority of lesions (87.1%) were stented. In 5 (7.1%) high‐risk lesions a proximal or distal neuroprotection system was used. There were no strokes or embolic events. Minor complications occurred in 7 (9.3%) cases. Fifty‐seven (89%) of 64 symptomatic patients had complete symptom resolution. The mean follow‐up was 24.4 ± 15.5 months (up to 66 months). Ten restenoses (15.6%), including 9 (13.8%) in‐stent restenoses and 1 (16.7%) restenosis after balloon angioplasty, were diagnosed in 64 patients and followed up for at least 6 months. Nine symptomatic restenoses were successfully treated with repeated angioplasty. Cox multivariable analysis revealed the following independent predictors of restenosis: implantation of more than one stent (P = 0.005), low stent diameter (P = 0.088), and postprocedural systolic blood pressure difference between upper extremities (P = 0.044). Conclusions: PTA is a safe and effective method for the treatment of the subclavian/innominate artery obstruction and leads to symptom resolution in majority of patients. Restenosis is not frequent and it can be effectively treated with repeat angioplasty. Low stent diameter, implantation of two stents, and upper limb systolic blood pressure difference are independent predictors of restenosis.

Fibrin clot properties in acute ischemic stroke: relation to neurological deficit

INTRODUCTION Hypercoagulable state occurs in patients with acute vascular events. We wondered whether clot structure/function is altered in acute ischemic stroke (AIS), like in acute myocardial infarction. PATIENTS AND METHODS In 45 consecutive patients with AIS (24M, 21F), aged 67.4+/-10.9 years, and 45 healthy controls matched for age and sex, we investigated plasma fibrin clot structure/function by permeation, turbidity, and efficiency of fibrinolysis. RESULTS Compared to controls, AIS patients produced clots that had 30.5% less porous network (p<0.0001), were less susceptible to fibrinolysis (10.8% longer lysis time, p=0.001), were 20.5% more compact (p<0.0001), had 17.1% higher clot mass (p<0.0001), and showed increased (by 10.2%) overall fiber thickness (p<0.0001) with 8% shorter lag phase of fibrin formation (p=0.0002). Maximum rate of D-dimer release from clots was similar. Multiple regression analyses for all subjects (n=90) showed that being a stroke patient (p<0.0001), fibrinogen (p<0.0001) and lipoprotein(a) (p=0.0075) were independent predictors of clot permeability (model R2 0.79). Only fibrinogen (p<0.0001) and lipoprotein(a) (p=0.0026) predicted lysis time. All other fibrin parameters were predicted only by being a stroke patient. Clot compaction was associated with neurological deficit on admission (r=-0.81; p<0.0001) and at discharge (r=-0.69; p<0.0001). Patients with 0 or 1 point in the modified Rankin scale (n=19) had 13.3% higher clot permeability compared to the remainder (p=0.02). CONCLUSIONS This study is the first to show that AIS is associated with unfavorably altered fibrin clot properties that might correlate with neurological deficit.

Fibrin clot properties are altered in patients with chronic obstructive pulmonary disease. Beneficial effects of simvastatin treatment.

Increased risk of thrombotic events occurs in chronic obstructive pulmonary disease (COPD). Elevated fibrinogen and C-reactive protein (CRP), being common in COPD, are associated with formation of dense fibrin clots resistant to lysis. Statins have been found to display anti-inflammatory and antithrombotic effects. We investigated fibrin clot properties in COPD patients prior to and following statin therapy. Ex vivo plasma fibrin clot permeability, compaction, and fibrinolysis were assessed in 56 patients with stable COPD, aged 64.9 +/- 9.2 years (mean FEV(1), 54.7 +/- 15.9% predicted), versus 56 controls matched for age, sex and cardiovascular risk factors. Patients were then randomly assigned to receive simvastatin 40 mg/day (n = 28) or to remain without statins for three months (n = 28). Patients with COPD had lower clot permeability (6.1+/- 1.07 versus 9.2 +/- 0.9 10(-9) cm(2), p < 0.0001), decreased compaction (44.9 +/- 4.5 versus 63.9 +/- 6.1%, p < 0.0001), higher maximum D-dimer levels released from clots (4.23 +/- 0.55 versus 3.53 +/- 0.31 mg/l, p < 0.0001) with a decreased rate of this release (75.0 +/- 8.3 versus 80.9 +/- 8.0 microg/l/min, p = 0.03) and prolonged lysis time (9.84 +/- 1.33 versus 8.02 +/- 0.84 min, p < 0.0001) compared with controls. Scanning electron microscopy confirmed denser clot structure in COPD. Multiple linear regression analysis after adjustment for age and fibrinogen showed that in the COPD patients, CRP was the only independent predictor of permeability (R(2) = 0.47, p < 0.001) and lysis time (R(2) = 0.43, p < 0.001). Simvastatin improved clot properties (p < 0.05) despite unaltered CRP and irrespective of cholesterol reduction. Our study shows that fibrin clots in COPD patients are composed of much denser networks that are more resistant to lysis, and these properties can be improved by statin administration.

Left ventricular geometry and function in patients with aortic stenosis: gender differences

BACKGROUND Gender differences in cardiac size have been described in normal and pathological conditions in human and animals. Sex determination of a pattern of hypertrophy as a response to pressure overload has not been extensively evaluated and is still poorly understood in humans. METHODS AND RESULTS To investigate the influence of gender in the left ventricle remodelling and preservation of the left ventricle function 195 adults (140 men and 55 women) with isolated aortic stenosis were evaluated. The mean age was 52 +/- 11 years for men and 53 +/- 13 years for women. All the patients had similar degree of aortic stenosis finally treated with valve replacement, similar clinical status and no signs of coronary artery disease in coronary angiograms. On echocardiography the left ventricle of women had a smaller the end systolic (30.5 +/- 7.8 vs. 39.4 +/- 11.2, P<0.001) and the end diastolic (49.4 +/- 9 vs. 57.3 +/- 11, P<0.001) chamber size. The female left ventricle generated a higher relative wall thickness (0.65 +/- 0.21 vs. 0.52 +/- 0.12, P<0.01), a greater fractional shortening (35.3 +/- 8.5 vs. 32.0 +/- 9.0, P<0.01) and a higher ejection fraction (64.4 +/- 12.7 vs. 57.5 +/- 14.6, P<0.001). The left ventricle posterior wall thickness and the septal thickness indexes were similar in both groups. There were also significant differences between the two groups in the left ventricle mass index. CONCLUSIONS Gender has an important influence on the left ventricle adaptation pattern to pressure overload due to aortic stenosis. Women developed a greater degree of left ventricle hypertrophy documented as changes in left ventricle geometry (increased relative wall thickness, left ventricular mass) and left ventricle function (fractional shortening and ejection fraction).

Systemic blood coagulation activation in acute coronary syndromes

We evaluated systemic alterations to the blood coagulation system that occur during a coronary thrombotic event. Peripheral blood coagulation in patients with acute coronary thrombosis was compared with that in people with stable coronary artery disease (CAD). Blood coagulation and platelet activation at the microvascular injury site were assessed using immunochemistry in 28 non-anticoagulated patients with acute myocardial infarction (AMI) versus 28 stable CAD patients matched for age, sex, risk factors, and medications. AMI was associated with increased maximum rates of thrombin-antithrombin complex generation (by 93.8%; P< .001), thrombin B-chain formation (by 57.1%; P< .001), prothrombin consumption (by 27.9%; P= .012), fibrinogen consumption (by 27.0%; P= .02), factor (f) Va light chain generation (by 44.2%; P= .003), and accelerated fVa inactivation (by 76.1%; P< .001), and with enhanced release of platelet-derived soluble CD40 ligand (by 44.4%; P< .001). FVa heavy chain availability was similar in both groups because of enhanced formation and activated protein C (APC)-mediated destruction. The velocity of coagulant reactions in AMI patients showed positive correlations with interleukin-6. Heparin treatment led to dampening of coagulant reactions with profiles similar to those for stable CAD. AMI-induced systemic activation of blood coagulation markedly modifies the pattern of coagulant reactions at the site of injury in peripheral vessels compared with that in stable CAD patients.

Carotid artery stenting with patient- and lesion-tailored selection of the neuroprotection system and stent type: early and 5-year results from a prospective academic registry of 535 consecutive procedures (TARGET-CAS).

Purpose: To develop and prospectively evaluate the safety and efficacy of an algorithm for tailoring neuroprotection devices (NPD) and stent types to the patient/lesion in carotid artery stenting (CAS). Methods: From November 2002 to October 2007, 499 patients (360 men; mean age 65.2±8.4 years, range 36–88) were prospectively enrolled in a safety and efficacy study of tailored CAS using proximal (flow blockade or reversal) or distal (filters or occlusion) NPDs and closed- or open-cell self-expanding stents. Of the 535 lesions treated in the study, 175 (32.7%) were “high risk” by morphology. Half (50.1%) the patients were symptomatic. Results: A quarter (137, 25.6%) of the procedures were performed under proximal protection and the remainder (398, 74.4%) with distal NPDs; the direct stenting rate was 66.9%. High-risk lesions were treated predominantly with a proximal NPD and closed-cell stent (77.1% and 82.9%, respectively) and less frequently by direct stenting (37.1%, p<0.0001 versus non-high-risk lesions). The in-hospital death/stroke rate was 2.0% (95% CI 0.85% to 3.23%), and the death/major stroke rate was 0.7% (95% CI 0.02% to 1.48%). There were no myocardial infarctions, but there was 1 (0.2%) further death within 30 days. With the tailored approach, symptom status and high-risk lesion morphology were not risk factors for an adverse outcome after CAS; only age >75 years (p<0.001) was a predictor of short-term death. Long-term survival (95.4% at 1 and 88.3% at 5 years) was similar for symptomatic versus asymptomatic patients, direct stenting versus predilation, and closed-vs. open-cell stent design; only coronary artery disease adversely impacted survival (p=0.04). The rates of freedom from death/ipsilateral stroke were 94.9% at 1 year and 85.9% at 5 years. Conclusion: Tailored CAS is associated with a low complication rate and high long-term efficacy. CAS operators should have a practical knowledge of different NPDs, including at least one proximal type.