Local catheter-based delivery of antithrombotic or antiproliferative drugs: a new concept for prevention of restenosis.

BACKGROUND: Drug eluting stents have reduced the incidence of restenosis after percutaneous coronary interventions significantly, but cause concern about long term safety. Local drug delivery using special application catheters is an alternative approach for intracoronary pharmacotherapy. Besides the fact, that no problematic coating as drug carrier has to be used, a local delivery independent of the stent itself by using catheter techniques offers further advantages - such as the possibility to treat the whole vessel wall, stent edges and adjacent vessel segments and not only the area close to the stent struts. METHODS AND RESULTS: We have developed a new local catheter-based delivery system for local intracoronary pharmacotherapy. An antithrombotic as well as an antiproliferative therapy concept for prevention of restenosis are presented in the manuscript. Our data show that local drug delivery of platelet glycoprotein VI and paclitaxel were effective in the reduction of thrombus formation and neointima formation in experimental animal models. CONCLUSIONS: A combination of early antithrombotic and antiatherosclerotic mechanisms may be a realistic and effective approach to minimize postinterventional thromboischemic events and neointima formation. These results may contribute to an advanced and even combined local intracoronary pharmacotherapy in near future, independent of stent coatings.

Local paclitaxel delivery after coronary stenting in an experimental animal model.

The goal of this study was to test the safety and efficacy of local paclitaxel delivery via a newly designed application catheter in an experimental animal study. Drug-eluting stents reduce restenosis in comparison to bare-metal stents. The drug-eluting polymer, however, may exert potential thrombogenic and inflammatory effects. A catheter-based local paclitaxel delivery offers further advantages, particularly a homogenous drug transfer into the vessel wall and a pharmacotherapy of the stent edges. In 30 pigs, both bare-metal stent (3.0 x 13 mm) implantation and balloon angioplasty were performed. Ten pigs received subsequent local delivery of paclitaxel-solution via a newly designed catheter (Genie, ACROSTAK corp., Switzerland), 10 animals served as a sham group and received vehicle (0.9% NaCl solution) and 10 animals were used as a control group. All animals were treated with aspirin and clopidogrel to prevent stent thrombosis. After final angiography the vessels were excised 42 days after intervention and prepared for histological and histomorphometric analysis. All coronary arteries showed complete endothelialization 42 days following treatment. Paclitaxel treatment led to a marked reduction of neointimal proliferation either post stent implantation (neointimal area: 1.04 +/- 0.10 mm(2) vs. 2.37 +/- 0.23 mm(2), p < 0.001) or post balloon dilatation (neontimal area: 0.35 +/- 0.14 mm(2), vs. 0.68 +/- 0.24 mm(2), p < 0.01). There were no significant angiographic or histomorphometric differences between the control and the sham group. In both paclitaxel groups neither angiographic edge phenomena nor a significant histomorphometric inflammatory response were found in the treated vessel segments. In conclusion, the local application of paclitaxel via the Genie catheter is safe and effective to significantly reduce the proliferative response post-stent implantation or balloon dilatation in an experimental animal model.

Impact of mitral E/A ratio on the accuracy of different echocardiographic indices to estimate left ventricular end-diastolic pressure.

The objective was to determine the influence of left ventricular (LV) inflow pattern on the accuracy of different echocardiographic indices for estimation of LV end-diastolic pressure (LVEDP). Echocardiography with color tissue Doppler imaging (TDI) and LVEDP measurements using fluid-filled catheters were performed in 176 consecutive patients on the same day. Mitral peak diastolic velocities (E, A) and the difference in duration between pulmonary venous retrograde velocity and mitral A-velocity (PV(R)-A) were recorded by pulsed Doppler. Propagation velocity of the early mitral inflow (V(P)) was assessed using color M-mode. Early diastolic longitudinal (E'(lat)) and radial (E'(radial)) velocities of mitral annulus were measured by TDI. Area under ROC curve (AUC) for prediction of elevated LVEDP (> or =15 mm Hg) was computed for each parameter. For E/A > or =1 (98 patients, 46 with elevated LVEDP), the AUC values were: PV(R)-A: 0.914; E/E'(lat): 0.780; E/E'(radial): 0.729; E/V(P): 0.712 (p < 0.001). When E/A <1 (78 patients, 26 with elevated LVEDP), only PV(R)-A reached statistical significance (AUC = 0.893, p < 0.001). The conclusions were: PV(R)-A enabled the most accurate noninvasive estimation of LVEDP irrespective of LV filling profile and combined indices E/V(P), E/E'(lat) and E/E'(radial) represent more feasible alternatives for patients with mitral E/A-1.

Prognostic value of plasma N-terminal pro-brain natriuretic peptide in patients with severe sepsis.

BACKGROUND: Increased plasma levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) have been identified as predictors of cardiac dysfunction and prognosis in congestive heart failure and ischemic heart disease. In severe sepsis patients, however, no information is available yet about the prognostic value of natriuretic peptides. Therefore, the aim of the present study was to determine the role of the N-terminal prohormone forms of ANP (NT-proANP) and BNP (NT-proBNP) in the context of outcome of septic patients. Furthermore, the effect of treatment with recombinant human activated protein C [drotrecogin alfa (activated)] on plasma levels of natriuretic peptides in severe sepsis was evaluated. METHODS AND RESULTS: Fifty-seven patients with severe sepsis were included. Levels of NT-proANP and NT-proBNP were measured on the second day of sepsis by ELISA. Septic patients with NT-proBNP levels >1400 pmol/L were 3.9 times more likely (relative risk [RR], 3.9; 95% CI, 1.6 to 9.7) to die from sepsis than patients with lower NT-proBNP values (P<0.01). NT-proANP levels, however, were not predictive of survival in our patient population. A highly significant correlation was found between troponin I levels and plasma concentrations of NT-proBNP in septic patients (r=0.68, P<0.0001). In addition, troponin I significantly accounted for the variation in NT-proBNP levels (P<0.0001), suggesting an important role for NT-proBNP in the context of cardiac injury and dysfunction in septic patients. Twenty-three septic patients who received treatment with drotrecogin alfa (activated) presented with significantly lower concentrations of NT-proANP, NT-proBNP, and troponin I compared with patients not receiving drotrecogin alfa (activated). CONCLUSIONS: NT-proBNP may serve as useful laboratory marker to predict survival in patients presenting with severe sepsis.

Side branch occlusion after coronary stent implantation in patients presenting with ST-elevation myocardial infarction: clinical impact and angiographic predictors.

BACKGROUND: The aim of this study was to assess the incidence and clinical outcome of the occlusion of major (> 1 mm) side branches following coronary stenting in patients undergoing percutaneous coronary intervention for acute ST-elevation myocardial infarction (STEMI). METHODS: Among 276 consecutive patients presenting with STEMI, we found 80 patients (29%) with 101 stent-covered side branches. Clinical data and quantitative angiographic analysis were evaluated. Angiographic follow-up was available in 56 (70%) patients, and clinical follow-up could be completed in all patients. RESULTS: Acute side branch occlusion after stent implantation (SBO) was observed in 10 (12.5%) patients involving 11 (10.9%) side branches. Predictors for SBO were: (1) reference side branch diameter at baseline < or = 1.4 mm; (2) ostial side branch stenosis > 50%; and (3) minimal side branch diameter at baseline < or = 0.6 mm. During hospitalization, in the SBO group, 2 patients died in cardiogenic shock and 1 underwent bypass surgery; no events were causally related to SBO. During long-term follow-up, 1 patient with SBO developed repeat MI as opposed to 7 patients in the non-SBO group who developed major adverse cardiac events (1 death, 6 repeat revascularizations). CONCLUSIONS: The presence of a side branch originating from the target lesion in patients undergoing coronary stenting for acute STEMI is a frequent observation (29%) and is associated with a low incidence of side branch occlusion. Major predictors for SBO are the side branch size and the presence of an ostial side branch stenosis.

Recombinant human activated protein C upregulates cyclooxygenase-2 expression in endothelial cells via binding to endothelial cell protein C receptor and activation of protease-activated receptor-1.

Prostacyclin (PGI(2)) has beneficial cytoprotective properties, is a potent inhibitor of platelet aggregation and has been reported to improve microcirculatory blood flow during sepsis. The formation of PGI(2) in response to proinflammatory cytokines is catalysed by the inducible cyclooxygenase (COX) isoform COX-2. Recombinant human activated protein C (rhAPC, drotrecogin alfa (activated)) was shown to have multiple biological activities in vitro and to promote resolution of organ dysfunction in septic patients. Whether rhAPC exerts its beneficial effects by modulating prostanoid generation is unknown up to now. It was therefore the aim of the study to examine the in vitro effect of rhAPC on COX-2-mRNA-expression and PGI(2) release from human umbilical vein endothelial cells (HUVEC). We found that rhAPC, at supra-therapeutical concentrations (500 ng/ml-20 microg/ml), upregulated the amount of COX-2-mRNA in HUVEC at t=3-9 h and caused a time- and dose-dependent release of 6-keto PGF(1 alpha), the stable hydrolysis product of prostacyclin. RhAPC further increased the stimulating effect of tumor necrosis factor-alpha (TNF-alpha) and thrombin on COX-2-mRNA-levels. Transcript levels of cyclooxygenase-1 (COX-1) and prostaglandin 12 synthase, however, were unaffected by the stimulation with rhAPC or thrombin. The upregulatory effect on COX2-mRNA levels was specific for rhAPC since the zymogen protein C in equimolar concentrations had no effect on COX-2-mRNA-levels or 6-keto PGF(1 alpha)-release. Western Blot analysis revealed an increase of COX-2-protein content in HUVEC after treatment with rhAPC. As shown by experiments using monoclonal antibodies against the thrombin receptor PAR-1 (mAb=ATAP2) and against the endothelial protein C receptor (EPCR; mAb=RCR-252), the effect of rhAPC on COX-2-mRNA upregulation was mediated by binding to the EPCR-receptor and signaling via PAR-1. These results demonstrate that induction of COX-2-expression is an important response of HUVEC to stimulation with rhAPC and may represent a new molecular mechanism, by which rhAPC promotes upregulation of prostanoid production in human endothelium.

Intravenous drug challenge using flecainide and ajmaline in patients with Brugada syndrome.

OBJECTIVES: The purpose of this study was to compare the effect of intravenous flecainide and ajmaline with respect to their ability to induce or accentuate the typical ECG pattern of Brugada syndrome. BACKGROUND: Brugada syndrome is associated with a high incidence of sudden cardiac death. The typical ECG pattern of ST-segment elevation in the right precordial leads often is concealed, but it can be unmasked with sodium channel blockers such as flecainide and ajmaline. Little is known about the relative effectiveness of these provocative agents in unmasking Brugada syndrome. METHODS: Intravenous pharmacologic challenge with flecainide and ajmaline was performed. Whole-cell patch clamp techniques were used to assess the relative potency of ajmaline and flecainide to inhibit the transient outward current (I(to)). RESULTS: A coved-type ST-segment elevation in the right precordial leads was induced or enhanced in 22 of 22 patients following ajmaline administration. Among the 22 patients, only 15 patients showed positive response to flecainide, resulting in a positive concordance of 68%. Both drugs produced equivalent changes in QRS and PQ intervals, suggesting similar effects on sodium channel current. Whole-cell patch clamp experiments revealed a reduction of the total charge provided by I(to) with an IC(50) of 216 and 15.2 microM for ajmaline and flecainide, respectively. CONCLUSIONS: Our data demonstrate disparate response of Brugada patients to flecainide and ajmaline, with a failure of flecainide in 7 of 22 cases (32%). Greater inhibition of I(to) by flecainide may render it less effective. These observations have important implication for identification of patients at risk for sudden death.

A novel regional right ventricular wall-motion abnormality observed in a case of acute pulmonary embolism (reverse McConnell sign).

Among various echocardiographic parameters for diagnosis of pulmonary embolism, an abnormal regional contraction pattern of the right ventricular free wall consisting of normokinesia of the apical segment and akinesia of the midfree wall with persistence of abnormal wall motion at the base has proved to be fairly specific for pulmonary embolism. This echocardiographic abnormality has been termed "McConnell sign." We describe the case of a patient with acute pulmonary embolism who developed reversible akinesia of the apex and right ventricular midfree wall, a finding we would like to term "reverse McConnell sign."

Utility of combined parameters of common carotid intima-media thickness or albuminuria in diagnosis of coronary artery disease in women.

BACKGROUND: Noninvasive testing for suspected coronary artery disease is challenging. We prospectively investigated whether measurements of carotid intima-media thickness in the presence or absence of albuminuria in patients with stable chest pain syndromes can be used as a noninvasive test algorithm for prediction of significant coronary artery disease. Additionally, this algorithm was tested with regard to gender differences. METHODS: Consecutive patients (79 men and 72 women) with stable chest pain syndromes and suspected coronary artery disease admitted for coronary angiography were studied. Measurements of intima-media thickness were performed by ultrasound. Urinary albumin excretion was measured in a random urine specimen. A positive test for coronary artery disease was defined as an intima-media thickness >or=1 mm or albuminuria. RESULTS: Sensitivity, specificity and positive likelihood ratio for a combination of intima-media thickness values >or=1 mm or presence of albuminuria to predict coronary artery disease were, respectively, 0.5, 0.73 and 1.27 in men and 0.68, 0.79 and 3.32 in women. Sensitivity, specificity and positive likelihood ratio for exercise ECG were, respectively, 0.54, 0.48 and 1.08 in men and 0.47, 0.45 and 0.8 in women. CONCLUSIONS: Intima-media thickness of the common carotid artery or presence of albuminuria are clinically valuable parameters in the noninvasive diagnostic work up of women with stable chest pain syndromes. Their value is limited in men.

Direct versus conventional stent implantation in patients with acute coronary syndrome just before the era of drug-eluting stents.

BACKGROUND: Direct stent implantation in patients, who undergo elective percutaneous coronary intervention (PCI) can be performed with a high success rate and clinical results that are comparable to those after predilatation. It was the aim of this prospective study to compare clinical, angiographic and procedural parameter of direct stent implantation (DS) and conventional stent implantation (CS) in patients with acute coronary syndrome (ACS). PATIENTS AND METHODS: We analysed 194 patients with ACS (ST-elevation myocardial infarction 66%, non-ST-elevation myocardial infarction 18%, unstable angina 16%), in whom primary PCI was performed between January and December 2002. In 156 (80%) patients glycoprotein IIb/IIIa inhibitors were administered during the procedure. In 73 patients (38%) direct stent implantation could be performed successfully. In 12 patients (6%) direct stent implantation failed due to the inability to pass the stenosis. In 121 patients (62%) the stent was implanted after predilatation. RESULTS: The clinical parameters were comparable in both groups. Reference luminal diameter before stent implantation did not differ in both groups (DS 3.01+/-0.54 vs. CS 2.84+/-0.43 mm). The final minimal luminal diameter was significantly higher in the DS group (DS 2.95+/-0.45 vs. CS 2.77+/-0.47 mm, p=0.01). The procedural time (DS 41.0+/-14.1 vs. CS 46.8+/-16.9 min, p=0.02), radiation exposure time (DS 7.3+/-4.6 vs. CS 8.9+/-4.6 min, p=0.002) and the amount of contrast agent (DS 216+/-90 vs. CS 235+/-79 ml, p=0.03) could be decreased by the technique of direct stent implantation. The incidence of major adverse cardiac events (death, myocardial infarction, CABG) during hospitalization was 4.1% in the DS group and 11.5% in the CS group (p=0.11). CONCLUSIONS: Direct stent implantation is safe and feasible in patients with acute coronary syndromes. The procedural time, radiation exposure time and the amount of contrast agent can be significantly decreased using the technique of direct stent implantation. The incidence of major adverse cardiac events was not significantly different in this subset of patients.

Physiological range of mechanical synchronicity of the human heart: comparison between different echocardiographic assessment modalities.

Tissue Doppler was performed to assess physiological ranges of mechanical synchronicity in 47 patients aged 38 to 81 y with normal coronary angiograms, ECG recordings and echocardiographic findings. Maximal time delays between two different left ventricular (LV) walls in long axis time-to-peak tissue displacement (TD_D), respectively in time-to-peak strain (TD_S), time-to-peak strain rate (TD_SR), time-to-peak systolic (TD_VS) and early diastolic (TD_VE) velocities of basal and midwall segments were determined as values corrected for heart rate in a 16-segment LV model and in the right ventricle (RV). Strain (TD_S: LV = 212 +/- 108 ms, RV = 195 +/- 15 ms) and strain rate (TD_SR: LV = 183 +/- 67 ms, RV = 120 +/- 60 ms) showed the highest dyssynchrony values (TD_D: LV = 110 +/- 96 ms, RV = 42 +/- 38 ms; TD_VS: LV = 82 +/- 47 ms, RV = 36 +/- 36 ms; TD_VE: LV = 73 +/- 36 ms, RV = 46 +/- 20 ms) in both ventricles. There was no significant association between a certain LV wall and the occurrence of the earliest, respectively latest peak values of any parameter.

Increased plasma levels of NT-proANP and NT-proBNP as markers of cardiac dysfunction in septic patients.

The family of natriuretic peptides comprises several structurally related 22-53-amino acid peptides, such as atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), which are vasoactive peptides with vasodilator and diuretic properties and play an important role in cardiovascular homeostasis. The salutary cardiovascular effects of natriuretic peptides suggest that ANP and BNP may have a pathophysiological significance in the cardiac dysfunction of septic patients. We determined plasma levels of the stable N-terminal prohormone forms of ANP (NT-proANP) and BNP (NT-proBNP) as well as troponin I (TNI) as a marker of myocardial cell injury by ELISA methods in 19 septic patients and 19 healthy controls at day one of severe sepsis. Left ventricular ejection fraction (LVEF) was determined on day 1 of severe sepsis by echocardiography. Significantly higher concentrations of NT-proANP were measured in non-survivors (mean = 13415 pmol/l +/- SEM = 4295) and survivors (mean = 7386 pmol/l +/- SEM = 1807) as compared to controls (mean = 1404 pmol/l +/- SEM = 181; p<0.001). Levels of NT-proBNP were also significantly higher in non-survivors (mean = 3439 pmol/l +/- SEM = 1246; p<0.05) and survivors (mean = 1009 pmol/l +/- SEM = 263; p<0.001) as compared to controls (mean = 200 pmol/l +/- SEM = 24) and correlated well with an increase in TNI-levels (r = 0.71; p<0.001). NT-proANP and NT-proBNP may serve as useful laboratory markers to indicate myocardial dysfunction and may help to differentiate between survivors and non-survivors of severe sepsis.

Anatomic Rerouting of Anomalous Left Coronary Artery From Right Coronary Sinus.

We herein present a new surgical technique in the treatment of an anomalous left coronary artery from the right coronary sinus in an 18-year-old patient with an intramural course of the left main coronary artery.

Interleukin-1 beta promotes matrix metalloproteinase expression and cell proliferation in calcific aortic valve stenosis.

Calcific aortic valve stenosis (AS), the main heart valve disease in the elderly, is characterized by extensive remodeling of the extracellular matrix. Matrix metalloproteinases (MMPs) are upregulated in calcific AS and might modulate matrix remodeling. The regulatory mechanisms are unclear. As recent studies have suggested that calcific AS might result from an inflammatory process involving leukocyte invasion and activation, the present study aimed to elucidate the role of the pro-inflammatory cytokine interleukin (IL)-1 beta on MMP expression and cell proliferation in human aortic valves. Immunohistochemistry for leukocytes, IL-1 beta and MMP-1 was performed on aortic valves with (n=6) and without (n=6) calcification obtained at valve replacement or autopsy. Stenotic valves showed marked leukocyte infiltration and associated expression of IL-1 beta and MMP-1. In control valves only scattered leukocytes, low staining for MMP-1 and no staining for IL-1 beta were present. Double-label immunostaining localized IL-1 beta expression mainly to leukocytes and MMP-1 expression to myofibroblasts. Stimulation of cultured human aortic valve myofibroblasts with IL-1 beta lead to a time-dependently increased expression of MMP-1 and MMP-2 by Western blotting and zymography, whereas MMP-9 remained unchanged. Cell proliferation was increased by IL-1 beta as determined by bromodesoxyuridine incorporation. Thus, IL-1 beta may regulate remodeling of the extracellular matrix in calcific AS.

Natural history of small and medium-sized side branches after coronary stent implantation.

OBJECTIVE: Our purpose was to identify angiographic and procedural predictors for acute and late side branch occlusion after coronary stent implantation. METHODS: We evaluated 185 patients with 185 lesions with 255 side branches with a mean reference diameter of 1.45 +/- 0.38 mm; the lesions were covered by 240 stents. Angiographic follow-up was completed in 99 patients with 133 side branches 206 +/- 120 days after stent implantation and clinical follow-up was available in 136 patients. Side branch occlusion (SBO) was defined as a Thrombolysis In Myocardial Infarction (TIMI) flow < or =1. RESULTS: Acute SBO affected 54 side branches in 49 patients and was not associated with death or Q-wave infarction. By logistic regression, independent predictors for acute SBO were (1) the reference side branch diameter (RLD) at baseline (OR [odds ratio] 0.217, 95% CI 0.07-0.67, P =.008); (2) an ostial side branch stenosis before stenting (OR 2.96, 95% CI 1.26-6.95, P =.013); (3) the involvement of the side branch origin within the lesion of the parent vessel (OR 2.77, 95% CI 1.17-6.57, P =.021); and (4) the balloon-to-artery ratio (OR 4.66, 95% CI 1.18-18.42, P =.028). Among the initially occluded side branches, 81.8% were spontaneously reperfused at follow-up. Late SBO involved 12% of the side branches without impaired antegrade flow after stenting and was predicted by the initial RLD of the side branch (OR 0.07, 95% CI 0.01-0.8, P =.032). Chronic SBO occurred in 13.5% of cases and was also predicted by the baseline RLD (OR 0.13, 95% CI 0.02-0.8, P =.028). CONCLUSIONS: Acute SBO after stenting occurred in 21.2% of cases and had a benign course. Most acutely occluded side branches underwent late spontaneous reperfusion. A baseline side branch diameter >1.4 mm predicted a preserved antegrade flow immediately after stent implantation, as well as during follow-up.

Course of indicators of thrombin activity in the early phase of acute myocardial infarction: effect of fibrinolytic therapy and acute percutaneous coronary angioplasty.

We evaluated assay systems for detection of in vivo thrombin activity in patients with acute myocardial infarction. The study included 31 consecutive patients with acute myocardial infarction treated either with fibrinolytic therapy (FLT), or acute PTCA. Blood samples were drawn at admission, after 30 min, 1 h, 3 h, 6 h, 12 h, 24, and 48 h. Assays related to the enzymatic action of thrombin included fibrinopeptide A ELISA, a novel latex-enhanced photometric immunoassay for soluble fibrin complexes, fibrin monomer antigen, D-dimer antigen, and soluble platelet glycoprotein V, which is released from the platelet surface by thrombin cleavage. The soluble fibrin assay displayed a high degree of correlation with fibrinopeptide A, and no correlation with D-dimer antigen, indicating that this parameter allows monitoring of in vivo thrombin activity in patients with acute myocardial infarction. Fibrin monomer antigen, and D-dimer antigen, were influenced by FLT, indicating cross-reactivity with proteolytic fragments of fibrin. No significant changes in soluble glycoprotein V were observed. The results show that the novel soluble fibrin assay appears to be a promising method for measurement of in vivo fibrin formation in patients with acute myocardial infarction, irrespective of the primary treatment decision for FLT or acute PTCA.

Utilization of eptifibatide for treatment of severe dissections as a bail-out procedure.

BACKGROUND: It has been shown in several large trials that the inhibition of glycoprotein (GP) IIb/IIIa receptors of platelets can reduce the rate of ischemic complications following percutaneous transluminal coronary angioplasty (PTCA). We sought to determine the efficacy of eptifibatide in patients with severe dissections or threatened vessel closure after PTCA in small coronary arteries (< 2.5 mm). METHODS: Eptifibatide was used in 51 patients after conventional balloon angioplasty complicated by severe dissections with or without threatened vessel occlusion. Eptifibatide was administered as a double-bolus of 180 microg/kg bodyweight, followed by a continuous infusion at a dosage of 2.0 microg/kg min over a time period of 20 h. In this situation, the implantation of a coronary stent was avoided if a prompt antegrade flow of contrast dye could be maintained. RESULTS: Using the GP IIb/IIIa antagonist eptifibatide, it was possible to increase or to maintain antegrade blood flow in 28 (55%) patients. In 45% of the patient population, however, repeat PTCA was needed, and in four patients (7.8%) an intracoronary stent had to be implanted. During hospitalization three (6%) patients underwent target lesion revascularization (two Re-PTCAs, one coronary bypass graft operation). There were no myocardial infarctions and there was no intrahospital death. The cumulative event rate including acute and long term events was 25%. CONCLUSIONS: The findings of our study indicate that eptifibatide is able to prevent vessel occlusion after PTCA complicated by severe dissections with or without threatened vessel occlusion associated with a low-in-hospital complication rate.

Pathogenetic role of Chlamydia pneumoniae in calcific aortic stenosis: immunohistochemistry study and review of the literature.

BACKGROUND AND AIM OF THE STUDY: Non-rheumatic, calcific aortic stenosis (AS) is the most prevalent heart valve disease in the elderly. It is based on a chronic inflammatory process with infiltration and activation of leukocytes, and a rise in systemic inflammatory markers. An association with Chlamydia pneumoniae infection has been discussed, but previous studies have yielded divergent results. METHODS: Tricuspid aortic valves with calcific AS were obtained from patients undergoing aortic valve replacement. Control valves from patients matched for age and cardiovascular risk factors were obtained at autopsy. Immunohistochemistry was performed using monoclonal antibodies directed against C. pneumoniae and against leukocyte common antigen. Cultured HEp-2 cells infected with C. pneumoniae were used as positive controls. RESULTS: Positive immunostaining for C. pneumoniae was demonstrated in 12 of 14 (86%) stenotic valves and in six of nine (67%) control valves. Immunostained cells were located mainly in cell- and leukocyte-rich areas. Although stenotic valves showed a higher staining intensity as assessed by semiquantitative scoring (1.8 +/- 0.4 versus 0.8 +/- 0.2 units, p < 0.05), there was no statistically significant difference between stenotic and control valves regarding the presence of C. pneumoniae (p = 0.90). CONCLUSION: Positive immunostaining for C. pneumoniae was not associated with the presence of calcific AS. As in previous serologic and molecular biology studies, a high prevalence of C. pneumoniae in the adult population was demonstrated, irrespective of heart valve disease. Thus, C. pneumoniae is most likely not involved in the pathogenesis of calcific aortic stenosis.

Expression of bone sialoprotein and bone morphogenetic protein-2 in calcific aortic stenosis.

BACKGROUND AND AIM OF THE STUDY: Calcific aortic stenosis, the major heart valve disease encountered in the elderly, leads to massive calcium deposition in the valve leaflets that morphologically resembles bone formation. Recent studies have demonstrated the expression of various bone-associated proteins in stenotic valves, suggesting that valvular calcification may be an actively regulated process. Bone sialoprotein (BSP), a non-collagenous bone matrix protein, and bone morphogenetic protein-2 (BMP-2), a member of the transforming growth factor cytokine superfamily, are known to participate in the regulation of bone development and maturation. Their pathogenetic role in calcific aortic stenosis is unknown. METHODS: Using an immunoperoxidase technique and antibodies against BSP and BMP-2, the expression of BSP and BMP-2 was examined in 16 human aortic valves with calcific aortic stenosis obtained at valve replacement, and in seven normal autopsy controls without signs of aortic stenosis. RESULTS: By semiquantitative scoring, stenotic valves showed a significantly increased staining of BSP in cells and extracellular matrix as compared to control valves (2.7 +/- 0.1 versus 0.6 +/- 0.2 score units, p <0.001). Marked BMP-2 expression was detected in stenotic valves, mostly in cell-rich areas associated with focal calcium deposits, but no specific staining for BMP-2 was detected in control valves (1.5 +/- 0.2 versus 0.0 +/- 0.0 score units, p <0.001). CONCLUSION: These results demonstrate for the first time that BSP and BMP-2 are differentially expressed in normal aortic valves and in aortic stenosis, thereby supporting the concept that valvular calcification might be based on an actively regulated process involving BSP and BMP-2.