Jonathan D. Marmur

Tissue factor is rapidly induced in arterial smooth muscle after balloon injury.

Tissue factor (TF) is a major activator of the coagulation cascade and may play a role in initiating thrombosis after intravascular injury. To investigate whether medial vascular smooth muscle provides a source of TF following arterial injury, the induction of TF mRNA and protein was studied in balloon-injured rat aorta. After full length aortic injury, aortas were harvested at various times and the media and adventitia separated using collagenase digestion and microscopic dissection. In uninjured aortic media, TF mRNA was undetectable by RNA blot hybridization. 2 h after balloon injury TF mRNA levels increased markedly. Return to near baseline levels occurred at 24 h. In situ hybridization with a 35S-labeled antisense rat TF cRNA probe detected TF mRNA in the adventitia but not in the media or endothelium of uninjured aorta. 2 h after balloon dilatation, a marked induction of TF mRNA was observed in the adventitia and media. Using a functional clotting assay, TF procoagulant activity was detected at low levels in uninjured rat aortic media and rose by approximately 10-fold 2 h after balloon dilatation. Return to baseline occurred within 4 d. These data demonstrate that vascular injury rapidly induces active TF in arterial smooth muscle, providing a procoagulant that may result in thrombus initiation or propagation.

Creatine Kinase-MB Elevation After Coronary Intervention Correlates With Diffuse Atherosclerosis, and Low-to-Medium Level Elevation Has a Benign Clinical Course Implications for Early Discharge After Coronary Intervention

OBJECTIVES The study evaluated the incidence and predictors of creatine kinase-MB isoenzyme (CK-MB) elevation after successful coronary intervention using current devices, and assessed the influence on in-hospital course and midterm survival. BACKGROUND The CK-MB elevation after coronary intervention predominantly using balloon angioplasty correlates with late cardiac events of myocardial infarction (MI) and death. Whether CK-MB elevation after nonballoon devices is associated with an adverse short and midterm prognosis is unknown. METHODS The incidence and predictors of CK-MB elevation after coronary intervention were prospectively studied in 1,675 consecutive patients and were followed for in-hospital events and survival. RESULTS CK-MB elevation was detected in 313 patients (18.7%), with 1-3x in 12.8%, 3-5x in 3.5% and >5x normal in 2.4% of patients. Procedural complications or electrocardiogram changes occurred in only 49% of the CK-MB-elevation cases; CK-MB elevation was more common after nonballoon devices (19.5% vs. 11.5% after percutaneous transluminal coronary angioplasty; p < 0.01). Predictors of CK-MB elevation on multivariate analysis were diffuse coronary disease (p = 0.02), systemic atherosclerosis (p = 0.002), stent use (p = 0.04) and absence of beta-blocker therapy (p = 0.001). Adverse in-hospital cardiac events were more frequent in patients with >5x CK-MB elevation, with no significant difference between 1-5x CK-MB elevation versus normal CK-MB group. During a mean follow-up of 13 +/- 3 months, the incidence of death in the CK-MB-elevation group was 1.6% versus 1.3% in the normal CK-MB group (p = NS). CONCLUSIONS The CK-MB elevation after coronary intervention was observed even in the absence of discernible procedural complications and was more common in patients with diffuse atherosclerosis. In-hospital clinical events requiring prolonged monitoring were higher in >5x CK-MB-elevation patients only. Midterm survival of CK-MB-elevation patients was similar to those with normal CK-MB. Our prospective analysis shows a lack of adverse in-hospital cardiac events and suggests that early discharge of stable 1-5x normal CK-MB-elevation patients after successful coronary intervention is safe.

Adjunctive thrombolytic therapy during angioplasty for ischemic rest angina. Results of the TAUSA Trial. TAUSA Investigators. Thrombolysis and Angioplasty in Unstable Angina trial.

BACKGROUND Acute closure is increased after angioplasty in unstable angina, and adjunctive intracoronary thrombolytic therapy has been used successfully to increase angiographic success. The role of prophylactic thrombolytic therapy during angioplasty in unstable angina is unknown. METHODS AND RESULTS Four hundred sixty-nine patients with ischemic rest pain with or without a recent (< 1 month) infarction were randomized in double-blind fashion to intracoronary urokinase or placebo. Randomization was carried out in two sequential phases. In phase I, 257 patients were randomized to 250,000 U of urokinase or placebo given in divided doses at the time of angioplasty. In phase II, 212 patients were randomized to 500,000 U of urokinase or placebo in divided doses. All patients were pretreated with aspirin, and activated clotting times were followed to maintain them at > 300 seconds during angioplasty. Angiographic end points of thrombus after angioplasty were insignificantly decreased by urokinase (30 [13.8%] versus 41 [18.0%] with placebo; P = NS). Acute closure, on the other hand, was increased with urokinase (23 [10.2%] versus 10 [4.3%] with placebo; P < .02). The difference in acute closure between urokinase and placebo was more striking at the higher dose of urokinase (P < .04) than in phase I at the lower urokinase dose (P = NS). Adverse in-hospital clinical end points (ischemia, infarction, or emergency coronary artery bypass surgery) were also increased with urokinase versus placebo (30 [12.9%] versus 15 [6.3%], respectively; P < .02). Angiographic and clinical end points were worse with urokinase in unstable angina without recent infarction than with angioplasty after a recent infarction. CONCLUSIONS Adjunctive urokinase given prophylactically during angioplasty for ischemic rest angina as administered in this trial is associated with adverse angiographic and clinical events. These detrimental effects may be related to hemorrhagic dissection, lack of intimal sealing, or procoagulant or platelet-activating effects of urokinase.

Rotational atherectomy for in-stent restenosis: acute and long-term results of the first 100 cases

OBJECTIVES This study evaluated the clinical safety and long-term results of rotational atherectomy (RA) followed by low-pressure balloon dilatation (percutaneous transluminal coronary angioplasty [PTCA]) for the treatment of in-stent restenosis (ISR). BACKGROUND In-stent restenosis is associated with a high incidence of recurrence after interventional treatment. Because ISR is due to neointimal hyperplasia, rotational ablation may be a more effective treatment than PTCA. METHODS Between November 1995 and November 1996, 100 consecutive patients with first-time ISR were treated by RA. Quantitative coronary angiography and intravascular ultrasound (IVUS) were used to analyze the acute procedural results. The incidence of repeat in-stent restenosis and target vessel revascularization (TVR) at follow-up was determined. RESULTS Procedural success without any major in-hospital complications was achieved in 100% of cases. Slow flow was observed in 3% and creatine kinase-MB enzyme elevation >3x normal occurred in 2%. The mean burr-to-artery ratio was 0.68+/-0.18 and adjuvant balloon dilatation was performed at 4.2+/-2.1 atm. Minimum luminal diameter increased from 0.86+/-0.28 mm to 1.89< or =0.21 mm after RA and to 2.56+/-0.29 mm after adjunct PTCA. Quantitative IVUS analysis showed that 77% of the luminal gain occurred due to rotational ablation of the restenotic tissue and only 23% occurred after adjunct balloon dilation, and further stent expansion did not contribute to the luminal enlarge. ment. At a mean follow-up of 13+/-5 months, repeat in-stent restenosis occurred in 28% of patients with TVR of 26%. Univariate predictors of repeat restenosis were burr-to-artery ratio <0.6, ISR in <90 days of stenting, ostial lesion, stent for a restenotic lesion and diffuse type ISR. CONCLUSIONS Rotational atherectomy is a safe and feasible technique for treatment of ISR and is associated with a relatively low recurrent restenosis in comparison to historical controls of balloon angioplasty.

Cardioprotective Effect of Prior β-Blocker Therapy in Reducing Creatine Kinase-MB Elevation After Coronary Intervention: Benefit Is Extended to Improvement in Intermediate-Term Survival

BACKGROUND Both retrospective studies and prospective randomized trials have shown that beta-blockers improve survival and reduce the risk of reinfarction in patients with myocardial infarction. To evaluate whether beta-blockers exert similar protective benefits during and after coronary intervention, we studied the incidence of postprocedure creatine kinase (CK)-MB elevation in patients with or without prior beta-blocker therapy and its effect on intermediate-term ( approximately 1 year) survival. METHODS AND RESULTS We prospectively analyzed 1675 consecutive patients undergoing coronary intervention; of these patients, 643 (38.4%) were on beta-blocker therapy before the intervention. The incidence of CK-MB elevation after coronary intervention was 13.2% in patients on beta-blocker therapy before intervention and 22.1% in patients who were not on beta-blockers (P<0.001). Patients with prior beta-blocker therapy had lower persistent/recurrent postprocedure chest pain and lower preprocedure and postprocedure heart rates and mean blood pressures compared with patients who were not on beta-blockers (P<0.001). Multiple linear regression analysis revealed prior beta-blocker therapy as the sole independent factor for lower CK-MB release after coronary intervention. During intermediate-term follow-up at 15+/-3 months, patients on beta-blocker therapy before intervention had lower mortality rates compared with those not on beta-blockers (0.78% versus 1.96%; P=0. 04), although the benefit was independent of the reduction in CK-MB release. CONCLUSIONS Our nonrandomized, prospective analysis suggests that prior beta-blocker therapy has a cardioprotective effect in limiting CK-MB release after coronary intervention and that it is associated with a lower mortality at intermediate-term follow-up.

Thrombin generation in human coronary arteries after percutaneous transluminal balloon angioplasty

OBJECTIVES The aim of this study was to investigate the relation between coronary atherosclerotic plaque injury and activation of the coagulation cascade. BACKGROUND Thrombus formation after atherosclerotic plaque disruption has been implicated in the pathogenesis of atherosclerosis, unstable angina and myocardial infarction. METHODS Biochemical markers of thrombin generation (prothrombin fragment F1+2) and thrombin activity (fibrinopeptide A) were measured in coronary blood before, during and immediately after percutaneous transluminal coronary angioplasty. After demonstrating that blood withdrawal through an angioplasty catheter does not artifactually elevate the plasma levels of these markers in patients after heparinization, coronary artery samples were collected proximal and distal to the lesion before and distal to the lesion after balloon inflation in 26 patients. RESULTS Plasma levels of F1+2 measured proximal to the lesion before angioplasty (median 0.47 nmol/liter, 95% confidence interval [CI] 0.40 to 0.50) were significantly elevated after angioplasty (median 0.55 nmol/liter, 95% CI 0.46 to 0.72, p = 0.001). In contrast, plasma fibrinopeptide A levels measured proximal to the lesion before angioplasty (median 2.0 ng/ml, 95% CI 1.3 to 2.2) were similar to those measured after angioplasty (median 1.8 ng/ml, 95% CI 1.3 to 3.0, p = NS). After we defined a normal range of interassay variability on the basis of values obtained from samples drawn proximal and distal to the lesion before angioplasty, seven patients (27%) had a significant increase in F1+2 plasma levels. A significant increase in plasma fibrinopeptide A occurred in five of these seven patients. Lesions with dissection, filling defects or haziness on postangioplasty angiography were associated with more thrombin generation than lesions without these features. CONCLUSIONS Markers of thrombin generation and activity can be collected safely and assayed accurately in heparinized blood withdrawn through an angioplasty catheter. Balloon dilation of coronary stenoses increases thrombin generation and activity within the coronary artery in a substantial subgroup of patients undergoing angioplasty.

Evolving role of tissue factor and its pathway inhibitor.

ObjectiveTo review the experimental and clinical evidence of the emerging role of tissue factor in intravascular thrombosis and to examine evidence supporting the potential use of tissue factor pathway inhibitor as an antithrombotic therapeutic agent. Data Sources and Study SelectionA PubMed search was conducted encompassing articles in the English language relating to tissue factor and tissue factor pathway inhibitor in intravascular coagulation. ConclusionsTissue factor, a membrane-bound procoagulant glycoprotein, is the initiator of the extrinsic clotting cascade, which is the predominant coagulation pathway in vivo. The traditional view localizes tissue factor to extravascular sites, where it remains sequestered from circulating factor VII until vascular integrity is disrupted or until tissue factor expression is induced in endothelial cells or monocytes. This perspective has been challenged since the discovery of tissue factor antigen in plasma, on circulating microparticles, and on leukocytes in whole blood. Recently, the apparent role of tissue factor has expanded with the demonstration that this molecule also functions as a signaling receptor. Recombinant tissue factor pathway inhibitor, an analogue of the physiologic inhibitor of tissue factor, is a potent inhibitor of thrombus formation in experimental models. In summary, the tissue factor pathway initiates thrombosis in vivo. In addition to its classic tissue-bound distribution, recently discovered blood-borne tissue factor may have an important procoagulant function. Despite showing promise in early human studies, a recently completed phase 3 trial of recombinant tissue factor pathway inhibitor in severe sepsis failed to show a reduction in the primary end point of 28-day all-cause mortality. Tissue factor pathway inhibitor, however, remains a plausible therapeutic agent in other conditions of increased thrombogenicity, such as acute coronary syndromes, and further studies to examine this potential are warranted.

Rotational Atherectomy: Improved Procedural Outcome With Evolution of Technique and Equipment. Single-Center Results of First 1,000 Patients

We present our single‐center experience of rotational atherectomy (RA) in the first 1,000 consecutive patients divided arbitrarily into three different time periods corresponding to significant changes in technique or equipment for RA. Period I (August 1994 to April 1995; 172 cases) is characterized by early experience, longer ablation, and frequent use of intra‐aortic balloon pump; period II (May 1995 to January 1996; 254 cases) is characterized by short ablation runs (20–30 sec) and use of rotaflush; period III (February 1996 to February 1997; 574 cases) is characterized by ReoPro use, neosynephrine boluses to avoid hypotension, and rota floppy wire and flexible shaft burrs. The procedural success rate has improved and complication rates have progressively declined over these three time periods. The incidence of lesion complexity (long and type C lesions) and patients with unstable rest angina have increased over these time periods of RA. Therefore, modification in procedural techniques and equipment over time have made RA a safe technique despite its use in very complex lesion subsets. Cathet. Cardiovasc. Intervent. 46:305–311, 1999.

Administration of Abciximab During Percutaneous Coronary Intervention Reduces Both Ex Vivo Platelet Thrombus Formation and Fibrin Deposition: Implications for a Potential Anticoagulant Effect of Abciximab

Abciximab (c7E3 Fab, ReoPro), a platelet glycoprotein (GP) IIb/IIIa inhibitor, decreases acute ischemic complications after percutaneous coronary interventions. Recently, abciximab was shown to decrease thrombin generation in vitro in a static system. To assess whether abciximab can decrease fibrin formation in blood from patients, we quantified both platelet thrombi and fibrin deposition by using an ex vivo flow chamber model. We prospectively studied 18 consecutive patients who underwent percutaneous interventions for unstable coronary syndromes. Blood was perfused directly from the patient through an ex vivo perfusion chamber at a high shear rate, thus mimicking mildly stenosed coronary arteries. Perfusion chamber studies were performed when patients were being treated with heparin plus aspirin before the procedure (baseline) and then repeated after the procedure, when patients were on either aspirin plus heparin alone (group 1, no abciximab, control) or aspirin plus heparin plus abciximab (group 2, abciximab treated). Each patient served as his or her own control. Specimens were stained with combined Massons trichrome-elastin and antibodies specific for fibrinogen, fibrin, and platelet GP IIIa. Total thrombus area and areas occupied by platelet aggregates and fibrin layers were quantified by planimetry. Group 1 demonstrated no significant change in thrombus area before versus after the procedure; in contrast, treatment with abciximab reduced total thrombus area by 48% in group 2 (after the procedure versus baseline, P=0.01). This decline was due to significant reductions in both platelet aggregates (55%, P=0.005) and fibrin layers (45%, P=0.03). The addition of abciximab to heparin and aspirin in patients undergoing coronary interventions significantly decreases ex vivo thrombus formation on an injured vascular surface. Treatment with abciximab appears to reduce both the platelet and the fibrin thrombus components. This finding supports a potential role for GP IIb/IIIa receptor blockade in decreasing fibrin formation in addition to inhibition of platelet aggregation. Thus, potent inhibitors of GP IIb/IIIa may also act as anticoagulants.

Incidence and mechanism of creatine kinase-MB enzyme elevation after coronary intervention with different devices†

The present study was conducted to evaluate the incidence of CK‐MB elevation and to identify the possible mechanisms of CK‐MB release after various coronary interventional devices. We prospectively studied 1,675 consecutive patients following various coronary interventions for CK‐MB elevation, from January 1997 to February 1998 and followed them for in‐hospital events. CK‐MB elevation was detected in 313 patients (18.7%); with 1–3 × normal in 12.8%, 3–5 × normal in 3.5%, and >5 × normal in 2.4%. CK‐MB elevation was more common after nonballoon devices (19.5% vs. 11.5% after balloon angioplasty; P < 0.01). Among the newer nonballoon devices, rotational atherectomy alone had a lower CK‐MB elevation compared to stent‐alone group (16.0% vs. 20.5%; P = 0.07). On univariate analysis, due to selective use of abciximab in high‐risk coronary interventions, there was higher incidence of CK‐MB elevation with abciximab (24.5% vs. 15.0% without abciximab; P < 0.01). Some kind of procedural complication was observed in 49% of the CK‐MB elevation group, with side‐branch closure being the most frequent (22.7%). In conclusion, CK‐MB elevation is common after successful coronary interventions and is higher after nonballoon devices. Cathet. Cardiovasc. Intervent. 48:123–129, 1999.