Design of the therapeutic angiogenesis with recombinant fibroblast growth factor-2 for intermittent claudication (TRAFFIC) trial.

The Therapeutic Angiogenesis With Recombinant Fibroblast Growth Factor-2 for Intermittent Claudication (TRAFFIC) is a large, randomized, placebo-controlled, regimen-finding trial of intra-arterial recombinant fibroblast growth factor-2 in patients with intermittent claudication. This report describes the major design considerations and end points in TRAFFIC.

Effect of balloon material and inflation strategy on arterial trauma and mechanisms of percutaneous transluminal coronary angioplasty as determined by intracoronary ultrasound.

Twenty-three patients were randomized to a minimally invasive strategy or to standard percutaneous transluminal coronary angioplasty followed by intracoronary ultrasound. There was no difference in intracoronary ultrasound-determined dissection after the procedure in the 2 groups, and the mechanism of lumen enlargement by percutaneous transluminal coronary angioplasty in both groups predominantly was due to vessel stretch.

Neovascularization in atherectomy specimens from patients with unstable angina: implications for pathogenesis of unstable angina.

Although neovascularization has been noted in atherosclerotic plaque, the presence of neovascularization has not been correlated with clinical syndromes. This study examined the relation between neovascularization in atherosclerotic plaque removed during directional coronary atherectomy and clinical status in 28 patients. Neovascularization was determined by immunohistochemistry with endothelial cell-specific monoclonal antibodies and was found in nine (50%) of 18 specimens from patients with unstable angina and in only one (10%) of 10 specimens from patients with stable angina (p < 0.05). There was no significant relation between neovascularization and other clinical factors (age, sex, race, hypertension, diabetes, tobacco use, hypercholesterolemia, positive family history of coronary artery disease, history of myocardial infarction, or stenosis severity). These results suggest that neovoscularization may play a role in the pathogenesis of unstable angina.

Intimal hyperplasia after balloon injury is attenuated by blocking selectins.

BACKGROUND: Cell adhesion molecules facilitate the adherence of platelets and leukocytes to the vascular endothelium in response to injury. Restenosis after balloon angioplasty is thought to represent the response to vascular injury. The role of cell adhesion in this process is unclear. METHODS AND RESULTS: This study was performed in New Zealand White rabbits that underwent balloon angioplasty of the iliac artery. Expression of the cell adhesion molecule E-selectin on endothelium was determined by immunohistochemistry and increased at 6 hours with a peak expression 24 to 48 hours after balloon injury, returning to baseline by 1 week. The expression of L-selectin on circulating leukocytes, measured by flow cytometry, was significantly increased at 48 hours, with return to baseline by 1 week. In seven animals, the selectins were blocked with an analogue of sialyl-Lewis(x) given as an I.V. bolus of 10 mg/kg followed by 2 mg x kg(-1) x h(-1) I.P. infusion for 7 days. After 4 weeks, compared with control animals, the study group had a larger lumen area (57.7 versus 44.7 mm2, P<.05), smaller intima area (9.0 versus 19.2 mm2, P<.01), smaller intima/media ratio (0.4 versus 1.0, P<.01), and a smaller percent area stenosis (15.6% versus 34.3%, P<.01). CONCLUSIONS: The cell adhesion molecules E-selectin and L-selectin are expressed after balloon injury. Blockade of the selectins has a favorable effect on the response to vascular injury.

Effect of short-term treatment with a monoclonal antibody to P-selectin on balloon catheter-induced: intimal hyperplasia, re-endothelialization, and attenuation of endothelial-dependent relaxation.

The effects of an anti-P-selectin monoclonal antibody (MAb, PB1.3; Cytel Corporation) on neoendothelialization; neoendothelial function, as evidenced by acetylcholine-induced relaxation (nitric oxide formation); and intimal hyperplasia following embolectomy catheter-induced injury to the rabbit thoracic aorta were investigated. Catheter injury was induced in two groups of New Zealand White rabbits. One group received no treatment, while the second group received short-term treatment with the MAb (i.p., immediately before and 12 h after induction of catheter injury). A third group underwent a sham operation and served as uninjured controls. Following sacrifice at 2 weeks after injury, aortic rings were assessed for degree of intimal hyperplasia, neoendothelial morphology (scanning electron microscopy), and acetylcholine-induced relaxation. Aortic tissue from catheter-injured animals that received treatment exhibited improved neoendothelial morphology, as compared with tissue from untreated but catheterized animals; however, no statistically significant attenuation of the hyperplastic response or improvement in the attenuated neoendothelial-dependent acetylcholine-induced relaxant response that is characteristic of neoendothelium that forms after catheter denudation was observed. These data suggest that short-term attenuation of P-selectin-mediated polymorphonuclear leukocyte (PMN)/endothelium, PMN/platelet interactions, and/or thrombin formation beneficially affects neoendothelialization of the vascular wall following balloon catheter-induced injury.

Levels of expression of P-selectin, E-selectin, and intercellular adhesion molecule-1 in coronary atherectomy specimens from patients with stable and unstable angina pectoris.

Unstable angina occurs when atherosclerotic plaque ruptures. Recent evidence suggests a role for inflammation in this process. Leukocyte-endothelial cell interactions are important in inflammation and are regulated by cell adhesion molecules. This study was designed to examine the vascular expression of cell adhesion molecules and cytokines in patients with unstable angina. Directional coronary atherectomy was performed in patients with unstable and stable angina. Expression of the cell adhesion molecules P-selectin, E-selectin, and intercellular adhesion molecule-1 in the tissue obtained was examined using immunohistochemistry. In addition, expression of the cytokines tumor necrosis factor-alpha and interleukin-1beta, which participate in the regulation of cell adhesion molecule expression, was also examined. Atherectomy specimens had significantly greater P-selectin expression from patients with unstable angina than from patients with stable angina. P-selectin expression was observed primarily on endothelial cells. There were no differences in any of the other factors between patients with unstable and stable angina. In addition, other clinical and angiographic variables were not associated with differential expression of any of the cell adhesion molecules or cytokines. These results indicate a possible role for P-selectin in the process of unstable angina.

Intravascular ultrasound and balloon percutaneous transluminal coronary angioplasty.

Intracoronary ultrasound provides unique information during percutaneous transluminal coronary angioplasty (PTCA), including more accurate measurement of vessel size and plaque burden as well as plaque characteristics such as composition and distribution. As a research tool, it has been useful in determining the mechanisms of PTCA, which primarily involves vessel stretch, plaque fracture/dissection, and plaque redistribution. It may be clinically useful in assessing lesion severity in patients with indeterminate clinical and angiographic findings. Plaque characteristics as determined by intracoronary ultrasound may also be helpful in developing an individualized interventional approach for each lesion. Finally, certain intracoronary ultrasound findings after PTCA, such as large dissections and large residual stenosis, are associated with increased risk of short-term and long-term adverse outcomes.

Spontaneous coronary artery spasm documented in a young woman. A case report.

A 35-year-old woman with coronary risk factors presented with nonexertional atypical burning chest pain of 1 week's duration. A myocardial perfusion study with Tc-99m MIBI revealed a severe stress induced anteroseptal perfusion defect that completely reperfused on a subsequent resting Tc-99m MIBI study. Coronary angiography showed mild nonobstructive coronary artery disease. At the termination of the procedure, a spontaneous episode of burning chest pain occurred. Left main coronary artery reinjection of contrast revealed proximal diffuse left anterior descending coronary artery spasm. The patient was followed for 2 years with no further episodes of chest pain, while on calcium channel-blocker medication. The phenomenon of vasospastic angina and the role of myocardial perfusion scintigraphy is discussed.

Lesion-directed administration of alteplase with intracoronary heparin in patients with unstable angina and coronary thrombus undergoing angioplasty.

Percutaneous coronary revascularization in patients with unstable angina and coronary thrombus carries a high complication rate. A new strategy to reduce thrombus burden before revascularization was tested in a multicenter prospective trial. Patients with unstable angina and coronary thrombus (n = 45) received alteplase through an infusion catheter at the proximal aspect of the target lesion and concomitant intracoronary heparin via a standard guiding catheter. Angiography was performed before and alter lesion-directed therapy and post-intervention. Systemic fibrinogen depletion and thrombin activation were not observed, while fibrinolysis was evident for > or = 4 hr after treatment. Target lesion stenosis did not change significantly after lesion-directed therapy, but thrombus score was reduced, particularly among patients who had large thrombi (mean 2.2 vs. 1.6, P = 0.02). Revascularization was successful in 89% of patients. Median final stenosis was 30% and mean final thrombus score was 0.4. Complications included recurrent ischemia (11%), MI (7%), abrupt closure (7%), severe bleeding (4%), and repeat emergency angioplasty (2%). Patients with overt thrombus appeared to derive the most angiographic benefit from lesion-directed alteplase plus intracoronary heparin. Later revascularization was highly successful. This strategy may be a useful adjunct to percutaneous revascularization for patients with unstable angina and frank intracoronary thrombus.

Lack of ventricular remodeling in non-Q-wave myocardial infarction.

We prospectively examined 45 patients with serial echocardiography to measure left ventricular end-diastolic volume index within 1 week and at 6 weeks after infarction. Left ventricular volume increased in patients with Q-wave infarction but not in those with non-Q or in control patients without recent infarction. Peak creatine phosphokinase levels were greater in Q-wave infarction compared with those in non-Q-wave infarction. There was a strong correlation between the change in the left ventricular end-diastolic index and the peak creatine phosphokinase level. After correcting for infarct size, there was still a difference between the two groups. Our data indicate that ventricular remodeling does not occur in non-Q-wave as opposed to Q-wave infarcts, and this may be related both to the limited amount of myocardial necrosis and to the nontransmural extent of the necrosis.

Intracoronary ultrasound: insights into mechanisms and results of coronary interventions.

Intracoronary ultrasound imaging is a modality which allows in vivo cross-sectional visualization of coronary arteries similar to that obtained by pathology. Compared with coronary angiography, intracoronary ultrasound provides more detail on plaque morphology and topography and more accurate quantification of lumen and plaque area. Thus, it has evolved into a valuable research tool. For example, intracoronary ultrasound imaging has increased understanding of the mechanisms of action of balloon angioplasty and new interventions such as atherectomy and laser treatment. It may prove to have clinical utility by helping to individualize device selection and sizing and by assessing treatment results more accurately. Coronary imaging may be performed at low risk. Future developments will include smaller catheters, combined ultrasound and therapeutic catheters, and three-dimensional reconstruction of images.

Predicting the risk of abrupt vessel closure after angioplasty in an individual patient.

OBJECTIVES: We proposed to examine the relation between angiographic morphologic characteristics and abrupt closure after coronary angioplasty and to develop an empirically based risk stratification system. BACKGROUND: Certain lesion morphologic characteristics are associated with higher rates of abrupt closure after coronary angioplasty. Previous approaches have been limited by relatively small sample sizes and an inability to combine multiple characteristics to predict risk in an individual patient. METHODS: Lesion morphology was determined for 779 lesions in 658 patients undergoing an elective first angioplasty. Abrupt closure occurred in 63 lesions (8.1%). Variables associated with abrupt closure were identified by univariate and stepwise multiple logistic regression analysis, and internal validity was assessed by use of bootstrapping. An empirically based scoring system was developed by assigning different weights to each predictive characteristic and was then validated. RESULTS: Almost all lesion characteristics previously labeled "adverse" were associated with an increased risk of abrupt closure, but only total occlusion, location at a branch point, increasing lesion length, evidence for thrombus and right coronary artery location were statistically significant independent predictors. Despite the large sample size, the study was underpowered to detect even a 50% increase in risk with many characteristics. Using a scoring system, we assigned each lesion a specific risk of abrupt closure. The distribution of risk was broad, with 20% of patients having < or = 2.5% risk and 25% having > 10% risk. Internal validation techniques revealed that when 10% of patients were randomly eliminated from the sample in multiple iterations, the risk estimates varied, again pointing to the need for a larger sample. CONCLUSIONS: Empirically based weighting of lesion characteristics could quantify the risk of abrupt closure for individual patients, but a very large sample will be required to understand the interplay of complex lesion characteristics in altering expected outcomes.

Long-term outcome following successful reopening of abrupt closure after coronary angioplasty.

Abrupt closure after coronary angioplasty is often successfully treated by repeat dilation. Long-term follow-up, including 6-month repeat catheterization and 12-month clinical evaluation, was obtained in 1,056 patients treated with acute (n = 335) or elective (n = 721) coronary angioplasty to evaluate the long-term impact of successful reopening of abrupt closure. Abrupt closure occurred in 13.5% of patients and was successfully reopened in 58%. Adverse outcomes including restenosis, death, bypass surgery, myocardial infarction and repeat angioplasty were compared between patients with successfully treated abrupt closure and those with successful procedures (residual diameter stenosis < or = 50%) without abrupt closure. For patients with acute angioplasty, the restenosis rates (> 50% diameter stenosis at follow-up) were 64% for those with successfully treated abrupt closure versus 36% for those with successful procedures without abrupt closure (p < 0.01). In addition, subsequent myocardial infarction (12 vs 3%; p = 0.01) and repeat angioplasty (21 vs 10%; p = 0.03) were more frequent in the group with abrupt closure. For patients with elective angioplasty, restenosis was 43% in those with successfully treated abrupt closure versus 45% in those without abrupt closure (p = NS). Subsequent death and myocardial infarction were more frequent in patients with abrupt closure (death: 12 vs 3% [p < 0.01]; myocardial infarction: 13 vs 3% [p < 0.01]). Long-term adverse events are increased in patients with successfully treated abrupt closure compared to those with successful procedures without abrupt closure.

Treatment of long coronary artery narrowings with long angioplasty balloon catheters.

Balloon angioplasty of long coronary artery narrowings has been associated with a lower rate of acute success, and a higher rate of acute complications and restenosis than that observed for short narrowings. Angioplasty catheters with longer length balloons (30 and 40 mm) are now available, and the objective of this study was to determine the acute and long-term success for patients with long coronary artery narrowings treated with these longer balloons. All patients with long narrowings (> or = 10 mm) treated with long balloons at 1 institution over a 1-year period were identified (93 narrowings in 89 patients), and acute and long-term outcomes were carefully documented. Procedural success (residual stenosis < or = 50%) was 97%. Abrupt closure occurred in 6% and major dissection in 11% of narrowings. Clinical success (procedural success without in-hospital death, bypass surgery or myocardial infarction) was achieved in 90% of patients. Repeat catheterization was performed in 61 patients (76% of those eligible), and restenosis was found in 50 to 55%, depending on the definition used. The treatment of long coronary artery narrowings using angioplasty catheters with longer balloons leads to high rates of acute success. However, there is a high rate of restenosis. New interventional devices for long lesions should be compared with long balloons in a randomized controlled trial.

Ultrasound guide wire-directed stent deployment.

A new mechanically rotated 20 MHz intravascular ultrasound guide wire (0.032 inch) with a transducer core was placed through the central lumen of a peripheral arterial balloon-expandable stent. Using an anesthetized canine model, 11 stents were then deployed into the iliac or femoral arteries. Eight stents were successfully deployed with proper position and full stent expansion documented by ultrasound imaging. Four of the stents were overlapping and the double row of stent struts at the region of overlap was easily seen. Three stents were unsuccessfully deployed because of undersizing, as clearly documented by ultrasound imaging showing stent strut recoil. As a result, the procedure was modified by performing ultrasound measurements of arterial dimensions before stent selection. There were no complications attributed to the ultrasound guide wire. This study demonstrates an effective combination of diagnostic and therapeutic devices that may allow more precise placement of intravascular stents.

In vivo validation of compensatory enlargement of atherosclerotic coronary arteries.

Necropsy examinations and epicardial ultrasound studies have suggested that atherosclerotic coronary arteries undergo compensatory enlargement. This increase in vessel size may be an important mechanism for maintaining myocardial blood flow. It also is of fundamental importance in the angiographic study of coronary disease progression and regression. The purpose of this study was to determine, using intracoronary ultrasound, whether coronary arteries undergo adaptive expansion in vivo. Forty-four consecutive patients were studied (30 men, 14 women; mean age 56 +/- 10 years). Eighty intravascular ultrasound images were analyzed (32 left main, 23 left anterior descending and 25 right coronary arteries). Internal elastic lamina area, a measure of overall vessel size increased as plaque area expanded (r = 0.57, p = 0.0001, SEE = 5.5 mm2). When the left main, left anterior descending and right coronary arteries were examined individually, there continued to be as great or greater positive correlation between internal elastic lamina and plaque area (left anterior descending: r = 0.75, p = 0.0001; right coronary arteries: r = 0.63, p = 0.0007; left main: r = 0.56, p = 0.0009), implying that each of the vessels and all in aggregate underwent adaptive enlargement. When only those vessels with < 30% area stenosis were examined, internal elastic lamina correlated well with plaque area (r = 0.79, and p = 0.0001), and for each 1 mm2 increase in plaque area, internal elastic lamina increased 2.7 mm2. This suggests that arterial enlargement may overcompensate for early atherosclerotic lesions.(ABSTRACT TRUNCATED AT 250 WORDS)

Unrecognized left main coronary artery disease in patients undergoing interventional procedures.

Selective, coronary arteriographic, catheter-based, intravascular ultrasound images were obtained to determine the presence and extent of angiographically undetected or underestimated left main (LM) coronary arterial narrowing in patients receiving coronary interventional therapy. Coronary arteriograms were determined to be either normal or abnormal by visual inspection. Abnormal arteriograms were digitized and quantitated using a semiautomated edge-detection algorithm. Thirty-eight patients receiving percutaneous treatment of stenoses in the left coronary artery system were studied. Optimal LM coronary angiograms were obtained in 2 views, and intravascular ultrasound images were obtained after the coronary interventional procedure. Intravascular ultrasound detected plaque in 24 of 27 angiographically normal LM arteries (89%), whereas narrowing was observed in 11 of 11 angiographically abnormal LM arteries (100%). Eight of 38 patients (21%) had > 40% area stenosis by intravascular ultrasound. In patients with angiographic disease, there was no correlation between quantitative angiographic and ultrasound percent area stenosis (r = 0.12; p = 0.72; SEE 19%). The median plaque area was not different between angiographically normal (0.05 cm2; 0.03, 0.08 [25th, 75th percentile]) and abnormal (0.06 cm2; 0.03, 0.1) patients. The median percent area stenosis in arteriographically normal subjects (26%; 14, 32%) was less than that in abnormal ones (37%; 20, 46%) (p = 0.03). Unrecognized LM disease is widespread and often underestimated in patients with normal LM angiograms undergoing interventional procedures. Plaque area is similar for angiographically normal and insignificantly abnormal vessels. This study suggests that intravascular ultrasound overcomes the limitations of silhouette imaging and can be a clinically useful, adjunctive method to evaluate LM coronary artery disease.

Angioplasty for acute coronary syndromes.

The acute ischemic syndromes (unstable angina and acute myocardial infarction) are often treated with percutaneous transluminal coronary angioplasty. Angioplasty should be considered in patients with unstable angina refractory to medical therapy and in those with evidence for ischemia after medical stabilization. Direct or primary angioplasty is indicated in patients with acute myocardial infarction with contraindications to thrombolytic therapy and is a reasonable alternative even in those eligible for thrombolytics. While there is no role for immediate angioplasty of a patent infarct-related artery following thrombolysis, rescue angioplasty of persistently occluded arteries may be beneficial, although further studies are needed.

Intracoronary ultrasound predictors of adverse outcomes after coronary artery interventions.

OBJECTIVES: The purpose of this study was to determine the association between qualitative and quantitative lesion characteristics as assessed by intracoronary ultrasound imaging and adverse outcomes after coronary artery interventions. BACKGROUND: Restenosis and other adverse outcomes after coronary artery interventions may be difficult to predict from clinical or angiographic data. Intracoronary ultrasound imaging provides additional data that could prove useful. METHODS: Immediately after successful coronary artery interventions (angiographic residual stenosis < or = 50%), 69 patients underwent intracoronary ultrasound imaging. Images were assessed qualitatively for plaque composition and topography and for dissection. Quantitative data included measurement of minimal lumen diameter, lumen area, plaque area and percent area stenosis at the treatment and adjacent reference sites. Adverse outcome was defined as death, coronary bypass surgery, myocardial infarction or angiographic restenosis. RESULTS: Of the 69 patients, 1 died, 3 had bypass surgery and 1 had a myocardial infarction before planned 6-month repeat catheterization. Two patients were lost to follow-up study. Of the remaining 62 patients, 56 (90%) agreed to follow-up catheterization and 25 (45%) of the 56 had restenosis. Thus, 30 patients had an adverse outcome and 37 had no adverse event. The incidence of dissection detected by ultrasound imaging after an intervention was significantly greater in patients with than in those without a subsequent adverse event (63% vs. 35%, p < 0.05). The severity of dissection also appeared to be related to outcome (p < 0.05). Other qualitative and quantitative variables were not significantly different between the two patient groups. CONCLUSIONS: Dissection, as assessed by intracoronary ultrasound imaging after a coronary artery intervention, can identify patients at increased risk of subsequent adverse events. Additional studies are warranted to explore whether such imaging may allow modification of interventional procedures to improve outcome.

Mechanisms of balloon angioplasty and directional coronary atherectomy as assessed by intracoronary ultrasound.

OBJECTIVE: This study was designed to use intracoronary ultrasound imaging to elucidate the physical effects of balloon angioplasty and directional coronary atherectomy in vivo in humans. BACKGROUND: The proposed mechanisms of coronary artery interventions such as balloon angioplasty and directional atherectomy are based on animal studies or pathologic findings and these data may not be applicable to living patients. Intracoronary ultrasound findings correlate highly with pathologic results and may allow in vivo assessment of the mechanisms of such interventions in humans. METHODS: Intracoronary ultrasound imaging was performed in 45 patients after a successful coronary intervention (balloon angioplasty in 30, directional coronary atherectomy in 15). Ultrasound images obtained at the treatment site and at an adjacent angiographically normal references site were analyzed quantitatively for minimal lumen diameter, cross-sectional lumen area, are enclosed by the internal elastic lamina, plaque area (internal elastic lamina area--lumen area) and percent area stenosis (plaque area/internal elastic lamina area). Qualitative analysis included assessment of presence of dissection, plaque composition and plaque topography. RESULTS: The results of the two procedures were similar with respect to minimal lumen diameter (angioplasty 2.6 +/- 0.5 vs. atherectomy 2.6 +/- 0.3 mm, p = NS), lumen area (0.07 +/- 0.03 vs. 0.07 +/- 0.02 cm2, p = NS) and percent area stenosis (59 +/- 14% vs. 51 +/- 21%, p = NS). However, after angioplasty, the internal elastic lamina area was significantly larger at the treated site than at the reference site (delta = +0.03 +/- 0.04 cm2, p = 0.01). There was no significant difference between the two sites after atherectomy (delta = -0.01 +/- 0.05 cm2, p = NS). In addition, dissection was seen significantly more often after balloon angioplasty than after atherectomy (50% vs. 7%, p less than 0.01). The results were similar when stratified for plaque composition and morphology. These data were confirmed in six additional patients who underwent ultrasound imaging before and after the intervention. CONCLUSIONS: Thus, the improvement in lumen dimensions after coronary balloon angioplasty is a result of both vessel stretch, demonstrated by a larger internal elastic lamina area at the treated site, and dissection. Both vessel stretch and dissection are uncommon after atherectomy, a finding consistent with plaque removal as the major mechanism for improved lumen area after this procedure.