John J. Lopez

VEGF administration in chronic myocardial ischemia in pigs

OBJECTIVE Previous investigations have shown the effectiveness of sustained intra- or extravascular administration of vascular endothelial growth factor (VEGF) in chronic myocardial ischemia in improvement of left ventricular function. The present investigations were undertaken in order to evaluate efficacy of a single bolus or local intracoronary delivery. METHODS Yorkshire pigs underwent placement of a left circumflex artery ameroid occluder. Three weeks later the animals were randomized to treatment with VEGF (20 micrograms) accomplished by local intracoronary delivery system (InfusaSleeve, n = 10), intracoronary bolus infusion (n = 7) or by epicardial implantation of an osmotic delivery system (n = 7). An additional group of animals received intracoronary administration of saline and served as a control (n = 9). Three weeks after initiation of therapy, the animals were evaluated with regard to myocardial perfusion and global as well as regional ventricular function. RESULTS All three VEGF treatment groups but not the control animals demonstrated a significant increase in the left-to-left (but not right-to-left) collateral index, myocardial blood flow (pre-therapy LCX vs. LAD (average of all groups): 0.76 +/- 0.35 vs. 0.96 +/- 0.38 ml*min-1*g-1, p = 0.03; post-therapy: LCX vs. LAD: 1.16 +/- 0.39 vs. 1.15 +/- 0.28 ml*min-1*g-1, p = NS) and coronary vasodilatory reserve 3 weeks after growth factor administration. The observed increase in VEGF-induced perfusion correlated with improvement in regional ventricular function in all VEGF-treated groups (pre-therapy vs. post-therapy: i.c. VEGF 20 +/- 5.1 vs. 33 +/- 4.8; local VEGF 16 +/- 2.8 vs. 33.6; pump VEGF 17 +/- 3.8 vs. 34 +/- 4.9 p < 0.05 for all) but not control animals (21 +/- 3.3 vs. 27 +/- 5.8, p = NS). CONCLUSION Single intracoronary delivery (intravascular bolus or local delivery) of VEGF is effective in stimulating physiologically significant angiogenesis in porcine model of chronic myocardial ischemia.

Effect of Continuous Quality Improvement Analysis on the Delivery of Primary Percutaneous Transluminal Coronary Angioplasty for Acute Myocardial Infarction

A successful primary percutaneous transluminal coronary angioplasty (PTCA) program requires a learning process whereby the efficiency of the cardiac catheterization laboratory to deliver prompt intervention can be refined. The purpose of this study was to (1) quantify this learning process in terms of shortening the time to reperfusion, (2) examine the changes in strategy that allowed for this, and (3) determine if expedited reperfusion by primary PTCA improved patient outcomes. A database of all primary PTCA procedures was established in February 1, 1994. Continuous quality assurance analysis was performed, and program modifications introduced as needed. Patients were separated into early (group A = February 1, 1994 through January 31, 1995) and late (group B1 = February 1, 1995 through June 31, 1995, and group B2 = July 1, 1995 through December 31, 1995) cohorts. Time intervals to certain treatment landmarks were compared among groups. In-hospital outcomes were tabulated. Fifty-two consecutive patients were included (group A = 19, group B1 = 17, group B2 = 16). Time intervals shortened significantly (group A vs group B1 vs group B2) with the time from hospital presentation to first balloon inflation decreasing progressively (from 205 to 119 to 97 minutes; p <0.001). Most of this decrease was obtained by shortening the time from hospital presentation to xylocaine administration (158 to 85 to 72 minutes; p <0.005), although the time from xylocaine to first balloon inflation also decreased (from 47 to 33 to 24 minutes; p <0.005). Parallel decreases for in-hospital mortality (26% vs 0%; p = 0.004), adverse events (47% vs 18%; p = 0.05), and length of hospital stay (13.3 +/- 13.7 vs 8.4 +/- 4.4 days; p = NS) were demonstrated for groups A versus B1 and B2. A learning effect following initiation of a primary PTCA program is demonstrated in which reperfusion was more rapidly achieved as the result of procedural changes directed by quality improvement analysis with a concurrent improvement in in-hospital outcomes.

Real-Time Three-Dimensional Transesophageal Echocardiography of the Left Atrial Appendage: Initial Experience in the Clinical Setting

BACKGROUND The aim of this study was to determine the feasibility and accuracy of a new real-time 3-dimensional (RT3D) matrix-array transesophageal echocardiographic probe for the determination of left atrial appendage (LAA) geometry. METHODS Sixty-six consecutive patients (mean age, 53 +/- 17 years) referred for 2-dimensional (2D) transesophageal echocardiography (TEE) underwent additional RT3D TEE. The feasibility of RT3D TEE for LAA geometry was studied in the first 37 patients, and 2D and RT3D transesophageal echocardiographic quantification of the LAA were compared in the subsequent 29 patients. The LAA orifice diameter and depth were measured using biplane 2D TEE, and LAA orifice area was calculated as an ellipse. LAA orifice area and depth were measured in 3D and correlated to 2D measurement and were also correlated to 64-slice cardiac computed tomography (CT) in 8 patients. RESULTS All 66 patients underwent RT3D matrix-array TEE without complication. In the feasibility study, the LAA was well visualized in 95%. In the quantitation study, 2D TEE underestimated LAA orifice area compared with 3D imaging (3.1 +/- 1.3 vs 4.2 +/- 2.2 cm(2); r = 0.55). LAA depth by 2D and 3D imaging were well correlated (3.7 +/- 0.7 vs 3.4 +/- 0.7 cm; r = 0.77). LAA orifice area on CT was well correlated with area on 3D TEE (r = 0.98) but not with area 2D TEE (r = 0.13). Bland-Altman analysis demonstrated that 2D TEE systematically underestimated LAA orifice area compared with 3D TEE (mean bias, -1.0 cm(2), with wide limits of agreement [-4.6 to 2.6 cm(2)]). In the 8 patients who underwent both 3D TEE and CT, the mean bias was 0.15 cm(2), with narrow limits of agreement (-0.50 to 0.20 cm(2)). CONCLUSIONS RT3D TEE for the visualization and quantitative analysis of LAA orifice area is feasible and correlates well with 64-slice cardiac CT.

Stent jail: A minimum-security prison

Small but significant side branches (particularly those with baseline ostial narrowing) may be further compromised by stent placement within parent vessel segments. Despite the theoretical risks associated with dilating branches in stent jail, the procedure was successfully completed in 84%, with minimal complications (mostly balloon rupture and local dissection) and no cases of balloon entrapment or deterioration of the final result achieved in the parent vessel.

Plaque development, vessel curvature, and wall shear stress in coronary arteries assessed by X-ray angiography and intravascular ultrasound

The relationships among vascular geometry, hemodynamics, and plaque development in the coronary arteries are complex and not yet well understood. This paper reports a methodology for the quantitative analysis of in vivo coronary morphology and hemodynamics, with particular emphasis placed on the critical issues of image segmentation and the automated classification of disease severity. We were motivated by the observation that plaque more often developed at the inner curvature of a vessel, presumably due to the relatively lower wall shear stress at these locations. The presented studies are based on our validated methodology for the three-dimensional fusion of intravascular ultrasound (IVUS) and X-ray angiography, introducing a novel approach for IVUS segmentation that incorporates a robust, knowledge-based cost function and a fully optimal, three-dimensional segmentation algorithm. Our first study shows that circumferential plaque distribution depends on local vessel curvature in the majority of vessels. The second study analyzes the correlation between plaque distribution and wall shear stress in a set of 48 in vivo vessel segments. The results were conclusive for both studies, with a stronger correlation of circumferential plaque thickness with local curvature than with wall shear stress. The inverse relationship between local wall shear stress and plaque thickness was significantly more pronounced (p<0.025) in vessel cross sections exhibiting compensatory enlargement (positive remodeling) without luminal narrowing than when the full spectrum of disease severity was considered. The inverse relationship was no longer observed in vessels where less than 35% of vessel cross sections remained without luminal narrowing. The findings of this study confirm, in vivo, the hypothesis that relatively lower wall shear stress is associated with early plaque development.

Feasibility of real-time three-dimensional transoesophageal echocardiography for guidance of percutaneous atrial septal defect closure

AIMS Intracardiac echocardiography (ICE) and two-dimensional transoesophageal echocardiography (2D TEE) are used in most centres for guiding transcatheter atrial septal defect (ASD) closure. ASDs have complex shapes that are not well characterized with 2D imaging. Real-time 3D TEE (RT3D TEE) provides en-face visualization of the ASD, allowing precise assessment of ASD dimensions. Accordingly, our aims were (i) to determine the feasibility of RT3D TEE to guide ASD closure and (ii) to compare ASD and balloon dimensions (BDs) using RT3D TEE vs. ICE and 2D TEE. METHODS AND RESULTS Thirteen patients with ostium secundum ASD underwent transcatheter ASD closure. 2D TEE, RT3D TEE, and ICE images were acquired sequentially. RT3D TEE was feasible in all patients. Comparing RT3D TEE and 2D imaging, the mean difference in long-axis dimension was +0.5 mm (P= NS for both), and -1.4 mm in short-axis (2D TEE, P < 0.05; ICE, P = 0.06). BD was greater with 3D TEE vs. ICE (+0.9 mm). CONCLUSION RT3D TEE can be used to guide transcatheter ASD closure with the advantages of lower cost than ICE, and ability to visualize en-face views of the ASD. ASD and BD as measured by RT3D TEE differ when compared with 2D imaging.

Clinical, procedural, and pharmacologic correlates of acute and subacute stent thrombosis: Results of a multicenter case-control study with 145 thrombosis events

OBJECTIVES The aim of this study was to determine correlates of acute/subacute coronary stent thrombosis among unselected patients treated in the era of routine dual antiplatelet therapy and specifically to investigate the influence of prophylactic administration of glycoprotein IIb/IIIa (GpIIb-IIIa) inhibitors and use of clopidogrel versus ticlopidine on the development of coronary stent thrombosis (ST). BACKGROUND Because of a relative infrequency of ST events and relatively uniform practice patterns within randomized trials, previous studies have had a limited ability to address whether the use of different antiplatelet regimens at the time of coronary stenting is associated with differences in ST. METHODS We performed a multicenter, case-control study to evaluate clinical, angiographic, and pharmacologic/procedural correlates of ST. Between 1996 and 2000, all cases of angiographically-confirmed ST (n = 145) among patients receiving dual antiplatelet therapy were identified from 10 participating clinical sites and were matched with a control without ST randomly selected from the same institution. RESULTS Multivariable conditional logistic regression identified higher pre-procedure platelet count, stenting for acute myocardial infarction, use of a coil or self-expanding stent, and overt angiographic thrombus prior to the procedure, as independent predictors of ST (all P < .05). After adjusting for these factors, the use of clopidogrel (vs ticlopidine) was independently associated with an increased risk of ST (OR 2.1, 95% CI 1.0-4.1, P = .04). The use of prophylactic glycoprotein IIb/IIIa inhibitors was not associated with reduced ST in the overall analysis, but appeared to confer some protection against ST within the first 24 hours post procedure (OR 0.5 [95% CI 0.2-1.1] for ST during first day, OR 1.7 [95% CI 0.7-4.3] for ST on subsequent days). CONCLUSION Both biologic and pharmacologic factors are independently associated with acute/subacute ST. The association between clopidogrel use (vs ticlopidine) and increased ST in this analysis requires confirmation in adequately powered clinical trials and suggests a potential role for newer and more potent antiplatelet agents.

Local Extravascular Growth Factor Delivery in Myocardial Ischemia

A number of angiogenic growth factors have been demonstrated in vivo to promote angiogenesis in ischemic myocardium, including basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF). We used the porcine ameroid constrictor model to simulate chronic ischemia in an effort to study the role of exogenous growth factor delivery in the development of coronary collateral circulation. Heparin alginate microspheres were used to deliver bFGF, while an implantable osmotic pump was used for VEGF delivery. Anti-von Willebrand antibody staining was used to visualize microvessels in the porcine heart sections obtained from both ischemic and non-ischemic myocardium. A significant increase in the number of microvessels in growth factor-treated pigs compared to control animals was noted. Myocardial blood flow was used to determine the physiologic impact of these findings. In bFGF and VEGF treated animals resting collateral flow values significantly exceeded those of the control group. In addition, both bFGF and VEGF administration resulted in improvements in myocardial perfusion sufficient to prevent stress-induced deterioration of myocardial performance. Results of the studies demonstrate that local perivascular drug delivery can be effectively used to induce angiogenesis in chronically ischemic myocardium.

Percutaneous occlusion of an latrogenic aortosaphenous vein‐coronary vein fistula via retrograde coronary sinus approach

Inadvertent aortosaphenous vein graft-coronary vein anastomosis during coronary bypass surgery is an uncommon complication. We describe a case of aortosaphenous vein side-to-side anastomosis to an obtuse marginal vein resulting in a large arteriovenous fistula and elective closure, using embolization coils delivered percutaneously via the coronary sinus. The clinical findings, interventional procedure, and follow-up are also presented, with a discussion of alternative techniques used previously to treat iatrogenic aortosaphenous vein graft venous fistulae.

Estimating the actual dose delivered by intravascular coronary brachytherapy using geometrically correct 3D modeling

Intravascular brachytherapy has shown to reduce re-occurrence of in-stent restenosis in coronary arteries. For beta radiation, application time is determined from source activity and the angiographically estimated vessel diameter. Conventionally used dosing models assume a straight vessel with the catheter centered and a constant-diameter circular cross section. Aim of this study was to compare the actual dose delivered during in-vivo intravascular brachytherapy with the target range determined from the patients prescribed dose. Furthermore, differences in dose distribution between a simplified tubular model (STM) and a geometrically correct 3-D model (GCM) obtained from fusion between biplane angiography and intravascular ultrasound were quantified. The tissue enclosed by the segmented lumen/plaque and media/adventitia borders was simulated using a structured finite-element mesh. The beta-radiation sources were modeled as 3-D objects in their angiographically determined locations. The accumulated dose was estimated using a fixed distance function based on the patient-specific radiation parameters. For visualization, the data was converted to VRML with the accumulated doses represented by color encoding. The statistical comparison between STM and GCM models in 8 patients showed that the STM significantly underestimates the dose delivered and its variability. The analysis revealed substantial deviations from the target dose range in curved vessels.