Daryl G. Schulz

A Novel Feature-Tracking Echocardiographic Method for the Quantitation of Regional Myocardial Function: Validation in an Animal Model of Ischemia-Reperfusion

OBJECTIVES The aim of this study was to validate a novel, angle-independent, feature-tracking method for the echocardiographic quantitation of regional function. BACKGROUND A new echocardiographic method, Velocity Vector Imaging (VVI) (syngo Velocity Vector Imaging technology, Siemens Medical Solutions, Ultrasound Division, Mountain View, California), has been introduced, based on feature tracking-incorporating speckle and endocardial border tracking, that allows the quantitation of endocardial strain, strain rate (SR), and velocity. METHODS Seven dogs were studied during baseline, and various interventions causing alterations in regional function: dobutamine, 5-min coronary occlusion with reperfusion up to 1 h, followed by dobutamine and esmolol infusions. Echocardiographic images were acquired from short- and long-axis views of the left ventricle. Segment-length sonomicrometry crystals were used as the reference method. RESULTS Changes in systolic strain in ischemic segments were tracked well with VVI during the different states of regional function. There was a good correlation between circumferential and longitudinal systolic strain by VVI and sonomicrometry (r = 0.88 and r = 0.83, respectively, p < 0.001). Strain measurements in the nonischemic basal segments also demonstrated a significant correlation between the 2 methods (r = 0.65, p < 0.001). Similarly, a significant relation was observed for circumferential and longitudinal SR between the 2 methods (r = 0.94, p < 0.001 and r = 0.90, p < 0.001, respectively). The endocardial velocity relation to changes in strain by sonomicrometry was weaker owing to significant cardiac translation. CONCLUSIONS Velocity Vector Imaging, a new feature-tracking method, can accurately assess regional myocardial function at the endocardial level and is a promising clinical tool for the simultaneous quantification of regional and global myocardial function.

In Vivo Plaque Characterization Using Intravascular Ultrasound–Virtual Histology in a Porcine Model of Complex Coronary Lesions

Objective—To determine the accuracy of detection of different tissue types of intravascular ultrasound–virtual histology (IVUS-VH) in a porcine model of complex coronary lesions. Methods and Results—Coronary lesions were induced by injecting liposomes containing human oxidized low-density lipoprotein into the adventitia of the arteries. IVUS-VH imaging was performed in vivo at 8.2±1.6 weeks after injection. A total of 60 vascular lesions were analyzed and compared with their correspondent IVUS-VH images. Correlation analysis was performed using linear regression models. Compared with histology, IVUS-VH correctly identified the presence of fibrous, fibro-fatty, and necrotic tissue in 58.33%, 38.33%, and 38.33% of lesions, respectively. The sensitivity of IVUS-VH for the detection of fibrous, fibro-fatty, and necrotic core tissue was 76.1%, 46%, and 41.1% respectively. A linear regression analysis performed for each individual plaque component did not show strong correlation that would allow significant prediction of individual values. Conclusions—In a porcine model of complex coronary lesions, IVUS-VH was not accurate in detecting the relative amount of specific plaque components within each individual corresponding histological specimen.

Late Positive Remodeling and Late Lumen Gain Contribute to Vascular Restoration by a Non-Drug Eluting Bioresorbable Scaffold: A Four-Year Intravascular Ultrasound Study in Normal Porcine Coronary Arteries

Background— The interplay between mechanical dilatation, resorption, and arterial response following implantation of bioresorbable scaffolds is still poorly understood. Methods and Results— Long-term geometric changes in porcine coronary arteries in relation to gradual degradation of bioresorbable scaffolds were assessed in comparison with bare metal stents (BMS). Intravascular ultrasound (IVUS)-derived lumen, outer stent/scaffold, and reference vessel areas were evaluated in 94 polymer scaffolds and 46 BMS at 5 days and 3, 6, 12, 18, 24, and 55 months, in addition to polymer scaffold radial crush strength and molecular weight (MW) at 3, 6, and 12 months. BMS outer stent area and lumen area remained constant through 55 months (P=0.05, but within 1 standard deviation of 100%, and P=0.58, respectively), while significant increases were exhibited by polymer-scaffolded vessels with the maximum late lumen gain at 24 months, paralleled by the outer scaffold area increase, and then remaining at that increased level at 55 months (P<0.01). By 12 months polymer scaffolds experienced significant reductions in radial strength and MW, while the animals underwent the largest weight gain. At 3 months and beyond, the patency ratio (lumen area/reference vessel area) of BMS remained constant (0.71 to 0.85, P=0.49). In contrast, that of polymer scaffolds increased and approached 1 (P=0.13). Conclusions— Bioresorbable polymer scaffolds allow restoration of the treated segments ability to remodel outward to achieve level lumen transition between reference vessel and scaffold-treated regions, a process mediated by animal growth and scaffold degradation. This also introduces a challenge to standard analyses of IVUS outcomes relying on constant stent diameters over time.

Long-term effects of intracoronary β-radiation in balloon- and stent-injured porcine coronary arteries

Background—The data on the long-term safety and efficacy of intracoronary β-radiation in animal models are limited. Methods and Results—A total of 30 coronary arteries in 15 swine were subjected to balloon or stent injury followed by β-radiation from a centered 32P source (2000 cGy to 1 mm beyond lumen surface) or a sham radiation procedure. The animals received aspirin for 6 months and ticlopidine for 30 days. Five of the 10 animals subjected to radiation died (at 5 days, 7 days, 3 months [n=2], and 4 months) as a result of layered, occlusive thrombus at the intervention site (3 stent and 2 balloon injury sites). No deaths occurred in the control group. In the surviving animals, balloon-injured and irradiated vessels showed a trend toward larger lumens than controls (2.15±0.17 versus 1.80±0.08 mm2, P=0.06) and larger external elastic lamina areas (3.32±0.21 versus 2.62±0.10 mm2, P=0.003). In the stent-injured vessels from surviving animals, lumen, neointimal, and external elastic lamina areas were 3.58±0...

Effects of SolCD39, a novel inhibitor of platelet aggregation, on platelet deposition and aggregation after PTCA in a porcine model

Introduction: This study evaluated CD39 in a porcine model of balloon angioplasty and in plasma of patients undergoing percutaneous intervention. CD39 (E-NTPDase1), is the endothelial ecto-ADPase inhibiting platelet function via hydrolysis of released platelet ADP.Methods and Results: A recombinant soluble form of CD39 (solCD39) given intravenously to pigs had an elimination half life of 5–7 days, increased the bleeding time to an extent similar to aspirin, and inhibits platelet aggregation by > 90%. Platelet counts and clot retraction remained normal following solCD39 administration. In a pig model of acute coronary balloon injury, solCD39 resulted in non-statistically significant decreases in platelet (7.7 ± 1.4 versus 11.7 ± 3.4) and fibrin (3.5 ± 0.4 versus 4.2 ± 0.7) deposition ratios. Adding ex vivo to human platelet rich plasma (PRP) solCD39 produced nearly 100% inhibition of ADP-induced platelet aggregation. A dose-response effect of solCD39 on platelet aggregation induced by collagen or a thrombin receptor activating peptide (TRAPSFLLRN) was noted in PRP obtained from volunteers and patients receiving aspirin, clopidogrel or ticlopidine. SolCD39 also provided additional and complete inhibition of TRAP-induced platelet aggregation in PRP from patients who had received abciximab, aspirin and clopidogrel.Conclusions: SolCD39, a novel inhibitor of platelet activation and recruitment with a relatively long half-life appears to be well tolerated and is a potent inhibitor of ADP-, collagen-, or TRAP-induced platelet activation. Its potential use in percutaneous coronary intervention requires further study.Abbreviated Abstract. E-NTPDase1/CD39 is the endothelial ecto-ADPase responsible for inhibition of platelet function. A recombinant soluble form (solCD39) had an elimination half life of 5–7 days in pigs, elevated bleeding times similar to aspirin, did not affect clot retraction, and inhibited platelet aggregation by > 90%. When combined with standard heparin therapy in a pig model of acute coronary balloon injury, solCD39 resulted in a trend toward a decrease in platelet and fibrin deposition. SolCD39 added ex vivo to human platelet rich plasma yielded nearly 100% inhibition of ADP-induced platelet aggregation and provided further inhibition when combined with standard therapy.

Use of nitric-oxide-eluting polymer-coated coronary stents for prevention of restenosis in pigs.

BackgroundRestenosis after angioplasty remains an unresolved problem despite an increase in use of coronary stents. It has been theorized that nitric oxide (NO) exerts several actions that can prevent restenosis. These include inhibition of proliferation of smooth muscle cells, prevention of arterial spasms, and decreasing aggregation of platelets in response to exposure to collagen. ObjectiveTo determine whether NO coated stents decrease restenosis in a pig balloon injury model. MethodsWe used coronary stents impregnated with a slow‐release precursor of NO in the porcine model of restenosis. Tantalum coil coronary stents (Cordis) were coated with a polymer impregnated with a slow‐release precursor of NO. Polymer‐coated stents without active precursors were used as controls. Oversized stents were mounted on a delivery balloon and subsequently deployed in the right coronary and left anterior descending arteries of each animal. ResultsRepeated recording of angiograms demonstrated that changes in minimum lumen diameter on going from immediately after stenting to 28‐day follow‐up for the control and NO‐eluting‐stent groups were similar, namely decreases of 1.89 ± 0.33 and 2.08 ± 0.28 mm, respectively. The morphometric results, showing that severe luminal narrowing occurred for both groups, were similar. The percentage area stenoses were 85 ± 5% for the control group and 84 ± 6% for the NO‐eluting group. Histology demonstrated that profuse formation of neointima and an inflammatory cell infiltrate occurred. ConclusionsSevere diameter stenosis occurred both for control and for treatment groups. The degree of angiographic stenosis was markedly worse than that previously reported for this model. Sustained release of a precursor of NO did not prevent restenosis in this model. This might have been due to a lack of efficacy of nitric oxide or to a profuse and overwhelming stimulatory effect of the polymer in the coated stents.

Endovascular needle injection of cholesteryl linoleate into the arterial wall produces complex vascular lesions identifiable by intravascular ultrasound : early development in a porcine model of vulnerable plaque

BackgroundWe attempted to create a pig model of complex arterial lesions through the percutaneous injection of cholesteryl linoleate into the vessel wall. Methods and resultsA total of 81 arterial segments (27 arteries) underwent percutaneous intramural injection of cholesteryl linoleate, in eight pigs. Intravascular ultrasound (IVUS) analysis and corresponding histology were obtained for analysis at 2 and 4 weeks after injection. Overall, 18 out of 27 (67%) of the injected arterial segments displayed lesions identifiable by IVUS as an eccentric echolucent zone present within the deeper layer of the lesion. Quantitative IVUS analysis demonstrated that these lesions were non-occlusive (36±8% area stenosis), eccentric (eccentricity index, 0.78±0.07) and located into positively remodeled vessels (remodeling index, 1.45±0.24). By histology, these lesions were eccentric and comprised less than a third of the vessel circumference. Medial thickening and a thickened intima containing lipid droplets and mononuclear cells were consistently found. The presence of lipids or local wall thickening seen by histology colocalized with the presence of echolucent structures seen by IVUS in 65% of the coronary segments and 70% of the iliac segments. ConclusionsThe intramural deposition of cholesteryl linoleate results in the development of complex, lipid-containing inflammatory lesions in less than 4 weeks. These lesions are already identifiable by IVUS at 2 weeks and colocalize with histologic findings. Further development of this model may allow the validation of technologies designed to detect and treat high-risk atherosclerotic lesions.

Dose-response study of intracoronary beta-radiation with 32P in balloon- and stent-injured coronary arteries in swine.

PURPOSE A dose-response study was performed in swine to investigate the vascular effects of 32P over a broad range of doses in order to define the therapeutic window of intracoronary radiotherapy (ICR) with 32P. METHODS AND MATERIALS A total of 131 porcine arteries were subjected to balloon injury or stenting followed by 0-36 Gy of ICR from a centered 32P source wire to 1 mm beyond lumen surface or a sham ICR procedure. Animals were euthanized at 4 weeks, and vessels were harvested for histomorphometry. RESULTS In the balloon-injured arteries, doses of 7 and 9 Gy did not impact restenosis. At doses of 14-36 Gy, neointima was markedly reduced, with mild dilatation at the highest dose, 36 Gy. In the stent-injured arteries, the lowest dose of 9 Gy failed to reduce neointimal growth, while 14-26 Gy showed the most favorable response. CONCLUSIONS ICR with 32P features a broad therapeutic window. Doses of 14-26 Gy to 1 mm beyond lumen surface provided an optimal combination of efficacy and safety. Doses of 7 and 9 Gy were generally ineffective, suggesting a minimum threshold for ICR with 32P to effectively inhibit restenosis.