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Purpose: To compare by intravascular ultrasound (IVUS) the efficacy of delivering the prescribed dose to the adventitia between two commonly used dose prescriptions for intracoronary radiotherapy. Methods and Materials: In 59 human postangioplasty coronary vessels, one IVUS cross-section (1 mm thick) with the highest plaque burden was used for creating dose-volume histograms with different hypothetical positions of the source. Results: On average, prescription to 1 mm beyond lumen surface resulted in delivery of the prescribed dose (20 Gy ± 20%) to a higher fraction of adventitial volume than with the prescription to 2 mm from the source, with source placed in vessel center, lumen center, or in the IVUS catheter position. Source placement in the lumen center resulted in a low dose heterogeneity to the adventitia and the least dose heterogeneity to the intima. Conclusions: Prescription to 1 mm beyond lumen surface appeared more effective in delivering the prescribed dose to the adventitia than the American Association of Physicists in Medicine (AAPM) recommended prescription to 2 mm from the source center. Moreover, centering the source in the lumen provides the better balance of effective adventitial targeting and intimal dose homogeneity. Modification of the current AAPM recommendation for dose prescription for intracoronary radiotherapy should be considered.

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 32 P 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 mm 2 , P =0.06) and larger external elastic lamina areas (3.32±0.21 versus 2.62±0.10 mm 2 , P =0.003). In the stent-injured vessels from surviving animals, lumen, neointimal, and external elastic lamina areas were 3.58±0.33, 3.16±0.35, and 8.12±0.42 mm 2 for irradiated vessel segments; these values were not different from those in controls (3.21±0.15, 2.84±0.27, and 7.76±0.28 mm 2 , respectively). Histologically, healing was complete in most survivors, although intramural fibrin and hemorrhage were occasionally seen. Conclusion —In the long-term (6 month) porcine model of restenosis, the inhibition by intracoronary β-radiotherapy of the neointimal formation that is known to be present at 1 month is not sustained. This lack of effect on neointimal formation after balloon and stent arterial injury is accompanied by subacute and late thrombosis that leads to cardiac death on a background of continuous aspirin but relatively brief ticlopidine treatment.

Objectives. We sought to evaluate the comparative accuracy of myocardial contrast echocardiography (MCE), quantitative rest-redistribution thallium-201 (Tl-201) tomography and low and high dose (up to 40 μg/kg body weight per min) dobutamine echocardiography (DE) in identifying myocardial hibernation.Background. Myocardial contrast echocardiography can assess myocardial perfusion and may therefore be useful in predicting myocardial hibernation. However, its accuracy in comparison to myocardial perfusion scintigraphy and to that of high dose DE remains to be investigated.Methods. Eighteen patients (aged [±SD] 57 ± 10 years) with stable coronary artery disease and ventricular dysfunction underwent the above three modalities before coronary revascularization. Myocardial contrast echocardiography was achieved with intracoronary Albunex. Rest echocardiographic and Tl-201 studies were repeated ≥6 weeks after revascularization.Results. Of 109 revascularized segments with severe dysfunction, 46 (42%) improved. Left ventricular ejection fraction increased from 38 ± 14% to 45 ± 13% at follow-up (p = 0.003). Rest Tl-201 uptake and the ratio of peak contrast intensity of dysfunctional to normal segments with MCE were higher (p < 0.01) in segments that recovered function compared with those that did not. Myocardial contrast echocardiography, thallium scintigraphy and any contractile reserve during DE had a similar sensitivity (89% to 91%) with a lower specificity (43% to 66%) for recovery of function. A biphasic response during DE was the most specific (83%) and the least sensitive (68%) (p < 0.01). The best concordance with MCE was Tl-201 (80%, kappa 0.57). Changes in ejection fraction after revascularization related significantly to the number of viable dysfunctional segments by all modalities (r = 0.54 to 0.65).Conclusions. In myocardial hibernation, methods evaluating rest perfusion (MCE, Tl-201) or any contractile reserve have a similar high sensitivity but a low specificity for predicting recovery of function. A limited contractile reserve (biphasic response) increases the specificity of DE. Importantly, the three techniques identified all patients who had significant improvement in global ventricular function.(J Am Coll Cardiol 1997;29:985–93)© 1997 by the American College of Cardiology

A 62-year–old man presented with progressive exertional dyspnea and angina. His past medical history is notable for coronary artery disease, for which he underwent a coronary artery bypass graft surgery 8 years earlier. A few years afterward, he underwent aortic valve (AV) bypass (AVB) surgery for severe aortic stenosis (AS) using an apicoaortic conduit to the descending aorta consisting of a 16-mm connector and an 18-mm valved conduit (Hancock valve; Medtronic, Minneapolis, MN; Figures 1 and 2; online-only Data Supplement Movie I). After a period of initial improvement in symptoms, the patient developed progressive dyspnea and angina and was referred for additional cardiac workup. Figure 1. An ECG-gated thin-slice contrast-enhanced cardiac computed tomography scan showing a heavily calcified native aortic valve (AV), hypertrophied left ventricle (LV), and the apical LV insertion site of the apicoaortic valved conduit. Figure 2. A 3-dimensional cardiac computed tomography reconstruction image showing the apicoaortic valved conduit, extending from its apical insertion site into the left ventricle (LV) to its insertion site into the descending aorta. Arrow , Conduit valve. The patient underwent a bicycle ergometer test, which showed a diminished functional capacity and was stopped because of fatigue and a hypotensive response. He underwent a 2-dimensional transthoracic echocardiogram with gradual dobutamine infusion. He was found to have a heavily calcified AV (online-only Data Supplement Movie II) with a rest mean transvalvular gradient of 34 mm Hg and velocity of 3.5 m/s, which increased to 50 mm Hg and 4.8 m/s, respectively, at peak dobutamine dose (Figure 3). This corresponded with a …

BACKGROUND Gene therapy has been proposed as a possible solution to the problem of restenosis after coronary angioplasty. The current study was undertaken to assess conventional methods of gene transfer and to develop percutaneous techniques for introducing genes directly into the coronary arteries of large mammals. Since the anticipated targets of gene therapy against restenosis include atherosclerotic and previously instrumented arteries, we also evaluated gene transfer in atherosclerotic coronary arteries and in two porcine models of restenosis: one using intracoronary stents and a second using balloon overstretch angioplasty. METHODS AND RESULTS The conventional method of using perforated balloon catheters to deliver Lipofectin-DNA complexes directly into the coronary arteries of intact animals was applied to 18 porcine coronary arteries including normal arteries, hypercholesterolemic arteries, and those simulating restenosis. The results of this study were consistent with previously published results indicating that only low levels of luciferase gene expression could be obtained by Lipofectin-mediated gene transfer. We therefore undertook a second, parallel study to evaluate percutaneous transluminal in vivo gene transfer using a replication-deficient adenoviral vector. A comparison of the two studies revealed that the mean level of reporter gene expression in the cohort undergoing adenoviral infection was 100-fold higher than in the cohort undergoing Lipofection. Analysis of luciferase activity over time in normal arteries revealed that recombinant gene expression was half-maximal after 1 day, peaked within 1 week, was still half-maximal at 2 weeks, and declined to low levels by 4 weeks. Histochemical analysis of coronary arteries treated with a second adenovirus expressing a nuclear-localized beta-galactosidase gene demonstrated gene transfer to a limited number of cells in the media and adventitia. Immunohistochemical analysis of Ad5-infused arteries using a monoclonal antibody directed against CD44 identified a periadventitial infiltrate composed of leukocytes. CONCLUSIONS The recombinant adenoviral vectors proved to be far more effective than Lipofectin at delivering foreign genes directly into the coronary arteries of living mammals. Furthermore, the influences of hypercholesterolemia and arterial injury appeared to have little effect on the levels of gene expression obtained using either method. The results demonstrate that low-level recombinant gene expression, the major obstacle impeding gene therapy for the prevention of restenosis, can potentially be overcome by using adenoviral vectors to mediate coronary gene transfer in vivo. The duration of gene expression provided by these vectors and their effective deployment in atherosclerotic, balloon-overstretched, and stented coronary arteries suggest that recombinant adenovirus may have potential for evaluating gene therapy in the clinically informative porcine models of coronary restenosis.

Omnicath™ is a directional atherectomy catheter that employs deflecting nontraumatizing wires to anchor the cutting window at the atherectomy site. This anchoring system regulates the depth of cut and provides directional control and distal perfusion. The system continuously removes debris through a suction port from the operative site. To demonstrate the performance of the device, the Omnicath™ was tested in the external iliac arteries of ten atherosclerotic Hanford miniature swine in which concentric and eccentric lesions were induced. Five animals were sacrificed 3 days after atherectomy; the remaining five animals were sacrificed 6 weeks after the procedure. The acute histology demonstrates depth of cuts varying from partial plaque removal to near full thickness removal of the arterial wall. Histologic sections of the 6 week follow-up group demonstrated minimal healing response. The anchoring wires did not induce either acute injury or neointimal proliferation in the 6 week follow-up period. In conclusion, the Omnicath™ permits effective and safe atherectomy in this investigative 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.

Intravascular brachytherapy may cause "exaggerated" vessel remodeling with late incomplete apposition in segments that have little disease, which are exposed to higher radiation doses. The long-term clinical impact of this finding is unclear.

More than 50 different pharmacological and mechanical interventions have been tested to date for prevention of vascular restenosis without success. Intracoronary radiotherapy is the first one showing promise of significantly attenuating neointimal proliferation, causing positive vascular remodelling and thus inhibiting restenosis. This promising modality has moved from animal experiments via safety and feasibility testing into the phase of clinical trials of efficacy in large numbers of patients. While ongoing research continues to search for new sources and delivery techniques, currently available technology is being optimized. The randomized clinical trials conducted to date have shown consistently a reduction of target site restenosis rates by 55-79%. Lower incidence of major adverse cardiac events after radiotherapy has also been demonstrated, primarily as a result of reduction in target site and target vessel revascularization rates. However, experimental and clinical research has identified two major complications of this approach: stenosis at the ends of the radiation zone ('edge effect' or 'candywrapper') as well as late thrombosis (beyond 30 days after intervention) of the angioplasty or stent site. If these two adverse effects can be minimized, intracoronary radiotherapy may prove to be a major breakthrough in percutaneous coronary interventions.

Background —Intracoronary γ- and β-radiation have reduced restenosis in animal models. In the clinical setting, the effectiveness of β-emitters has not been studied in a broad spectrum of patients, particularly those receiving stents. Methods and Results —A prospective, randomized, sham-controlled study of intracoronary radiotherapy with the β-emitting 32 P source wire, using a centering catheter and automated source delivery unit, was conducted. A total of 105 patients with de novo (70%) or restenotic (30%) lesions who were treated by stenting (61%) or balloon angioplasty (39%) received 0 (control), 16, 20, or 24 Gy to a depth of 1 mm in the artery wall. Angiography at 6 months showed a target site late loss index of 11±36% in radiotherapy patients versus 55±30% in controls ( P P =0.012) and at target site plus adjacent segments (22% versus 50%; P =0.018). Target lesion revascularization was needed in 5 radiotherapy patients (6%) and 6 controls (24%; P Conclusions —β-radiotherapy with a centered 32 P source is safe and highly effective in inhibiting restenosis at the target site after stent or balloon angioplasty. However, minimizing edge narrowing and late thrombotic events must be accomplished to maximize the clinical benefit of this modality.

Background Restenosis 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. Objective To determine whether NO coated stents decrease restenosis in a pig balloon injury model. Methods We 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. Results Repeated 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. Conclusions Severe 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.

Importance The US Food and Drug Administration recently approved the use of a transcatheter aortic valve in patients for whom traditional valve replacement surgery poses a high or prohibitive risk. Our hospital was one of the first Veterans Affairs facilities to launch a transcatheter aortic valve replacement (TAVR) program. Objective To evaluate our early experience with transfemoral TAVR. Design and Setting We retrospectively reviewed the records of all patients who underwent TAVR during the first year of our program at the Department of Cardiothoracic Surgery, Michael E. DeBakey Veterans Affairs Medical Center. Participants The mean (SD) age of the patients was 77 (9) years, and their mean (SD) Society of Thoracic Surgeons predicted risk of mortality score was 8.8 (10.7). Interventions All patients underwent TAVR with the SAPIEN transcutaneous valve. Main Outcome Measures We evaluated operative mortality and major operative morbidity (stroke, myocardial infarction, renal failure necessitating dialysis, and requirement for mechanical circulatory support, as well as vascular complications and requirement for permanent pacemaker), in addition to length of hospital stay and discharge status. Results Between December 21, 2011, and December 13, 2012, a total of 19 transfemoral TAVR procedures were performed at our center. Implantation was successful in all cases. There were no reports of operative (30-day) mortality, prosthetic valve endocarditis, renal failure necessitating dialysis, perioperative myocardial infarction or stroke, or conversion to surgical aortic valve replacement. Seven patients (37%) had mild paravalvular leak, 3 patients (16%) had moderate paravalvular leak, 2 patients (11%) had groin wound complications, 2 patients (11%) required a permanent pacemaker, 1 patient (5%) had a vascular access complication requiring endovascular repair, and 1 patient (5%) required temporary circulatory support (with extracorporeal membrane oxygenation). The mean (SD) length of hospital stay after TAVR was 8.0 (5.9) days. All patients were discharged home. Conclusions and Relevance Transcatheter aortic valve replacement can be performed safely and with good outcomes at a Veterans Affairs facility with a committed multidisciplinary team and substantial experience in heart valve and endovascular therapies.

Side branch occlusion may occur in the course of percutaneous transluminal coronary angioplasty (PTCA), particularly if complicated by site dissection. Concern that the additional placement of a stent may further jeopardize side branches is logical. Consequently, this study analyzed pre-PTCA, post-PTCA, poststent, and 6-month follow-up angiograms of 100 consecutive patients in whom 103 Gianturco-Roubin stents were implanted for acute or threatened closure after PTCA. Side branches were defined as major (>50% of the stented vessel diameter) and minor ( 50% stenosis), and 129 minor branches were analyzed. Seven major branches (6%), all of which were diseased before PTCA, and 23 minor branches (18%) were lost after PTCA. Immediately after stent insertion, only 1 additional major and 1 minor branch were lost, whereas 2 of 7 major (29%) and 9 of 23 minor (39%) branches reappeared. At follow-up angiography, 7 major branches (6%) were more stenosed and 6 (6%) were improved compared with the angiogram before PTCA. Only 2 major (2%) and 5 minor (4%) branches remained occluded. Additionally, 2 major and 1 minor branch, which were patent after PTCA and stenting, were occluded at follow-up as a result of total occlusion of the stented segment. It is concluded that: (1) stent implantation is rarely associated with side branch loss; (2) more typically, recovery of patency of branches occluded by PTCA occurs immediately after stenting; (3) as a delayed effect, a stent may facilitate later reopening of branches occluded after PTCA; and (4) excellent patency of branches of the stented segment is maintained in the followup period.

The vascular response to any given combination of gene transfer vector and catheter delivery system is an important factor to consider in developing gene therapy strategies for preventing coronary restenosis. In order to study the vascular response to adenoviral (Ad5) vectors following transluminal delivery by perforated balloon catheter, we constructed a replicationdeficient Ad5 expressing a nuclear-localized, β -galactosidase and deployed it in porcine coronary arteries using Wolinsky Infusion Catheters (USCI, Billerica, MA). Viral infections were performed under fluoroscopy by infusing 4 ml (2 × 10 10 pfu) of the virus into the coronary arteries of intubated swine at 8 atm of pressure. Three days later, the arteries were removed and fixed prior to a 6 hr incubation in X-gal. The nuclear localization of the indigo reaction product provided for unambiguous detection of Ad5-infected smooth muscle cells in the media; however, specific staining of cells in the near adventitia was also noted suggesting distribution of virus by the vasa vasorum. The endothelial denudation and medial disorganization observed in Ad5-infected arteries were similar to that found in balloon-injured and vehicle-infused control arteries. The most remarkable histologic finding was a pronounced cellular infiltrate in the adventitia and periadventitia of the Ad5-infected arteries that was absent in the vehicle-infused controls. Immunohistochemical staining of arterial cross-sections using a monoclonal antibody directed against the porcine lymphocyte homing receptor (CD44) identified the infiltrating cells as leukocytes. These results suggest that Ad5-mediated gene transfer to the coronary arteries of Hanford miniature swine elicits an inflammatory response mediated by cytotoxic T-cells, monocytes/macrophages, andlor natural killer cells. The natural response of the host to viral infection may therefore contribute to the precipitous decline in Ad5-mediated gene expression observed in this animal model and others. Potential strategies for controlling the inflammatory response to Ad5 vectors will be discussed, including immunosuppression of the host. modifications to the Ad5-genome, and the long-term possibility of using synthetic complexes to emulate vital gene transfer without eliciting inflammation.