Motoya Hayase

Percutaneous Mitral Valve Repair for Chronic Ischemic Mitral Regurgitation A Real-Time Three-Dimensional Echocardiographic Study in an Ovine Model

Background—Although surgical annuloplasty is the standard repair for ischemic mitral regurgitation (IMR), its application is limited by high morbidity and mortality. Using 2D and real-time 3D echocardiography in an ovine model of chronic IMR, we evaluated the geometric impact and short-term efficacy of a percutaneous transvenous catheter-based approach for mitral valve (MV) repair using a novel annuloplasty device placed in the coronary sinus. Methods and Results—Six sheep developed IMR 8 weeks after induced posterior myocardial infarction. An annuloplasty device optimized to reduce anterior-posterior (A-P) mitral annular dimension and MR was placed percutaneously in the coronary sinus. Mitral annular A-P and commissure-commissure dimensions and MV tenting area (MVTa) in 3 parallel A-P planes (medial, central, and lateral) were assessed by real-time 3D echocardiography with 3D software. The annuloplasty device reduced MR jet area from 5.4±2.6 to 1.3±0.9 cm2 (P<0.01), mitral annular A-P dimension in both systole and diastole (24.3±2.5 to 19.7±2.4 mm; P<0.03; 31.0±3.9 to 24.7±2.1 mm; P<0.001), and MVTa at mid systole in all 3 planes (153±46 to 93±24 mm2, P<0.01; 140±47 to 88±23 mm2, P<0.03; and 103±23 to 87±26 mm2, P<0.03). Conclusions—Percutaneous coronary sinus–based mitral annuloplasty reduces chronic IMR by reducing mitral annular A-P diameter and MVTa. This suggests the potential clinical application of a new nonsurgical therapeutic approach in patients with IMR.

Sirolimus (rapamycin) halts and reverses progression of allograft vascular disease in non-human primates.

Background. Current immunosuppressive protocols fail to prevent chronic rejection often manifested as graft vascular disease (GVD) in solid organ transplant recipients.Several new immunosuppressants including sirolimus, a dual function growth factor antagonist, have been discovered, but studies of drug efficacy have been hampered by the lack of a model of GVD in primates, as a prelude to clinical trials. As described earlier, we have developed a novel non-human primate model of GVD where progression of GVD is quantified by intravascular ultrasound (IVUS). Methods. Twelve cynomolgus monkeys underwent aortic transplantation from blood group compatible but mixed lymphocyte reaction-mismatched donors. To allow the development of GVD in the allograft, no treatment was administered for the first 6 weeks. Six monkeys were treated orally with sirolimus from day 45 after transplantation to day 105. Results. Progression of GVD measured as change in intimal area from day 42 to 105 was halted in sirolimus-treated monkeys compared to untreated monkeys (P <0.001, general linear model). On day 105, the intimal area±SEM was 3.7±1.0 and 6.4±0.5 mm2, respectively (P <0.05, t test). The magnitude of allograft intimal area on day 105 correlated inversely with sirolimus trough levels (R2=0.67, P <0.05). Regression of the intimal area was seen in four of six sirolimus-treated monkeys, which was significantly different from the untreated monkeys (P <0.05). Conclusions. Our results in the first non-human primate model of GVD showed that treatment with sirolimus not only halted the progression of preexisting GVD but also was associated with partial regression. Sirolimus trough blood levels were correlated with efficacy. Therefore, sirolimus has the potential to control clinical chronic allograft rejection.

Detection of Monocyte Chemoattractant Protein-1 Receptor Expression in Experimental Atherosclerotic Lesions An Autoradiographic Study

Background—Monocytes, a common component of atheroma, are attracted to the lesion site in response to chemotactic signals, particularly expression of monocyte chemoattractant peptide 1 (MCP-1). This study assessed the feasibility of using radiolabeled MCP-1 to identify monocytes and macrophages that have localized at sites of experimental arterial lesions. Methods and Results—The biodistribution of radiolabeled MCP-1 was determined in normal mice, and localization in experimental atheroma was determined in cholesterol-fed rabbits 4 weeks after arterial injury of the iliac artery (9 rabbits) and the abdominal aorta (1 rabbit). Vessels were harvested and autoradiographed after intravenous administration of 125I-labeled MCP-1 and Evans blue dye. The arteries were evaluated histologically by hematoxylin and eosin staining and immune staining with a monoclonal antibody specific for rabbit macrophages (RAM-11). 125I-MCP-1 has a blood clearance half-time of ≈10 minutes and circulates in association with cells. The liver, lungs, and kidneys had the highest concentration of 125I-MCP-1 at 5 and 30 minutes after tracer administration. Autoradiograms revealed accumulation of 125I-MCP-1 in the damaged artery wall, with an average ratio of lesion to normal vessel of 6:1 (maximum 45:1). The accumulation of 125I-MCP-1 in the reendothelialized (plaque formation) areas was greater than in the deendothelialized (Evans blue-positive) areas (6.55±2.26 versus 4.34±1.43 counts/pixel, P <0.05). The uptake of 125I-MCP-1 correlated with the number of macrophages per unit area (r =0.85, P <0.0001). Conclusions—Radiolabeled MCP-1 may be a useful tracer for imaging monocyte/macrophage-rich experimental atherosclerotic lesions.

Quality of computer enhanced totally endoscopic coronary bypass graft anastomosis – comparison to conventional technique

OBJECTIVE Aims of the study were to develop an endoscopic technique to perform robot assisted coronary anastomoses, using a computer enhanced telemanipulator and to compare the quality of the anastomoses with those performed using a standard open technique. METHODS A surgical telemanipulator with two instrument arms and a central videoscopic arm was used to perform remote endoscopic coronary artery bypass grafting on isolated porcine hearts. The end effectors and the videoscope were placed through three 10 mm port incisions. All anastomoses (Cx to LAD) were performed using a double armed 7-0 Prolene suture of 5 or 7 cm in length. All operations were performed remotely from the master console using ten times magnification, tremor filtering and 3:1 motion scaling. Initially 20 anastomoses were performed to develop and train the technique. Then, 20 robot-assisted anastomoses (group I) were compared with 20 anastomoses using a standard open parachute technique (group II). All anastomoses were checked for patency and leakage. Patency was confirmed by bench angiography. After fixation, all anastomoses were macroscopically evaluated for patency, intactness, alignment, intimal tears and dehiscence. Both angiographic and pathologic evaluations were performed with the examiners blinded to the technique of anastomosis. RESULTS In the initial feasibility series, time for anastomosis was 18.2 +/- 9.1 min. All anastomoses were patent although minor stenoses were found in two and minor leakage was noted in five anastomoses. In the second series all anastomoses were patent, not leaking and showed a good run-off at angiography. Mean time for anastomosis in group I was 12.8 +/- 2.4 min as compared with 6.3 +/- 0.2 min in group II (P < 0.001), respectively. Macroscopic analysis demonstrated equal quality for both groups. There were no stenoses, no intimal tears and no dehiscences. All anastomoses had a normal alignment and intact suture lines. CONCLUSION Using the Intuitive surgical telemanipulator, it is possible to remotely perform endoscopic coronary anastomoses with the same quality as with an open standard technique after a brief learning curve. This will enable true endoscopic coronary artery bypass grafting with a precision that has not been achieved with any other previously applied endoscopic technique.

Percutaneous method of laser transmyocardial revascularization

Laser transmyocardial revascularization (TMR) creates conduits from the left ventricular cavity into the myocardium and has been forwarded as a potential method of perfusing ischemic myocardium. The procedure typically employs a CO2 laser to produce transmyocardial channels from the epicardial to the endocardial surface via an open thoracotomy. Preliminary studies in animals and human subjects have yielded promising results, and clinical trials evaluating the long-term efficacy of the procedure are in progress. We now report the use of a percutaneous method of TMR using a laser delivered through a novel catheter system. To assess the feasibility of performing percutaneous TMR, studies were performed on 15 adult canine subjects utilizing a holmium:YAG laser. Via a femoral artery approach, novel laser catheters were introduced into the left ventricular cavity under fluoroscopic guidance. Biplane coronary angiography, ventriculography, and transesophageal echocardiography were employed to direct catheters to specific regions and assess the efficacy of creating transmyocardial channels. Multiple channels could be created in the anterior, lateral, inferoposterior, and septal regions as demonstrated by contrast ventriculography with confirmation by subsequent gross and histologic examination. The procedure was tolerated well without any ventricular dysfunction or sustained ventricular arrhythmias. We have demonstrated that laser transmyocardial revascularization via a percutaneous approach is feasible with creation of channels from the endocardial surface of the left ventricle into the myocardium. On gross and histological examination, these channels are similar in appearance to those created by the currently employed open chest, epicardial method of TMR.

The porcine coronary model of in-stent restenosis: Current status in the era of drug-eluting stents

Drug‐eluting stents are revolutionizing interventional cardiology. Sirolimus‐eluting stents are in widespread clinical use, associated with well‐documented remarkably low restenosis rates, and a number of other agents appear promising in clinical trials. These human studies have been preceded by numerous animal studies, foremost among them the pig coronary model of in‐stent restenosis (ISR). The histologic response to porcine coronary stenting was described over a decade ago. Porcine stenting studies now provide examinations not only of histology, but also mechanisms of action, toxicity, and biocompatibility. This review therefore examines the current status of this porcine coronary model of ISR. Contemporary methods of pig coronary stenting are discussed. The morphometric, cellular, and molecular analyses of the responses to stent injury are then described. Finally, recent pig coronary drug‐eluting stent studies are examined, with a discussion of their advantages, limitations, and possible future modifications. Catheter Cardiovasc Interv 2003;60:515–523.

Local l-Arginine Delivery After Balloon Angioplasty Reduces Monocyte Binding and Induces Apoptosis

BACKGROUND Local administration of L-arginine after balloon angioplasty has been shown to enhance NO generation and inhibit lesion formation. In this study, we assessed the mechanisms by which local delivery of L-arginine inhibits lesion formation. METHODS AND RESULTS New Zealand White rabbits (n=56) were fed a 1% cholesterol diet. After 1 week, both iliac arteries were balloon-denuded, and a local drug delivery catheter was introduced into both iliac arteries to deliver either L-arginine (800 mg/5 mL with and without 100 microCi L-[2,3-(3)H]-arginine) or saline. Monocyte-endothelial interaction was assessed by functional binding assay; NO activity was measured by chemiluminescence. Intramural administration of radioactively labeled L-arginine led to significantly higher counts in comparison to the contralateral segment for up to 1 week after delivery (676+/-223 versus 453+/-93 cpm/mg; P<0.02); this was associated with significantly higher NO levels in the L-arginine-treated segments (394.4+/-141.6 versus 86.3+/-34.3 nmol/mg; P<0.01). Even after 2 to 3 weeks, monocyte binding was significantly decreased by treatment with L-arginine as compared with saline infusion (P<0.01). After 4 weeks, there was a 9-fold greater number of apoptotic cells in the vessel wall of L-arginine as compared with the saline-treated segments (P<0.05). CONCLUSIONS Intramural delivery of L-arginine immediately after angioplasty causes a sustained increase in tissue L-arginine levels associated with enhancement of local NO synthesis. The local increase in NO synthesis is associated with an attenuation of monocyte binding and increased apoptosis of resident macrophages. This treatment strategy could be valuable for the prevention and management of restenosis.

Preintervention Arterial Remodeling Affects Clinical Outcome Following Stenting: An Intravascular Ultrasound Study

OBJECTIVES The study was done to elucidate the relationship between baseline arterial remodeling and clinical outcome following stenting. BACKGROUND The impact of preintervention arterial remodeling on subsequent vessel response and clinical outcome has been reported following nonstent coronary interventions. However, in stented segments, the impact of preintervention remodeling on clinical outcome has not been clarified. METHODS Preintervention remodeling was assessed in 108 native coronary lesions by using intravascular ultrasound (IVUS). Positive remodeling (PR) was defined as vessel area (VA) at the target lesion greater than that of average reference segments. Intermediate or negative remodeling (IR/NR) was defined as VA at the target lesion less than or equal to that of average reference segment. Remodeling index expressed as a continuous variable was defined as VA at the target lesion site divided by that of average reference segments. RESULTS Positive remodeling was present in 59 (55%) and IR/NR in 49 (45%) lesions. Although final minimal stent areas were similar (7.76 +/- 1.80 vs. 8.09 +/- 1.90 mm2, p = 0.36), target vessel revascularization (TVR) rate at nine-month follow-up was significantly higher in the PR group (22.0% vs. 4.1%, p = 0.01). By multivariate logistic regression analysis, higher remodeling index was the only independent predictor of TVR (p = 0.02). CONCLUSIONS Lesions with PR before intervention appear to have a worse clinical outcome following IVUS-guided stenting. Intravascular ultrasound imaging before stenting may be helpful to stratify lesions at high risk for accelerated intimal proliferation.

Intravascular Sonotherapy Decreases Neointimal Hyperplasia After Stent Implantation in Swine

BackgroundIntimal hyperplasia and subsequent in-stent restenosis remain a major limitation after stent implantation. In vitro cell culture studies show that low-frequency, noncavitational ultrasound energy may impact smooth muscle cell proliferation. Accordingly, we assessed the efficacy of intravascular sonotherapy treatment on intimal hyperplasia in a swine stent model. Methods and ResultsAfter balloon injury, biliary stents (Johnson & Johnson) were implanted in the femoral arteries of 14 swine. A total of 48 stented sites were randomized to sonotherapy or sham treatment using a custom-built, 8-French catheter intravascular sonotherapy system (URX, PharmaSonics Inc). After stent deployment, ultrasound energy (700 KHz) was applied to the treatment group for up to 5 minutes. Smooth muscle cell proliferation was assessed using bromodeoxyuridine histology preparation (BrdU) at 7 days in 28 stented sites. At 28 days, the neointimal thickness and the ratio of neointimal/stent area (percent stenosis) was calculated by histomorphometric quantification in 20 stented sites. At 7 days, percent of BrdU staining was significantly reduced in the sonotherapy group compared with the sham group (24.1±7.0% versus 31.2±3.0%, P <0.05). At 28 days, percent stenosis was significantly less in the sonotherapy group than in the sham group (36±24% versus 44±27%, P <0.05), and the mean neointimal thickness in the sonotherapy group was less than in the sham group (417±461 &mgr;m versus 643±869 &mgr;m, P =0.06). ConclusionsIn this swine peripheral model, intravascular sonotherapy seemed to decelerate cellular proliferation and decrease in-stent hyperplasia. Therefore, intravascular sonotherapy may be an effective form of nonionizing energy to reduce in-stent restenosis.

An optimal diagnostic threshold for minimal stent area to predict target lesion revascularization following stent implantation in native coronary lesions.

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