Tumor Growth Ameliorates Cardiac Dysfunction.

Heart failure and cancer are the deadliest diseases worldwide. Murine models for cardiac remodeling and heart failure demonstrate that cardiac dysfunction promotes cancer progression and metastasis spread. Yet, no information is available on whether and how tumor progression affects cardiac remodeling. Here, we examined cardiac remodeling following transverse aortic constriction (TAC) in the presence or absence of proliferating cancer cells. We show that tumor-bearing mice, of two different cancer cell lines, display reduced cardiac hypertrophy, lower fibrosis and improved cardiac contractile function following pressure overload induced by TAC surgery. Integrative analysis of qRT-PCR, flow cytometry and immunofluorescence identified tumor-dependent M1-to-M2 polarization in the cardiac macrophage population as a mediator of the beneficial tumor effect on the heart. Importantly, tumor-bearing mice lacking functional macrophages fail to improve cardiac function and display sustained fibrosis.

Usability, performance and safety of a new device for degenerative mitral regurgitation: in vivo chronic evaluation.

OBJECTIVES: This study aimed to evaluate the usability, performance and safety of an innovative mitral valve device in the chronic setting characterized by an intraventricular bridge, which enables artificial chordae anchoring and/or direct posterior leaflet fixation. METHODS: Ten female sheep were employed and underwent device implantation. Any interference of the device with leaflet motion, ease of device use, correct chordae length estimation and implantation were evaluated. Post-procedural valve competence and device performance were verified by periodic postoperative echocardiograms and laboratory examinations. Following euthanasia, gross anatomy and histology evaluation of the hearts and valves were performed to detect tissue abnormalities and inflammation reaction related to the device. RESULTS: The procedure was successfully completed in all 10 sheep. Lengths of the 2 chordae implanted were 23 (21.5-24) mm and 23 (22.5-24) mm. The time required to suture both pairs of the artificial chordae was 2.7 ± 0.7 min. At the 3-month follow-up, left ventricular function was normal. The transvalvular peak pressure gradient was 9 (7.5-10) and the mean gradient was 4 (3.5-4) mmHg. Upon necropsy and histological evaluation, no damage to left ventricle wall, valve leaflets, chordae and papillary muscles and absence of thrombus formation and inflammatory reaction were observed. Radiological images showed neither fracture of the device nor calcifications. Laboratory tests showed no signs of haemolysis. CONCLUSIONS: In vivo late tests confirmed the ease of correct chordal length estimation prior to implantation, short operative time and usability in flailed anterior leaflet repair. The absence of negative impact of the device on mitral leaflets motion, function and structure and successful repair might suggest that the device would be useful in complex degenerative mitral disease.

Evaluation of an Innovative Device for Mitral Valve Regurgitation: Experimental Acute In Vivo Results.

Objective: Currently, mitral prosthetic rings are intended only to reshape the annulus. We present in vivo results of an innovative device characterized by an intraventricular segment designed to enable artificial chordae implantation and simplify leaflets and subvalvular apparatus correction. Methods: Eight sheep were employed. The first 4 underwent solely device implantation. In the last 4, primary chordae of the anterior leaflet (A2) were torn to induce severe mitral regurgitation. The severed chordae were replaced by 2 pairs of 5-0 Gore-Tex artificial chordae previously measured and anchored to the device bridge. Ease of device and chordae implantation were evaluated, and postprocedural valve competence was verified by postoperative echocardiogram. Results: The procedure was completed in all 8 sheep. In the 4 sheep with induced severe mitral regurgitation, repair could be achieved by means of artificial chordae implantation. Length of the 2 chordae implanted was 21.6 ± 2 mm and 22 ± 3 mm, respectively. The time required to suture the artificial chordae was 2.5 ± 1.2 min. Postoperative echocardiograms showed normal left ventricular ejection fraction and free motion of the mitral leaflets. Mitral regurgitation was absent in 5 cases and trivial in 3. The transvalvular peak pressure gradient was 9.5 ± 6 mm Hg, and mean gradient was 3.7 ± 4 mm Hg. Postprocedural evaluation of the heart and mitral valve showed no damage to the left ventricle wall, valve leaflets, chordae, and papillary muscles. Conclusions: In vivo tests confirm safety of the device, ease of chordal length estimation prior to implantation, short operative time, and no negative impact of the device on mitral leaflet motion, function, and structure.

Early Cardiac Remodeling Promotes Tumor Growth and Metastasis.

BACKGROUND: Recent evidence suggests that cancer and cardiovascular diseases are associated. Chemotherapy drugs are known to result in cardiotoxicity, and studies have shown that heart failure and stress correlate with poor cancer prognosis. However, whether cardiac remodeling in the absence of heart failure is sufficient to promote cancer is unknown. METHODS: To investigate the effect of early cardiac remodeling on tumor growth and metastasis colonization, we used transverse aortic constriction (TAC), a model for pressure overload-induced cardiac hypertrophy, and followed it by cancer cell implantation. RESULTS: TAC-operated mice developed larger primary tumors with a higher proliferation rate and displayed more metastatic lesions compared with controls. Serum derived from TAC-operated mice potentiated cancer cell proliferation in vitro, suggesting the existence of secreted tumor-promoting factors. Using RNA-sequencing data, we identified elevated mRNA levels of periostin in the hearts of TAC-operated mice. Periostin levels were also found to be high in the serum after TAC. Depletion of periostin from the serum abrogated the proliferation of cancer cells; conversely, the addition of periostin enhanced cancer cell proliferation in vitro. This is the first study to show that early cardiac remodeling nurtures tumor growth and metastasis and therefore promotes cancer progression. CONCLUSIONS: Our study highlights the importance of early diagnosis and treatment of cardiac remodeling because it may attenuate cancer progression and improve cancer outcome.

JDP2 and ATF3 deficiencies dampen maladaptive cardiac remodeling and preserve cardiac function.

c-Jun dimerization protein (JDP2) and Activating Transcription Factor 3 (ATF3) are closely related basic leucine zipper proteins. Transgenic mice with cardiac expression of either JDP2 or ATF3 showed maladaptive remodeling and cardiac dysfunction. Surprisingly, JDP2 knockout (KO) did not protect the heart following transverse aortic constriction (TAC). Instead, the JDP2 KO mice performed worse than their wild type (WT) counterparts. To test whether the maladaptive cardiac remodeling observed in the JDP2 KO mice is due to ATF3, ATF3 was removed in the context of JDP2 deficiency, referred as double KO mice (dKO). Mice were challenged by TAC, and followed by detailed physiological, pathological and molecular analyses. dKO mice displayed no apparent differences from WT mice under unstressed condition, except a moderate better performance in dKO male mice. Importantly, following TAC the dKO hearts showed low fibrosis levels, reduced inflammatory and hypertrophic gene expression and a significantly preserved cardiac function as compared with their WT counterparts in both genders. Consistent with these data, removing ATF3 resumed p38 activation in the JDP2 KO mice which correlates with the beneficial cardiac function. Collectively, mice with JDP2 and ATF3 double deficiency had reduced maladaptive cardiac remodeling and lower hypertrophy following TAC. As such, the worsening of the cardiac outcome found in the JDP2 KO mice is due to the elevated ATF3 expression. Simultaneous suppression of both ATF3 and JDP2 activity is highly beneficial for cardiac function in health and disease.

Coronary sinus reducer for the treatment of chronic refractory angina pectoris-results of the preclinical safety and feasibility study.

BACKGROUND: Narrowing of the coronary sinus (CS) has recently emerged as a new therapeutic option for the treatment of patients with chronic refractory angina pectoris. The results of the preclinical study presented here, evaluate the safety, feasibility, and efficacy of reducer implantation in a swine model with and without myocardial ischemia. METHODS AND RESULTS: The study included a safety/feasibility arm, and a safety/efficacy arm. In the safety/feasibility arm, reducers were implanted in 26 mini swine; follow up of up to 6 months included cardiac catheterization with CS angiogram, and histological evaluation of the stented segments of the CS. In the safety/efficacy arm, eight swine with evidence of inducible myocardial ischemia were divided into reducer implantation group (n = 4) and a control group (n = 4). Follow-up in this arm included 6 weeks and 6 months dobutamine stress echo and myocardial contrast echo to evaluate severity and extent of ischemia. In the safety/feasibility arm (n = 26), reducers were implanted with procedural success rate of 100% and with no short or long-term complications. All CS reducers were found to be patent at the time of sacrifice. In the safety/efficacy arm, all four animals with myocardial ischemia that underwent reducer implantation showed improvement in ischemia parameters at 6 weeks and 6 months follow-up, with no mortality. Among the control group, no improvement in ischemia parameters was observed and three out of four animals died. CONCLUSIONS: Narrowing of the CS using percutaneous implantation of the reducer in swine is feasible, safe, and improves the extent and severity of ischemia.

Extracellular signal-regulated kinase (ERK) activation preserves cardiac function in pressure overload induced hypertrophy.

BACKGROUND: Chronic pressure overload and a variety of mediators induce concentric cardiac hypertrophy. When prolonged, cardiac hypertrophy culminates in decreased myocardial function and heart failure. Activation of the extracellular signal-regulated kinase (ERK) is consistently observed in animal models of hypertrophy and in human patients, but its role in the process is controversial. METHODS: We generated transgenic mouse lines with cardiomyocyte restricted overexpression of intrinsically active ERK1, which similar to the observations in hypertrophy is phosphorylated on both the TEY and the Thr207 motifs and is overexpressed at pathophysiological levels. RESULTS: The activated ERK1 transgenic mice developed a modest adaptive hypertrophy with increased contractile function and without fibrosis. Following induction of pressure-overload, where multiple pathways are stimulated, this activation did not further increase the degree of hypertrophy but protected the heart through a decrease in the degree of fibrosis and maintenance of ventricular contractile function. CONCLUSIONS: The ERK pathway acts to promote a compensated hypertrophic response, with enhanced contractile function and reduced fibrosis. The activation of this pathway may be a therapeutic strategy to preserve contractile function when the pressure overload cannot be easily alleviated. The inhibition of this pathway, which is increasingly being used for cancer therapy on the other hand, should be used with caution in the presence of pressure-overload.

Nanoparticle-in-microparticle oral drug delivery system of a clinically relevant darunavir/ritonavir antiretroviral combination.

Nanonizationhas been extensively investigated to increase theoral bioavailability of hydrophobicdrugsin general andantiretrovirals(ARVs)used inthe therapy of the human immunodeficiency virus (HIV) infection in particular. Weanticipatedthatin the caseofprotease inhibitors, a family of pH-dependent ARVsthatdisplay high aqueous solubility undertheacidconditionsof thestomach andextremely low solubilityunder the neutral ones ofthe small intestine, this strategy might failowing to an uncontrolled dissolution-re-precipitation process that will take place along the gastrointestinal tract.To tackle thisbiopharmaceutical challenge, in this work, wedesigned, produced and fully characterized a novelNanoparticle-in-MicroparticleDelivery System(NiMDS)comprised of pure nanoparticlesofthefirst-line protease inhibitor darunavir(DRV) and itsboosting agentritonavir (RIT) encapsulated within film-coated microparticles.For this, a clinically relevant combination of pure DRV and RIT nanoparticles wassynthesized by a sequential nanoprecipitation/solvent diffusion and evaporation method employing sodium alginateas viscosity stabilizer. Then, pure nanoparticles were encapsulated within calcium alginate/chitosanmicroparticlesthat were film-coated with a series ofpoly(methacrylate) copolymers with differential solubility in the gastrointestinal tract. This coating ensured full stability under gastric-like pH and sustained drug release under intestinal one. PharmacokineticstudiesconductedinalbinoSpragueDawleyratsshowed that DRV/RIT-loadedNiMDSs containing 17% w/w drug loading based on dry weight significantlyincreasedthe oral bioavailabilityof DRVby 2.3-foldwith respect to both theunprocessedandthenanonized DRV/RIT combinations that showed statistically similar performance. Moreover, they highlighted the limited advantage of only drugnanonizationto improve the oral pharmacokinetics of protease inhibitors and the potential of our novel delivery approach to improve the oral pharmacokinetics of nanonized poorly water-soluble drugs displaying pH-dependent solubility. STATEMENT OF SIGNIFICANCE: Protease inhibitors (PIs) are gold-standard drugs in many ARV cocktails. Darunavir (DRV) is the latest approved PI and it is included in the 20th WHO Model List of Essential Medicines. PIs poorly-water soluble at intestinal pH and more soluble under gastric conditions. Drug nanonization represents one of the most common nanotechnology strategies to increase dissolution rate of hydrophobic drugs and thus, their oral bioavailability. For instance, pure drug nanosuspensions became the most clinically relevant nanoformulation. However, according to the physicochemical properties of PIs, nanonization does not appear as a very beneficial strategy due to the fast dissolution rate anticipated under the acid conditions of the stomach and their uncontrolled recrystallization and precipitation in the small intestine that might result in the formation of particles of unpredictable size and structure (e.g., crystallinity and polymorphism) and consequently, unknown dissolution rate and bioavailability. In this work, we developed a sequential nanoprecipitation method for the production of pure nanoparticles of DRV and its boosting agent ritonavir in a clinically relevant 8:1 wt ratio using alginate as viscosity stabilizer and used this nanosuspension to produce a novel kind of nanoparticle-in-microparticle delivery system that was fully characterized and the pharmacokinetics assessed in rats. The most significant points of the current manuscript are.

Topical Erythropoietin Treatment Accelerates the Healing of Cutaneous Burn Wounds in Diabetic Pigs Through an Aquaporin-3-Dependent Mechanism.

We have previously reported that the topical application of erythropoietin (EPO) to cutaneous wounds in rats and mice with experimentally induced diabetes accelerates their healing by stimulating angiogenesis, reepithelialization, and collagen deposition, and by suppressing the inflammatory response and apoptosis. Aquaporins (AQPs) are integral membrane proteins whose function is to regulate intracellular fluid hemostasis by enabling the transport of water and glycerol. AQP3 is the AQP that is expressed in the skin where it facilitates cell migration and proliferation and re-epithelialization during wound healing. In this report, we provide the results of an investigation that examined the contribution of AQP3 to the mechanism of EPO action on the healing of burn wounds in the skin of pigs with experimentally induced type 1 diabetes. We found that topical EPO treatment of the burns accelerated their healing through an AQP3-dependent mechanism that activates angiogenesis, triggers collagen and hyaluronic acid synthesis and the formation of the extracellular matrix (ECM), and stimulates reepithelialization by keratinocytes. We also found that incorporating fibronectin, a crucial constituent of the ECM, into the topical EPO-containing gel, can potentiate the accelerating action of EPO on the healing of the burn injury.

Strain Analysis in the Detection of Myocardial Infarction at the Acute and Chronic Stages.

BACKGROUND: Myocardial ischemia causes contractile dysfunction in ischemic, stunned, and tethered regions with larger infarcted zones having a negative prognostic impact on patients' outcomes. To distinguish the infarcted myocardium from the other regions, we investigated the diagnostic potential of circumferential strain (CS) and radial strain (RS) during the acute and chronic stages of myocardial infarction. METHODS: Ten pigs underwent 90-minute occlusion of the left anterior descending artery, followed by reperfusion. Echocardiography was performed at baseline, after 90-minute occlusion, and at 2 hours, 30, and 60 days postreperfusion. CS and RS were measured using speckle tracking echocardiography. Subsequently, the pigs were sacrificed, and histological analysis for infarct size was performed. RESULTS: After 90-minute occlusion, reduced strains were detected for all segments (infarcted anterior wall - baseline: CS: -17.6 ± 5.7%, RS: 54.4 ± 16.9%; 90 min: CS: -10.3 ± 3.0%, RS: 23.3 ± 7.0%; tethered posterior wall - baseline: CS: -18.4 ± 3.5%, RS: 68.7 ± 21.1%; 90 min: CS: -10.7 ± 6.4%, RS: 34.5 ± 14.7%, P < 0.001). However, postsystolic shortening was detected only in the infarcted segments, and the time-to-peak CS was 25% longer (P < 0.05). At 30 and 60 days postreperfusion, time-to-peak CS could only detect large scars in the anterior and anterior-septum walls (P < 0.05), while peak CS also detected smaller scars in the lateral wall (P < 0.05). RS failed to distinguish between normal, stunned/tethered, and infarcted myocardium. CONCLUSIONS: During occlusion and 2 hours postreperfusion, time-to-peak CS could distinguish between infarcted and stunned/tethered myocardial segments, while at 30 and 60 days postreperfusion, peak CS was the best detector of infarction.

TVP1022: A Novel Cardioprotective Drug Attenuates Left Ventricular Remodeling After Ischemia/Reperfusion in Pigs.

BACKGROUND: The current cornerstone treatment of myocardial infarction (MI) is restoration of coronary blood flow by means of thrombolytic therapy or primary percutaneous coronary intervention. However, reperfusion of ischemic myocardium can actually provoke tissue damage, defined as "ischemia-reperfusion (I/R) injury." TVP1022 [the S-isomer of rasagiline (Azilect), FDA-approved anti-Parkinson's drug] was found to exert cardioprotective activities against various cardiac insults, such as chronic heart failure and I/R, in rat models. Therefore, we tested the hypothesis that TVP1022 will provide cardioprotection against I/R injury and post-MI remodeling in a pig model. METHODS: For inducing MI, we used an I/R model of midleft anterior descending artery occlusion for 90 minutes followed by follow-up for 8 weeks in 18 farm pigs (9 pigs in each group, MI + TVP1022 or MI + Vehicle). Echocardiographic measurements were performed and cardiac scar size was calculated using histopathological methods. For fibrosis evaluation, we measured the interstitial collagen volume fraction in the remote noninfarcted tissue. RESULTS: TVP1022 administration significantly decreased cardiac scar size, attenuated left ventricular dilation, and improved cardiac function assessed by segmental circumferential strain analysis. Furthermore, TVP1022 significantly reduced myocardial fibrosis 8 weeks post-MI. CONCLUSIONS: Collectively, these findings indicate that TVP1022 provides prominent cardioprotection against I/R injury and post-MI remodeling in this I/R pig model.

Expandable external support device to improve Saphenous Vein Graft Patency after CABG.

OBJECTIVES: Low patency rates of saphenous vein grafts remain a major predicament in surgical revascularization. We examined a novel expandable external support device designed to mitigate causative factors for early and late graft failure. METHODS: For this study, fourteen adult sheep underwent cardiac revascularization using two vein grafts for each; one to the LAD and the other to the obtuse marginal artery. One graft was supported with the device while the other served as a control. Target vessel was alternated between consecutive cases. The animals underwent immediate and late angiography and were then sacrificed for histopathologic evaluation. RESULTS: Of the fourteen animals studied, three died peri-operatively (unrelated to device implanted), and ten survived the follow-up period. Among surviving animals, three grafts were thrombosed and one was occluded, all in the control group (p = 0.043). Quantitative angiographic evaluation revealed no difference between groups in immediate level of graft uniformity, with a coefficient-of-variance (CV%) of 7.39 in control versus 5.07 in the supported grafts, p = 0.082. At 12 weeks, there was a significant non-uniformity in the control grafts versus the supported grafts (CV = 22.12 versus 3.01, p < 0.002). In histopathologic evaluation, mean intimal area of the supported grafts was significantly lower than in the control grafts (11.2 mm^2 versus 23.1 mm^2 p < 0.02). CONCLUSIONS: The expandable SVG external support system was found to be efficacious in reducing SVG's non-uniform dilatation and neointimal formation in an animal model early after CABG. This novel technology may have the potential to improve SVG patency rates after surgical myocardial revascularization.

Energy transfer from systole to diastole: a novel device-based approach for the treatment of diastolic heart failure.

UNLABELLED: We hypothesized that attachment of elastic coil to the left ventricular (LV) wall, capable of exerting outward forces may allow the transfer of energy from systole to diastole and improve diastolic function. METHODS AND RESULTS: An extra-ventricular-device, composed of a series of elastic elements interposed between spiral screws attached to the epimyocardium of the LV free-wall was developed. The hemodynamic and mechanical effects of the device were tested using a computerized model, an in vitro model utilizing a computerized-controlled fluid pump, eight healthy sheep and 10 mini-pigs induced with diastolic dysfunction by renal wrapping. The computerized and in vitro models predicted a reduction of the LV diastolic pressure curve and partial normalization of the pressure-volume loop. The sheep study demonstrated preservation of animal's wellbeing including maintaining cardiac mechanical function with stable energy transfer from systole to diastole throughout the 6 months follow-up. The mini-pigs study showed an increase in the early diastolic to systolic strain-rate ratio in the mid-endocardial level (23 ± 10%, P = 0.008) and an increase in early apical reverse rotation rate of 50% (P = 0.016 compared to control). CONCLUSIONS: This study presents a novel concept of using a mechanical device to transfer energy from systole to diastole, potentially enhancing diastolic function.

Stability, visibility, and histologic analysis of a new implanted fiducial for use as a kilovoltage radiographic or radioactive marker for patient positioning and monitoring in radiotherapy.

PURPOSE: To analyze the stability, visibility, and histology of a novel implantable soft-tissue marker (nonradioactive and radioactive) implanted in dog prostate and rabbit liver. METHODS AND MATERIALS: A total of 34 nonradioactive and 35 radioactive markers were implanted in 1 dog and 16 rabbits. Stability was assessed by measuring intermarker distance (IMD) variation relative to IMDs at implantation. The IMDs were measured weekly for 4 months in the dog and biweekly for 2-4 weeks in the rabbits. Ultrasound and X-ray imaging were performed on all subjects. Computed tomography and MRI were performed on the dog. Histologic analysis was performed on the rabbits after 2 or 4 months. RESULTS: A total of 139 measurements had a mean (+/- SD) absolute IMD variation of 1.1 +/- 1.1 mm. These IMD variations are consistent with those reported in the literature as due to random organ deformation. The markers were visible, identifiable, and induced minimal or no image artifacts in all tested imaging modalities. Histologic analysis revealed that all pathologic changes were highly localized and not expected to be clinically significant. CONCLUSIONS: The markers were stable from the time of implantation. The markers were found to be compatible with all common medical imaging modalities. The markers caused no significant histologic effects. With respect to marker stability, visibility, and histologic analysis these implanted fiducials are appropriate for soft-tissue target positioning in radiotherapy.

Ventricular rate control using a novel vagus nerve stimulating system in a dog with chronic atrial fibrillation.

A 4-year-old, intact male Dogue de Bordeaux dog with congenital valvular pulmonic stenosis, tricuspid valve dysplasia, and chronic atrial fibrillation underwent ultrasound-guided balloon valvuloplasty in addition to pharmacological treatment. Owner compliance to prescribed pharmacotherapy proved very poor, and concerns developed regarding the ability to successfully control heart rate and symptoms using drug therapy alone. These concerns were addressed by the implantation of a novel vagal stimulation system that was programmed to prevent a ventricular rate of >145 bpm. Consequently, post-operative ventricular response rate decreased from up to 250 to 140 bpm. Successful ventricular rate control was maintained for 291 days post-operatively, following which euthanasia was elected by the owner due to persistent right-sided congestive heart failure. To the authors' knowledge, this is the first report of successful continuous rate control using a vagal stimulating system in a closed-chest, client-owned dog with chronic atrial fibrillation secondary to spontaneously occurring organic heart disease.

Sentinel node detection in an animal study: evaluation of a new portable gamma camera.

We tested the capacity of a newly developed portable gamma camera to precisely locate sentinel nodes by injecting a radiotracer. Two sets of experiments were performed on eight pigs under general anesthesia. 99mTc-Nanocolloid and dye complex was injected in the submuscular layer of the small bowel in the first set and subcutaneously in the knee region in the second set of experiments. Image acquisition of the sentinel nodes was performed with the Camera placed at various angles. A mosaic of images was obtained encompassing the injection sites, lymphatic pathways, and sentinel lymph nodes. Three-dimensional visualizations were obtained, allowing the precise location and complete excision of these nodes. The use of the portable gamma camera allowed the rapid visualization of the lymphatic pathways leading from the injection sites to the sentinel nodes and precise location of these nodes. The Camera was also useful to verify the complete removal of the labeled target tissues.

The LightWire technology for catheter-based interventions.

BACKGROUND: The LightWire is a newly developed opto-acoustic coronary imaging guidewire that was designed to be used during angioplasty procedures and provide 'online' information on lumen and vessel wall dimensions. METHODS: We designed in vitro models and performed animal trials to confirm proper device sensing capabilities and performance in the coronary arteries. This report focuses on maneuverability, compatibility with other catheterization devices, and vessel measurements. RESULTS: Measurement ability was initially validated in vitro. Diameter measurements of coronary and peripheral arteries with and without stent based on ultrasound technology were then demonstrated in a pig model, whereas retaining easy navigation and maneuverability, as well as compatibility with other catheterization equipments. The LightWire device acquired proper and accurate multi-location measurements of coronary and femoral artery diameters. CONCLUSION: Using a miniaturized opto-acoustic technology can aid incoronary imaging, while maintaining standard guidewire performances. Thus, the LightWire device holds promise as a diagnostic and guidance tool during coronary and peripheral angioplasty procedures.

Endothelial cells are activated by angiopoeitin-1 gene transfer and produce coordinated sprouting in vitro and arteriogenesis in vivo.

RATIONAL AND OBJECTIVES: Activation of fully differentiated vascular cells using angiogenic genes can lead to phenotypic changes resulting in formation of new blood vessels. We tested whether Ang-1 gene transfer to endothelial cells (EC) activates these cells. METHODS AND RESULTS: EC and SMC were transduced using retroviral or adenoviral vectors to produce Ang-1 or vascular endothelial growth factor (VEGF). EC Tie-2 receptor was phosphorilated by autologous secretion of Ang-1. Transduced EC and SMC sprouting capacity was tested using collagen embedded spheroids assay and capacity to produce arteriogenesis was tested in a hind limb model of ischemia. EC expressing Ang-1 in the presence of SMC expressing VEGF exhibited high levels of sprouting of the two cell types. Flow and numbers of arteries were increased after transduced cells implantation in vivo. CONCLUSIONS: Autologous secretion of Ang-1 by transduced EC resulted in Tie-2 activation and in the presence of SMC expressing VEGF resulted in coordinated sprouting in vitro and increase in flow and number of arteries in vivo.

Concept, design and pre-clinical studies for remote control percutaneous coronary interventions.

INTRODUCTION: Percutaneous Coronary Interventions (PCI) is conducted manually with the operator standing at the bed side, exposed to continuous X-ray radiation. A system where the operator can remotely navigate the wire and device during PCI may improve operator safety and convenience and can possibly enhance procedural precision. AIM: To develop a remote navigation system (RNS) that will allow computer controlled, remote manipulation of percutaneous coronary interventions.. METHODS AND RESULTS: The remote navigation system (RNS) is designed to handle both coronary guide wire and balloon / stent delivery system and can be loaded either with the coronary wire or with both wire and device in parallel. The RNS is comprised of a bedside unit and a remote manipulation unit. The bed side unit has individual wire and device manipulators, capable of precise maneuvering and positioning of the wires and devices. The system was tested in a wire glass model and was evaluated in a normal coronary sheep model. The wire glass model experiments showed that the wire could be navigated to the required branch and the stent/ balloon adequately positioned, as required. The animal experiments showed that the wire could access any required coronary branch and the stent could be adequately positioned under x-ray fluoroscopy, without causing dissection or other vessel trauma. CONCLUSION: A system that enables remote control percutaneous coronary procedures was developed and tested in vitro and in vivo models. Preclinical studies have demonstrated the feasibility of the concept of remote control PCI and have provided the basis for the pilot clinical study of remote control, stent-assisted PCI.