Gladwin S. Das

Experimental atrial septal defect closure with a new, transcatheter, self-centering device.

BackgroundDespite two decades of research, a transcatheter atrial septal defect closure device is not available for clinical use. We have designed a new superelastic Nitinol-Dacron, double-disk, selfcentering, atrial septal defect closure device and studied its efflicacy in a canine model of atrial septal defects. Methods and ResultsAtrial septal defects were created surgically in 20 adult dogs using either a 7.5-mm or 10-mm punch. Percutaneous transcatheter closures were attempted using a new device. The device sizes used were 20 mm in 6 dogs, 22 mm in 9, and 25 mm in 5 (22.1±1.9 mm, mean±SD). The stretched atrial septal defect diameter was 10.5±13 mm, and the device to stretched atrial septal defect diameter ratio was 2.1±03. Closures were successful in 19 studies and unsuccessful in 1. Angiography showed a left-to-right shunt in all 20 dogs before closure. Immediately after closure (n= 19), there were no shunts in 17 and trivial shunts in 2. Six dogs were followed for a period of 4.7±3.0 months (range, 2 to 8 months). The trivial shunt present in 1 animal immediately after closure had closed by the time of the repeat study. Spontaneous embolization of the device was not seen during follow-up. A solitary wire fracture was found 8 months after closure in 1 device. Light microscopy at 8 weeks in 3 dogs showed the devices to be covered by smooth endocardium, enmeshed in mature collagen tissue, with a minimal mononuclear cell infiltration. Retrievability was assessed by deliberately embolizing 4 devices in 2 dogs into the right atrium (n=l) and pulmonary artery (n=3). All devices were successfully retrieved with a snare.Concusions. This feasibility study demonstrates that this new self-centering atrial septal defect closure device has a number of design features that permit effective and safe closures in a canine model. These results support the investigation of this device in human clinical trials.

Use of plasma glow for surface-engineering biomolecules to enhance bloodcompatibility of Dacron and PTFE vascular prosthesis.

The search for a nonthrombogenic material having patency to be used for small diameter vascular graft applications continues to be a field of extensive investigation. The purpose of the present study was to examine whether surface modification of polytetra fluoroethylene (PTFE, Teflon) and polyethylene-terephthalate (Dacron) vascular grafts might extend graft biocompatibility without modifying the graft structure. A series of surface coatings were prepared by modifying the argon plasma-treated PTFE and Dacron grafts with collagen IV and laminin and subsequently immobilizing bioactive molecules like PGE1, heparin or phosphatidyl choline via the carbodiimide functionalities. Surface analysis by Fourier transform infrared spectroscopy-attenuated total reflectance revealed the presence of new functional groups on the modified graft surfaces. In vitro studies showed that fibrinogen adsorption and platelet adhesion on modified grafts were significantly reduced. This study proposes that surface grafting of matrix components (collagen-type IV and laminin) and subsequent immobilization of bioactive molecules (PGE1, heparin or phosphatidyl choline) changed the surface conditioning of vascular grafts and subsequently improved their biocompatibility. However, more detailed in vivo studies are needed to confirm these observations.

Changes in Cisplatin Delivery Due to Surface-Coated Poly (Lactic Acid)–Poly(∊-Caprolactone)Microspheres

Smooth muscle cell proliferation plays a major role in the genesisof restenosis after angioplasty or vascular injury. Local delivery of agents capable of modulating vascular responses, have the potential to prevent restenosis. However, the development of injectable microspheres for sustained drug delivery to the arterial wall is a major challenge. We demonstrated the possibility of entrapping an antiproliferative agent, cisplatin, in a series of surface coated biodegradable microspheres composed of poly(lactic acid)– poly(caprolactone) blends, with a mean diameter of 2–10 mm. The microspheres were surface coated with poly ethylene glycol (PEG), chitosan (Chit), or alginate (Alg). A solution of cisplatin and a 50: 50 blend of polylactic acid (PLA)– polycaprolactone (PCL) dissolved in acetone–dichloromethane mixture was poured into an aqueous solution of PEG (or polyvinyl alcohol or Chit or Alg) with stirring using a high speedhomogenizer, for the formation of microspheres. Cisplatin recovery inmicrospheres ranged from 25–45% depending on the emulsification system used for the preparations. Scanning electron microscopy revealed that the PLA–PCL microspheres were spherical in shape and had a smooth surface texture. The amount of drug release was much higher initially (20–30%), this was followed by a constant slow-release profile for a 30-day period of study. It has been found that drugrelease depends on the amount of entrapped drug, on the presence of extra cisplatin in the dispensing phase, and on the polymer coatings.This PEG or Alg-coated PLA/PCL microsphere formulation may have potential for the targeted delivery of antiproliferative agents to treat restenosis.

Delivery of LMW Heparin via Surface Coated Chitosan/peg-Alginate Microspheres Prevents Thrombosis

Heparin remains the gold-standard inhibitor of the process involved in the vascular response to injury. Continued anticoagulation is achieved by subcutaneous administration of low-molecular-weight heparin (LMW Hep) or with an orally active anticoagulant such as warfarin. An oral heparin would avoid the inconvenience of subcutaneous injections and adverse events associated with warfarin. A mild chitosan/PEG/calcium alginate microencapsulation process, as applied to encapsulation of biological macromolecules such as heparin and LMW Hep was investigated. Heparin and LMW Hep entrapped alginate beads were further surface/enteric coated with chitosan and cellulose acetate phthalate (CAP) via carbodiimide (EDC) functionalities. It was observed that approximately 70% of the content is being released into Tris-HCl buffer, pH 7.4 within the initial 6 hours and no significant release of LMW Hep was observed from enteric coated microspheres (12%) during treatment with 0.1 M HCl, pH 1.0 for 4 hours. But acid treated capsules had released almost all the entrapped LMW Hep into Tris-HCl, pH 7.4 media within 6 hours. From scanning electron microscopic and swelling studies, it appeared that the surface coatings (via chitosan and CAP) had modified the alginate microspheres and subsequently the drug release. The released heparin and LMW Hep had shown their anticoagulant functions. These results established the feasibility of modifying the formulation in order to obtain the desired controlled release of bioactive agent (LMW Hep), for a convenient pH dependent delivery system.

Development of Poly(Lactic Acid)/Chitosan Co-Matrix Microspheres: Controlled Release of Taxol-Heparin for Preventing Restenosis

Smooth muscle cell proliferation plays a major role in the genesis of restenosis after angioplasty or vascular injury. Controlled release of appropriate drugs alone and in combinations is one approach for treating coronary obstructions, balloon angioplasty, restenosis associated with thrombosis, and calcification. We demonstrated the possibility of encapsulating taxol-loaded polylactic acid (PLA) microspheres within heparin-chitosan spheres to develop a prolonged release co-matrix form. The in vitro release profile of taxol and heparin from this co-matrix system was monitored in phosphate buffered saline pH 7.4, using an ultraviolet spectrophotometer. The amount of taxol/heparin release was initially much higher, followed by a constant slow release profile for a prolonged period. The initial burst release of taxol (15.8%) and heparin (32.7%) from the co-matrix was modified with polyethylene glycol coatings (13.5% and 25.4%, respectively, for 24 hr). From scanning electron microscopy studies, it appears that these drugs diffuse out slowly to the dissolution medium through the micropores of the co-matrix. However, the surface micropores were modified with polyethylene glycol (PEG) coatings for a constant slow release profile. This PEG-coated PLA/chitosan co-matrix may target drug combinations having synergestic effects for prolonged periods to treat restenosis.Smooth muscle cell proliferation plays a major role in the genesis of restenosis after angioplasty or vascular injury. Controlled release of appropriate drugs alone and in combinations is one approach for treating coronary obstructions, balloon angioplasty, restenosis associated with thrombosis, and calcification. We demonstrated the possibility of encapsulating taxol-loaded polylactic acid (PLA) microspheres within heparin-chitosan spheres to develop a prolonged release co-matrix form. The in vitro release profile of taxol and heparin from this co-matrix system was monitored in phosphate buffered saline pH 7.4, using an ultraviolet spectrophotometer. The amount of taxol/heparin release was initially much higher, followed by a constant slow release profile for a prolonged period. The initial burst release of taxol (15.8%) and heparin (32.7%) from the co-matrix was modified with polyethylene glycol coatings (13.5% and 25.4%, respectively, for 24 hr). From scanning electron microscopy studies, it appears that these drugs diffuse out slowly to the dissolution medium through the micropores of the co-matrix. However, the surface micropores were modified with polyethylene glycol (PEG) coatings for a constant slow release profile. This PEG-coated PLA/chitosan co-matrix may target drug combinations having synergestic effects for prolonged periods to treat restenosis.

Controlled delivery of taxol from poly(ethylene glycol)‐coated poly(lactic acid) microspheres

The development of injectable microspheres for sustained drug delivery to the arterial wall is a major challenge. We demonstrated the possibility of entrapping an antiproliferative agent, taxol, in poly(ethylene glycol) (PEG)-coated biodegradable poly(lactic acid) (PLA) microspheres with a mean diameter of 2-6 microm. A solution of taxol and PLA dissolved in an acetone/dichloromethane mixture was poured into an aqueous solution of PEG [or poly(vinyl alcohol) (PVA] with stirring with a high-speed homogenizer for the formation of microspheres. Taxol recovery in PLA-PEG microspheres was higher (61.2 +/- 2.3%) than with PVA-based (41.6 +/- 1.8%) preparations. An analysis by diffuse reflectance infrared Fourier transform spectroscopy revealed that PEG was incorporated well on the PLA microsphere surface. Scanning electron microscopy revealed that the PEG-coated PLA microspheres were spherical in shape and had a smooth surface texture like those of PVA-based preparations. The amount of drug release was much higher initially (25-30%); this was followed by a constant slow-release profile for a 30-day period of study. This PEG-coated PLA microsphere formulation may have potential for the targeted delivery of antiproliferative agents to treat restenosis.

Transcatheter Closure of Patent Foramen Ovale for Hypoxemia During Left Ventricular Assist Device Support

A patent foramen ovale with right-to-left shunting was responsible, in part, for profound hypoxemia in a patient who required mechanical support with a left ventricular assist device for cardiogenic shock. The patent foramen ovale was detected with contrast transesophageal echocardiography, and the defect was closed successfully with a transcatheter septal defect closure device.

The Development of Porous Alginate/Elastin/PEG Composite Matrix for Cardiovascular Engineering

The development of suitable three-dimensional matrices for the maintenance of cellular viability and differentiation is critical for applications in tissue engineering and cell biology. To this end, gel matrices of different proportions of alginate/elastin/polythylene glycol (Alg/Ela/PEG) were prepared and examined. The composite matrix membranes were evaluated for their porous scaffold using SEM, enzymatic degradation and water content. An equal blend of Alg/Ela with a ratio of Alg/Ela: PEG (7: 3) was selected for fabricating Alg/Ela/PEG scaffolds for this study. The Alg/Ela/PEG membranes fabricated at 20°C and -20°C had a mean surface pore size of 35-45 μm. However, their ultrastructures had shown bigger pore structures (60-75 μm) compared to their surface. It is interesting to note that the membranes of Alg/Ela/PEG prepared at 20°C had larger ultrastructural pores than that of membranes prepared at -20°C. Further, the SEM studies revealed that in the absence of PEG the composite membranes of Alg/Ela formed with less porous structures. The water content of membranes prepared at 20°C was higher with Alg/Ela/PEG (61.6 ± 4.8%), compared to Alg/Ela (49.9 ± 0.3%). The enzymatic degradation and water content studies also revealed that the membranes fabricated at -20°C had high water uptake and low enzymatic degradation, as that of the membranes prepared at 20°C. In other words the larger pore structured membranes had less water content and high degradation profile. This study proposes that this novel composite matrix produces a hierarchical structure that is useful for generating tissue scaffolds for repairing the failing cardiac muscles. However, more detailed investigations with cytocompatibility studies are needed to find applications.

Cardiac Platypnea‐Orthodeoxia Syndrome: An Often Unrecognized Malady

Platypnea‐orthodeoxia syndrome (POS) is a rare but clinically important form of dyspnea. The syndrome is characterized by dyspnea and arterial oxygen desaturation that occurs in the upright position and improves with recumbency. In cardiac POS, an atrial septal defect or patent foramen ovale allows communication between the right‐ and left‐sided circulations. A second defect, such as a dilated aorta, prominent eustachian valve, or pneumonectomy, then contributes to right‐to‐left shunting through the interatrial connection. Diagnosis is made through pulse oximetry to confirm orthodeoxia and through transesophageal echocardiography with bubble study to visualize the shunt. Although data are limited for this rare syndrome, percutaneous closure has thus far proven safe and effective.

Catheter ablation of hemodynamically unstable ventricular tachycardia with mechanical circulatory support

BACKGROUND Catheter ablation of hemodynamically unstable ventricular tachycardia (VT) is possible with mechanical circulatory support (MCS), little is known regarding the relative safety and efficacy of different supporting devices for such procedures. METHODS AND RESULTS Sixteen consecutive patients (aged 63 ± 11 years with left ventricular ejection fraction of 20 ± 9%) who underwent ablation of hemodynamically unstable VT were included in this study. Hemodynamic support included percutaneous (Impella® 2.5, n = 5) and implantable left ventricular assist devices (LVADs, n = 6) and peripheral cardiopulmonary bypass (CPB, n = 5). Except for 2 Impella cases, hemodynamic support was adequate (with consistent mean arterial pressure of > 60 mmHg) to permit sufficient activation mapping for ablation. In the Impella and CPB groups, mean time under hemodynamic support was 185 ± 86 min, and time in VT was 78 ± 36 min. Clinical VT could be terminated at least once by ablation in all patients except 1 case with Impella due to hemodynamic instability. Peri-procedural complications included hemolysis in 1 patient with Impella and surgical intervention for percutaneous Impella placement problems in another 2. The median number of appropriately delivered defibrillator therapies was significantly decreased from 6 in the month before VT ablation to 0 in the month following ablation (p = 0.001). CONCLUSIONS Our data suggest that peripheral CPB and implantable LVAD provide adequate hemodynamic support for successful ablation of unstable VT. Impella® 2.5, on the other hand, was associated with increased risk of complications, and may not provide sufficient hemodynamic support in some cases.