Ann Thorac Surg 2002;74:488-492
© 2002 The Society of Thoracic Surgeons
Original article: cardiovascular
Transmyocardial coil implants: a novel approach to transmyocardial revascularization
David Meerkin, MBBSc,d,
Michel Pellerin, MDb,
H. Thomas Aretz, MDe,
Patrice Paiement, MSa,
Stuart L. Houser, MDe,
Raoul Bonan, MD*a
a Department of Medicine, Montreal Heart Institute, Montreal, Quebec, Canada
b Department of Surgery, Montreal Heart Institute, Montreal Quebec, Canada
c Department of Medicine, Shaare Zedek Medical Center, Jerusalem, Israel
d Department of Cardiology, Shaare Zedek Medical Center, Jerusalem, Israel
e Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA
Accepted for publication April 25, 2002.
* Address reprint requests to Dr Bonan, Montreal Heart Institute, 5000 Belanger St, Montreal, Quebec HIT 1C8, Canada
e-mail: raoul.bonan{at}mmic.net
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Abstract
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Background. Transmyocardial laser revascularization (TMLR) has potential benefit for patients with end-stage coronary artery disease and intractable angina not amenable to conventional revascularization techniques. Neovascularization has been proposed to occur around the laser channels. Our aim was to determine the feasibility of a novel nonlaser myocardial revascularization technique and its effect on angiogenesis in a nonischemic porcine model.
Methods. In the first phase, six transmyocardial stainless steel coil implants (TMI) were deployed to the lateral wall of the left ventricle in each of 6 pigs. The animals were sacrificed at 8 and 12 weeks, with a single animal dying prematurely at 4 weeks, and the myocardium was assessed for new vessel growth. In the second phase, 8 implants were deployed in each of 12 pigs with regular fluoroscopic follow-up until sacrifice at 2 weeks to assess implant stability.
Results. The deployment procedure was safe and feasible with no complications evident. A significant increase in new vessels at implant sites with 5.43 ± 3.67, 4.97 ± 2.44, and 3.57 ± 2.29 seen per high power field at 12, 8, and 4 weeks, respectively, compared to 1.00 ± 1.06 (p < 0.0001) in control myocardium. There was no evidence of implant migration in Phase 2.
Conclusions. TMIs can feasibly be deployed in the nonischemic pig model with a high success rate. The presence of angiogenesis at the implant site and the maintenance of this reaction for 3 months implies that TMI may offer an alternative to TMLR while providing a platform for delivery of angiogenic factors.
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Introduction
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End-stage coronary artery disease with refractory angina represents a therapeutic challenge that is as yet unconquered by our modern day armamentarium. One of the approaches to this problem is transmyocardial laser revascularization. This technique, initially described by Mirhoseini and Cayton in 1981, involves the use of laser energy to create channels from the epicardial surface through the myocardium to the left ventricular chamber [1, 2]. Studies in ischemic animal models have demonstrated improved perfusion and left ventricular (LV) function [3, 4] and reduction of infarct size [5, 6] following this treatment. In human studies, improvements in anginal status and nitrate use have been most marked [7, 8]. More recently, feasibility of percutaneous endocardial approaches have been demonstrated, as well as initial patient experience reported [9, 10]. Although the mechanism of action remains unclear, this technique’s ability to stimulate new vessel formation and favorably alter the epicardial endocardial flow ratio [11, 12] appears most appealing. Fitting with this concept, animal models have demonstrated that at the site of laser lesions there is a multiplicity of new vessels. This has been evident in both ischemic [4, 13–15] and nonischemic models [16, 17], and in different animal models including dogs, pigs, and sheep. Furthermore, some preliminary studies suggest that this may be a nonspecific response to the degree of injury rather than related specifically to the laser lesion [16]. However, it is apparent that, over a period of 3 months, a process of healing takes place with a decrease in the number of vessels and a reduction in the caliber and even obliteration of the initial laser channel [18]. In view of these findings, there would appear to be a role for a device that could stimulate a longer-term angiogenic response with the added benefit as a potential synergistic platform for angiogenic factors. The purpose of this study was to, firstly, determine the safety and feasibility of a transmyocardial implant and, secondly, to assess the response of the myocardium to the stainless steel, coil-shaped implant. Specifically, we sought to determine the patency of the channels within the implants, the degree and duration of the angiogenic response, and its relationship to the expected implant strut related inflammation. The second phase of the study was to determine the stability of the implants in the myocardium.
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Material and methods
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All animals were cared for in accordance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" prepared by the National Academy of Sciences (NIH publication 85-23, revised 1985).
This study was divided into two portions. The first phase was to study feasibility and efficacy assessing the ability to deploy transmyocardial implants in the lateral aspect of the left ventricle and determining the response of the myocardium to the implants in a nonischemic porcine model. The second phase was to determine the stability of the implants within the myocardium in this model.
Phase 1
Six juvenile Yorkshire pigs weighing 25 to 30 kg were treated with 650 mg aspirin and 30 mg nifedepine 24 hours prior to the procedure. The animals received an intramuscular injection of ketamine (12 mg/kg) and xylazine (8 mg/kg) as a premedication before anesthesia to allow easy endotracheal intubation. Anesthesia was induced and maintained with 1% halothane in a 1:2 mixture of oxygen and air. Following percutaneous puncture of right or left femoral artery, an 8F femoral sheath was placed and heparin (150 U/kg) and xylocaine (100 mg) were administered as intra-arterial boluses. An 8F pigtail catheter was advanced into the left ventricular chamber. A baseline left ventricular angiogram was performed to confirm normal left ventricular function.
Surgery
Using sterile technique, the heart was exposed through a small left thoracotomy and the pericardium was opened. Continuous electrocardiographic and blood pressure monitoring were performed. The lateral wall of the left ventricle was identified. Six myocardial implants were deployed to this region. Each myocardial implant was made of 316L stainless steel and configures in the shape of a coil with a single retaining loop for positioning on the epicardium (Fig 1).
The implant was 9.1 mm in length and 2.2 mm in diameter with a central core of 1.8 mm. It was mounted on a delivery obturator. Deployment was performed by direct puncture of the epicardium until bleed back was noted through the obturator or the device was fully deployed. The obturator was then removed using a rotating motion. Any bleeding was controlled by digital pressure. In each animal, a single control puncture was performed using the identical technique with the obturator alone with no implant deployed. The procedure was performed over an area of approximately 5 cm2. At the completion of the deployments, the pericardium was not closed, a chest drain was placed, and the chest was closed. If the animal was stable, the chest drain was removed 1 hour after surgery. The entire surgical procedure lasted 20 to 25 minutes. Following the surgery, a left ventricular angiogram was repeated to confirm maintained LV function and to assess mitral valve function.
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Fig 1. Myocardial implant made of 316L stainless steel. Epicardial retaining ring evident as large loop.
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Follow-up
The follow-up period was designated as 8 weeks in 3 animals and 12 weeks in 3 animals. Prior to sacrifice by IV KCL (20 meq), each animal again underwent LV angiogram to assess LV and mitral valve function.
Pathological assessment
The hearts were explanted and placed in 10% neutral buffered formalin. They were x-rayed to confirm the presence and position of all the implants. Each implant was then identified and removed. Attempts were made to identify the control puncture based on the surgical note and diagram. Specifically noted were the location of the implants, the level of penetration including visibility and protrusion from the endocardial surface, and its epicardial appearance as well as evidence of migration. Histological preparations were then made of the zones with the implants, control myocardium, and control punctures with Mason’s elastic trichrome and hematoxylin and eosin stains. Vessels greater than 20 µm were counted using a micrometer, and the results were expressed as number of vessels per high power field (HPF; magnification x 400). Vessels were counted in the core of the implants, one HPF adjacent to the implants, and 1 cm away from the implants.
Phase 2
During phase 1, a single implant was noted to have been displaced and so a second study phase was performed on 12 juvenile Yorkshire pigs, weighing 25 to 30 kg, to further assess the stability of the implants with minor procedural differences. Specifically, (1) eight implants were deployed per animal; (2) no control puncture was performed; and (3) the pericardium was closed at the end of the procedure.
Follow-up
The animals underwent daily fluoroscopic examination over the 1st week and every 2nd day over the 2nd week until sacrifice at the completion of the 2nd week. Following sacrifice with a rapid injection of IV KCL (20 meq), the hearts were explanted and x-rayed to determine the position of all the implants. Macroscopic inspection of all of the implants was performed to detect any evidence of device migration. No microscopic analysis was performed.
Statistical analysis
All values are provided as mean ± 1 standard deviation. A two-tailed nonpaired Student’s t test was used in comparisons of 12-, 8-, and 4-week specimens with control. Statistical significance was indicated by p < 0.05.
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Results
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Acute surgical results
In all 20 animals, surgery was uncomplicated and the implants were deployed without incident. Specifically, there was no evidence of arrhythmia or bleeding. There was no pleural or pericardial effusion or tamponade. The implants did not impair LV function or cause mitral incompetence.
Phase 1
A single pig died prematurely at 4 weeks. The cause was due to a severe respiratory infection. All implants were in position and did not involve the mitral valve. The remaining animals were sacrificed at 8 and 12 weeks as per protocol. A single implant was displaced in the epicardial direction into the chest wall, probably at the time of chest drain removal soon after the index procedure. There were no complications associated with this event. All remaining implants were identified and inspected macroscopically and microscopically. There was no other evidence of migration of the implants. The majority of implants were evident at the epicardial surface. They were generally flush with the epicardium, however four implants were embedded 1 to 4-mm deep to the surface. Fourteen of the 35 identified implants protruded beyond the endocardium into the LV cavity a distance of 1 to 4 mm. They were not associated with thrombus. A single implant was entangled in the two chordae originating from the posterior papillary muscle. A second implant was caught in the posterior leaflet of the mitral valve. No mitral incompetence was detected in either case.
Histology
Histologically, control punctures were extremely difficult to detect, in spite of being marked with sutures. Aside from evidence of minimal scar formation, no difference was detected between these lesions and control myocardium. Microscopically, the implants had a fibrous core with prominent vascularization, and a mild-to-moderate inflammatory response surrounding the struts was noted in the majority of cases (Fig 2).
Vessel counts demonstrated significant increase of vessel numbers in the implant core with a less-pronounced increase noted surrounding the devices. This was noted especially at 12 weeks (Table 1).
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Fig 2. Low-power photomicrograph of lesions at 4 weeks (A) and 8 weeks (B). The semicircular defect corresponds to the site of the implant. The neovascularization in the fibrous core is readily apparent, and the 4-week lesion shows a greater amount of inflammation surrounding the implant. (Masson’s trichrome stain; original magnification x25).
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Phase 2
All 12 animals in the migration study had an uncomplicated course until sacrifice at 2 weeks. At fluoroscopy, there was no evidence of device migration. This was confirmed at sacrifice, on x-ray film of the explanted heart, and by macroscopic analysis and confirmation that all implanted devices were present and firmly embedded with no evidence of migration (Fig 3).
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Comment
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This study demonstrates the feasibility and safety of deploying coil-shaped myocardial implants in the nonischemic porcine model. The obliteration of the lumen within the implants is consistent with other findings of closure of laser and mechanically induced channels [15, 16, 19]. In spite of "stenting," these channels were consistently occluded. This study also reconfirms that new vessel formation is not a phenomenon that is specifically related to laser injury [16]. Rather, this response is part of the inflammatory and healing processes following injury to the myocardium. This novel approach, however, results in a predictable response to controlled injury with a prolonged stimulus for angiogenesis. These findings improve over a 3-month period without evidence of a chronic inflammatory response.
There have been reports suggesting that the entire benefit of laser revascularization results from denervation and is unrelated to any neovascularization or healing [20–21]. It is unclear what influence these implants have on this potential effect, although no clear benefit should be gained by mechanical disruption of the nerves by laser or other means. Multiple reports have emerged demonstrating the feasibility of intravenous, intracoronary, and direct epicardial and endocardial injection of factors and genes coding for factors stimulating angiogenesis. The efficacy of these techniques has been demonstrated with increased expression of the encoded factor in humans and in animal models [22–24], with a reduction of symptoms and/or ischemic burden reported in selected patients with chronic ischemia [24].
Recently, the combined use of laser transmyocardial revascularization (TMR) with direct myocardial injection of plasmid DNA encoding the gene for vascular endothelial growth factor demonstrated complete reversal of ischemic wall motion abnormalities in a porcine model that did not occur with TMR alone [25]. Transgene expression was also significantly increased when transfection was associated with TMR. It seems likely that augmentation of the results of each individual modality can be achieved when they are used in combination. Theoretically desirable characteristics of such a system would include the ability to couple the mechanical stimulatory effects of channel formation with the ability to deliver the angiogenic factors, genes, or vectors to the site. The advantages of a long-term platform such as an implant, include allowing the deployment of a long-acting or slow-release angiogenic stimulant factor with a resultant quantitatively increased and more durable effect. Although the bare implant as such may not confer any direct benefit above laser TMR, the feasibility of a well-tolerated myocardial implant provides an ideal vehicle for factors to further stimulate angiogenesis. The ability to subsequently progress to a biodegradeable implant of the same design that would carry angiogenesis stimulating factors has the potential to achieve more effective alternative revascularization than any of the techniques alone.
Study limitations
Transmyocardial implants were performed in a nonischemic porcine model. Ischemia itself is a powerful stimulus for angiogenesis. In spite of this, most laser animal studies have shown similar responses in both ischemic and nonischemic models. This study was also limited to the determination of neovascularization and did not make any attempt to assess functional improvement based on perfusion of left ventricular function.
Conclusions
It is feasible and safe to deploy transmural left ventricular metallic implants in a nonischemic porcine model. The implants resulted in no LV dysfunction based on LV angiogram. In spite of "stenting," the formed channels did not remain patent. Optimization of the implant design and delivery technique is required to reduce the risk of submitral entanglement. The implants result in a nonspecific reaction to injury with a mild-to-moderate inflammatory response and prominent vascularization akin to that seen in TMLR and much greater than a control mechanical puncture. This long-term implant results in a longer-term stimulus for tissue reaction in the myocardium and potentially more prolonged angiogenetic response. Finally, a myocardial implant may provide a platform for the rapid, delayed or long-term delivery of angiogenic factors or vectors for genetic manipulation.
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Acknowledgments
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This work was supported in part by the Bard Myocardial Angiogenesis Research Group, C.R. Bard, Inc, Lowell, MA.
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Abstract
Introduction
