We describe a novel, cost-effective, and efficient technique for percutaneous delivery of three-dimensionally printed coronary implants to create closed-chest swine models of ischemic heart disease. The implants were fixed in place using a mother-and-child extension catheter with high success rate.
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Hollowed, J. J., Colbert, C. M., Currier, J. W., Nguyen, K. L. Novel Percutaneous Approach for Deployment of 3D Printed Coronary Stenosis Implants in Swine Models of Ischemic Heart Disease. J. Vis. Exp. (156), e60729, doi:10.3791/60729 (2020).
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Minimally invasive methods for creating models of focal coronary narrowing in large animals are challenging. Rapid prototyping using three-dimensionally (3D) printed coronary implants can be employed to percutaneously create a focal coronary stenosis. However, reliable delivery of the implants can be difficult without the use of ancillary equipment. We describe the use of a mother-and-child coronary guide catheter for stabilization of the implant and for effective delivery of the 3D printed implant to any desired location along the length of the coronary vessel. The focal coronary narrowing was confirmed under coronary cineangiography and the functional significance of the coronary stenosis was assessed using gadolinium-enhanced first-pass cardiac perfusion MRI. We showed that reliable delivery of 3D printed coronary implants in swine models (n = 11) of ischemic heart disease can be achieved through repurposing mother-and-child coronary guide catheters. Our technique simplifies the percutaneous delivery of coronary implants to create closed-chest swine models of focal coronary artery stenosis and can be performed expeditiously, with a low procedural failure rate.
Ischemic heart disease continues to be the number one cause of death in the United States1. Large animal models have been used experimentally to understand and characterize mechanisms driving coronary artery disease (CAD) and associated complications (including myocardial infarction, arrhythmic events, and heart failure), as well as for testing of new therapeutics or diagnostic modalities. Results from these studies have helped to broaden the understanding, diagnosis, and monitoring of ischemic heart disease and to advance clinical practice2. Several animal models including rabbits, dogs, and swine have been used. However, coronary stenoses, particularly discrete lesions, occur very rarely in these animals and are difficult to induce reproducibly3. Prior work described the creation of artificial coronary stenoses using ligation, occluders, or external clamps. Recently, we described how to use 3D printing technology to manufacture coronary implants that can be used to percutaneously create discrete artificial coronary narrowing4. Using computer-aided design software, we designed coronary artery implants as hollow tubes with varying inner and outer diameters as well as implant length and then fabricated them using commercially available additive materials. The implants are smooth, hollow, 3D printed tubes with rounded edges. We designed a library of implant sizes with a range of inner diameter, outer diameter, and length. The outer diameter of the implant is based on the size of the coronary guide catheter. The inner diameter is based on the size of a deflated coronary angioplasty balloon. We varied the length of the implant to tailor the desired severity of perfusion. However, safe percutaneous delivery of such devices can be challenging due to the lack of wires and catheters manufactured specifically for large animal use. In contrast, an extensive collection of catheters, wires, and supportive equipment are available for clinical use in human coronary arteries. In this work, we show how to repurpose a clinical grade mother-and-child coronary guide catheter for the delivery of the 3D printed coronary implants.
The GuideLiner catheter (Figure 1A) was developed for percutaneous coronary intervention (PCI) to allow for deep catheter seating and increased support for complex cases5. In our investigation, the GuideLiner catheter was chosen due to familiarity of use and availability, but similar catheters, where available, may also be considered. Considered a "mother-and-child" guide catheter (Figure 1B), the device fits inside a typical coronary guide catheter ("mother") and is a coaxial flexible tube ("child"). This catheter can be inserted over a guidewire and effectively lengthens the reach of a typical coronary guide catheter by extending beyond the end of the coronary guide. The GuideLiner or a similar mother-and-child catheter can be used as added support for deployment of the 3D printed coronary implants. Because the implants are mounted over angioplasty balloons to be inserted as a unit over a coronary wire into the vessel (Figure 1B,1C), the catheter offers additional support to deliver the implant to the desired site. By positioning the mother-and-child catheter just proximal to the balloon, the implant remains at the desired location during balloon deflation and retraction. Despite having some firmness to its structure, the mother-and-child catheter's unique ability to be advanced deep into coronary arteries over a guidewire and the radiopaque marker at the catheter tip were essential characteristics for implantation.
Our assembled delivery apparatus consisted of a typical coronary guide catheter, the mother-and-child catheter, and a 3D printed implant fixed onto a deflated coronary angioplasty balloon (Figure 1B). As a functional delivery unit, the mother-and-child catheter not only provided stable additional support for the delivery of the equipment but was also uniquely applied as a shearing device to keep the implants in place during deflation and removal of the balloon. The radiopaque marker at the catheter tip served as a positioning guide for the assembled apparatus and sits proximal to the angioplasty balloon. These characteristics allowed for precise deployment of the flow-limiting implants. The process was designed to be reproducible, efficient, and humane for the animal subjects.
In our application, the mother-and-child percutaneous delivery technique was used to create swine models with focal coronary stenosis for evaluation of contrast-enhanced stress cardiac perfusion magnetic resonance imaging (MRI). However, the technique may be employed in other investigations including vascular systems outside the coronary vessels.
We conducted the experiments according to the guidelines by the Animal Welfare Act, the National Institutes of Health, and the American Heart Association on Research Animal Use. Our Institutional Animal Care and Use Committee approved the animal study protocol.
1. Preprocedural preparation of 3D printed coronary stenosis implants
- Using tweezers, dip-coat the printed implants in a 25% heparin solution to prevent thrombus formation and allow to air dry for 24 h.
2. Preprocedural preparation of animal subjects
- Have male Yorkshire swine (SNS Farms, 30–45 kg) arrive at the institution 1 week prior to the experiment date and allow them to acclimate.
- Keep the swine in a fasting state after midnight the day prior to the procedure.
3. Procedural anesthesia
- Sedate the swine with intramuscular ketamine (10 mg/kg) and intravenous midazolam (1 mg/kg).
- Ventilate the animals with an oxygen-isoflurane (1–2%) mixture.
- Perform endotracheal intubation once the animal subject is sedated.
- Infuse intravenous (IV) rocuronium (2.5 mg/kg/h) and give additional boluses (1–3 mg/kg IV every 20–30 min) when needed to achieve diaphragmatic immobilization.
- Maintain a surgical plane of anesthesia throughout the procedure by checking for awakening, movements, wide fluctuation in vital signs, and other signs of distress or discomfort throughout the duration of the experiment. We monitored the swine for roughly 6 h under anesthesia.
4. Vascular access
- Using the Seldinger technique, insert the arterial and venous sheaths into the bilateral femoral arteries and veins of the subjects.
- Flush all catheter ports continuously with heparinized normal saline.
5. Preprocedural medication administration
- Administer amiodarone intramuscularly (1.5 mg/kg), lidocaine intravenously (2 mg/kg), and esmolol intravenously (1 mg/kg) as needed for prophylaxis against arrhythmia. Give repeat dosages of amiodarone, lidocaine, and esmolol as needed throughout the course of the experiment to suppress ventricular rhythms and control heart rate response.
- After vascular access is obtained, administer heparin (5,000–10,000 units) to keep an activated clotting time (ACT) >300 s. Check the ACT every hour during the course of the experiment and give additional intravenous heparin as needed to maintain the ACT goal.
6. Hemodynamic monitoring
- Use a single lateral electrocardiography (ECG) chest lead for recording changes in ST segment, T-waves, and heart rate during the entire experimental period.
- Use a pressure transducer to record continuous femoral arterial pressure throughout the procedure.
- Attach a pulse oximeter to the animal's ear or lip for continuous pulse oximetry recordings.
7. Preparation of implant delivery equipment
- Prior to performing coronary angiography, insert a deflated NC Trek over-the-wire coronary balloon through a mother-and-child catheter of the desired size such that the balloon tip extends beyond the tip of the catheter.
- Mount the 3D printed implant onto the deflated angioplasty balloon such that the implant is positioned between the markers of the balloon and close to the proximal marker (Figure 1B).
- Inflate the balloon with an insufflator to 2–3 atm in order to fix the implant onto the balloon. Verify that the implant is positioned closer to the proximal half of the balloon so it will be closest to the mother-and-child catheter when ready for removal (Figure 1B).
8. Coronary angiography and deployment of coronary implant
- Position the fluoroscopic C-arm in the anteroposterior (AP) projection.
- Attach a control valve (see Table of Materials) to a left or right coronary guide catheter (see Table of Materials).
- Introduce the guide catheter over a J-tipped wire through the right femoral artery sheath and, under fluoroscopic guidance, advance the catheter to the aortic root.
- Selectively (or nonselectively) engage the catheter into the left main coronary artery (LMCA) and inject 5 mL of iodinated contrast under fluoroscopy to visualize the left coronary system.
- Position the guide catheter towards the LMCA for the second angiogram (Figure 2). If coronary artery engagement proves difficult, due in part to the short aortic arch of the swine, consider performing non-selective angiograms as long as they provide adequate visualization of the vessels.
- Once engaged within, or positioned near the LMCA, under fluoroscopy, advance a 0.014", 300 cm coronary wire (see Table of Materials) into the LMCA and further advance the wire to the distal left anterior descending artery (LAD) or left circumflex coronary artery (LCX) if desired (Figure 3).
- Under fluoroscopic guidance, insert the previously assembled mother-and-child catheter with the inflated coronary angioplasty balloon and implant over the coronary wire and advance to the desired location along the coronary vessel. Inject 5 mL of iodinated contrast to visualize a discrete narrowing at the desired location where the coronary implant should be deployed (Figure 4).
- Once the implant is in position, advance the mother-and-child catheter to the proximal marker of the inflated balloon.
- Deflate the balloon and retract it through the mother-and-child catheter. This process allows the mother-and-child catheter to shear the implant off the balloon as it is retracted and fixes the position of the implant in the designated segment of the vessel.
- Remove the balloon, mother-and-child catheter, and coronary wire.
- Perform final angiograms to document the location of the new artificial stenosis within the vessel. When feasible, angiograms should be performed in two orthogonal views to acquire visual estimation of stenosis severity. A final angiography (Figure 5) can also be performed with subselective positioning of the mother-and-child catheter in the proximal vessel, which provides excellent opacification with minimal contrast.
- Immediately transfer the animal to the MR suite to undergo cardiac stress perfusion MRI using gadobutrol (0.1 mM/kg) injected at a rate of 2 mL/sec.
NOTE: The stress agent used was a 4 min infusion of adenosine at 300 µg/kg/min. The imaging protocol included 1) cine imaging (field of view [FOV] = 292 x 360 mm, matrix size = 102 x 126, repetition time [TR] = 5.22 ms, echo time [TE] = 2.48 ms, slice thickness = 6 mm, pixel bandwidth = 450 Hz, flip angle = 12˚); 2) first-pass perfusion at rest and at peak adenosine vasodilator stress using a spoiled gradient echo sequence (FOV = 320 x 320 mm, matrix size = 130 x 130, TR = 2.5 ms, TE = 1.1 ms, slice thickness = 10 mm, pixel bandwidth = 650 Hz, flip angle = 12˚; and 3) late gadolinium enhancement imaging using an ECG-gated, segmented, spoiled gradient-echo phase-sensitive-inversion-recovery sequence (FOV = 225 x 340 mm, matrix size = 131 x 175 mm, TR = 5.2 ms, TE = 1.96 ms, slice thickness = 8 mm, inversion time (TI) = optimized to null the myocardium, pixel bandwidth = 465 Hz, flip angle = 20˚). An illustrative first-pass perfusion image is shown in Figure 6.
- After completion of the MRI protocol, euthanize the swine by an infusion of sodium pentobarbital (100 mg/kg).
- Perform a lateral thoracotomy, excise the heart, and dissect the ex vivo heart to expose the coronary vessels. Note the location of the implant in relationship to either the diagonal branches (LAD territory) or obtuse marginal branches (LCX territory), and retrieve the implants.
- Using blunted and curved Metzenbaum scissors, open the coronary vessel and inspect the vessel for gross injury (see Figure 7). Photograph the heart tissue for gross pathology and stain with triphenyltetrazolium chloride to exclude myocardial infarction (see Figure 8).
After initial optimization of the procedure, the intervention component was completed within 30 min. The implants were successfully delivered in all 11 subjects (100%). The implant was retrieved at the autopsy in all 11 subjects (100%). Using the diagonal branches (along the LAD) or obtuse marginal branches (along the LCX) as positional markers, we found the position of the implant at fluoroscopic-guided deployment and at autopsy to be consistent in 10 of the 11 (91%) subjects where the implant was retrievable. In one subject, there was slight distal migration of the implant, which may be related to vasodilation induced by intracoronary nitroglycerin injection for coronary spasm. Of the 11 subjects studied, 9 survived for the entire catheterization and completed the MRI protocol, giving us an 82% procedural success rate. Two subjects died after the implants were deployed. The first subject developed ventricular fibrillation in the MRI suite well after deployment of the implant. The second died in the MRI scanner in the setting of hypotension midway through the experiment. At the time of dissection, we did not see thrombus within the implants or other signs of structural injury to the vessels. The high survival rate (2 deaths, 9 of 11 survived) highlights the importance an effective anti-arrhythmic prophylaxis regimen. An illustrative example of stress cardiac perfusion MRI is provided in Figure 6. Detailed implant design and full results of the MRI validation will be reported separately.
Figure 1: Catheter design and assembled apparatus with mounted coronary implant. (A) Diagram of the components of the mother-and-child catheter6. (B) Assembled apparatus showing the coronary balloon inflated with the 3D printed implant mounted and fixed at the leading head of the catheter, which protrudes through the guide catheter. (C) A magnified image of the 3D printed implant is shown mounted onto the angioplasty balloon. Please click here to view a larger version of this figure.
Figure 2: Coronary angiogram in the anteroposterior projection shows selective contrast-enhancement of the left main coronary artery system. Please click here to view a larger version of this figure.
Figure 3: Coronary angiogram in the anteroposterior projection shows the 0.014" 300 cm coronary wire in the left anterior descending artery. Please click here to view a larger version of this figure.
Figure 4: Coronary angiogram in the anteroposterior projection. The image on the left shows the assembled mother-and-child catheter with the inflated coronary balloon and implant in the mid to distal segment of the left anterior descending artery. A higher magnification of the assembled apparatus within the coronary vessel is shown in the right panel. Please click here to view a larger version of this figure.
Figure 5: Anteroposterior angiogram. The image on the left shows a focal stenosis in the distal left anterior descending artery after deployment of the implant. A higher magnification of the discrete coronary narrowing induced by the implant is shown in the right panel. Please click here to view a larger version of this figure.
Figure 6: Stress cardiac perfusion magnetic resonance images of a coronary implant deployed in the proximal to mid left anterior descending artery. The images at rest (upper panel) and peak adenosine vasodilator stress (lower panel) show inducible perfusion defects in the segments subtended by the left anterior descending artery. Please click here to view a larger version of this figure.
Figure 7: Autopsy images. (A) The implant at the distal left anterior, descending artery. (B) The absence of gross injury to the coronary vessel. (C) Implant without thrombus. Please click here to view a larger version of this figure.
Figure 8: Histopathology of swine myocardial tissue. (A) Gross pathology and (B) triphenyltetrazolium chloride stains in one subject showed no evidence of myocardial tissue infarction. Please click here to view a larger version of this figure.
In this work, we focused on a novel percutaneous deployment strategy for coronary stenosis-inducing implants and showed that a mother-and-child catheter can be repurposed for effective percutaneous delivery of 3D printed coronary implants. Discrete artificial coronary stenoses of variable severity can be created quickly in swine models with a high success rate and in a minimally invasive manner using standard human percutaneous coronary interventional techniques and equipment. These implants were shown to be safe in the acute setting and were also effective at creating severe angiographic stenoses, which correlated with stress-induced perfusion defects during vasodilator stress cardiac MRI. Compared to open-chest techniques, percutaneous delivery of stenosis-inducing implants is less invasive and more humane.
There are several other minimally invasive techniques currently available to create flow reduction in large animal models. The 3D printed coronary implants differ fundamentally from balloon occlusion and coil occlusion in that the stenoses induced by the 3D printed implants do not completely occlude the vessel. This is a major difference that allows for modelling of stress-induced ischemia rather than infarction7,8. Rissanen et al.9 describe a percutaneous technique that creates flow limiting, non-obstructive stenoses in swine models using a coronary stent wrapped in a polytetrafluoroethylene tubing. The tubing could be shaped by employing needles and heat to create luminal narrowing of various degrees. It is clear that the implants we used differ in design and thorough description with full validation is beyond the scope of the current work, which is to describe the novel methodology used for delivery of 3D printed coronary implants. Utilizing the mother-and-child catheter allowed for precise deployment of the implants deep in the coronary arteries. It is difficult to compare procedural success between our studies as other investigators explored a chronic model and kept the swine alive for an extended period of time9. Bamberg et al. described a method using balloon catheters inflated within 3 mm stents to create stenoses of 50% and 75% in the left anterior descending artery. This latter method differs from our investigation in that the stenoses created required catheters to be left inside the animals. There is no way to create an artificial lesion and remove all equipment. While viable, the Bamberg method does not allow for investigation of ischemia beyond the acute setting and residual wires would cause image artifacts10.
The role of mother-and-child catheters in coronary interventions has been well established, but their use to deliver implants into vascular beds has not been previously described5,6. The two most challenging aspects of percutaneous implant delivery include selective deployment into a precise coronary segment and prevention of retrograde migration. Attempting to deploy the device over angioplasty balloons was not effective because the implant could be pulled proximally in the vessel after balloon deflation. For several reasons, the mother-and-child catheter proved to be a valuable tool for fixing the implants in place during balloon withdrawal. The mother-and-child catheters fit easily in the coronary guide catheters and their size was ideal for our intervention. They were slightly larger than the deflated coronary balloon, allowing us to shear the implant off and to prevent retrograde migration of the implant as the balloon was withdrawn. The support provided by the mother-and-child catheter enabled the implants to be deeply seated in the coronary artery with strong apposition to the vessel lumen. Additionally, the radiopaque marker on the tip of the mother-and-child catheter helped position the catheter just proximal to the implant, as identified by the marker on the delivery balloon. Though the technique was mostly effective, in one subject there was slight distal migration after implant delivery. This may have been due to injection of intracoronary nitroglycerin for coronary vasospasm and resultant vasodilation leading to distal migration of the implant. The GuideLiner catheter was chosen due to familiarity of use, but there are a number of other similar devices which could potentially be used in its place. The Guidezilla Guide Extension Catheter (Boston Scientific, Marlborough, Massachusetts, USA) is also available in a 6F size and has a similar structure to the GuideLiner. There is also a Guidion rapid exchange guide extension catheter (Interventional Medical Device Solutions, Roden, The Netherlands) which comes in sizes 5–8F and could also potentially be used in place of the GuideLiner catheter.
Our deployment technique can be performed efficiently and humanely in swine with a low procedural failure rate. In our preliminary study the procedural failure rate was 18%. There was a learning curve associated with the technique as we streamlined our interventions. However, despite the learning curve, all animal subjects survived the initial implant deployment intervention. The lesions created were focal and the narrowing ranged in severity, but they were not occlusive. These stenoses were angiographically significant and produced inducible perfusion defects during stress perfusion MRI. Figure 6 is an example of a focal perfusion defect seen on MRI after successful implant deployment to the LAD. We aimed to create ischemia rather than infarction. Figure 8 shows an example of histopathologic analysis of the myocardial tissue, which shows no evidence of infarction. The method relies on human coronary angioplasty equipment, and the similarity in swine coronary size to those of humans. The outer diameter of the 3D printed implant was based on the inner diameter of the guiding catheter and the inner diameter of the mother-and-child catheter. The minimal luminal diameter of the stenosis was based on the size of the deflated coronary balloon. The final flow-limiting severity of the discrete stenosis is based on the inner diameter and the length of the implant. Although resting angiographic flow was preserved, maximal coronary blood flow was reduced, as evidenced by the MRI perfusion scans. Future work will focus on replacing the balloon delivery wire with a pressure wire and measurement of fractional flow reserve or instantaneous flow reserve. Similarly, downstream microvascular injury can be produced by local injections of microspheres either through the delivery balloon or the mother-and-child catheter itself.
Our low procedural failure rate in a closed-chest swine model shows promise for future implementation. Because complete total occlusion was not performed, myocardial infarction was avoided, and may have contributed to the lower rate of malignant arrhythmias. In our study only 1 subject developed ventricular fibrillation. After an initial period of optimization, we cut down procedural time to roughly 30 min per case.
In summary, our results demonstrate a novel technique for deployment of 3D printed coronary implants and show the feasibility of creating a closed-chest swine model of discrete focal coronary stenosis. This minimally invasive technique can be used for testing and development of new diagnostic imaging techniques in ischemic heart disease. We used stress cardiac perfusion MRI, but other modalities may include nuclear imaging, ultrasound, and computed tomography. Although this model is immediately applicable to ischemic heart disease, with minor modifications, the technique can be employed for other occlusive vascular disease states.
The authors have nothing to disclose.
We thank staff members at the UCLA Translational Research Imaging Center and the Department of Laboratory Animal Medicine at University of California, Los Angeles, CA, USA for their assistance. This work is supported in part by the Department of Radiology and Medicine at David Geffen School of Medicine at UCLA, the American Heart Association (18TPA34170049), and by the Clinical Science Research, Development Council of the Veterans Health Administration (VA-MERIT I01CX001901).
|3D-Printed coronary implants||Study Site Manufactured|
|Amiodarone IV solution||Study Site Pharmacy|
|Amplatz Left-2 (AL-2) guide catheter (8F)||Boston Scientific, Marlborough, Massachusetts, USA|
|Balance Middleweight coronary wire (0.014” 300cm)||Abbott Laboratories, Abbott Park, Illinois, USA|
|COPILOT Bleedback Control valve||Abbott Laboratories, Abbott Park, Illinois, USA|
|Esmolol IV solution (1 mg/kg)||Study Site Pharmacy|
|Formlabs Form 2 3D-printer with a minimum XY feature size of 150 µm||Formlabs Inc., Somerville, Massachusetts, USA|
|Formlabs Grey Resin (implant material)||Formlabs Inc., Somerville, Massachusetts, USA|
|Gadobutrol 0.1 mmol/kg||Gadvist, Bayer Pharmaceuticals, Wayne, NJ|
|GuideLiner catheter (6F)||Vascular Solutions Inc., Minneapolis, Minnesota, USA|
|Heparin IV solution||Surface Solutions Laboratories Inc., Carlisle, Massachusetts, USA|
|Ketamine IM solution (10 mg/kg)||Study Site Pharmacy|
|Lidocaine IV solution||Study Site Pharmacy|
|Male Yorkshire swine (30-45 kg)||SNS Farms|
|Midazolam IV solution||Study Site Pharmacy|
|NC Trek over-the-wire coronary balloon||Abbott Laboratories, Abbott Park, Illinois, USA|
|Oxygen-isoflurane 1-2% inhaled mixture||Study Site Pharmacy|
|Rocuronium IV solution||Study Site Pharmacy|
|Sodium Pentobarbital IV solution (100mg/kg)||Study Site Pharmacy|
|Triphenyltetrazolium chloride stain||Institution Pathology Lab|
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