Abstract
Purpose
We describe our initial experience with on-bypass and off-bypass (off-pump) mitral valve replacement with the modified version of our novel catheter-based sutureless mitral valve (SMV2) technology, which was developed to atraumatically anchor and seal in the mitral position.
Description
The SMV is a self-expanding device consisting of a custom designed nitinol framework and a pericardial leaflet valve mechanism. For the current studies our original device was modified (SMV2) to reduce the delivery profile and to allow for controlled deployment whilst still maintaining the key principles necessary for atraumatic anchoring and sealing in the MV position.
Evaluation
Ten Yorkshire pigs underwent successful SMV2 device implantation via a left atriotomy (on-pump N=6; off-pump N=4). Echocardiography and angiography revealed excellent LV systolic function, no significant perivalvular leak, no MV stenosis, no left ventricular (LV) outflow tract obstruction and no aortic valve insufficiency. Necropsy demonstrated that the SMV2 devices were anchored securely.
Conclusions
This study demonstrates the feasibility and short-term success of off-pump mitral valve replacement using a novel, catheter-based device in a porcine model.
Introduction
Transcatheter mitral valve replacement (TMVR) represents an exciting new frontier in cardiac device technology development(1, 2), with the potential to revolutionize the management of heart failure in older, high-risk patients suffering from inoperable mitral regurgitation (MR). The potential impact of this technology cannot be understated as the prevalence of moderate and severe MR is currently estimated to be between 2 to 4 million patients in the United States alone, and is expected to increase substantially in the next few decades as the population ages(3). An approved TMVR device would permit restoration of MV competence at a lower risk than current surgical approaches in this comorbid population, and further refinement of this technology will potentially allow for expansion into standard-risk adults, and possibly even into children afflicted with congenital heart disease in the years ahead.
Emboldened by the success of both transcatheter aortic valve replacement (TAVR)(4) and transcatheter pulmonary valve replacement (TPVR)(5), TMVR is being aggressively pursued by multiple groups around the world, including ours(1). We have previously reported our experience with on-pump implantation of a Sutureless Mitral Valve (SMV) device in an ovine model of open-heart surgical MV replacement(2). The SMV was the manifestation of extensive preclinical work elucidating the critical principles required for a secure sutureless TMVR device implantation. These obligatory principles can be characterized into three main concepts: 1) an anchoring mechanism which distributes the anchoring forces across the mitral apparatus (annulus and sub-annular); 2) a perivalvular sealing strategy; and 3) device foldability for catheter based delivery.
This study describes the next steps in the ongoing evolution of our TMVR technology, including the on-pump and off-pump implantation of a modified SMV device – the SMV2 in pigs. The SMV2 incorporates all of the anchoring and sealing principles described in our first report,(2) with the added properties of a lower delivery profile.
Technology
Modified Sutrureless Mitral Valve (SMV2) Replacement Device
The SMV2 device tested in these experiments is the result of progressive, serial iteration on prior prototypes, each based on the theme of atraumatic anchoring and sealing. The current device is comprised of 2 major components; a nitinol frame, and a tissue valve mechanism (Figure 1). As in previous prototypes(2), the current frame was designed to exert a combination of anchoring forces, including a radial (expansive) force and “cinching” or “grasping” force on the sub-annular tissue (MV leaflets and chordae) – all while maintaining a hollow lumen for housing the valve mechanism.
Figure 1.
The modified version of the Sutureless Mitral Valve (SMV2) device is shown in 1A and 1B. As part of ongoing design iteration, the device was modified from it’s original wire weave design to lower the device profile for catheter delivery, while still delivering the necessary anchoring and sealing forces. The SMV2 consists of a custom nitinol frame with “ventricular arms” designed to capture the native mitral valve leaflets in the space between the stent body and the “arms”. The atrial end of the device is designed to augment anchoring and seal, and also to permit attachment to, and controlled deployment from, the delivery catheter.
Technique
SMV2 Implantation procedure
Following approval by The University of Pennsylvania’s Animal Care and Use Committee, 10 male Yorkshire pigs were subjected to study.
On-pump studies (N= 6)
In all animals, a left thoracotomy was performed. Using standard cardiac surgical techniques cardiopulmonary bypass (CPB) was instituted, the heart was arrested and a left atriotomy was created. The SMV2 was packaged into a custom delivery device and then advanced through a 2 cm left atrial incision into the left ventricle. Then, in a step-wise process, the SMV2 device was delivered under direct visualization into the MV space as previously described (2).
Off-pump studies (N=4)
As in the on-pump studies, a left thoracotomy was performed, and the left atrium was exposed. A 12mm ePTFE tube graft was sewn onto the left atrium (LA) creating a “hemostatic chimney” (Figure 2), through which the SMV2 delivery system was advanced for deployment under fluoroscopic guidance. Several sighting injections were recorded to confirm appropriate device positioning, and then in a careful stepwise manner, the device was deployed and released (Figure 3).
Figure 2.
Intraoperative picture showing the ePTFE graft which was sewn on to the left atrium to provide a hemostatic chimney for transatrial off-pump SMV2 implantation.
Figure 3.
Panels 3A–3C show the sequence of the off-pump SMV2 implantation procedure. Panel 3A represents a sighting left ventriculogram. The SMV2 device is compressed within the delivery catheter, which was advanced across the MV plane via the LA chimney. Panel 3B shows the blossoming of the ventricular arms as the device is partially opened. A hemostat clamp (marked by “*”) corresponding to the mitral valve leaflets and annulus is placed externally on the chest wall to mark the target under fluoroscopy for opening the ventricular arms. The ventricular arms are designed to capture the anterior and posterior MV leaflets. Once the ventricular arms are seated appropriately, the atrial sided of the device is opened in the left atrium allowing it to expand to its nominal shape. Once the positioned is confirmed the device is released as shown in Panel 3C. The inset pictures in Panels 3A–3C correspond to the various conformational changes of the SMV device during staged deployment. LA=left atrium; LV = left ventricle; SMV2 = Sutureless Mitral Valve2 device
Following implant in both groups, epicardial echocardiography was performed. The chest wall was then closed, and all animals underwent hemodynamic and angiographic assessment.
After a 3-hour survival, all animals were euthanized as per protocol. Necroscopy was performed including gross inspection of the SMV2 device in situ, and evaluation of the surrounding tissues for evidence of device related trauma.
Statistical Analysis
Hemodynamic measurements after SMV2 implantation were summarized using standard descriptive statistics and reported as mean ± standard.
Clinical Experience
All implant procedures [on-pump N=6; off-pump N=4] were successful and resulted in secure SMV2 anchoring in the mitral position. The operative data is summarized in Table 1. The mean CPB and aortic cross clamp (XC) times were 39.4 ± 2.1 and 7.3 ± 1.8 minutes, respectively for the on-pump cases. Total procedure time, defined as the time from thoracotomy to valve implantation, was 44 ± 8 minutes in the off-pump implant group. Placement of the LA vascular graft represented the most time consuming part of the procedure. Once the LA chimney was secured, the SMV2 implant took less than 15 minutes in each of the animals. Following SMV2 implantation, epicardial echocardiography revealed excellent LV systolic function and no mitral regurgitation (Figure 4). There was no perivalvular leak, and no inflow acceleration in diastole. (mean ECHO Doppler velocity = 1.7 ± 0.7 m/sec with normal doppler inflow pattern). There was no left ventricular outflow tract obstruction, and no aortic valve insufficiency.
Table 1.
Procedural Variables
| Variable | Mean ± SD |
|---|---|
| Weight (kg) | 53.2 ± 4.3 |
| Mitral Annulus dimensions (mm x mm) | 33 ± 2.8 × 27 ± 5.2 |
| CPB time (min) | 39.4 ± 2.1 |
| Aortic Cross Clamp time (min) | 7.3 ± 1.8 |
| MR grade post-implantation (ECHO 0 – 4) | 1 [0 – 1] median [range] |
| MV gradient (mean) by ECHO post-implantation (m/sec) | 1.7 ± 0.7 |
CPB = cardiopulmonary bypass; ECHO = echocardiography; Kg = kilogram; m/sec = meters per second; mm = millimeters; MR = mital regurgitation; MV = mitral valve
Figure 4.
Angiographic assessment of the SMV2 device, 3 hours following off pump transatrial implantation. The device is securely anchored. Panel A shows a systolic frame with no mitral regurgitation (MR) and no left ventricular outflow tract (LVOT) obstruction. Panel B shows a diastolic frame. There is no aortic valve insufficiency (AI), and normal coronary arteries. [Panel C]. LV = left ventricle; LA = left atrium; RCA = right coronary artery; LCx = left circumflex coronary artery.
Post SMV2 implant hemodynamic data, including cardiac output, and chamber pressures, were recorded. The mean cardiac output was 3.9 ± 1.8 L/min. There was no significant difference between the mean left atrial (LA) and LV end diastolic pressures (16.8 ± 4.1 vs. 16.1 ± 5 mmHg; p = 0.80), and there was no LV outflow tract obstruction (LV = 111.9± 10.8; Ascending aorta = 108.1 ± 10.3 p = 0.77).
Follow up angiography revealed stable device position and excellent left ventricular function. There was no significant mitral regurgitation, no LV outflow tract obstruction, no aortic valve insufficiency, and normal coronary arteries (Figure 5).
Figure 5.
Echocardiographic assessment following transatrial off-pump SMV2 implantation. Panel A show color Doppler interrogation of the SMV2 in systole. There is no mitral regurgitation. Panel B shows low velocity flow from the left atrium through the SMV into the left ventricle. There is no stenosis.
Following euthanasia, necropsy demonstrated that the SMV2 devices were anchored securely, with the ventricular arms of the device insinuated around the MV leaflets as intended in all animals (Figures 6). There was a complete circumferential seal around the SMV2, and, upon removal of the device from the mitral annulus, no evidence for significant device related trauma.
Figure 6.
Postmortem pictures of the Sutureless Mitral Valve2 (SMV2) device from the left atrial (Panel A) and left ventricular (Panel B) perspectives. There is a tight seal posteriorly between the body of the SMV2 and the native mitral valve leaflet. Panel B shows a view from the apex to the underside of the aortic valve. The ventricular arms of the SMV2 capture the anterior mitral leaflet in the space between the arms and the body of the SMV2. The LVOT appears unobstructed.
Comment
Transcatheter mitral valve replacement (TMVR) is the next frontier in catheter-based valve replacement therapy(1). Percutaneous mitral valve-in-valve (VIV) and valve-in-ring (VIR) procedures using devices originally designed for implantation into the aortic or pulmonary position are already well established(6–9). Though impressive and technically demanding in their own right, mitral VIV and VIR procedures are relatively simple when compared to the daunting challenge of secure implantation of a device into the mitral space in the absence of a pre-existing “landing zone”.
In our previous report, we described the anchoring and sealing demands that need to met by any device for successful TMVR(2). The SMV device described in that report was designed to fit within the mitral “leaflet cone” and exhibit a combination of anchoring/sealing forces, including radial expansion at the mitral annulus (a so-called “interference fit”), and sub-annular anchoring via “arms” emanating from the ventricular aspect of the device frame which insinuate themselves around the mitral leaflet and chordal tissue. This combination yielded a remarkably strong yet atraumatic seal.
In this current study, the SMV2 represents iterative changes geared towards lowering the device delivery profile and adapting it for controlled catheter-based delivery while adhering to the same fundamental principles manifest in the SMV. Implantation - both on-pump and off-pump - yielded secure anchoring in all 10 of the animals studied, with no significant mitral regurgitation, no perivalvular leak, no LVOT obstruction and no aortic insufficiency in this acute animal model.
This report once again illustrates the rising potential for catheter-based valve therapies and adds to the growing literature supporting the feasibility of non-surgical MV replacement(1, 10). Although many questions remain unanswered and many technical challenges remain to be addressed, this experience is an important step in the development of a broadly applicable TMVR technology. We anticipate that TMVR in the presence of significant cardiac morbidity from chronic mitral regurgitation (ischemic or degenerative) will only add to the complexity of TMVR by presenting a host of potential anatomic and physiologic hurdles to overcome. At this early stage of TMVR development, challenges such as these are most appropriately anticipated and addressed in a preclinical model of MV disease.
Limitations
This was a proof of principle study designed to test the feasibility of on-pump and off-pump suturelss mitral valve replacement using a customized device (SMV2) engineered to anchor and seal within the MV annulus in an atraumatic fashion. This was an acute study, therefore we cannot comment on the durability and functionality of the SMV2 device in the longer term.
Acknowledgments
This work was supported by grants from the National Heart, Lung and Blood Institute of the National Institutes of Health, Bethesda, MD (HL63954 and HL73021). R. Gorman and J. Gorman are supported by individual Established Investigator Awards from the American Heart Association, Dallas, TX.
Footnotes
Disclosure and Freedom of Investigation
These studies were funded exclusively by the NIH grant as listed above.
All authors had full control of the study design, methods used, outcome parameters, analysis of the data, and production of the written report.
The devices tested in the study were designed and developed at the University of Pennsylvania by Drs. Gillespie, R. Gorman, and J. Gorman.
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References
- 1.De Backer O, Piazza N, Banai S, et al. Percutaneous transcatheter mitral valve replacement: An overview of devices in preclinical and early clinical evaluation. Circ Cardiovasc Interv. 2014;7(3):400–409. doi: 10.1161/CIRCINTERVENTIONS.114.001607. [DOI] [PubMed] [Google Scholar]
- 2.Gillespie MJ, Minakawa M, Morita M, et al. Sutureless mitral valve replacement: Initial steps toward a percutaneous procedure. Ann Thorac Surg. 2013;96(2):670–674. doi: 10.1016/j.athoracsur.2013.02.065. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Nkomo VT, Gardin JM, Skelton TN, Gottdiener JS, Scott CG, Enriquez-Sarano M. Burden of valvular heart diseases: A population-based study. Lancet. 2006;368(9540):1005–1011. doi: 10.1016/S0140-6736(06)69208-8. [DOI] [PubMed] [Google Scholar]
- 4.Cribier A, Eltchaninoff H, Tron C, et al. Early experience with percutaneous transcatheter implantation of heart valve prosthesis for the treatment of end-stage inoperable patients with calcific aortic stenosis. J Am Coll Cardiol. 2004;43(4):698–703. doi: 10.1016/j.jacc.2003.11.026. [DOI] [PubMed] [Google Scholar]
- 5.Khambadkone S, Coats L, Taylor A, et al. Percutaneous pulmonary valve implantation in humans: Results in 59 consecutive patients. Circulation. 2005;112(8):1189–1197. doi: 10.1161/CIRCULATIONAHA.104.523266. [DOI] [PubMed] [Google Scholar]
- 6.Webb JG, Wood DA, Ye J, et al. Transcatheter valve-in-valve implantation for failed bioprosthetic heart valves. Circulation. 2010;121(16):1848–1857. doi: 10.1161/CIRCULATIONAHA.109.924613. [DOI] [PubMed] [Google Scholar]
- 7.Shuto T, Kondo N, Dori Y, et al. Percutaneous transvenous melody valve-in-ring procedure for mitral valve replacement. J Am Coll Cardiol. 2011;58(24):2475–2480. doi: 10.1016/j.jacc.2011.09.021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Hasan BS, McElhinney DB, Brown DW, et al. Short-term performance of the transcatheter melody valve in high-pressure hemodynamic environments in the pulmonary and systemic circulations. Circ Cardiovasc Interv. 2011;4(6):615–620. doi: 10.1161/CIRCINTERVENTIONS.111.963389. [DOI] [PubMed] [Google Scholar]
- 9.Zou Y, Ferrari E, von Segesser LK. Off-pump transapical mitral valve-in-ring implantation. Eur J Cardiothorac Surg. 2012 doi: 10.1093/ejcts/ezs407. [DOI] [PubMed] [Google Scholar]
- 10.Attmann T, Pokorny S, Lozonschi L, et al. Mitral valved stent implantation: An overview. Minim Invasive Ther Allied Technol. 2011;20(2):78–84. doi: 10.3109/13645706.2011.554559. [DOI] [PubMed] [Google Scholar]