Ann Thorac Surg 2008;85:1771-1775. doi:10.1016/j.athoracsur.2007.11.036
© 2008 The Society of Thoracic Surgeons
New Technology
Acute Reduction of Functional Mitral Regurgitation in Canine Model Using an Epicardial Device
Masatoshi Akiyama, MD, PhDa,
Zoran B. Popovi
, MD, PhDb,
Keiji Kamohara, MDa,
Faruk Cingoz, MDa,
Masao Daimon, MDb,
Chiyo Ootaki, MDa,
Yoshio Ootaki, MD, PhDa,
Maureen Martin, RDCSb,
Jenny Liu, BAa,
Michael W. Kopcak, Jr, BAa,
Raymond Dessoffy, AAa,
Kiyotaka Fukamachi, MD, PhDa,*
a Department of Biomedical Engineering, Lerner Research Institute, Cleveland, Ohio
b Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio
Accepted for publication November 12, 2007.
* Address correspondence to Dr Fukamachi, Department of Biomedical Engineering, ND20, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195 (Email: fukamak{at}ccf.org).
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Abstract
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Purpose: This study evaluated the short-term feasibility of a novel epicardial device that treats functional mitral regurgitation by simultaneously changing the mitral and the left ventricular geometry.
Description: We implanted a prototype device that consists of 2 tissue anchors, a deflector, and a flexible tightening chord in 7 mongrel dogs with heart failure and functional mitral regurgitation induced by rapid ventricular pacing. Hemodynamic and echocardiographic data were obtained before and after device implantation.
Evaluation: The device acutely reduced the mitral regurgitation grade from 3.2 ± 0.3 to 0.9 ± 0.5 (p < 0.001). Left ventricular end-diastolic volume (79.6 ± 23.6 to 61.2 ± 16.9 mL; p = 0.004) and end-systolic volume (63.1 ± 17.3 to 49.2 ± 12.3 mL; p = 0.006) decreased substantially. End-systolic elastance significantly increased from 1.9 ± 1.0 to 2.6 ± 1.4 mm Hg/mL (p = 0.02). Device implantation did not alter coronary perfusion.
Conclusions: The epicardial device acutely reduced functional mitral regurgitation and improved left ventricular geometry. Further studies are required to demonstrate the long-term safety and efficacy of this concept.
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Technology
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Functional mitral regurgitation (MR) has multifactorial causes, including both annular and ventricular dilatation that produces tethering of the mitral leaflets [1, 2]. Undersized mitral annuloplasty has become frequently recommended to treat functional MR [3, 4]; however, its acceptance for these patients has been limited because of the associated morbidity and mortality.
In an effort to address these limitations, alternative, less invasive approaches are being developed. We previously reported the Coapsys system (Myocor Inc, Maple Grove, MN) as an alternative approach [5]; however, the Coapsys device still necessitates a surgical procedure. If the concept of Coapsys could be translated into an interventional access method, it would have the potential to be a less invasive alternative. We developed the novel concept of an epicardial device to reduce or eliminate functional MR. The purpose of this study was to evaluate the short-term feasibility and efficacy of the concept.
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Technique
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Device Design
The epicardial device consists of 2 tissue anchors, a deflector, and a flexible tightening chord. The tissue anchors are secured on the left ventricle (LV) with curved metallic pins and are connected by a flexible tightening chord. A deflector is attached to the tightening chord midway between the 2 anchors and is positioned at the middle of the posterior mitral leaflet (Fig 1). The deflector is sufficiently long to influence the mitral valve at both the annular and papillary muscle levels. As the flexible chord is tightened, the 2 tissue anchors are drawn together, causing the deflector to change the shape of the mitral annulus and LV.
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Fig 1. Illustration of the epicardial device. (A = anterior tissue anchor; AML = anterior mitral leaflet; AV = aortic valve; CS = coronary sinus; D = deflector; LCX = left circumflex coronary artery; P = posterior tissue anchor; PML = posterior mitral leaflet; RV = right ventricle.)
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Induction of Heart Failure and Functional Mitral Regurgitation
This study was approved by The Cleveland Clinic's Institutional Animal Care and Use Committee, and all animals received humane care in accordance with the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (National Institutes of Health Publication 85-23, revised 1996).
Functional MR with heart failure was induced by rapid ventricular pacing at 230 beats/min for 4 to 5 weeks, and the MR grade was assessed with two-dimensional transthoracic echocardiography according to the extent, width, and duration of the regurgitant jet (grade 0 to 4) [1].
Preparation for Device Implantation
Before anesthesia was induced, the pacemaker was turned off to restore normal sinus rhythm. Under general anesthesia, an 8F sheath was inserted into the left carotid artery, and a fluid-filled line was connected to the sheath for arterial pressure monitoring. A conductance catheter with 2 Millar pressure sensors (model SPC-562; Millar Instruments Inc, Houston, TX) was inserted through the sheath and advanced into the LV to record LV pressure and volume. A 7.5F Swan-Ganz catheter (Baxter Healthcare, Irvine, CA) was advanced into the pulmonary artery to monitor pulmonary arterial pressure and central venous pressure. After median sternotomy, a Millar catheter (Millar Instruments) was inserted into the left atrium to monitor the left atrial pressure, and a 14-mm Transonic flow probe (model 14A165; Transonic System Inc, Ithaca, NY) was placed around the ascending aorta to measure forward cardiac output. Coronary angiography was performed to determine the proper location of the device and to evaluate the coronary perfusion.
Before the device was implanted, coronary angiography images were collected, and the corresponding pressure-volume loop was obtained as described subsequently.
Device Implantation
The epicardial device was implanted using epicardial echocardiography, coronary angiography, and external landmarks. The posterior tissue anchor was placed approximately 1 cm lateral to the posterior descending coronary artery and 2 cm apical to the atrioventricular groove. The deflector was threaded over the flexible tightening chord and placed opposite the middle of the posterior mitral leaflet. The anterior tissue anchor was threaded over the flexible tightening chord and placed approximately 1 cm lateral to the left anterior descending coronary artery and 2 cm apical to the atrioventricular groove. The device was then sized by tensioning the flexible tightening chord with a sizing instrument. The final tightening level was determined under epicardial color Doppler echocardiography.
Once the device was placed on the heart but not yet tightened, epicardial echocardiography images were collected (pre-T data point). To evaluate the real-time effect of the device on the hemodynamic status, hemodynamic data was collected by continuously tightening the device in 1-cm/min increments up to the final tightening level. The data just before device tightening (continuous pre-T data point) and that at the final tightening level (continuous post-T data point) were compared.
Finally, the anterior tissue anchor was fixed to the flexible tightening chord, and the excess chord was removed. After device implantation, epicardial echocardiography, coronary angiography images, and LV pressure-volume loops were obtained (post-T data point).
Echocardiographic Analysis
The MR grade was assessed in the same manner as previously described. The ratio of MR jet area/left atrial area was calculated, and the MR volume was measured using the proximal isovelocity surface area method.
Left ventricular end-diastolic (LVEDV) and end-systolic volumes (LVESV), mitral annular area, and left atrial volume were measured by three-dimensional (3D) epicardial echocardiography (Vivid 7; GE Medical, Milwaukee, WI).
Mitral annular and LV cross-sectional dimensions in the septal-lateral (S-L) and the commissure-commissure (C-C) planes were measured using full-volume 3D echocardiography data. The C-C plane was defined as an orthogonal plane to the S-L plane. Left ventricular cross-sectional dimensions were measured using the reconstructed cross-sectional view at the mid-papillary muscle level.
Pressure-Volume Loop Analysis
Left ventricular pressure-volume loops were obtained by bicaval occlusion with umbilical tapes placed around the superior and inferior vena cavae. The LV volumes measured with a conductance catheter were calibrated to 3D epicardial echocardiography, using a 2-point calibration based on matching LVEDV and LVESV [6]. By connecting the upper left corners of the pressure-volume loops using an iterative linear regression method, the end-systolic elastance was determined [7].
Statistical Analysis
Data are expressed as mean ± standard deviation. A paired t test was used to analyze data obtained before and after the device implantation. In all analyses, a value of p < 0.05 was considered statistically significant.
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Pre-Clinical Experience
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The device was implanted on the beating heart without cardiopulmonary bypass in 7 dogs (body weight, 19.4 ± 3.3 kg). Fig 2
shows an intraoperative view of the implanted device.
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Fig 2. Intraoperative view of the device placement. The heart is maneuvered to facilitate exposure of the implanted device. (A = anterior tissue anchor; D = deflector; P = posterior tissue anchor.)
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Analysis of echocardiography data obtained is summarized in Table 1. The device significantly reduced the MR grade, the MR jet area/left atrial area ratio, and MR volume (Fig 3). The mitral annular area and mitral annular S-L dimension were reduced, but the mitral annular C-C dimension was unchanged. The S-L and C-C dimensions at LV mid-papillary muscle level were significantly reduced. The LVEDV and LVESV were significantly reduced, and the LV ejection fraction was unchanged.
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Fig 3. Two-dimensional epicardial echocardiography before (pre-T) and after (post-T) device tightening. The mitral regurgitation (arrow), as seen at (A) the pre-T data point, was remarkably reduced at (B) the post-T data point. (LA = left atrium; LV = left ventricle; MR = mitral regurgitation.)
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Analysis of hemodynamic data obtained by continuous device tightening is summarized in Table 2. A slight but significant increase was noted in left atrial pressure and LV end-diastolic pressure after device implantation. No significant differences were found in the other measured hemodynamic indices. End-systolic elastance significantly increased after device implantation from 1.9 ± 1.0 to 2.6 ± 1.4 mm Hg/mL (p = 0.02).
When the initial sites for device implantation were evaluated with coronary angiography, the deflector had disturbed the left circumflex coronary artery circulation in 2 of the 7 dogs. The device deflectors were repositioned to restore coronary perfusion in those dogs.
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Comment
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Our study demonstrated that displacing the mitral annulus and posterior LV using an epicardial device significantly reduced functional MR. This study shows the combined effect of mitral annular and LV geometric changes on reducing functional MR with an epicardial device.
One of the alternative approaches for functional MR is percutaneous, catheter-based annuloplasty, which attempts to duplicate the technique of surgical mitral annuloplasty. These approaches, in which devices are placed in the coronary sinus, have demonstrated the ability to reduce the functional MR in animal experiments. However, anatomic studies have demonstrated that these devices shrink the mitral annulus only by indirect traction mediated by the left atrial wall and that a risk of coronary artery branch compression exists in humans [8]. Furthermore, the distance between the coronary sinus and mitral annulus is generally unfavorable and is increased in patients with severe MR and annular dilation [9]. These results indicate that catheter-based annuloplasty might induce coronary ischemia and that the device may not be efficient in the most severe patients.
The Coapsys, which we have previously reported, uses a transventricular chord and 2 epicardial pads to reduce the S-L dimension at the mitral annular and papillary muscle levels and thereby improve leaflet coaptation. Early results from ongoing clinical trials have demonstrated that the Coapsys device acutely reduced ischemic MR and provided significantly greater LV reshaping than did annuloplasty [10].
Although the prototype device is epicardial in nature, the mechanism of action is somewhat different from that of the Coapsys device. The tension mechanism that shifts the deflector of the prototype device acts circumferentially, concentric to the atrioventricular groove, causing both anchors to simultaneously draw the anterior and posterior LV walls together. As expected, the prototype device caused a decrease in both the S-L and C-C dimensions at the mid-papillary muscle level. The physiologic effect included a significant decrease in LVEDV by 23%, and end-systolic elastance increased by 39%, likely due to the positive effects of LV shape change. The effect on hemodynamics, however, can be characterized as a slight but significant increase in LV filling pressure. Further studies will be required to more fully characterize these hemodynamic changes and clearly determine their origins.
A caution with the use of an epicardial device is the potential for a decrease in coronary perfusion. To avoid this problem, this device is designed such that the deflector elevates the tightening chord off of the epicardial surface. Coronary angiography after device implantation showed patent vasculature, which clearly indicated that the device pressed on the posterior LV wall without affecting coronary perfusion.
An epicardial device was easily implanted on the beating heart of a canine heart failure and functional MR model. The prototype device has high potential for a minimally invasive approach, as all of its elements are placed external to the heart. This device acutely reduced functional MR by altering the mitral annular and LV geometries with an improvement in LV contractility. Although further study is necessary to demonstrate the long-term safety and efficacy of this concept, it may have significant utility in reducing the degree of invasiveness required to correct functional MR.
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Disclosures and Freedom of Investigation
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This study was financially supported by Myocor Inc (Maple Grove, MN). Myocor Inc provided the study material. The authors performed a free and independent evaluation of this technology.
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Footnotes
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Disclaimer The Society of Thoracic Surgeons, the Southern Thoracic Surgical Association, and The Annals of Thoracic Surgery neither endorse nor discourage use of the new technology described in this article.
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References
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- Timek TA, Dagum P, Lai DT, et al. Pathogenesis of mitral regurgitation in tachycardia-induced cardiomyopathy Circulation 2001;104(suppl):I47-I53.[Medline]
- Otsuji Y, Kumanohoso T, Yoshifuku S, et al. Isolated annular dilation does not usually cause important functional mitral regurgitation: comparison between patients with lone atrial fibrillation and those with idiopathic or ischemic cardiomyopathy J Am Coll Cardiol 2002;39:1651-1656.[Abstract/Free Full Text]
- Matsunaga A, Tahta SA, Duran CM. Failure of reduction annuloplasty for functional ischemic mitral regurgitation J Heart Valve Dis 2004;13:390-397discussion 397–8.[Medline]
- McGee EC, Gillinov AM, Blackstone EH, et al. Recurrent mitral regurgitation after annuloplasty for functional ischemic mitral regurgitation J Thorac Cardiovasc Surg 2004;128:916-924.[Abstract/Free Full Text]
- Inoue M, McCarthy PM, Popovic ZB, et al. The Coapsys device to treat functional mitral regurgitation: in vivo long-term canine study J Thorac Cardiovasc Surg 2004;127:1068-1076discussion 1076–77.[Abstract/Free Full Text]
- Kass DA, Wolff MR, Ting CT, et al. Diastolic compliance of hypertrophied ventricle is not acutely altered by pharmacologic agents influencing active processes Ann Intern Med 1993;119:466-473.[Abstract/Free Full Text]
- Suga H, Sagawa K, Shoukas AA. Load independence of the instantaneous pressure-volume ratio of the canine left ventricle and effects of epinephrine and heart rate on the ratio Circ Res 1973;32:314-322.[Abstract/Free Full Text]
- Maselli D, Guarracino F, Chiaramonti F, Mangia F, Borelli G, Minzioni G. Percutaneous mitral annuloplasty: an anatomic study of human coronary sinus and its relation with mitral valve annulus and coronary arteries Circulation 2006;114:377-380.[Abstract/Free Full Text]
- Choure AJ, Garcia MJ, Hesse B, et al. In vivo analysis of the anatomical relationship of coronary sinus to mitral annulus and left circumflex coronary artery using cardiac multidetector computed tomography: implications for percutaneous coronary sinus mitral annuloplasty J Am Coll Cardiol 2006;48:1938-1945.[Abstract/Free Full Text]
- Grossi EA, Saunders PC, Woo YJ, et al. Intraoperative effects of the Coapsys annuloplasty system in a randomized evaluation (RESTOR-MV) of functional ischemic mitral regurgitation Ann Thorac Surg 2005;80:1706-1711.[Abstract/Free Full Text]
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