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J Thorac Cardiovasc Surg 2001;122:482-490
© 2001 The American Association for Thoracic Surgery
Evolving Technology (ET) |
From the Departments of Cardiology and Thoracic and Cardiovascular Surgery,a Kaufman Center for Heart Failure, and the Department of Biomedical Engineering,b Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio; and Myocor, Inc,c Maple Grove, Minn.
This study was funded by Myocor, Inc.
Received for publication June 15, 2000. Revisions requested Dec 11, 2000; revisions received Jan 17, 2001. Accepted for publication Feb 20, 2001. Address for reprints: Patrick M. McCarthy, MD, Department of Thoracic & Cardiovascular Surgery, Cleveland Clinic Foundation, 9500 Euclid Ave, F25, Cleveland, OH 44195 (E-mail: mccartp{at}ccf.org).
Abstract
Objective: We tested a unique new device, the Myosplint device (Myocor, Inc, Maple Grove, Minn), which is designed to change left ventricular shape, reduce left ventricular wall stress, and improve left ventricular systolic function.
Methods: Heart failure was induced in 15 dogs over 27 days by rapid pacing (230 beats/min). Seven animals underwent sham surgery, and 8 animals received 3 transventricular Myosplint devices each. Myosplint devices were tightened to create a symmetric bilobular left ventricular shape and were adjusted to produce a calculated 20% reduction in wall stress. Hemodynamic, 2-dimensional, and 3-dimensional echocardiographic studies were recorded at baseline, immediately after Myosplint placement (acute change), and at 1 month after both groups had a reduced rate (190 beats/min) of pacing designed to maintain heart failure.
Results: The Myosplint group had significant sustained improvements in left ventricular ejection fraction from baseline, to the acute change, to 1 month (19% ± 5%; 36% ± 8%; 39% ± 13%) and reductions of left ventricular end-systolic volumes (73 ± 9 mL; 34 ± 5 mL; 42 ± 12 mL) and end-systolic wall stress by 39% (341 ± 68 103 dynes · cm– 2 to 206 ± 28 103 dynes · cm–2) acutely and 31% (372 ± 83 103 dynes · cm–2 to 250 ± 40 103 dynes · cm–2) at 1 month. There were no significant changes in mitral regurgitation.
Conclusion: Application of a Myosplint device to a dilated impaired left ventricle resulted in reduced wall stress and improved left ventricular systolic function that was sustained at 1 month. Device-based shape change is a promising new opportunity to treat patients with dilated cardiomyopathy.
See related editorial on page 421.
A common theme in the progression and pathogenesis of heart failure is the development of left ventricular (LV) remodeling with cardiac decompensation.
1,2 The remodeled LV geometry creates dilatation, increased LV sphericity, and wall thinning. Physiologic disadvantages created by LV remodeling include increased LV wall stress, increased myocardial oxygen consumption, and episodic subendocardial hypoperfusion. Increased LV wall stress may lead to the expression of stretch-activated genes with worsening compensatory mechanisms including further dilation, myocyte hypertrophy, and interstitial fibrosis.
The Batista procedure, or partial left ventriculectomy, reduced the size of the pathologically remodeled LV and improved LV systolic function and early subjective and objective measurements of heart failure. 3-5 However, the operation fell into disfavor in large measure because of a high early failure rate associated with the morbidity of the invasive and complex LV resection and reconstruction. 6 We sought a solution to the mechanical disadvantages of pathologic LV remodeling that could be applied easily without cardiopulmonary bypass, that improved global LV function without removing a large segment of otherwise viable LV muscle, and that would have a low procedure-related and device-related morbidity.
A novel device, the Myosplint device (Myocor, Inc, Maple Grove, Minn), was developed to change LV shape, decrease LV wall stress, and improve LV function and efficiency. The purposes of this article are (1) to introduce the thought process behind this unique concept, (2) to describe the current generation of the device, and (3) to review the experimental studies to prove the concept.
Methods
The Myosplint concept
The Myosplint device consists of an implantable transventricular splint and two epicardial pads that are adjusted to draw the walls of the LV together and thereby reduce the LV radius. The Myosplint is positioned to bisect the enlarged LV, effectively creating two smaller LV chambers. According to the law of Laplace for cylindrical chambers, circumferential wall stress is directly proportional to LV radius, R1(Figure 1). The law of Laplace simplifies the stress modeling difficulties associated with biologic material properties and complex geometries. The relationship assumes that stresses are uniform across the wall and around the LV circumference and are due exclusively to chamber pressure. With the use of the same assumptions about material properties and stress distribution, equilibrium formulas can be developed and a stress relationship derived for the mid-chamber annular region of the splinted bilobular chamber (two cylinders). The derivation yields the formula T = PR2/h, where T is wall stress, P is chamber pressure, and R2 is the reduced effective radius of the bilobular chamber. This equation provides a useful approximation for circumferential wall stress and has correlated well with significantly more complex finite element modeling.
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Development phase, in vivo experimental work, and current in vivo study
A number of factors were addressed in the initial development of the device and the experimental model. The initial work was performed as acute experiments, in dogs with normal LV function, using a variety of biomaterials for the Myosplint device, and devices were developed to place the Myosplints and measure the amount of shape change. The concept was then tested in short-term experiments with pacing-induced models of heart failure. 7 Also, echocardiographic and hemodynamic studies of the complex shape change effects were undertaken, 8 eventually leading to the use of 3-dimensional (3-D) echocardiographic studies. Finally, a model of maintenance heart failure with reduced pacing rates was developed, 9 after the initial model led to the death of approximately 50% of control animals before the 30-day end point.
After this developmental work, the device design and materials were frozen and the following in vivo study was undertaken. The hypotheses of this study are that (1) the Myosplint device will reduce LV wall stress, (2) the device will improve LV systolic function, and (3) these changes will be sustained at 1 month in this canine model of pacing-induced heart failure. The study was approved by the institutional animal care committee, and all animals received humane care in compliance with the "Guide for the Care and Use of Laboratory Animals" prepared by the Institute of Laboratory Animal Resources, National Research Council, and published by the National Academy Press, revised 1996.
Induction of heart failure, baseline measurements, and surgery
Twenty-seven adult mongrel dogs (body weight 26.4 ± 1.4 kg) were paced into heart failure as per previous studies. 10,11 The animals were anesthetized with thiopental (15 mg/kg), intubated, and the anesthesia was maintained with isoflurane (0.5%-2.5%). Under sterile conditions, a bipolar pacemaker lead (Medtronic 4068; Medtronic, Inc, Minneapolis, Minn) was placed in the right ventricle via the right jugular vein. This was connected to a pulse generator (Medtronic 8086) and buried in a subcutaneous cervical pocket. The animal received antibiotics for 5 days. After a minimum of 2 days of recovery, rapid asynchronous ventricular pacing at 230 beats/min was used for an average of 27 ± 4 days to induce heart failure. No medications for heart failure, including diuretics, were given during the heart failure induction phase. During this phase, the animal was under careful daily observation for signs or symptoms of congestive heart failure.
At the conclusion of the induction phase, transthoracic 2-dimensional (2-D) echocardiograms were obtained during temporary resumption of normal sinus rhythm to evaluate the progression of cardiac remodeling, the reduction of LV function, and the development of mitral and tricuspid regurgitation. A total of 7 animals were excluded from the study at this point because ejection fraction was greater than 35% (n = 4) or mitral regurgitation was 4+ (n = 3).
On the date of study, the pacemaker was reduced to demand mode at 30 beats/min so that the animal would resume normal sinus rhythm, and the animal was placed under general anesthesia as previously described. A catheter with two Millar pressure sensors (model SPC-562; Millar Instruments, Inc, Houston, Tex) was placed via the carotid artery to record aortic and LV pressures. A thermistor-tip balloon catheter (Criticath SP5507 TD catheter; Becton Dickinson Infusion Therapy Systems Inc, Sandy, Utah) was passed from the jugular vein to the pulmonary artery to monitor the pulmonary artery pressure, pulmonary capillary wedge pressure, and the central venous pressure. Cardiac output (CO) was measured by the thermodilution method, and stroke volume (SV = CO/[Heart rate]) and stroke work (SW = SV x [LV systolic pressure – LV end-diastolic pressure] x 0.0136) were calculated. These hemodynamic measurements were recorded as baseline closed chest. Hemodynamic indices were digitized in real time at a sampling rate of 200 Hz with a data acquisition system (PowerLab; AD Instruments, Inc, Mountain View, Calif) and stored on a hard disk for subsequent complete analysis. Ventilatory support was transiently stopped during data acquisition periods. An additional 3 dogs were excluded from the study with mild heart failure defined as central venous pressure less than 8 mm Hg and pulmonary capillary wedge pressure less than 13 mm Hg.
To most accurately assess the changes in LV volumes and ejection fractions before and after LV shape change, we used a 3-D ultrasound system (Volumetrics Medical Imaging Inc, Durham, NC). Transthoracic 3-D images were obtained in real time and stored in a digital format. Subsequently, LV end-diastolic and end-systolic volumes were determined by rotated apical 6-plane views with a multiplanar Simpson method. 12 Stroke volume (SV3D = LV end-diastolic volume – LV end-systolic volume), stroke work (SW3D = SV3D x [LV systolic pressure – LV end-diastolic pressure] x 0.0136), cardiac output (CO3D = SV3D x Heart rate), and LV ejection fraction (SV3D/LVEDV x 100) were calculated. Transthoracic 2-D images were obtained to assess mitral and tricuspid regurgitation by color flow Doppler imaging and to measure wall thickness and LV dimensions at various levels.
Circumferential end-systolic and end-diastolic wall stresses were calculated from the 2-D echocardiogram short-axis view at the papillary muscle level in combination with LV pressure using the following formula: Wall stress = 1.33 x LV pressure x (LV radius)/h, where h is wall thickness. 13,14 After implantation of the Myosplint device, the 2-D short-axis view showed two symmetric lobes; one consisted of the anteroseptal wall and the other consisted of the posterolateral wall, as shown inFigure 3
. The wall stress of each lobe was calculated separately using the radius and the wall thickness of each lobe; then the two values were averaged.
Implant surgery, heart failure maintenance, and 1-month studies
After acquisition of closed chest baseline data(Tables 1 and 2; baseline, closed chest), a sternotomy incision was made and the chest was opened. Hemodynamic, 2-D, and 3-D echocardiographic measurements were repeated(Tables 1 and 2; baseline, open chest).
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Nine animals received 3 Myosplint devices each. There were no arrhythmias or bleeding complications during implantation. The appropriate location for Myosplint implantation was guided by epicardial 2-D echocardiogram to avoid the mitral valve structures and by direct visualization to avoid epicardial vessels. The first Myosplint device was placed 2 cm from the atrioventricular groove and the next two were spaced approximately 2 cm apart toward the LV apex(Figure 3).
Each Myosplint device was then tightened to draw the LV walls inward creating a symmetric, bilobular LV. The tightening level was adjusted to produce a calculated 20% reduction in wall stress determined by the pre-tightening LV end-diastolic diameter. In other words, the radius of each lobe of the LV was approximately 80% of the radius of the pre-tightened LV. Ten minutes after tightening, hemodynamic and echocardiographic measurements were repeated(Tables 1 and 2; acute change, open chest). The chest was then closed.
Animals in both groups were treated the same; analgesics and antibiotics were administered, but no anticoagulants or antiplatelet drugs were administered. After the animals recovered from the operation, 3 days after the operation, rapid ventricular pacing at a reduced rate, 190 beats/min, was resumed. This was maintained for 4 weeks and prevented the recovery of LV function with pacing cessation 11 but allowed a more controlled maintenance of congestive heart failure so that the animals survived until study completion. Animals were carefully observed daily. A 40-mg dose of furosemide was given daily to both groups of animals because of fluid overload noted in the control animals in the developmental phase of the study. One control animal died with signs of pneumonia, pleural effusion, and ascites on the seventh postoperative day. One test animal was put to death on the 20th postoperative day because of pacing failure. Consequently, 8 test and 7 control animals were included in the statistical analysis as shown inTables 1 and2.
At the completion of the follow-up period, the animals were anesthetized as per the previous studies and hemodynamic monitoring lines were replaced. Then, 2-D and 3-D echocardiographic studies were repeated(Tables 1 and 2; 4 weeks, closed chest). The animals were killed with sodium phenobarbital (100 mg/kg) and potassium chloride (80 mEq). A complete autopsy was performed, and tissues from the heart, liver, spleen, kidneys, and lungs were taken for histologic examination.
Statistical analysis
Data were expressed as mean ± SD. For the test animals, there were two pairs of data: open chest data (baseline and acute change) for acute evaluation and closed chest data (baseline and chronic change) for chronic evaluation. For the control animals, there was one pair of data: closed chest data (baseline and chronic change) for chronic evaluation. A paired t test was used for each paired data. For the comparison between the test and control groups, an unpaired t test was used.
Results
By 3-D echocardiographic calculations, LV ejection fraction significantly increased from 19% at baseline (closed chest) to 36% (P = .001) acutely and remained at 39% (P = .005) at 1 month(Figure 4) after Myosplint implantation. Also, LV end-diastolic and end-systolic volumes significantly decreased(Table 1) and were sustained at 1 month. End-systolic wall stress significantly decreased by 39% (341 ± 68 103 dynes · cm–2 to 206 ± 28 103 dynes · cm–2; P < .0001) acutely and by 31% (372 ± 83 103 dynes · cm–2 to 250 ± 40 103 dynes · cm–2; P = .003) at 1 month(Figure 5). Also, end-diastolic wall stress was significantly reduced by 30% (107 ± 39 103 dynes · cm–2 to 76 ± 33 103 dynes · cm–2; P = .002) acutely and by 41% (127 ± 53 103 dynes · cm–2 to 74 ± 36 103 dynes · cm–2; P = .006) chronically. Among those parameters, only the reduction (by 29%; P = .02) in end-diastolic wall stress was significant in the control group. There were no significant chronic changes in either the test or control groups regarding mitral or tricuspid regurgitation(Table 1).
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No change in cardiac output was measured by the thermodilution method from baseline to 4 weeks in the test or control animals. However, cardiac output calculated from 3-D echocardiographic volumes significantly increased from baseline to 4 weeks (1.98 ± 0.74 L/min to 3.80 ± 1.54 L/min; P = .008) in the test animals. Similarly, although there was no change in stroke work calculated by thermodilution cardiac output from baseline to 4 weeks in the test or control animals, 3-D stroke work calculated from 3-D echocardiographic volumes significantly increased (17.7 ± 7.2 g · m to 29.6 ± 10.7 g · m; P = .04) in the test animals.
Hypertrophy of the cardiac myofibers, interstitial edema, and mild interstitial fibrosis was present in all animals. The gross necropsy revealed that the epicardial pads become rapidly encapsulated in fibrous tissue. At a histologic level, the anticipated foreign body response to the biomaterials used was observed: a proliferation of fibroblasts and macrophages, coupled with the presence of occasional foreign body giant cells. Overall, we judged this a normal chronic wound healing response in the presence of foreign material. There was no evidence of toxic or neoplastic response to the device. Fibrous encapsulation and endothelialization were observed around the intraventricular portion of the device. Thrombi at the LV apex were observed in 6 control and 3 test animals. Their location and presence in both groups suggest that they are related to the placement of the Millar catheter in a nonheparinized subject. Examination of downstream organs revealed the limited presence of infarction or emboli: kidney (2 control and 1 test animals), lung (1 control and 1 test animals), and liver (1 test animal) that segregated into no particular group.
Discussion
The dilated, impaired, remodeled LV is a poor prognostic sign indicating a high mortality in both medically and surgically treated patients. 15,16 Medical therapy, such as angiotensin-converting enzyme inhibitors and ß-blockers, have shown a reduction in mortality associated with a reduction in LV size and increase in LV ejection fraction. 17-19 These subjective and objective improvements, as well as reduction in mortality, with medical therapy are usually not from an increase in cardiac output, 17-19 indicating that their effectiveness rests on fundamental changes in the heart failure milieu. 1,2,18
The salutary effects of the Myosplint device in this experimental study, a significant reduction in wall stress and volumes and a significant increase in ejection fraction, also were accomplished without a major change in thermodilution cardiac output. In the current understanding of heart failure, cardiac output has assumed less importance, which explains why some outpatients with compensated congestive heart failure have a cardiac index of 1.8 L · min–2 · m–2 and some hospitalized end-stage inotrope-dependent patients have a cardiac index of 2.4 L · min–1 · m–2. 1,2 By 3-D echocardiogram, however, stroke work and cardiac output did improve, although mitral regurgitation may cause inaccurate calculations of forward LV stroke volumes. Which modality is more accurate cannot be determined from this study. Thermodilution measurements also cause inaccuracies in the setting of tricuspid regurgitation.
The Myosplint device was designed to alter a major common theme of chronic cardiomyopathy, LV dilation. Direct LV reduction operations, such as LV aneurysmectomy and the Batista procedure, 3-6 have demonstrated early LV function improvements separate from associated procedures such as valve repair or coronary artery bypass. However, the Batista procedure in particular had a high early failure rate. This was explained in part by the operation itself: a major surgical procedure performed with cardiopulmonary bypass that discarded a large segment of otherwise viable myocardium and may have worsened preexisting diastolic dysfunction. 6,20,21 Unlike the Batista operation, the current procedure involves placement of the Myosplint device on a beating heart, produces a measurable adjustable reduction in LV size, recruits other areas of LV to improve function (like the Dor procedure 22) rather than removing muscle, and likely does not create major changes in diastolic function. 8 However, further studies are needed with the Myosplint device to more precisely document changes in diastolic function.
By splinting the enlarged heart, we showed improved LV function and reduced wall stress. By the law of Laplace, we had predicted we would create a 20% reduction in wall stress. Instead, we found a 39% reduction in end-systolic wall stress and a 30% reduction in end-diastolic wall stress acutely. What we observed was increased end-systolic wall thickness and a greater decrease in the actual radius due to improved LV systole accounting for the greater reduction in wall stress than would have been predicted just on the basis of change in radius mathematically. Whereas the Myosplint changes occurred immediately and were maintained at 1 month, changes resulting from drug administrations have been more modest and take longer to develop. Further studies are needed to determine whether the changes in wall stress and the effects on the expression of stretch-activated genes will also translate into beneficial molecular cytokine and neurohormone effects that are equivalent to, or also superior to, the effects of heart failure medications.
The device underwent significant evolution from concept to a practical, easily deployed system. We were encouraged that it could be easily applied on the beating heart, with minimal localized bleeding and no sustained arrhythmia. The Myosplint itself occludes the ventricular needle holes, and the epicardial pads tamponade bleeding. Furthermore, the pads disperse the ventricular compression so that the likelihood of erosion is small.
Two limitations to the current study are the model itself and measurements in the setting of a complicated LV shape change. We chose the paced heart failure model to simulate global idiopathic cardiomyopathy. However, because only 2 months had transpired from the beginning of pacing until study termination, the myocardial interstitial changes, such as fibrosis, were not as pronounced as they would be in most patients with chronic idiopathic cardiomyopathy. Therefore, systolic and diastolic function in human beings may be different from that in this experimental model, and Myosplint effects may be blunted. Because of the severity of the model of congestive heart failure as seen in our earlier developmental studies, we did not do extended studies because we expected a high attrition rate. Also, another series of animals will be studied with additional measurements including myocardial oxygen consumption and the construction of pressure-volume loops.
Because the Myosplint device creates a complicated LV geometry, our method to calculate wall stress is new. The circumferential wall stress of each anteroseptal and posterolateral lobe at the papillary muscle level was calculated separately by means of the law of Laplace for cylindrical chambers; then the two values were averaged. This method of averaging wall stress for two lobes has never been used or validated, because there has been no need. Furthermore, wall stress reduction at the level where the Myosplint was placed may be different from that at different levels, such as the one between two Myosplints where the shape change was more modest. Because of these complexities, computer-based finite element analysis may provide the best method of calculating wall stresses throughout the LV wall. As demonstrated by Ratcliffe and others, 20 these models are refined to the point that they provide a reasonably accurate method of calculating myocardial wall stresses and cardiac function. At this point, however, finite element methods are not yet practical for analyzing empiric data generated in investigational studies and would have limitations because of heterogeneity in the ventricular wall, especially during active contraction. To provide a straightforward yet accurate method of analyzing changes in myocardial wall stress as a result of a shape change, we have used a thin-walled circumferential wall stress calculation based on Laplace's law for cylindrical chambers. Laplace's law makes the following assumptions: (1) The muscle tissue behaves similar to nonbiologic materials and is therefore assumed to be elastic, isotropic, and homogeneous; (2) the geometry of the LV is a uniform-walled cylinder, sphere, or ellipsoid of revolution; (3) the stresses are uniform around the circumference and are due exclusively to the LV pressure; and (4) radial and bending stresses are ignored (thin walled). This analysis uses the Laplace assumptions and makes the assumption that the mid-chamber annular region of the ventricle is substantially cylindrically shaped before and after bilobular shape change. Circumferential wall stress was chosen in this study because it appears to be the most influential on cardiac function; as other authors have described, the mid to basal chamber region of the LV consists of primarily circumferential orientation of the muscle fibers. 23
Measurements of LV volumes by 3-D echocardiogram are more accurate than 2-D echocardiogram, because 3-D echocardiogram does not require any geometric assumptions of the LV cavity. We previously reported the accuracy of 3-D echocardiogram for determining LV volumes using magnetic resonance imaging as a reference standard in our patients after LV reconstruction surgery, another complex LV shape change procedure. 12,24,25 In human studies we anticipate obtaining sequential 3-D echocardiogram and magnetic resonance imaging studies in Myosplint-treated patients. Unfortunately, we were not able to do magnetic resonance imaging studies in animals.
In conclusion, this experiment served as "proof of concept" of the Myosplint theory and answered the hypotheses that the Myosplint device reduced LV wall stress, improved LV systolic function, and sustained these changes for 1 month. The device was easily applied and consists of common biomaterials. Further testing in ischemic cardiomyopathy and studies to include molecular markers of heart failure and measures of diastolic function will provide further clarification. The device will be studied in patients with dilated hearts as an adjunct for those needing valve or bypass surgery or as sole surgical therapy for patients with idiopathic cardiomyopathy.
Appendix: Discussion
Dr Hani Shennib (Montreal, Quebec, Canada). This is an elegant study that requires a lot of mathematical equations to figure out. It is an interesting approach to fixing heart failure. Is it exactly a 50:50 Myosplint or is there potentially a variation in where you localize the pad?
Dr. McCarthy. Currently the initial patient population is going to be patients with a globular dilated cardiomyopathy. The mathematics and the engineering get even more difficult when there is a more discrete infarct in the left anterior descending distribution, but making those changes will be a later area for investigation.
Dr Alain F. Carpentier (Paris, France). This reminds me of my past experience using transmural pledget-supported sutures to hold papillary muscles in homograft mitral valve replacement. We were facing problems of bleeding around the transmural suture and progressive perforation due to excess tension. I am afraid that you could encounter the same problem in patients. Could you elaborate on that?
Dr McCarthy. There have been 117 animal experiments to my knowledge. The first thing that surgeons think when they look at this is that the pads are going to tear, that there will be bleeding, or that there will be some major trauma. We have seen none of that in any of the animals nor in any of the patients whom we have treated. The needle that goes through is smaller than the braided tension member, which partially seals the hole. Also, the pads are much larger and help tamponade some of the bleeding that might have occurred at that point, but they also disperse some of the pressure over a wider area. Therefore, I think there will be a very low likelihood of the pads pulling through.
Footnotes
Read at the Eightieth Annual Meeting of The American Association for Thoracic Surgery, Toronto, Ontario, Canada, April 30–May 3, 2000. 
References
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