Ann Thorac Surg 2003;76:141-147
© 2003 The Society of Thoracic Surgeons
Original article: cardiovascular
Ventricular constraint in severe heart failure halts decline in cardiovascular function associated with experimental dilated cardiomyopathy
Jai S. Raman, MMed, FRACSa*,
Melissa J. Byrne, BSc, BAppSc (Hons)b,
John M. Power, BVSc, PhDb,
Clif A. Alferness, BSEEc
a Department of Cardiac Surgery, Austin and Repatriation Medical Centre, Heidelberg, Melbourne, Victoria, Australia
b Baker Medical Research Institute, Prahran, Melbourne, Victoria, Australia
c Acorn Cardiovascular, Inc, St. Paul, Minnesota, USA
Accepted for publication January 18, 2003.
* Address reprint requests to Dr Raman, University of Chicago Hospital, Section of Cardiothoracic Surgery, 5841 S Maryland, Suite E-500, MC 5040, Chicago, IL 60637, USA.
e-mail: jraman{at}surgery.bsd.uchicago.edu
 |
Abstract
|
|---|
BACKGROUND: We have shown that passive ventricular constraint during moderate heart failure can halt progressive deterioration in cardiac function in an experimental model of ovine pacing induced heart failure (HF). We report on ventricular constraint in severe heart failure.
METHODS: Eighteen adult merino sheep were used. Severe heart failure was induced in two stages, ie, high rate ventricular pacing for 21 days to produce moderate HF and then for 42 days to induce severe HF. A custom-made polyester mesh cardiac support device ([CSD] Acorn Cardiovascular, St Paul, MN) was implanted snugly around both ventricles through a lower partial sternotomy in 9 sheep (group 1). Rapid ventricular pacing was continued for a further 28 days in all animals to induce advanced HF. Cardiovascular functional indicators were determined using echocardiography and a submaximal treadmill exercise protocol at base line, moderate, severe, and advanced stages. The 9 sheep in group 2 were used as controls.
RESULTS: Cardiovascular function was significantly depressed in all animals in advanced heart failure compared with base line, with left ventricular ejection fraction (LVEF) falling from 50% to 25% (p < 0.05) and LV +dp/dt(max) declining from 1,777 to 1,243 (p < 0.05). However after CSD implantation cardiovascular function during exercise improved significantly despite ongoing rapid pacing, with LVEF increasing to 30% and LV +dp/dt to 1,499 (p < 0.05) in group 1. There were no significant changes in left ventricular long axis area (157 to 151 cm2) and short axis (6.8 to 6.1 cm) dimensions at the termination of pacing compared with those at time of CSD implant. Mitral regurgitation improved slightly from 2.5 to 2.19 after containment (p < 0.05) in group 1 but increased to 2.83 in group 2.
CONCLUSIONS: Ventricular constraint in advanced heart failure with a custom-made polyester mesh device halted the decline in cardiac function seen in untreated animals with this pacing-induced animal model of heart failure. These results indicate potential clinical implications for ventricular containment in the treatment of end-stage heart failure.
|
Introduction
|
|---|
| Doctors Power and Alferness disclose that they have a financial relationship with Acorn Cardiovascular Inc.
|
We have previously shown in an ovine model of rapid pacing induced moderate dilated cardiomyopathy that passive ventricular constraint with an Acorn polyester mesh cardiac support device ([CSD] Acorn Cardiovascular, St Paul, MN) halts the progression of heart failure observed in sham operated animals with ongoing rapid ventricular pacing [1]. Similar positive results have been reported elsewhere in a canine multifocal embolic canine model of heart failure [2]. In this study we examined, using submaximal exercise testing and echocardiography, the outcome of CSD implantation in sheep with severe heart failure.
|
Material and methods
|
|---|
The animals used in this study were cared for according to the standards set down by the National Health and Medical Research Council of Australia.
Initial surgical preparation
Eighteen healthy adult merino sheep trained and accustomed to walking on a treadmill were surgically instrumented with permanent central venous and arterial lines and an endocardial right ventricular screw-in pacing lead (Tendril DX, Model 1388T; St Jude Medical, Sylmar, CA). A Transonic continuous cardiac output flow probe 20A (Transonic Systems, Ithaca, NY) was implanted around the main pulmonary artery through a minithoracotomy. All leads were tunneled subcutaneously to exit the body on the dorsal aspect of the animal.
Assessment of cardiac function and extent of heart failure
Left ventricular pressure was continuously measured with a temporary micro manometer-tipped catheter (Millar Instruments) during 30 minutes of submaximal treadmill exercise at 2 km/h and a 5-degree incline followed by a 10-minute recovery period. We considered that the standard exercise challenge in these trained animals provided a focus that was more stable than measuring them in a conscious resting state. Signals from the manometer tipped catheter were processed, digitised and recorded using a MacLab data acquisition system (MacLab 8; ADI Instruments, Dunedin, New Zealand), and a Macintosh computer to determine left ventricle (LV) +dp/dtmax. A transthoracic echocardiographic (Hewlett Packard Sonos 1000; Hewlett Packard, Palo Alto, CA) examination was undertaken to determine left ventricular ejection fraction (EF) and mitral valve regurgitation (MR). All measurements were made in normal sinus (unpaced) rhythm at least 30 minutes after the cessation of pacing.
Experimental protocol
Once the animals had recovered from the surgical preparation a base line cardiovascular assessment was made as described above. Pacing was commenced at 190 beats per minute for 21 days to induce moderate HF. A second cardiovascular assessment was then conducted. Pacing was reinstated at a higher rate (210 bpm) for another 42 days to induce severe heart failure followed by a third cardiovascular assessment. The animals were then randomly assigned to two groups. Group 1 had ventricular constraint performed at this stage and group 2 animals were maintained as controls.
The group 1 sheep were anesthetized with propofol (10 mg/kg), intubated, positively ventilated with oxygen and maintained with a continuous infusion of propofol 0.2 mg · kg-1 · h-1, and ketamine 0.2 mg · kg-1 · h-1. Sheep were positioned on their backs and a lower ministernotomy performed. The pericardium was opened and an Acorn CSD implanted around both ventricles. The CSD was anchored to the base of the heart either directly to the atrioventricular groove or to the pericardial reflection adjoining that portion of the heart using a combination of sutures and metal clips. Excess mesh was excised and the CSD tightened only sufficiently to ensure a snug wrinkle-free fit. Figure 1
shows the implanted mesh with the excess material excised to allow a good fit. The pericardium was closed and the sternum sutured with wires.
Pacing was recommenced 24-hours after surgery at 210 bpm in the group 1 animals and also in the nonimplanted group 2 control animals for an additional 28 days, for a total of 13 weeks of pacing. A fourth cardiovascular assessment was then conducted in all animals at the advanced heart failure stage.
Echocardiography
Right sided transthoracic echocardiography was used to obtain images of the LV and left atrium (LA) using a Sonos 1000 Hewlett-Packard unit with a 3 mHz probe. This was performed with the sheep lightly anesthetized, using a combination of propofol 0.1 mg · kg-1 · h-1, and ketamine 0.2 mg · kg-1 · h-1 as a continuous intravenous infusion, with the pacing off. Planimetered LA and LV cross-sectional areas were plotted and calculated in diastole from a uniform long-axis view. Ejection fraction was also calculated using cross-sectional views of diastolic and systolic LV areas. The degree of mitral regurgitation was assessed using color Doppler and scored 0 to 3, in degrees of increasing severity.
Statistical methods
Data were collected using the MacLab computerized system and stored on a MacIntosh computer. Data were analyzed using the Sigma Stat computerized statistical program and plots made using the Sigma Plot program (Sigma Stat, SSPS, Chicago, IL. Comparisons were made between base line and moderate heart failure to demonstrate the progressive decline in cardiac function and between severe and advanced heart failure for both nonimplant and preimplanted (subsequently implanted) animals. The test used was one-way analysis of variance (ANOVA) for repeated measures followed by Student-Neuman-Keuls post hoc test. The nonparametric data of mitral valve regurgitation was tested using ANOVA on ranks. Results were expressed as mean ± SEM (standard error of the mean), and a p value of less than 0.05 was considered significant.
|
Results
|
|---|
The mean values of the measured variables and their statistical relationships for both implanted and nonimplanted animals are tabulated in Table 1.
The terms "preimplant" and "nonimplant" refer to animals that were subsequently implanted with the CSD and those that were not.
Left ventricular ejection fraction decreased significantly in all animals between base line and moderate heart failure. Despite continued rapid ventricular pacing, the mean LVEF increased significantly in advanced heart failure in implanted animals and was significantly greater than the nonimplanted animals at this stage (Fig 2).
View larger version (42K):
[in this window]
[in a new window]
|
Fig 2. Mean values for left ventricular ejection fraction throughout the protocol. Hatched bars = cardiac support device (CSD); open bars = nil implant protocol; arrow = CSD implantation.
|
|
Mean LV +dp/dtmax followed a similar pattern with significantly higher contractility in the implanted animals than the nonimplanted in advanced heart failure (Fig 3).
Left ventricular long axis area continued to increase in nonimplanted animals but was halted after CSD implantation in that treatment group (Fig 4).
Mitral valve regurgitation was significantly less in implanted animals compared with untreated animals at the final stage of advanced heart failure (Fig 5).
Left ventricular end diastolic pressure increased significantly in all animals with rapid ventricular pacing; however it was significantly less in the CSD treated animals at the end of the pacing (Fig 6).
There were no significant changes in cardiac output during the study period (Fig 7).
View larger version (23K):
[in this window]
[in a new window]
|
Fig 3. Submaximal exercise protocol: mean positive ratio of change of ventricular pressure to change in time ([+dP/dtmax] mm Hg/s). Solid boxes = baseline cardiac support device (CSD) implant; open boxes = baseline nil procedure; solid circles = advanced heart failure, CSD implant; open circles = advanced heart failure, nil procedure; dashed vertical line = stop treadmill.
|
|
View larger version (40K):
[in this window]
[in a new window]
|
Fig 4. Mean values for left ventricular long axis area (cm2) at each stage of the protocol. Hatched bars = cardiac support device (CSD) implant protocol; open bars = nil implant protocol; arrow = CSD implantation.
|
|
View larger version (37K):
[in this window]
[in a new window]
|
Fig 5. Mean mitral regurgitation (scored 0 to 3) throughout the protocol. Hatched bars = cardiac support device (CSD) implant protocol; open bars = nil implant protocol; arrow = CSD implantation.
|
|
View larger version (32K):
[in this window]
[in a new window]
|
Fig 6. Mean resting left ventricular end diastolic pressure (mm Hg). Hatched bars = cardiac support device (CSD) implant protocol; open bars = nil implant protocol; arrow = CSD implantation.
|
|
View larger version (43K):
[in this window]
[in a new window]
|
Fig 7. Mean cardiac output values (L/min). Hatched bars = cardiac support device (CSD) implant protocol; open bars = nil implant protocol; arrow = CSD implantation.
|
|
A measure of relaxation, -(dp/dt)max, was significantly less during exercise in the non-CSD implanted animals in advanced HF when compared with the CSD implanted animals at the same stage in the protocol (Fig 8).
Mean LV wall stress, calculated using the formula of LaPlace, was significantly greater in advanced heart failure in the untreated controls than in the CSD implanted animals at the same stage in the protocol, 32,025 ± 13,380 dynes/cm2 versus 9,464 ± 3,864 dynes/cm2 (Fig 9).
View larger version (23K):
[in this window]
[in a new window]
|
Fig 8. Submaximal exercise protocol: mean -dP/dtmax (mm Hg/s). Solid boxes = baseline cardiac support device (CSD) implant; open boxes = baseline nil procedure; solid circles = advanced heart failure, CSD implant; open circles = advanced heart failure, nil procedure; dashed vertical line = stop treadmill.
|
|
View larger version (26K):
[in this window]
[in a new window]
|
Fig 9. Mean resting left ventricular wall stress (dynes/cm2). Hatched bars = cardiac support device (CSD) implant protocol; open bars = nil implant protocol; arrow = CSD implantation.
|
|
The animals were observed for 6 months after the termination of pacing. All CSD implanted animals were alive at the end of this period; however 5 of the 9 nonimplanted animals died of heart failure and dilated cardiomyopathy. Postmortem findings confirmed the presence of ascites, anasarca, gross cardiac enlargement, and other features of decompensated heart failure.
|
Comment
|
|---|
The concept of passive ventricular constraint as a treatment for dilated cardiomyopathy arose from observations surrounding the apparent functional improvement in patients who had undergone dynamic cardiomyoplasty [3]. Despite a lack of objective improvement in ejection fraction patients appeared to enjoy a better quality of life after the procedure. It was also shown either in studies where the muscle stimulation was stopped either deliberately or inadvertently as a result of loss of capture that the improvement was relatively independent of paced contractions of the relocated latissimus dorsi muscle [4]. These observations were the basis for the hypothesis that the mechanism for this apparent improvement was the containment and support (and the related decrease in ventricular wall stress) offered to the ventricles by the implanted muscle. This hypothesis has been subsequently shown to be valid in a series of animal studies [1, 2] and in a recent report of ours where the Acorn CSD was implanted in a small number of patients [5] and from a larger series of patients in another study [6].
Cardiac support device implantation offers a unique opportunity to examine the role of ventricular dilatation in the pathophysiological cascade that characterizes the syndrome of heart failure. Implantation of the Acorn CSD device in both animal models and heart failure patients has been shown to result in a significant degree of functional ventricular reverse remodeling. Interestingly this very positive outcome is accompanied by a minimal degree of structural remodeling and minimal volume reduction; however these changes may be more evident with longer-term postimplant periods.
The rapid ventricular model of heart failure has been used in countless animal studies. The usual methodology involves pacing for 3 to 4 weeks at around 220 to 240 bpm and is reversible within 24 to 48 hours after cessation of pacing [7]. In this study we used an extended pacing protocol (13 weeks) with lower initial pacing rates (180 to 190 bpm). In this model the changes invoked by the pacing and expressed in the control animals were irreversible.
It could be hypothesized that any surgical procedure, which entails enclosing the ventricles with a constraining adherent membrane duplicates the conditions found in restrictive pericarditis. We found no suggestion of a restrictive pattern in this study, LVED pressure was less than half of that found in control animals and only slightly more than that found in these animals at base line. Other studies have looked at this question and have failed to find any evidence of a restrictive cardiac pattern in both animal models and patients [8–10]. Pericarditis is a progressive inflammatory condition, associated with gross thickening of the pericardium and it commonly occurs in a nondilated heart. In contrast the inflammatory process associated with polyvinylchloride and a polyester device provoked by the encapsulating material is minimal and may decrease rather than increase with time (Fig 9).
Some interesting biochemical work and sophisticated muscle pathophysiological work suggests that ventricular containment probably initiates reverse remodeling in many ways. Progressive ventricular dilatation is limited however; probably more importantly the device may lower wall stress by acting as a "scaffold" around the ventricular freewall (Fig 10).
Ventricular containment also has been shown to reduce myocardial fiber slippage and improve contractile function of isolated cardiomyocytes [11]. Cell stretch response proteins such as p21ras and c-fos were shown to be down regulated along with improved calcium cycling in the sacroplasmic reticulum [12].
View larger version (86K):
[in this window]
[in a new window]
|
Fig 10. Histologic hematoxylin and eosin stained sections taken from the left ventricular freewall in sheep with cardiac support device (CSD) implants of (A) 1 month, (B) 6 month, and (C) 12 month duration. The F denotes the cut edges of the yarn from the Acorn Corcap CSD.
|
|
|
Conclusions
|
|---|
Ventricular containment or passive ventricular constraint has been shown in this study to ameliorate the effects of long-term rapid ventricular pacing in this model when compared with control animals. These findings replicate those reported from safety studies with the same device in CHF patients. We believe that the Acorn CSD device has a positive role to play in the expanding field of surgical treatment of HF. ([13]
|
References
|
|---|
- Power J.M., Raman J., Dornom A., et al. Passive ventricular constraint amends the course of heart failure: a study in an ovine model of dilated cardiomyopathy. Cardiovasc Res 1999;44:549-555.[Abstract/Free Full Text]
- Chaudhry P.A., Mishima T., Sharov V.G., et al. Passive epicardial containment prevents ventricular remodeling in heart failure. Ann Thorac Surg 2000;70:1275-1280.[Abstract/Free Full Text]
- Magovern J.A., Furnary P.A., Christlieb I.Y., Kao R.L., Partk S.B., Magovern G.J. Indications and risk analysis for clinical cardiomyoplasty. Semin Thorac Cardiovasc Surg 1991;3:145-148.[Medline]
- Kass D.A., Baughman K.L., Pak P.H., et al. Reverse remodeling from cardiomyoplasty in human heart failure. External constraint versus active assist. Circulation 1995;91:2314-2318.[Abstract/Free Full Text]
- Raman J.S., Power J.M., Buxton B.F., Alferness C.A., Hare D. Ventricular containment as an adjunctive procedure in ischemic cardiomyopathy: early results. Ann Thorac Surg 2000;70:1124-1126.[Abstract/Free Full Text]
- Konertz W.F., Shapland J.E., Hotz H., et al. Passive containment and reverse remodeling by a novel textile cardiac support device. Circulation 2001;104(Suppl 1):270-275.
- Howard R.J., Stopps T.P., Moe G.W., Gotleib A., Armstrong P.W. Recovery from heart failure: structural and functional analysis in a canine model. Can J Physiol Pharmacol 1988;66:1505-1512.[Medline]
- Konertz W.S., Dushe S., Braun J.P., et al. Safety and feasibility of a cardiac support device. J Card Surg 2001;16:113-117.[Medline]
- Sabbah H.N., Kleber F.X., Konertz W.F. Efficacy trends of the acorn cardiac support device in patients with heart failure: a one year follow-up. J Heart Lung Transplant 2001;20:217.
- Saavedra W.F., Tunin R.S., Paolocci N., Mishima T., et al. Reverse remodeling and enhanced adrenergic reserve from passive external support in experimental dilated heart failure. J Am Coll Cardiol 2002;39:2069-2076.[Abstract/Free Full Text]
- Sabbah H.N., Maltsev V.A., Chaudhry P.A., Mishima T., Undrovinas A.I. Contractile function of cardiomyocytes isolated from dogs with heart failure is enhanced after chronic therapy with passive ventricular constraint using the Acorn cardiac support device. Circulation 1999;100(Suppl 2):439.
- Sabbah H.N., Gupta R.C., Sharov V.G., et al. Prevention of progressive left ventricular dilation with the Acorn Cardiac Support Device down regulates stretch-mediated p21ras, attenuates myocyte hypertrophy and improves sacroplasmic reticulum calcium channel cycling in dogs with heart failure. Circulation 2000;104(Suppl 2):556.
- Carpentier A., Chachques J.C. Clinical dynamic cardiomyoplasty: method and outcome. Semin Thorac Cardiovasc Surg 1991;3:136-139.[Medline]
This article has been cited by other articles:
|
|
|
|
 
J. Raman
Invited commentary.
Ann. Thorac. Surg.,
September 1, 2009;
88(3):
726 - 726.
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Bredin, J. Liska, and A. Franco-Cereceda
Changes in natriuretic peptides following passive containment surgery in heart failure patients with dilated cardiomyopathy
Interactive CardioVascular and Thoracic Surgery,
February 1, 2009;
8(2):
191 - 194.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. George, Y. Cheng, G.-H. Yi, K.-L. He, X. Li, M. C. Oz, J. Holmes, and J. Wang
Effect of passive cardiac containment on ventricular synchrony and cardiac function in awake dogs
Eur. J. Cardiothorac. Surg.,
January 1, 2007;
31(1):
55 - 64.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Cheng, T. C. Nguyen, M. Malinowski, F. Langer, D. Liang, G. T. Daughters, N. B. Ingels Jr, and D. C. Miller
Passive Ventricular Constraint Prevents Transmural Shear Strain Progression in Left Ventricle Remodeling
Circulation,
July 4, 2006;
114(1_suppl):
I-79 - I-86.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Lembcke, S. Dushe, S. Sonntag, C. Kloeters, C. N. H. Enzweiler, T. H. Wiese, B. Hamm, F.-X. Kleber, and W. F. Konertz
Changes in right ventricular dimensions and performance after passive cardiac containment
Ann. Thorac. Surg.,
September 1, 2004;
78(3):
900 - 905.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Lembcke, S. Dushe, C. N.H. Enzweiler, C. Kloeters, T. H. Wiese, K.-G. A. Hermann, B. Hamm, and W. F. Konertz
Passive external cardiac constraint improves segmental left ventricular wall motion and reduces akinetic area in patients with non-ischemic dilated cardiomyopathy
Eur. J. Cardiothorac. Surg.,
January 1, 2004;
25(1):
84 - 90.
[Abstract]
[Full Text]
[PDF]
|
|
|
Top
Abstract
Introduction
