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ORIGINAL ARTICLE |
1 Department of Cardiovascular Surgery, Pompidou Hospital, Paris, France
2 Department of Cardiovascular Surgery, Louis Pradel Hospital, Lyon, France
3 Department of Cardiovascular Surgery, La Timone Hospital, Marseille, France
4 Department of Cardiovascular Surgery, Rangueil Hospital, Toulouse, France
5 Bakken Research Center, Maastricht, The Netherlands
Juan C Chachques, MD, Tel: +33 613144398, Fax: +33 140728608, Email: j.chachques{at}brs.aphp.fr, Department of Cardiovascular Surgery, Pompidou Hospital, 20 rue Leblanc, 75015 Paris, France.
ABSTRACT
The French multicenter experience (6 centers) of dynamic cardiomyoplasty was analyzed for long-term survival and functional outcome, the most important endpoints in congestive heart failure therapy. Cardiomyoplasty was performed in 212 patients with symptoms of chronic heart failure despite maximal pharmacological therapy. The etiology was ischemic (48%), idiopathic (45%) or other (7%). Cardiomyoplasty was performed using the latissimus dorsi muscle which was electrostimulated after surgery. During follow-up, 88% of patients improved clinically. Hospital death occurred in 29 (14%) patients and was related to the severity of preoperative heart failure symptoms. Late mortality occurred in 99 patients due to heart failure (44%), sudden death (37%), or noncardiac causes (18%). Combined dynamic cardiomyoplasty and implantation of a cardiac rhythm management system was safely achieved in 22 patients, and 26 underwent heart transplantation for recurrent heart failure. Long-term functional improvements were observed in most patients, and the best outcome was achieved in those with isolated right ventricular failure. Dynamic cardiomyoplasty can be considered as a destination therapy or a mid- to long-term biological bridge to heart transplantation.
Key Words: Cardiomyoplasty • Cardiomyopathies • Heart Failure • Myocardial Ischemia
INTRODUCTION
Heart failure with systolic dysfunction leads to progressive increases in the size of the cardiac chambers. The interaction of hemodynamic processes influences this dilatation, and the actin-myosin crossbridges stretch beyond their physiologic limits, causing a decrease instead of an increase in contractile strength as well as structural and hemodynamic changes. The increased end-diastolic pressure that accompanies dilatation may affect the coronary circulation during diastole, resulting in structural myocardial changes and extracardiac modifications such as metabolic and neuroendocrine changes at the systemic level. The growing prevalence of heart failure has prompted development of new therapies to support the failing heart. Important advances have been made in cardiac bioassist approaches both as a bridge to transplantation and recovery therapy.1 Latissimus dorsi dynamic cardiomyoplasty (DCMP), introduced in the 1980s, has been followed by aortomyoplasty, atriomyoplasty, and skeletal muscle ventricles. With advances in cellular and molecular biology, the concept of ventricular assistance by biological means seems promising.2 Worldwide, cardiomyoplasty has been performed in over 2,000 clinical cases, aortomyoplasty counterpulsation in 100 cases, cellular cardiomyoplasty in 3,000 cases, and cellular cardiomyoplasty associated with a bioartificial myocardium in 50 cases. DCMP aims to support cardiac function in patients with chronic heart failure by wrapping the (usually left) latissimus dorsi muscle around the failing ventricles and stimulating it electrically in synchrony with ventricular function.3 The first successful clinical case was treated in 1985 in Broussais Hospital, Paris. This retrospective analysis gives an overview of the collective DCMP experience in France.
PATIENTS AND METHODS
Since the first clinical case in January 1985, 212 cardiomyoplasty procedures have been performed in 6 centers in France. The last patient in this series was operated on in November 2006. Patient characteristics are summarized in Table 1
. All patients had chronic heart failure refractory to pharmacological therapy. Their mean left ventricular ejection fraction was 22% ± 9%. The causes of right ventricular (RV) failure were arrhythmogenic cardiomyopathy in 7 patients, ischemic in 2, Uhl’s disease in 1, and endomyocardial fibrosis in 1. Arrhythmogenic RV dysplasia/cardiomyopathy is characterized by progressive fibrofatty replacement of the myocardium, which predisposes to ventricular tachycardia and sudden death in young individuals and athletes. It primarily affects the RV, but with time, it may also involve the left ventricle (LV). DCMP was performed as an isolated procedure in 74% of patients, without the need for extracorporeal circulation; 26% had additional procedures including LV resection (7.3%), tricuspid repair or replacement (7%), coronary artery bypass grafting (6.6%), ventricular tumor resection (2.7%), and mitral valve repair or replacement (2.4%).
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). Intramuscular pacing electrodes were implanted. The muscle and pacing leads were transferred to the left thoracic cavity after resection of a segment of the 2nd rib. The heart was exposed via a median sternotomy, and 1 or 2 epicardial leads were implanted for myocardial sensing. The latissimus dorsi muscle was wrapped around both ventricles and fixed to the pericardium with interrupted sutures (Figure 1B). Depending on the indication, different latissimus dorsi wrapping methods were used. The muscle was wrapped around dilated ventricles to reinforce the myocardium, or used to replace a portion of myocardium after aneurysm or tumor resection.4 Anterior-to-posterior wrapping of the RV was carried out for specific diseases such as arrhythmogenic RV dysplasia, which was generally associated with tricuspid valve annuloplasty (Figure 2).5
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Twenty-two (10%) patients concomitantly received cardiac rhythm management implants: 6 had a dual-chamber pacemaker for atrioventricular block and/or chronotropic incompetence, 10 had cardiac resynchronization devices for left bundle branch block (QRS>130 ms) and heart failure symptoms, and 6 had defibrillators for ventricular tachycardia/arrhythmias.
When indicated, heart transplants were performed in the standard fashion by anastomosing a donor heart to the remnant atria and great vessels. During surgery, the latissimus dorsi wrap was divided as far as possible inside the left pleural cavity, and its vascular pedicle was obturated. The proximal portion of the muscle as well as the intramuscular pacing electrodes were kept in place in the left pleural cavity. Adhesions between the muscle and the heart were not released so as to achieve en-bloc resection of the heart and muscle wrap. The latissimus dorsi was divided using electrocautery. The incidence of bleeding from the skeletal muscle stump was generally low. During removal of the recipient’s heart, care was taken to avoid injuring the left phrenic nerve which was frequently close to the latissimus dorsi muscle.
RESULTS
Hospital death (within 30 days) occurred in 29 (14%) patients, and was related to the severity of preoperative heart failure symptoms: mortality was 31.8% for those in New York Heart Association (NYHA) functional class IV, 12.4% in class III, and 5.8% in class II. The most important cause of mortality was heart failure (83%). Survival data were to December 2008. From January 1985, 99 patients died (mean time to death, 4 years). Causes of death were heart failure (44%; mean time, 3.4 years), sudden death (37%; mean time, 4.1 years), and noncardiac causes (18%; mean time, 5.4 years). Noncardiac causes of death were stroke, cancer, and gastric bleeding. In addition, 26 patients underwent heart transplantation for recurring symptoms of heart failure. Data were analyzed for freedom from cardiac death or transplantation for the 3 types of predominant ventricular dysfunction (LV, RV, or biventricular). The best results were achieved for isolated RV dysfunction (5-year survival 78%; 10-year survival 69%); while LV and biventricular dysfunction had 48% and 39% survival at 5 years, and 30% at 10 years (Figure 3). Data were also analyzed for freedom from severe cardiac decompensation episodes: 61% of patients were free from severe decompensation at 5 years, 51% at 10 years, and 43% at 15 years. During follow-up, 88% of patients improved clinically as measured by NYHA class which improved by at least 1 class. The mean NYHA class of hospital survivors just before sudden death or death from a noncardiac cause was 1.66 (class III 11%, class II 44%, class I 45%; Figure 4). Mean NYHA class was 3.0 preoperatively and 1.7 postoperatively at a mean follow-up time of 7.2 years.
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Heart transplantation was indicated in 26 patients for persistent heart failure (no immediate improvement after DCMP) in 19% and for recurring heart failure symptoms, mostly due to progression of the underlying cardiac disease, in 81%. The mean age of these 26 patients was 51 ±11 years, and the interval after DCMP was 2.3 ±3 years (range, 0–16.7 years). The etiology in these cases was mostly ischemic (50%) and idiopathic (42%). LV ejection fraction at DCMP was 19% ±6%, and the predominant ventricular failure was LV in 76%, RV in 5%, and biventricular in 19%. Survival after heart transplantation (mean, 5.5 years; longest, 13.5 years) is shown in Figure 5. For the urgent subgroup in which there was no clinical benefit after DCMP, the transplant was carried out within 4 months (mean, 1 month; range, 0.1–2.1 months). In the elective subgroup, transplantation was performed after a mean period of 3 years (range, 0.5–16.7 years). Hospital mortality was higher in the urgent subgroup compared to electively treated patients (60% vs. 17%). Early deaths were due to septicemia (2) and graft failure (5). Late deaths were caused by graft failure (4), rejection (1), and gastric bleeding (1). The muscle wrap was found to be well preserved in 9 patients, there was slight hypertrophy and mild fibrosis in 11, and severe ultrastructural impairment and atrophy in 9. Tight adhesions between the muscle wrap and the heart wall were frequently observed.
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The 30-day hospital mortality includes data from the pilot and feasibility phase during which the surgical method was developed. As expected, hospital mortality was strongly linked to the preoperative NYHA class. With implementation of improvements, later multi-center studies (e.g. C-SMART in the USA) have focused on NYHA class III patients and used risk-stratification strategies, with 30-day hospital mortality of 4%.6 As expected, our hospital mortality was higher when urgent transplantation was required due to postoperative heart failure or early inefficient DCMP support, but it was not significantly different to that after elective transplantation performed later due to progression of underlying cardiac disease resulting in DCMP inefficiency. This experience confirms that heart transplantation is feasible and safe after DCMP. For non-urgent transplants, the results were similar to those reported for primary transplant procedures.7
DCMP provided long-term cardiac benefits as demonstrated by a reduction of NYHA class by at least 1 class in 88% of patients discharged from hospital. Long-term event-free survival, defined as no cardiac death or transplantation, depended on cardiac indication; it was best for isolated RV failure. Muscle contraction can be maintained in the long term.7–11 The effect of muscle stimulation, efficacy of contraction, and the need to be stimulated were not tested prospectively. However, some clinical observations could be undertaken, e.g., when the stimulator reached its end of service and the device was not replaced on time (battery depleted) because the patient lived overseas, or when muscle stimulation stopped due to lead fracture. Most of these events occurred>10 years after DCMP. In each of these cases, the patient returned to hospital with recurring symptoms of heart failure. Correction of the problem by exchanging the stimulator or repairing the lead allowed the patient to gradually recover to their previous clinical condition. These anecdotal observations confirm that muscle function can be preserved in the long term, and that long-term muscle stimulation is needed to maintain the clinical benefits.
In this study, all patients followed the original progressive stimulation protocol developed at Broussais Hospital. Implementation of recent improved understanding of muscle physiology and adapting stimulation protocols to the patient’s physiological status, such as customizing the stimulation pattern to the muscle response and allowing for a mixed fiber composition, indicates that use of skeletal muscle pharmacological support would certainly improve results. A major impact might result from a protocol or procedure that would obviate the need for a muscle rest period after surgery as this would permit cardiac support during the early postoperative phase. Surgical improvements aimed at optimizing energy transfer from muscle to cardiac hemodynamics might also be important.
Nearly all of these cardiomyoplasty operations used cardiomyostimulators supplied by Medtronic, Inc. The commercial decision by Medtronic to withdraw from the field was damaging as it led to the widespread conclusion that the technique was inherently flawed. Ironically, it was the drive to meet regulatory requirements that discouraged departure from a fixed protocol, isolating clinical practice from progress in the underlying basic science. New devices are now available, such as the Microstim Myostimulator (Microstim, Germany) and the LD-PACE II (CCC, Uruguay); these may revive cardiomyoplasty and related research.12,13
Because 37% of late deaths during follow-up were sudden, a cardiomyostimulator that includes defibrillation therapy has the potential to improve clinical outcomes. This experience indicates that concomitant implantation of a cardiac rhythm management device can be undertaken safely, and confirms previous case reports of the benefit of a combination of cardiomyostimulators and implantable defibrillators. Appropriate long-term function of both devices can be maintained. The cumulative experience in this cohort amounted to 54 patient-years. Device interactions must be verified after implantation, and systems adjusted to avoid interaction of the bursts with cardiac rhythm detection. After defibrillation, checking cardiomyostimulator function by electrocardiography or telemetry is recommended. The addition of ventricular resynchronization could be an added benefit for heart failure patients, and should be considered in combination with a defibrillator function. Basic research in recent years on the vascular anatomy of the latissimus dorsi muscle and its adaptive response to electrostimulation has improved the viability and function of skeletal muscle grafts. DCMP performed with emerging pacing protocols could well reduce systolic wall stress and provide beat-to-beat assistance in the short term, together with reverse remodeling and extra myocardial revascularization in the long term.14–16 Implementation of the latest findings on muscle preservation, activation, energy transfer from muscle to heart, as well as combinations of defibrillators and resynchronization devices might improve survival and efficacy.15 In the case of recurrent heart failure, heart transplantation is still feasible. Therefore DCMP could be considered as either a destination therapy or as a mid-to long-term biological bridge to heart transplantation.
The knowledge acquired with DCMP has been applied to regenerative cardiology. Stem cell therapy in ischemic and nonischemic cardiomyopathies is a rapidly growing field.17 The benefits of stem cell delivery to injured myocardium have been demonstrated, and recent reports have described bioartificial matrices that may provide mechanical support and enhance myocardial regeneration. It is important to remark that current indications for cell-based regenerative therapy are small ischemic scars and not the large ischemic lesions responsible for end-stage ventricular failure. Electrostimulation combined with cellular cardiomyoplasty could transform passive cell therapy into "dynamic cellular support". The principles of electrophysiological conditioning of skeletal muscle fibers developed for DCMP are now applied in cellular cardiomyoplasty. The hypothesis is that electrostimulation of both ventricles following skeletal myoblast implantation induces contraction of the transplanted cells and greater expression of slow myosin which is better for chronic ventricular assistance. Electrostimulation seems to drive stem cells to differentiate into cardiac-type myogenic cells.18 This type of differentiation should include the induction of gap junction formation, improving stem cell engraftment and reducing the risk of arrhythmogenic events. In-vitro electrostimulation of cell cultures induced both morphological and biochemical changes in mesenchymal stem cells, realizing a shift towards a striated muscle cell phenotype expressing cardiac-specific markers.19 Cardiac tissue engineering is emerging as a new therapeutic tool, extending the amazing possibilities of cardiac bioassist procedures and promising the creation of a bioartificial myocardium. The stem cell niche, a specialized environment surrounding stem cells, provides crucial support for stem cell maintenance. Compromised niche function may lead to selection of stem cells that no longer depend on self-renewal factors. If the stem cell niche has aged, it might not be capable of supporting autogenous or transplanted stem cells. Cardiac tissue engineering is developing biodegradable scaffolds to support cell survival and early extracellular instruction. The MAGNUM trial showed that cellular cardiomyoplasty associated with a cell-seeded collagen matrix increased the thickness of the infarct scar with viable tissue, and helped to normalize cardiac wall stress in injured regions, thus limiting ventricular remodeling and improving diastolic function.20 The creation of functional biocompatible contractile tissues remains challenging. Future developments include bioengineered platforms where stem cells are preconditioned to resist implantation into highly stressed myocardial tissue.
Presented at the 4th International Cardiac Bio-Assist Association Congress, Singapore, March 12–13, 2008.
ACKNOWLEDGMENTS
The French cardiomyoplasty investigators: F Delahaye, P Mikaeloff; V Bors, I Ganjbakhch, A Pavie; D. Metras, A Mouly-Bandini, G Fournial, D Roux, T Popof, JP Elbèze, T Lavergne, A Berrebi, S Mihaileanu, JP Marino, F Monsonego.
REFERENCES
Asian Cardiovasc Thorac Ann 2009;
17:573-580
© 2009 by SAGE Publications
DOI: 10.1177/0218492309349371
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