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Cardiomyoplasty: Present and Future

Juan C. Chachques MD, PhD

Department of Cardiac Surgery, Broussais and Pompidou Hospitals,
and Surgical and Clinical Research Unit, University of Paris, Paris, France

INTRODUCTION
   The management of patients with end stage heart failure is a daily challenge in cardiac surgery. Cardiac transplantation and mechanical assist devices do not cover all the needs.

   Cardiac transplantation is a limited option for end-stage heart failure because of the shortage of donor organs. Left ventricular assist devices are currently under investigation as permanent therapy for end-stage heart failure, but long-term successful device implantation is limited because of a high rate of serious infections and the financial cost of the device and the follow-up.

   The aim of dynamic cardiomyoplasty (CMP) is to restore or enhance the myocardial contractility using the patient's latissimus dorsi muscle (LDM) which is wrapped around the ventricles and electrostimulated in synchrony with the contractions of the heart.

   The recent progress in cellular and molecular biology allows the development of new therapies for heart failure. One of the most innovative consists in the transplantation of autologous expanded cells into the myocardium for heart muscle regeneration. This approach was called «cellular cardiomyoplasty».

LATISSIMUS DORSI CARDIOMYOPLASTY
   This surgical procedure consists in the dissection and the transposition into the chest of the entire left latissimus dorsi muscle flap, which will be positioned around both ventricles. Afterwards, the LDM will be chronically electrostimulated in synchrony with ventricular systole. The biological support of this operation consists of chronic muscle electrostimulation which induces a physiological adaptation of skeletal muscle to cardiac work. The metabolism of the rapid glycolytic fatigue-sensitive muscle fibers (type II) are transformed into slow oxidative fatigue-resistant muscle fibers (type I).

   The electronic stimulation materials consist of an implantable Cardio-Myostimulator, muscle stimulation electrodes and systole detection electrodes which allow the synchronization of muscle contractions to the heart beat. In order to imitate the duration of a systolic contraction, the skeletal muscle should be electrostimulated using train impulsions with a duration close to the ventricular ejection time span.

   Cardiomyoplasty has been used in our institution for heart failure patients refractory to medical therapy, 112 cases were operated at Broussais Hospital and 75 patients by our team abroad, in the scope of an international cooperative program.

ACTION MECHANISMS
   The many proposed mechanisms of action of LDM dynamic cardiomyoplasty are: 1) systolic assist, 2) limitation of ventricular dilation, 3) reduction of ventricular wall stress (sparing effect), 4) reverse ventricular remodeling with an active girdling effect.

   CMP leads to an increase in ventricular mass by adding a new contractile muscular wall which allows, in turn, to reestablish the ratio between the mass and the ventricular diameter in dilated cardiomyopathies.

INDICATIONS
   CMP is recommended to patients suffering from severe chronic cardiac deficiency. The ischemic myocardial deficiency (patients presenting successive infarctions or one largely extended), as well as the dilated cardiomyopathies (generally of unknown origin) are considered to be indications for CMP. Hypertrophic or obstructive cardiomyopathies, however, are excluded for CMP.

   The time to perform a CMP can be concluded from the postoperative results. The hemodynamic advantage of the CMP is only achieved after a delay of several weeks corresponding to the adaptation period of the LDM to its new cardiac assistance function. Therefore, the residual myocardial function has to be taken into account in patient selection.

CLINICAL EXPERIENCE
   Patient Population: 112 patients aged 15 to 72 years (mean 51 years) were operated on in our Institution. All patients presented a severe cardiac deficiency refractory to maximal pharmacological therapy; 86 were in NYHA class III and 26 in class IV. LV ejection fraction averaged 17%, EDLV volume 178 ± 31 ml/m2. The cause of heart failure was ischemia in 59 patients, dilated cardiomyopathy in 46 patients and ventricular tumors in 7 patients. Associated pathology (pulmonary hypertension, diabetes...) was present in 60%. The technique has evolved from "open fixation" (58 patients), to "non-suture wrapping" (41 patients), to "mini-invasive technique" (13 patients). Two-stage operations in high risk patients with mitral valve insufficiency or severe arrhythmia were performed in 6 patients. Associated procedures were performed in 24 patients (CABG=14, valve=10).

   Results: Hospital mortality was 53% between 1985-1987, 13% between 1988-1997, and 8% since the introduction of mini-invasive techniques. Actuarial survival at 10 years was 70% for preop class III patients and 28% for class IV patients. Average NYHA class was 3.3 preoperative and 1.4 postoperative. Nine patients heart required transplantation. Hemodynamic investigations in the survivors showed significant improvement in ejection fraction (21% to 31%) and cardiac index (1.9 to 2.8 L/mn/m2). The quality of life of the patients, evaluated every six months postoperatively by questionnaire, significantly improved since most patients had increased their daily and social activities and 62% had started working again.

CONCLUSIONS
   The clinical evaluation and the postoperative studies show that CMP is an efficient technique to assist chronic patients who suffer from severe cardiac deficiency. The technique allows a functional improvement of the patients of their capacity during exercise, as well as a decrease in medication. In operated patients a decrease was noted in deterioration of their state which would have required hospitalization. The CMP results improved through experience, through rigorous patient selection, through progress in the operation technique, and through improved postoperative care. The post-operative course was often critical (30 % low cardiac output syndrome), particularly in ischemic etiology. Cardiomyoplasty has been associated with better results due to technical improvements, the most significant being less-invasive techniques, the latest the use of growth factors to enhance muscle vascularisation. Cardiac transplantation is technically feasible after a CMP. Risk factors have been identified resulting in more precise indications, a lower hospital mortality and a wider use of this operation.

ELECTROPHYSIOLOGICAL TREATMENTS ASSOCIATED WITH CMP
   The patients who have been subjected to a CMP, suffering from an ischemic or severe idiopathic cardiomyopathy, present a great risk ventricular arrhythmias which is potentially responsible for the occurrence of sudden death. At the same time, electrical and mechanical asynchronisms between the ventricles are frequently observed in these patients. In recent clinical cases, CMP has been associated with an implantable defibrillator or multisite cardiac pacing (for atrio-ventricular and interventricular re-synchronization). The positive results obtained foresee an important expansion of this associated techniques.

CELLULAR CARDIOMYOPLASTY
   Cellular cardiomyoplasty consists of cell implantation to grow of new muscle fibers in the damaged myocardium that potentially may contribute to the contractile performance of the heart.

   In adults, myocardium can not repair after infarction due to the absence of stem cells. Thus, the injury is irreversible For this reason, cell transplantation strategies for heart failure have been designed to replace damaged cells with cells that can perform cardiac work. Therefore, the aim of cellular cardiomyoplasty is the repair of injured myocardium by cell transplantation, either in ischemic or idiopathic cardiomyopathies.

Cell types for cellular cardiomyoplasty
   Current possibilities in cell therapy for heart failure is the transplantation into the infarcted myocardium of:

1. CARDIOMYOCYTES: fetal or embryonic.
2. ADULT CARDIOMYOCYTES.
3. SKELETAL MYOBLASTS (SATELLITE CELLS).
4. SMOOTH MUSCULAR CELLS.
5. BONE MARROW STROMAL CELLS.
6. UNDIFFERENTIATED BLOOD CELLS.
7. CELL LINES (this approach can be related with oncogenic risks).

   Cellular cardiomyoplasty research is at a developing stage in our institution. The main questions are how satellite cells integrate into myocardial tissue and whether the cells can provide an improvement in contractile force.

   Fetal cardiomyocytes have been successfully grafted into the myocardium, but their use raises immunological, ethical and availability problems. There are two major disadvantages in using these cells: 1) the availability of embryonic (or fetal) tissue is limited. 2) an immunosuppressive treatment is required after implantation of cardiomyocytes.

   An alternative strategy to increase the amount of contractile tissue in the infarcted myocardium is transplantation of skeletal muscle cells. Satellite cells or myoblasts can be obtained in large quantities, the implantation of these autologous cells does not cause any immunological rejection problems. Differently from myocardial muscle, the cells of skeletal muscle are able to regenerate after injury because of the presence of satellite cells. These cells are a morphologically undifferentiated cells that lie dormant between the plasma membrane and basal lamina of mature skeletal muscle, when activated by appropriate stimuli, satellite cells, proliferate and differentiate into new skeletal muscle fibers. In addition, skeletal muscle are more resistant to ischemia than cardiac myocytes. These skeletal myoblast can survive and make stable grafts in the myocardium. Our experimental work demonstrated that skeletal myoblasts transplantation improves the function of failing hearts.

Cell expansion and implantation procedures
   The following steps are necessary to perform a cellular cardiomyoplasty procedure (myoblasts approach):
1) Skeletal muscle biopsy: 2 cm3 skeletal muscle piece (10 grams) is explanted from the patient leg or arm.

2) Satellite cell isolation and culture: myoblasts are isolated after mecanical and enzymatic treatment of the muscle fragments. After 3 weeks of culture, around 100 million cells are ready to be transplanted.

3) Satellite cell implantation: the cell suspension (volume 3 ml) are injected in the ventricular lesion. The heart is exposed by minithoracotomy or sternotomy. The infarction site is identified. Satellite cells are then injected by multiple points (5 to 10) depending of the size and the configuration of the myocardial infarcted area. Idiopathic dilated cardiomyopathies can be also treated by cell therapy. Multiple injection points should be performed in both ventricles.
Figure 1

Mechanisms of action
   The beneficial mechanism effects of skeletal myoblast transplantation remains controversial. It is not certain whether improvement in left ventricular performance is mediated by an increased systolic function caused by synchronous contraction of the graft. Experimental studies have shown that transplanted cells within a normal or infarcted myocardium remain viable for months and can proliferate and differentiate in situ. The presence of intercalated disks and connexin 43, a marker gap junctions required for cell to cell electrical coupling, has been demonstrated within grafted tissue and between grafted cells and host myocytes in the case of fetal transplantation, but not in skeletal myoblast transplantation.

   The functional benefits of cellular cardiomyoplasty could be due to the improvement of the elastic properties of the diseased myocardium, limiting the scar expansion and progressive ventricular chamber dilatation, resulting in a better compliance of cardiac tissue. One other hypothesis is that these grafted cells could liberate angiogenic factors, creating a neovascularization that limits the scar zone expansion and remodels the left ventricle. Growth factors can provide an adjuvant therapy with direct myocardial protection and increase the viability and function of the ischemic myocardium. We are working with angiogenic growth factors associated to cellular cardiomyoplasty in a ischemic heart model. We think that this adjuvant therapy may provides a better myocardium perfusion. Thus, cellular transplantation into a damaged myocardium results in an improvement in the left ventricular performance and remodeling.

   From the clinical perspective, the use of cultured autologous cells requires a strict protection against bacterial, viral, fungus or prion contamination, and a high efficacy of cell expansion. The clinical applications should be in patients candidates to myocardial revascularization surgery presenting one infarctus zone with the objective of limitate infarctus area expansion and cardiac remodeling, leading to a better compliance of cardiac tissue. Or patients presenting a cardiac dysfunction due to ischemic cardiomyopathy whereas it is not possible a myocardial revascularization surgery.

   Another potential indication for cell therapy would be idiopathic dilated cardiomyopathies. In these cases the number of implanted cells should be more important and the injections should be performed by multiple points in both ventricles.

Preliminary Conclusions
   Myoblast implantation was associated with the recovery of myocardial contractility in experimental models (infarct-like myocardial lesions and dilated cardiomyopathy models). Healthy myoblasts and myotubes were observed 2 months after myocardial implantation. Clinical studies are now in progress.

   Cellular cardiomyoplasty is particularly attractive for a number of reasons, foremost among which is potential for replacement or infiltration of myocardial scar with a variety of beneficial cell types. In addition, once established within the heart, transplanted cells may alter the regional myocardium, through induction of angiogenesis, formation of syncitial relationships with viable native myocardium, and the restoration of function to terminally injured and dysfunctional myocardium. Cells also might be delivered using intracardiac catheters instead of thoracotomy, this technology is currently tested in our institution.

   Cells transplanted into myocardium may first impact diastolic dysfunction, and later, when sufficient organization of the grafts occur, systolic performance may improve. Our experimental results and the international literature support this concept.

   In summary, cell transplantation offers the promise of restoring regional ventricular function, limit remodeling and stimulate angiogenesis for patients who have had an extensive myocardial infarction or dilated cardiomyopathy. Clinical feasibility of this new surgical technique has already started raising. Future studies will need to establish the efficacy of this approach.

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2nd Virtual Congress of Cardiology

Dr. Florencio Garófalo
Steering Committee
President
Dr. Raúl Bretal
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