Abdel Shafy

From dynamic to cellular cardiomyoplasty.

Abstract Dynamic Cardiomyoplasty. Latissimus dorsi dynamic cardiomyoplasty has been used in our institution for heart failure patients refractory to medical therapy; 113 cases were operated at Broussais and Pompidou Hospitals and 75 patients by our team abroad, in the scope of an international cooperative program. Cardiomyoplasty has been associated with better results due to technical improvements, the most significant mini‐invasive techniques, the latest the use of growth factors to enhance muscle vascularization. Risk factors have been identified, resulting in more precise indications, a lower hospital mortality, and a wider use of this operation. There has been a new tendency to associate cardiomyoplasty with electrophysiological therapies: implantation of ventricular defibrillators and multisite cardiac pacing (for atrioventricular and interventricular resynchronization). Cellular Cardiomyoplasty. Adult myocardium cannot repair after infarction due to the absence of stem cells. Cell transplantation strategies for heart failure have been designed to replace damaged cells with cells that can perform cardiac work. Current possibilities in cell therapy for heart failure is the transplantation into the infarcted myocardium of autologous myoblasts (satellite cells originated from skeletal muscle), fetal cardiomyocytes, autologous heart cells, cells derived from bone marrow stem cells, and smooth muscle cells. Experimental studies demonstrated that cell transplantation into the myocardium was associated with the recovery of myocardial contractility and compliance, as well as the diastolic pressure‐strain relationship in animal models (infarctlike 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 for Myocardial Regeneration

The evolving challenge of managing patients with congestive heart failure is the need to develop new therapeutic strategies. The cellular, molecular, and genetic approaches investigated aim to reinforce the weak, failing heart muscle while restoring its functional potential. This approach is principally cellular therapy (i.e. cellular cardiomyoplasty), the preferred therapeutic choice because of its clinical applicability and regenerative capacity. Different stem cells: bone marrow cells, skeletal and smooth muscle cells, vascular endothelial cells, mesothelial cells, adipose tissue stroma cells, dental stem cells, and embryonic and fetal cells, have been proposed for regenerative medicine and biology. Stem cell mobilization with G-CSF cytokine was also proposed as a single therapy for myocardial infarction. We investigated the association of cell therapy with electrostimulation (dynamic cellular cardiomyoplasty), the use of autologous human serum for cell cultures, and a new catheter for simultaneous infarct detection and cell delivery. Our team conducted cell-based myogenic and angiogenic clinical trials for chronic ischemic heart disease. Cellular cardiomyoplasty constitutes a new approach for myocardial regeneration; the ultimate goal is to avoid the progression of ventricular remodeling and heart failure for patients presenting with ischemic and non-ischemic cardiomyopathies.

Development of cardiac support bioprostheses for ventricular restoration and myocardial regeneration

OBJECTIVES Ventricular constraint devices made of polyester and nitinol have been used to treat heart failure patients. Long-term follow-up has not demonstrated significant benefits, probably due to the lack of effects on myocardial tissue and to the risk of diastolic dysfunction. The goal of this experimental study is to improve ventricular constraint therapy by associating stem cell intrainfarct implantation and a cell-seeded collagen scaffold as an interface between the constraint device and the epicardium. METHODS In a sheep ischaemic model, three study groups were created: Group 1: coronary occlusion without treatment (control group). Group 2: postinfarct ventricular constraint using a polyester device (Acorn CorCap). Group 3: postinfarct treatment with stem cells associated with collagen matrix and the polyester device. Autologous adipose mesenchymal stem cells cultured in hypoxic conditions were injected into the infarct and seeded into the collagen matrix. RESULTS At 3 months, echocardiography showed the limitation of left ventricular end-diastolic volume in animals both treated with constraint devices alone and associated with stem cells/collagen. In Group 3 (stem cell + collagen treatment), significant improvements were found in ejection fraction (EF) and diastolic function evaluated by Doppler-derived mitral deceleration time. In this group, histology showed a reduction of infarct size, with focuses of angiogenesis and minimal fibrosis interface between CorCap and the epicardium due to the interposition of the collagen matrix. CONCLUSIONS Myocardial infarction treated with stem cells associated with a collagen matrix and ventricular constraint device improves systolic and diastolic function, reducing adverse remodelling and fibrosis. The application of bioactive molecules and the recent development of nanobiotechnologies should open the door for the creation of a new semi-degradable ventricular support bioprosthesis, capable of controlled stability or degradation in response to physiological conditions of the left or right heart.

Partial replacement of the tricuspid valve by mitral homografts in acute endocarditis

BACKGROUND Seven patients with acute tricuspid endocarditis underwent partial replacement of the tricuspid valve using mitral homograft tissue. Valve function was evaluated at midterm. METHODS Operative indications were uncontrolled sepsis in all cases associated with heart failure symptoms in 3 patients and septic pulmonary emboli in 2 patients. These patients were referred to our institution after a course of antibiotic treatment ranging from 7 to 12 weeks. Lesions found at the level of the anterior leaflet of the tricuspid valve were vegetations and rupture of more than half of the marginal cords in all patients. Vegetations were also found on the posterior leaflet in 5 patients. In all instances the septal leaflet was free of lesions. The aortic valve was involved in 4 patients and the pulmonary valve in 1 patient. All patients underwent resection of the anterior and posterior leaflets of the tricuspid valve with their corresponding papillary muscles leaving the septal leaflet in place. Replacement of the tricuspid valve was performed through a right longitudinal atrial access, using the anterior leaflet of a mitral homograft alone in 3 patients and the anterior leaflet with part of posterior leaflet in 4 patients. Associated procedures included aortic valve replacement by a homograft (n = 4) and pulmonary valve reconstruction (n = 1). RESULTS No hospital deaths are reported. One late death, at 16 months, is reported after reoperation due to recurrent aortic valve endocarditis. At midterm (mean follow-up, 30 months) patients had excellent functional status and normal valvular function during echocardiographic studies. CONCLUSIONS We conclude that when the degree of tricuspid valve destruction prevents repair, partial homograft replacement can be used as an extension of the already existing reconstructive techniques, with excellent functional results.

Mesothelial Cells vs. Skeletal Myoblasts for Myocardial Infarction

Cell transplantation for the regeneration of ischemic myocardium is limited by poor graft viability and low cell retention. Omental flaps in association with growth factors and cell sheets have recently been used to increase the vascularization of ischemic hearts. This experimental study was undertaken to evaluate the hemodynamic evolution and histological modifications of infarcted myocardium treated with mesothelial cells, and to compare the results with those of hearts treated with skeletal myoblasts. Myocardial infarction was created by surgical ligature of 2 coronary branches in 34 sheep; 6 died immediately due to ventricular fibrillation. Mesothelial cells were isolated from greater omentum, and myoblasts from skeletal muscle. After expanding the cells for 3 weeks, infarcted areas were treated with culture medium (control group), mesothelial cells, or myoblasts. After 3 months, echocardiographic studies showed significant limitation of ventricular dilatation and improved ejection fractions in both cell-treated groups compared to the controls. In the mesothelial cell group, histological studies showed significantly more angiogenesis and arteriogenesis than in the control and skeletal myoblast groups. Mesothelial cells might be useful for biological revascularization in patients with ischemic heart disease.

Comparison of the Effects of Adenosine, Inosine, and Their Combination as an Adjunct to Reperfusion in the Treatment of Acute Myocardial Infarction

Adenosine and inosine are both key intracellular energy substrates for nucleotide synthesis by salvage pathways, especially during ischemic stress conditions. Additionally they both possess cell protective and cell repair properties. The objective of this study is to detect potential advantages of the combination of adenosine and inosine versus each drug alone, in terms of ventricular function, infarct size reduction and angiogenesis. Myocardial ischemia was created in rodents and treated with adenosine, inosine or their combination. Results of experiments showed that the combination of both drugs significantly reduced infarct size and improved myocardial angiogenesis and ventricular function. The two compounds, while chemically similar, use different intracellular pathways, allowing for complementary biological activities without overlapping. The drug combination at specific 1 : 5 adenosine : inosine dose ratio demonstrated positive cardiologic effects, deserving further evaluation as an adjunct to reperfusion techniques during and after acute coronary syndrome. The association of adenosine and inosine may contribute to reduce myocardial infarction morbidity and mortality rates.

Evaluation of a new left atrial retractor for minimally invasive mitral valve surgery

FIGURE 1. The MitraXs (St Jude Medical Inc, Minneapolis, Minn) is a self-supporting atrial retractor. A, In deployed position with 1 overmoduled pivoting rivet that makes its conical shape self-expanding and auto-adjusting. B, In rolled and compressed position, with triangular tab protruding out of the cylinder, which makes introduction into the left atrium easy. CLINICAL SUMMARY The MitraXs retractor is a pattern-cut polymer sheet that once deployed and secured by a pivoting rivet generates a conical volume (Figure 1). The device is a self-expanding, auto-adjusting, single-use left atrial retractor that does not require a supporting arm. The retractor has 2 sizes (A and B) according to valve diameter and 2 lengths (regular or ‘‘ þ’’) according to atrium depth to accommodate anatomic variations. The introduction and deployment of the MitraXs device are key points. After the folding step, the MitraXs device is rolled and compressed from a conical shape to a cylinder with a reduced diameter creating a protruding triangular tab (Figure 1). By using a locking forceps, theMitraXs device is introduced via a minithoracotomy and an atriotomy, the tab with the rivet at the top loading the atrial septum first; then, with a clockwise rotation of a half turn, the device is progressively pushed into the left atrium in a screwing movement. When the MitraXs device is completely engaged in the left atrium, centered on the valve, with the rivet down in the posterior position, the forceps is released and the retractor deploys back into an optimal conical shape, working as an ‘‘expander’’ and maintaining the left atriumwide open in a symmetric manner. The effectiveness of the MitraXs device was evaluated in 62 patients who consecutively underwent MIMVS during a 20-month period at the Louis Pradel Hospital. There