Cellular transplantation: new horizons in the surgical management of heart failure.

End-stage heart failure results from the irreversible destruction of cardiomyocytes, which do not have the capacity to regenerate. Transplantation of myogenic cells into the damaged myocardium is an emerging therapeutic alternative in the management of this major public health problem. Experimental and clinical data suggest that cellular transplantation could improve ventricular function in ischaemic or dilated cardiomyopathies. Implantation of allogeneic and autologous cell types has been applied to induce cardiac myogenesis and, recently, other cell types have been tested for the induction of myocardial angiogenesis. The results of cellular transplantation are encouraging although the role of therapeutic angiogenesis remains to be clarified and the full potential of cellular transplantation to be determined

Is skeletal myoblast transplantation clinically relevant in the era of angiotensin-converting enzyme inhibitors?

BACKGROUND: There is compelling experimental evidence that autologous skeletal muscle (SM) cell transplantation improves postinfarction cardiac function. This study assessed whether this benefit is still manifested in the clinically relevant setting of a treatment by ACE inhibitors. METHODS AND RESULTS: A myocardial infarction was created in 99 rats by coronary artery ligation. They were divided into 4 groups. Two groups did not receive any drug and were intramyocardially injected 7 days after the infarct with either culture medium alone (control rats, n=16) or autologous SM cells (2.3x10(6) myoblasts) previously expanded ex vivo for 7 days (myoblasts, n=24). Two other groups received the ACE inhibitor perindoprilat (1 mg. kg(-1). d(-1)), started the day of the infarct and continued uninterruptedly thereafter, and underwent time-matched procedures, that is, they were intramyocardially injected at 7 days after infarction with either culture medium alone (ACE inhibitors, n=22) or autologous SM cells (2.5x10(6) myoblasts) previously expanded ex vivo for 7 days (ACE inhibitors+myoblasts, n=37). Left ventricular function was assessed by 2D echocardiography. At the end of the 2-month study, left ventricular ejection fraction (%, mean+/-SEM) was increased in all groups (myoblasts, 37.4+/-1.2; ACE inhibitors, 31.6+/-1.7; ACE inhibitors+myoblasts, 43.9+/-1.4) compared with that in control rats (19.8+/-0.7) (P<0.0001). The improvement in ejection fraction was similar in the ACE inhibitor and the myoblast groups (31.6+/-1.7 versus 37.4+/-1.2, P=0.0636). However, in the ACE inhibitor+myoblast group, this improvement was greater than that seen in hearts receiving either treatment alone (43.9+/-1.4 versus 31.6+/-1.7 in the ACE inhibitor group and 43.9+/-1.4. versus 37.4+/-1.2 in the myoblast group, P<0.0001 and P=0.0084, respectively). CONCLUSIONS: These data provide further support for the clinical relevance of autologous SM cell transplantation in that its cardioprotective effects are additive to those observed with ACE inhibitors.

[Autologous skeletal myoblast transplantation for cardiac insufficiency. First clinical case]. / Greffe de myoblastes squelettiques pour insuffisance cardiaque. Premier cas chez l'homme.

The authors report the first intramyocardial transplantation of autologous skeletal myoblasts in a patient with severe ischaemic cardiac failure. The encouraging result after eight months' follow-up underlines the potential of this new approach.

Factors affecting functional outcome after autologous skeletal myoblast transplantation.

BACKGROUND: This study assessed the extent to which the initial degree of functional impairment and the number of injected cells may influence the functional improvement provided by autologous skeletal myoblast transplantation into infarcted myocardium. METHODS: One week after left coronary artery ligation, 44 rats received into the infarcted scar, autologous skeletal myoblasts expanded in vitro for 7 days (mean, 3.5 x 10(6), n = 21), or culture medium alone (controls, n = 23). Left ventricular function was assessed by two-dimensional echocardiography. RESULTS: When transplanted hearts were stratified according to their baseline ejection fraction, a significant improvement occurred at 2 months in the less than 25% (from 21.4% to 37%), 25% to 35% (from 29% to 43.8%), and in the 35% to 40% (from 37.2% to 41.7%) groups, compared to controls (p = 0.048, 0.0057, and 0.034, respectively), but not in the more than 40% stratum. A significant linear relationship was found between the improvement in ejection fraction and the number of injected myoblasts, both at 1 and 2 months after transplantation (p < 0.0001). CONCLUSIONS: Autologous myoblast transplantation is functionally effective over a wide range of postinfarct ejection fractions, including in the sickest hearts provided that they are injected with a sufficiently high number of cells.

Myoblast transplantation for heart failure.

Intramyocardial skeletal muscle transplantation has been shown experimentally to improve heart function after infarction. We report success with this procedure in a patient with severe ischaemic heart failure. We implanted autologous skeletal myoblasts into the postinfarction scar during coronary artery bypass grafting of remote myocardial areas. 5 months later, there was evidence of contraction and viability in the grafted scar on echocardiography and positron emission tomography. Although this result is encouraging, it requires validation by additional studies.

Pressure-adjusted antegrade brain perfusion for surgery of the aortic aneurysm.

Determining cerebral blood flow during circulatory arrest in patients undergoing surgery for aortic aneurysms has been traditionally based on body weight. We report the use of per-aortic antegrade cerebral perfusion regulated by perfusion pressure using a triple lumen cardioplegia catheter thus optimising cerebral flow.

Intramyocardial transplantation of autologous myoblasts: can tissue processing be optimized?

BACKGROUND: Autologous skeletal myoblast (SM) transplantation improves function of infarcted myocardium, but pretransplantation cultures remain a complex process. This study assessed whether it could be optimized by muscle preconditioning with the local anesthetic bupivacaine or even bypassed with the use of the so-called mince technique. METHODS AND RESULTS: Muscle preconditioning consisted of intramuscular injections of the tibialis anterior of rats, 2 days before harvest. After 7 days of culture, the number of available myoblasts was significantly increased compared with nonconditioned controls (1 683 147 versus 85 300, P:=0.0013). The mince technique was then assessed. A myocardial infarction was created in 66 rats by coronary artery ligation. One week later, rats were reoperated on and intramyocardially injected with culture medium alone (controls, n=23), autologous cultured SM (3.5 x 10(6), n=21), or autologous muscle minced into a fine slurry, which was immediately transplanted (n=22). All muscles had been preconditioned. Left ventricular function was assessed by 2D echocardiography. Whereas end-diastolic volumes expanded over time in all groups, left ventricular ejection fraction (%, mean+/-SEM) was increased only in the cultured SM-transplanted group at 1 (P:=0. 0006) and 2 months (P:=0.0008) versus baseline (37.52+/-1.92 and 40. 92+/-2.17 versus 30.34+/-1.74), with a significant additional benefit between 1 and 2 months (P:=0.0069). CONCLUSIONS: Cell culture remains mandatory for SM transplantation to be successful but, in a clinical perspective, this process can be made more expeditious by preharvest muscle conditioning with bupivacaine, which greatly enhances the baseline cell yield.

Comparison of the effects of fetal cardiomyocyte and skeletal myoblast transplantation on postinfarction left ventricular function.

OBJECTIVES: Transplantation of fetal cardiomyocytes improves function of infarcted myocardium but raises availability, immunologic, and ethical issues that justify the investigation of alternate cell types, among which skeletal myoblasts are attractive candidates. METHODS: Myocardial infarction was created in rats by means of coronary artery ligation. One week later, the animals were reoperated on and intramyocardially injected with culture growth medium alone (controls, n = 15), fetal cardiomyocytes (5 x 10(6) cells, n = 11), or neonatal skeletal myoblasts (5 x 10(6) cells, n = 16). The injections consisted of a 150-microL volume and were made in the core of the infarct, and the animals were immunosuppressed. Left ventricular function was assessed by echocardiography immediately before transplantation and 1 month thereafter. Myoblast-transplanted hearts were then immunohistologically processed for the expression of skeletal muscle-specific embryonic myosin heavy chain and cardiac-specific connexin 43. RESULTS: The left ventricular ejection fraction markedly increased in the fetal and myoblast groups from 39.3% +/- 3.9% to 45% +/- 3.4% (P =.086) and from 40.4% +/- 3.6% to 47.3% +/- 4.4% (P =.034), respectively, whereas it decreased in untreated animals from 40.6% +/- 4% to 36.7% +/- 2.7%. Transplanted myoblasts could be identified in all animals by the positive staining for skeletal muscle myosin. Conversely, clusters of connexin 43 were not observed on these skeletal muscle cells. CONCLUSIONS: These results support the hypothesis that skeletal myoblasts are as effective as fetal cardiomyocytes for improving postinfarction left ventricular function. The clinical relevance of these findings is based on the possibility for skeletal myoblasts to be harvested from the patient himself.

Effective reduction of a giant left atrium by partial autotransplantation.

Although many surgical procedures have been proposed to reduce the size of a left atrium, their effectiveness is not well established. We present a case of mitral and tricuspid valve insufficiency with a giant left atrium. Partial heart autotransplantation was used in a mitral and tricuspid valve operation with a successful outcome. This procedure can be an effective method to treat giant left atrium.

[Cellular cardiomyoplasty: state of the art, evaluation, and future possibilities]. / Cardiomyoplastie cellulaire. Etat des lieux, évaluation et avenir.

Cellular cardiomyoplasty, or the transplantation of myogenic cells into the myocardial tissues, could emerge as a therapeutic alternative in patients with cardiac failure. It depends on several procedures: implantation of cell types, syngenic embryonic cardiomycocytes, allogenic and autogenic cardiac muscle cells. These cells carne into contact with host cardiomyocytes and could contract in a synchronous fashion. Experimental data suggests that this technique could improve global left ventricular function in the post-infarction period or in dilated cardiomyopathy even though the precise mechanism of this improvement is not fully understood. Many difficulties remain, the cell types have an oncogenic potential; syngenic foetal cells are weakly immunogenic but their use is limited by ethical and problems of supply. Therefore, auto-transplantation either of cardiomycocytes obtained by endomyocardial biopsy or of adult skeletal muscle, could be a potential clinical option.

Can cellular transplantation improve function in doxorubicin-induced heart failure?

BACKGROUND: Transplantation of fetal cardiomyocytes has been shown to improve function of regionally infarcted myocardium, but its effects on global heart failure are still unknown. METHODS AND RESULTS: Heart failure was induced in female mice by intraperitoneal injection of doxorubicin (2 mg/kg twice per week over 2 cycles of 2 weeks separated by a 2-week drug-free period). One week after the end of treatment, left ventricular function was assessed by transthoracic echocardiography (baseline). Animals were then randomized into 3 groups: The treated group (n = 12) received an intramyocardial injection of fetal cardiomyocytes (1 x 10(6) in 10 microL) harvested from transgenic mice expressing the gene of beta-galactosidase, the control group (n = 15) received an equivalent volume of culture medium alone, and 10 sham mice had no surgery. Two weeks and 1 month after transplantation, function was again assessed echocardiographically. At baseline, fractional shortening was not significantly different between the 3 groups. It then significantly increased in cell-treated mice at 2 weeks and 1 month after transplantation (P < 0.002 and P < 0.03 versus baseline, respectively), whereas it did not change in untreated animals. Transplanted cells could not be identified by beta-galactosidase activity or presence of Y chromosome (with 1 exception). CONCLUSIONS: Cellular transplantation can improve function of globally failing hearts by a mechanism that might not necessarily involve the sustained presence of transplanted cells but rather the effects of cardioprotective factors released by them.

Advancement flaps to treat superficial wound infections after cardiac operations.

The management of superficial sternal wound infections is not well-codified. In case of large necrosis or tissue defect we use a two-stage approach, consisting of a first surgical debridement, followed a few days later by wound closure by means of two lateral advancement flaps. We have used this technique with good cosmetic results and shorter hospital stays.

[Mitral valvuloplasty for asymptomatic or pauci-symptomatic mitral insufficiency]. / Valvuloplastie mitrale pour insuffisance mitrale asymptomatique ou paucisymptomatique.

The aim of this study was to assess the results of mitral valvuloplasty for chronic asymptomatic or paucisymptomatic mitral regurgitation. Of 584 patients operated for chronic mitral regurgitation between January 1989 and December 1994, 175 were in NYHA Classes I and II and made up the study population. All had chronic grade 3 or 4/4 mitral regurgitation suitable for mitral valvuloplasty. The average follow-up was 34.3 months. Mitral valvuloplasty was performed in 174 patients, the other patient requiring mitral valve replacement. Three patients died (1.7%) and the actuarial 5 year survival was 98.2 +/- 1.0%. The probability of absence of reoperation and absence of thrombo-embolic complications at 5 years were 97 +/- 0.8% and 96.3 +/- 1.7% respectively. The residual regurgitation at Doppler echocardiography was minimal or absent in 94% of patients at the last follow-up control. The mean end-systolic and end-diastolic left ventricular dimensions decreased from 40.0 +/- 6.8 mm and 64.8 +/- 7.0 mm before surgery to 34.6 +/- 6.7 mm (p < 0.001) and 52.7 +/- 7.4 mm (p < 0.001) at the last control. The authors conclude that conservative mitral valve surgery for NYHA Classes I and II patients with chronic mitral regurgitation is feasible with a low risk and is associated with a significant reduction in ventricular volumes and stability of valvular continence at medium-term. When performed by teams trained in techniques of mitral valvuloplasty, these results suggest that surgery should be performed early.

Clinical evaluation of the Physio annuloplasty ring.

STUDY OBJECTIVES: Prospective evaluation of a selectively flexible annuloplasty ring was undertaken to assess its safety and efficacy. PATIENTS: Between December 1992 and November 1996, 190 patients with mitral regurgitation underwent mitral valve repair using an annuloplasty ring (Carpentier-Edwards Physio; Baxter-Edwards CVS Laboratories; Irvine, Calif). Ninety-four were in New York Heart Association class I or II. Etiology was degenerative in 74% of the patients. RESULTS: Four patients died early for a hospital mortality of 2.1%, and one late death occurred. Two patients with systolic anterior motion required early valve replacement. Two transient episodes of hemiparesis occurred during the first postoperative month. There were no late thromboembolic complications, no late reoperation, and no endocarditis. Mean follow up of 23+/-13 months was complete in 99% of the patients. Seventy-seven patients (40.5%) have had Doppler echocardiography > 1 year after surgery: 61 (80%) of them have no residual regurgitation, 15 have grade 1+/4+ mitral regurgitation, while 1 has grade 2+/4+ insufficiency. Left ventricular end-diastolic volume index (mL/lm2) decreased from 107.4+/-35.5 preoperatively to 74.2+/-24.4 at last control (p<0.001). CONCLUSION: The physio annuloplasty ring provided reliable and stable results at medium-term follow-up with a very low incidence of valve-related complications.

Continuous warm blood cardioplegia pitfalls and solutions.

BACKGROUND: Continuous warm blood cardioplegia offers superior preservation in both routine and complicated cardiac cases. Management of continuous perfusion is an important task during each case. METHODS: The authors have developed several specific techniques to ensure stable catheter insertion and placement for continuous coronary sinus or antegrade ostial perfusion. RESULTS: Over 3,800 patients have been operated on with continuous warm blood cardioplegia using catheter techniques as described in this article. The overall 30-day mortality was 3.9%. CONCLUSIONS: Safe application of continuous warm blood cardioplegia has many advantages over prior cold techniques, but surgeons must know certain technical modifications to be able to universally apply continuous techniques safely.

Does transplantation of cardiomyocytes improve function of infarcted myocardium?

BACKGROUND: The feasibility of successfully grafting fetal cardiomyocytes into infarcted myocardium is now established, but the functional effects of such a procedure still remain elusive. METHODS AND RESULTS: Twenty-three female rats underwent 45 minutes of coronary artery occlusion followed by 30 minutes of reperfusion. At this time point, 13 animals received intramyocardial injections of fetal cardiomyocytes (6 x 10(6) cells in 60 microL of culture medium) in the once ischemic area, whereas the 10 control rats were injected with an equivalent volume of culture medium alone. One month after transplantation, left ventricular function was assessed by two-dimensional (2D) and Doppler echocardiography using a short focus 10- to 13-MHz transducer, and a numeric acquisition of 2D images up to 65.5 frames/second. Explanted hearts were then processed for histological assessment of infarct size. The presence of male donor cells into female recipient myocardium was detected by fluorescent in situ hybridization using a deoxyribonucleic acid probe specific for Y chromosome. Cellular transplantation resulted in an improved left ventricular function, as demonstrated by significantly higher 2D ejection fraction and cardiac output (P<.02 and P<.02 versus control hearts, respectively). The histological sections of female recipient myocardium were Y-positive in all but one heart, thereby suggesting that this improvement of function was causally related to the presence of transplanted cells. CONCLUSIONS: These data suggest that transplantation of cardiomyocytes might be an effective means of improving function of infarcted myocardium.

[Initial results of mitral valvuloplasty using the Physio-Carpentier-Edwards ring]. / Résultats préliminaires de la plastie mitrale avec l'anneau physio-carpentier-edwards.

The Physio-Carpentier-Edwards ring is a new prosthetic ring developed to allow mitral annuloplasty associating remodelling and flexibility of the native mitral annulus. The object of this study was to assess the feasibility and reliability of mitral valvuloplasty with the Physio ring. Between December 1992 and October 1995, 100 patients with an average age of 56.8 years suffering from mitral insufficiency underwent mitral valvuloplasty with a Physio ring. The mitral insufficiency was degenerative in 94% of cases. The degree of regurgitation was scored 3+ or 4/+4/+ in 94 patients. Mitral valve prolapse was observed in 83 patients. Mitral reconstruction was undertaken using Carpentier's techniques. One patient died in the immediate postoperative period. Two patients were reoperated for valve replacement because of systolic anterior motion (SAM). One patient had SAM which regressed with medical treatment. There were no deaths after the hospital period. There were no late reoperations of thrombo-embolic complications. The average follow-up period was 19 +/- 8 months; 77 patients were followed up for over 1 year and all underwent control Doppler echocardiography. Sixty-one patients had no residual mitral insufficiency: 15 patients had grade 1/4 regurgitation and one patient had grade 2/4 regurgitation. The average mitral valve surface area was 2.8 +/- 0.3 cm2. The average left ventricular end diastolic volume decreased from 186 +/- 59 cm3 before surgery to 129 +/- 37 cm3 at the last control (p < 0.001). The authors conclude that the Physio ring enables reliable and effective mitral valvuloplasty with excellent short term results. The benefits of the flexibility of the Physio ring remain to be evaluated by a randomised trial.

Surgical treatment of asymptomatic and mildly symptomatic mitral regurgitation.

OBJECTIVE: The purpose of this study was to review the risk-benefit ratio of mitral valve repair in patients with severe mitral regurgitation and no or mild symptoms. METHODS: From January 1989 to December 1994, 584 patients were operated on for mitral regurgitation. Of these, 175 patients were in New York Heart Association class I or II with grade 3 to 4 isolated chronic mitral regurgitation. They comprise our study population. Mean age was 51.3 +/- 14.3 years. Principal causes of mitral regurgitation were degenerative in 128 (73%) and rheumatic in 26 patients (15%). Leaflet prolapse was the mechanism responsible for regurgitation in 152 patients (86%). Mitral valve repair was performed in 174 patients, and one patient required initial valve replacement. Mean follow-up was 34.3 +/- 18.8 months. RESULTS: Three patients died, for an overall mortality of 1.7%. Five patients were reoperated on, for an actuarial freedom from reoperation of 97.0% +/- 0.8% at 5 years. Actuarial freedom from thromboembolism and endocarditis was 96.3% +/- 1.7% and 99.4% +/- 0.6%, respectively, for an event-free survival of 91.0% +/- 2.0% at 5 years. Left atrial diameter decreased from 54.3 +/- 11.6 mm to 43.6 +/- 10.5 mm (p < 0.001). Left ventricular end-systolic and end-diastolic diameters decreased from 40.0 +/- 6.8 mm and 64.8 +/- 7.0 mm to 34.6 +/- 6.7 mm (p < 0.001) and 52.7 +/- 7.4 mm (p < 0.001), respectively. Mean residual mitral regurgitation was 0.44 +/- 0.6. CONCLUSION: Mitral valve repair for chronic mitral regurgitation in patients having mild or no symptoms was performed with low mortality and morbidity, good valve function, and preserved late left ventricular performance. Early repair may be advocated on the basis of severity of regurgitation and valve repairability, regardless of symptoms.