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J Thorac Cardiovasc Surg 2002;123:583-584
© 2002 The American Association for Thoracic Surgery

Letters to the Editor

Reply

Department of Cardiovascular Surgery
Broussais Hospital
96 rue Didot
Paris 75014, France

Reply to the Editor:

The prevalence of severe heart failure and the clear clinical limitations of conventional interventions have encouraged the development of new methods based on regenerating the pool of myocardial contractile cells. This approach is supported by recent advances in cellular and molecular biology. Historically, tissue regeneration techniques based in cell transplantation technology had been used for the treatment of hemopathies, diabetes mellitus (Langerhans islets), neurology (Huntington and Parkinson diseases, spinal cord regeneration), hepatology (implantation of hepatocytes as a bridge to liver transplantation), myology (transplantation of myoblasts in Duchenne dystrophy), and orthopedics (implantation of chondrocytes in knee articulations).

Left ventricular remodeling is a major cause of progressive heart failure and death after myocardial infarction. Although neoangiogenesis within the infarcted tissue is an integral component of the remodeling process, the capillary network is unable to support the greater demands of the hypertrophied myocardium, resulting in progressive loss of viable tissue, infarct extension, and fibrous replacement. Intramyocardial cell grafting aims at limiting the consequences of the loss of contractile function of damaged ventricles. Cellular cardiomyoplasty is particularly attractive for a number of reasons, foremost among which is the potential for replacement or infiltration of myocardial scar with a variety of cell types (skeletal myoblasts, embryonic or fetal cardiomyocytes, smooth muscle cells, bone marrow stromal cells). Once established within the heart, transplanted cells may alter the regional myocardium through induction of angiogenesis, formation of syncytial relationships with viable native myocardium, and the restoration of function to terminally injured and dysfunctional myocardium. The mechanisms of beneficial effects of cellular cardiomyoplasty appear to be as follows: direct systolic effect, improvement of left ventricular wall compliance (the diastolic pressure-strain relationship), angiogenesis, and delivery of paracrine factors. Cells transplanted into myocardium first affect diastolic dysfunction, and later, when sufficient organization of the grafts occurs, systolic performance improves. Our experimental results and the international literature support this concept.

It is true that myocardial infarction also destroys the collagen matrix. However, during the "in vitro" process of myoblast expansion, around 20% to 30% of fibroblasts remain in mixture with the muscle cells. After implantation, these fibroblasts would indeed contribute to the regeneration of the myocardial collagen matrix. On the other hand, putting a Marlex mesh onto myocardial infarctions as proposed by Gorman and Gorman (reference 5 in their letter) is not a physiologic way to mend systolic and diastolic myocardial dysfunction. This classic and mechanical approach will only increase fibrosis, remodeling, and ventricular dysfunction. This is not the future of cardiac surgery; this is the past. Most will agree that such a repair technique has strong limitations and can only be successfully applied to a small number of patients.

Skeletal myoblasts (satellite cells) are stem cells located at the basal lamina of skeletal muscle fibers. They are highly resistant to ischemia and multiply after injury, presenting a high power for multiple mitosis. At terminal differentiation, skeletal muscle myoblasts fuse to form multinucleated myotubes. This fusion process is crucial for the development of skeletal muscles and, in the adult, for muscle repair and hypertrophy. Fusion is strictly Ca²⁺-dependent. After implantation in a postinfarction lesion, myoblasts merge into myotubes within the scar, decreasing fibrosis. Recent experimental and clinical studies demonstrated recovery of contraction of previously akinetic scars and assessment of a new metabolic activity after cell therapy. Another potential indication for cellular cardiomyoplasty would be idiopathic dilated cardiomyopathies. The survival of implanted cells should be more important in these cases because of a better irrigation of the host pathologic myocardium. ¹

The encouraging results of experimental studies have opened the way to the clinical application of cellular cardiomyoplasty in patients with akinetic and nonviable postinfarction scar and low ejection fraction. Cultured autologous skeletal myoblasts do not raise immunologic, ethical, tumorigenesis, or donor availability problems. In our opinion, the development of cell therapy for heart failure is progressing according to a rigorous scientific methodology, from observation to experimentation to a careful evaluation of preliminary clinical results.

Future perspectives are very encouraging, based on the potential to perform cellular cardiomyoplasty associating myoblasts with stem cells from bone marrow (that can multiply, migrate into the scar, and transform into heart muscle cells, developing intercellular connections). ^2,3 Neovascularization of ischemic myocardium could also be obtained by intramyocardial cell grafting of human bone marrow–derived angioblasts. This neoangiogenesis resulted in decreased apoptosis of hypertrophied myocytes in the peri-infarct region, long-term salvage and survival of viable myocardium, reduction in collagen deposition, and sustained improvement in ventricular function. ⁴

New technologies for cell implantation, derived from interventional cardiology procedures, are emerging. Catheter-based myocardial gene transfer for therapeutic angiogenesis using left ventricular electromechanical mapping has been performed in a randomized clinical trial with positive results. ⁵ This percutaneous endoventricular technology is now tested in our institution for intramyocardial cell delivery. In this way, cellular cardiomyoplasty will be in the armamentarium of surgeons and interventional cardiologists. New generations of surgeons, believing in a more scientific and academic field of surgery, are now involved in the development of new surgical techniques associating cellular and molecular biology with surgery. The 21st century needs innovative spirits. If not, cardiac surgeons will lose the opportunity to be associated with novel scientific developments.

In summary, cell transplantation already offers the promise of restoring regional ventricular function, limiting remodeling, and stimulating angiogenesis for patients who have had an extensive myocardial infarction and probably for patients with dilated cardiomyopathy. Clinical feasibility of this new surgical technique has already become apparent (unpublished data).

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References

1. Yoo KJ, Li RK, Weisel RD, Mickle DA, Jia ZQ, Kim EJ, et al. Heart cell transplantation improves heart function in dilated cardiomyopathic hamsters. Circulation. 2000;102(Suppl):III-204-9.
   
2. Wang JS, Shum-Tim D, Galipeau J, Chedrawy E, Eliopoulos N, Chiu RC. Marrow stromal cells for cellular cardiomyoplasty: feasibility and potential clinical advantages. J Thorac Cardiovasc Surg. 2000;120:999-1005.[Abstract/Free Full Text]
   
3. Tomita S, Li RK, Weisel RD, Mickle DA, Kim EJ, Sakai T, et al. Autologous transplantation of bone marrow cells improves damaged heart function. Circulation. 1999;100(Suppl):II-247-56.
   
4. Kocher AA, Schuster MD, Szabolcs MJ, Takuma S, Burkhoff D, Wang J, et al. Neovascularization of ischemic myocardium by human bone-marrow–1–derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med. 2001;7:430-6.[Medline]
   
5. Vale PR, Losordo DW, Milliken CE, McDonald MC, Gravelin LM, Curry CM, et al. Randomized, single blind, placebo-controlled pilot study of catheter-based myocardial gene transfer for therapeutic angiogenesis using left ventricular electromechanical mapping in patients with chronic myocardial ischemia. Circulation. 2001;103:2138-43.[Abstract/Free Full Text]
   

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