Ted Diethrich explained why he had been invited to speak at Cardiostim, the meeting on electrophysiology and cardiac rhythm disorders, by saying that he was there because cardiovascular surgeons used to make a living by putting in pacemakers. However, in truth, it was because this year saw the start of Endostim at Cardiostim. This meeting was organised by Jacques Busquet and Albert Claude Benhamou as part of the 13th International Cardiostim Congress. Endostim covered a number of hot topics and controversial debates including angiogenesis.
New revascularisation techniques
Despite decades of intensive research, cardiovascular disease remains the number one cause of morbidity and mortality in most of the Western world. Cardiomyocytes, the cells responsible for cardiac contractility, are uniquely sensitive to the reductions in blood flow and oxygen delivery that accompany atherosclerosis. However, unlike skeletal muscle, cardiac muscle has no inherent mechanism for self-renewal. Lost cardiomyocytes are replaced by scar, and depending upon the extent of myocardial damage, heart failure can ensue. A significant portion of the deaths attributed to heart disease could be prevented if an adequate means of cardiac muscle repair could be developed.
The Endostim session ‘Stem Cells, Myoblasts and Clinical Applications’was opened by Brad Martin from Baltimore speaking on the potential of human mesenchymal stem cells (hMSCs).
hMSCs have the potential to differentiate into a muscle phenotype and to regenerate muscle tissue in the failing heart. Culture conditions to induce myogenic differentiation of hMSCs have been developed by Osiris Therapeutics and researchers have also implanted hMSCs into the hearts of animal models.
When the human mesenchymal stem cells are injected into a healthy mouse heart, the injected cells become striated and active. However, in long-injured myocardium the cells are not driven to myocardial lineage. Ten minutes after infarction, injected human mesenchymal stem cells still differentiate into heart cells, but if injected two weeks after infarction the cells migrate to the bone marrow. In an open-heart procedure, researchers have implanted hMSCs by a needle injection directly into the ventricle wall of athymic rats. This verified that hMSCs engraft in the heart at various times following introduction, and demonstrated the expression of muscle specific proteins. Studies in the large animal model (porcine) have likewise demonstrated the retention of porcine hMSCs after implantation and early data are suggestive of a positive impact on maintenance of myocardial wall thickness and contractility compared to control infarcts. Clinical trials for injection seven days after MI are planned.
Doris Taylor of Duke University then discussed which cells should be used for cardiac repair. Skeletal myoblasts and bone marrow stroma cells (mesenchymal stem cells), both survive in infarcted tissue. So far other cell types have not been shown to survive, such as foetal cardiomyocytes (which in any case cannot be obtained in sufficient number for use in a clinical setting), haematopoietic stem cells and embryonic stem cells.
Skeletal myoblasts are precursor cells of human muscle tissue. They normally lie in a quiescent state under the basal membrane of muscular fibres. In response to injury, skeletal myoblasts have the potential to re-enter the cell cycle, divide and differentiate into functional muscle. These cells theoretically have a better chance of cell engraftment and survival in infracted regions of the heart, because normally capillary density in skeletal muscle is similar to that of infracted myocardium and skeletal myoblasts are relatively resistant to ischaemia.
With myoblasts there is already 10 years worth of preclinical experience, but still problems are being encountered. By using the most immature stem cells possible the maximum lineage possibilities are available.
Taylor explained that it is an “exciting time, and that there is “a lot of enthusiasm, but we need to zero in on the science.
As well as the question of which cells to deliver to the heart there also remains the question: Where is the best place to deliver them in the region of infarction or on the border?
The great debates continue
A series of controversial debates helped to define the certainties and uncertainties in endoluminal therapies. One of the debates focused on renal artery stenosis. The topic was whether renal artery stenosis should be treated with angioplasty and stent regardless of symptoms or hypertension. Andr© Nevelsteen questioned whether you should intervene if the renal artery stenosis was less than 80% and asymptomatic.
The next topic was whether “femoral and popliteal occlusive disease is best managed with endoluminal therapies.”Marc van Sambeek presented the options that include brachytherapy, drug-eluting stents, subintimal angioplasty and endovascular grafting. In the discussion, Benhamou asked why the use of subintimal angioplasty is restricted to a few centres. Van Sambeek answered that he did not know as the technique has excellent results and is cost effective as it uses just a guidewire and a small balloon: “When Amman Bolia does it in live case, it does not seem difficult but when I tried it, it did not work so well.”Frank Veith commented that it is a worthwhile procedure and his centre has a modest experience with short lesions and the patency rates at two years are 60-70%. However, the technique is not promoted by industry as no device is involved: “Industry supports things that make money.
Air traffic control strikes across Europe affected attendance and many faculty members were unable to travel to the meeting. However, the meeting was a small start and the organisers hope for a bigger event inside what is already a large meeting attracting more than 5,000 cardiologists.