Biomedical subjects

Jochen Müller-Ehmsen

Publications and source records attributed to Jochen Müller-Ehmsen.

23 records · Page 2Linked to original sources

PubMed2003

[Therapeutic perspectives in heart failure]].

Many different diseases may lead to heart failure. Nevertheless, the symptoms and pathophysiological changes in heart failure are uniform as are the basic principles of treatment. Although significant progress has been achieved in understanding the biology of heart failure and the therapeutic options, the quality of life of heart failure patients and their survival are often poor. Since cardiac transplantation as a final therapeutic option is limited by the availability of donor organs, new strategies and technologies need to be explored to treat the failing heart effectively. Approaches to improve the medical therapy of heart failure mainly focus on strategies to escape the vicious circle of decreased contractility and neurohumoral activation. Substances with promising experimental and clinical results include neutral endopeptidase inhibitors, endothelin antagonists or cytokine inhibitors, e.g. TNF antagonists. Mechanical and electrical devices are under development such as left ventricular assist devices (LVADs), biventricular pacemakers and artificial hearts, which may become valuable alternative therapies. Gene therapy approaches aim to improve the vascularization of the heart, the Ca-homeostasis of the myocytes or the survival of cardiac cells in disease. Finally, cellular cardiomyoplasty is a relatively novel approach to replace or support the cardiomyocytes of the diseased heart by implanting new ones. Which cell type under which conditions will turn out to be the most suitable is still unknown and subject to debate. Ongoing clinical studies will only help to demonstrate the safety and feasibility of this technique but not determine its long-term efficacy. It is highly desirable that one of these new therapeutic strategies or a combination of them will have a significant impact on the future management of heart failure. Currently, our main clinical focus must be to treat as many patients as possible with drugs that are known to improve symptoms and survival, like ACE inhibitors, beta-blockers, cardiac glycosides, diuretics and spironolactone.

Heart Failure↗

PubMed2002

Rebuilding a damaged heart: long-term survival of transplanted neonatal rat cardiomyocytes after myocardial infarction and effect on cardiac function.

BACKGROUND: The long-term effects of cardiac cell transplantation on cardiac function are unknown. Therefore, we tested the survival and functional impact of rat neonatal cardiac myocytes up to 6 months after transplantation into infarcted hearts. METHODS AND RESULTS: Cardiomyocytes from male neonatal Fischer 344 rats (1 to 2 days, 3 to 5x10(6)) or medium was injected into the infarcts of adult syngeneic female animals 1 week after left coronary artery ligation. Six months later, implanted cardiomyocytes were still present by quantitative TaqMan polymerase chain reaction and histology. In all treated hearts, discrete lumps of cells were present within the infarct scar, which was not observed in media-injected hearts typified by a transmural infarct scar. Infarct thickness was greater in treated animals versus control animals (909+/-97 versus 619+/-43 microm, P<0.02), whereas infarct size and left ventricular volumes were similar. By biplane angiography, left ventricular ejection fractions at 6 months were greater (0.36+/-0.03 versus 0.25+/-0.02, P<0.01) and significantly less infarct zone dyskinesis was seen (0.30+/-0.08 versus 0.55+/-0.07, P=0.035, lateral projection) in treated animals versus control animals. CONCLUSIONS: Grafted neonatal cardiomyocytes were present in infarcts 6 months after transplantation; they thickened the wall of the left ventricle and were associated with enhanced ejection fraction and reduced paradoxical systolic bulging of the infarct. Therefore, neonatal cardiac cell transplants exhibit long-term survival in a myocardial infarct model and contribute to long-term improved cardiac function. These results suggest that a damaged heart can be rebuilt.

Animals↗

PubMed2002

Survival and development of neonatal rat cardiomyocytes transplanted into adult myocardium.

Transplantation of neonatal cardiomyocytes is a novel approach for the treatment of heart failure and myocardial infarction, but quantitative information on long-term cell survival and development is limited. Male donor cardiomyocytes were isolated from neonatal Fischer 344 rats (1-2 days), purified, and injected into the left ventricular wall of female syngeneic adult rats. One hour to 12 weeks later, genomic DNA was isolated from recipient hearts. The amount of male DNA per sample was determined by quantitative real-time TaqMan PCR of the male-specific Sry gene. Transplanted cell survival was 57 +/- 9% at 0-1 h, 24 +/- 6% at 24 h, 28 +/- 11% at 7 days, 27 +/- 3% at 14 days, 23 +/- 8% at 4 weeks and 15 +/- 3% at 12 weeks. The caspase inhibitor AcYVADcmk failed to improve transplanted cell survival at 24 h, suggesting that apoptosis did not play a major role in cell loss. Histology revealed that transplanted cells became more elongated over time, developed cross-striations, and that their nuclei increased in size. However, at 12 weeks, transplanted cells and their nuclei were still smaller than those of host myocardium. We established a quantitative survival profile for neonatal cardiomyocytes transplanted into normal adult myocardium. There was significant loss of cells within 24 h, but 15% of transplanted cells survived 12 weeks. Those cells that did survive underwent differentiation and developed visible sarcomeres, suggesting a potential contribution toward ventricular function.

Age Factors↗

PubMed2002

Sodium pump isoform expression in heart failure: implication for treatment.

In the human heart several isoforms of the sodium pump (Na,K-ATPase, the cardiac glycoside receptor) are expressed (alpha1beta1, alpha2beta1, and alpha3beta1). Their expression is regulated in a highly specific manner, so that there are region specific differences in the expression pattern. The isoform expression pattern is also known to be organ specific in many cases (e.g., kidney, skeletal muscle), suggesting isoform specific functions. In human heart, we have demonstrated that the isoform composition of the left ventricle is altered during heart failure in man and postulate a role of Na,K-ATPase isoforms in the compensatory mechanisms of this disease. When Na,K-ATPase isoforms were expressed separately in yeast cells, we found that the affinities of K and ouabain were lower for alpha2beta1 than for alpha1beta1 or alpha3beta1. In addition, alpha3beta1 had a lower turnover rate than alpha1beta1. Similar results were found in a study, where Na,K-ATPase isoforms were expressed in Xenopus oocytes. Thus, there is evidence for specific biochemical properties of the Na,K-ATPase isoforms. In heterozygous knock-out mice, in which either alpha1 or alpha2 isoforms were selectively reduced, only the lower expression and activity of alpha2 led to a hypercontractile response as seen with cardiac glycosides. Therefore in mice, the effect of cardiac glycosides seems to be mediated specifically by alpha2. In summary, there is a tissue-specific regulation of Na,K-ATPase isoform expression in humans, as well as a highly specific regulation of the isoforms during disease, e.g., heart failure. There is also evidence for specific biochemical properties of different isoforms of the human Na,K-ATPase as well as for a specific functional impact on cardiac contractility in mice. Therefore, the isoforms of human Na,K-ATPase are not exchangeable and targeting specific isoforms by drugs or gene therapy may promise therapeutic benefit in diseases like heart failure or atrial fibrillation.

Animals↗

PubMedDate not supplied

Cellular cardiomyoplasty--a novel approach to treat heart disease.

Cell transplantation is a novel experimental strategy to treat heart disease, such as myocardial infarction and heart failure. Its beneficial effects may include active contribution of transplanted cells to contractile function, passive improvement of the mechanics of the heart, induction of neoangiogenesis or other indirect influences on the biology of the heart. Several cell types have been used for cardiac cell transplantation including cardiac cells from fetal or newborn animals and cardiac muscle cell lines, skeletal myoblasts and skeletal muscle cell lines, smooth muscle cells, and a variety of stem cells, either adult or embryonic. With many of these cells, encouraging results in experimental ischemic and nonischemic heart disease have been obtained including successful cell survival after transplantation, integration into the host myocardium, and improvement of the function of diseased hearts. Most of these studies found cardiac contractility improved and some found enhanced angiogenesis. However, the mechanisms of these effects remain obscure, and the impact of dosage (cell number) on functional response is completely unclear. In addition, not enough comparative studies were performed to allow preference of one cell type over the other. The current data suggest that whatever cell species is used, the best survival and integration may be accomplished if immature and undifferentiated cells are used. Any kind of stem cell has obvious advantages in terms of endless reproducibility and plasticity, but the complete differentiation and maturation into cardiac myocytes still needs to be proven. At present several clinical studies are exploring the therapeutic benefits of cellular cardiomyoplasty in patients with ischemic heart disease, but it has to be noted that there are many issues that need to be addressed before this strategy will add to the therapeutic options for patients with heart disease.

Animals↗