Showing papers by "Kishore B.S. Pasumarthi published in 2008"

Cardiomyocyte cell cycle activation improves cardiac function after myocardial infarction

Abstract: Aims Cardiomyocyte loss is a major contributor to the decreased cardiac function observed in diseased hearts. Previous studies have shown that cardiomyocyte-restricted cyclin D2 expression resulted in sustained cell cycle activity following myocardial injury in transgenic (MHC-cycD2) mice. Here, we investigated the effects of this cell cycle activation on cardiac function following myocardial infarction (MI). Methods and results MI was induced in transgenic and non-transgenic mice by left coronary artery occlusion. At 7, 60, and 180 days after MI, left ventricular pressure–volume measurements were recorded and histological analysis was performed. MI had a similar adverse effect on cardiac function in transgenic and non-transgenic mice at 7 days post-injury. No improvement in cardiac function was observed in non-transgenic mice at 60 and 180 days post-MI. In contrast, the transgenic animals exhibited a progressive and marked increase in cardiac function at subsequent time points. Improved cardiac function in the transgenic mice at 60 and 180 days post-MI correlated positively with the presence of newly formed myocardial tissue which was not apparent at 7 days post-MI. Intracellular calcium transient imaging indicated that cardiomyocytes present in the newly formed myocardium participated in a functional syncytium with the remote myocardium. Conclusion These findings indicate that cardiomyocyte cell cycle activation leads to improvement of cardiac function and morphology following MI and may represent an important clinical strategy to promote myocardial regeneration.

Embryonic stem cell transplantation: promise and progress in the treatment of heart disease.

Abstract: Cardiovascular diseases remain the leading cause of death worldwide, and the burden is equally shared between men and women around the globe. Cardiomyocytes that die in response to disease processes or aging are replaced by scar tissue instead of new muscle cells. Although recent reports suggest an intrinsic capacity for the mammalian myocardium to regenerate via endogenous stem/progenitor cells, the magnitude of such a response appears to be minimal and has yet to be realized fully in cardiovascular patients. Despite the advances in pharmacotherapy and new biomedical technologies, the prognosis for patients diagnosed with end-stage heart failure appears to be grave. While heart transplantation is a viable option, this life-saving intervention suffers from an acute shortage of cardiac organ donors. In view of these existing issues, donor cell transplantation is emerging as a promising strategy to regenerate diseased myocardium. Studies from multiple laboratories have shown that transplantation of donor cells (e.g. fetal cardiomyocytes, skeletal myoblasts, smooth muscle cells, and adult stem cells) can improve the function of diseased hearts over a short period of time (1-4 weeks). While long-term follow-up studies are warranted, it is generally perceived that the beneficial effects of transplanted cells are mainly due to increased angiogenesis or favorable scar remodeling in the engrafted myocardium. Although skeletal myoblasts and bone marrow stem cells hold the highest potential for implementation of autologous therapies, initial results from phase I trials are not promising. In contrast, transplantation of fetal cardiomyocytes has been shown to confer protection against the induction of ventricular tachycardia in experimental myocardial injury models. Furthermore, results from multiple laboratories suggest that fetal cardiomyocytes can couple functionally with host myocytes, stimulate formation of new blood vessels, and improve myocardial function. While it is neither practical nor ethical to test the potential of fetal cardiomyocytes in clinical trials, embryonic stem (ES) cells serve as a novel source for generation of unlimited quantities of cardiomyocytes for myocardial repair. The initial success in the application of ES cells to partially repair and improve myocardial function in experimental models of heart disease has been quite promising. However, multiple hurdles need to be crossed before the potential benefits of ES cells can be translated to the clinic. In this review, we summarize the current knowledge of cardiomyocyte derivation and enrichment from ES-cell cultures and provide a brief survey of factors increasing cardiomyogenic induction in both mouse and human ES cultures. Subsequently, we summarize the current state of research using mouse and human ES cells for the treatment of heart disease in various experimental models. Furthermore, we discuss the challenges that need to be overcome prior to the successful clinical utilization of ES-derived cardiomyocytes for the treatment of end-stage heart disease. While we are optimistic that the researchers in this field will sail across the hurdles, we also suggest that a more cautious approach to the validation of ES cardiomyocytes in experimental models would certainly prevent future disappointments, as seen with skeletal myoblast studies.

Quantification of cardiac fibrosis by colour-subtractive computer-assisted image analysis.

Abstract: SUMMARY 1 Quantification of fibrosis is a key parameter in the assessment of the severity of cardiovascular disease and efficacy of future candidate therapies. Computer-assisted methods are frequently used to assess cardiac fibrosis in several experimental models. A brief survey indicated that there is a clear dearth of literature outlining detailed methodologies for computer-based assessment of cardiac fibrosis. The purpose of the present study was to provide a reliable method for a systematic assessment of cardiac fibrosis. 2 We induced cardiac fibrosis by isoproterenol (ISO) infusion in adult CD1 male mice and quantified fibrosis using a recently developed colour-subtractive computer-assisted image analysis (CS-CAIA) technique. Here, we provided a detailed description of our methodology to facilitate its wider use by other researchers. 3 We showed that the severity of ISO-induced cardiac fibrosis was similar in the apex, mid-ventricular ring and base of the adult CD1 mouse heart. In contrast with other species, such as rats and dogs, we found that uniform expression of b1-adrenoceptors between different regions in CD1 mouse hearts correlated well with uniform induction of cardiac fibrosis. 4 A previous study found a negative correlation between levels of myocardial fibrosis and the degree of cardiac hypertrophy in ISO-treated Wistar rats. In contrast, we found a similar degree of cardiac fibrosis in our ISO-treated CD1 mice. 5 Our results suggest that CD1 mice are an ideal model system to study catecholamine-induced cardiac remodelling, as well as to screen candidate antifibrotic agents for future therapies.