Today the pharmacological possibilities of treating cancer are expanding and as a result, life expectancy is increasing against the background of chemotherapy and supportive treatment. In the conditions of successful antitumor treatment, complications associated with its toxic effect on healthy tissues and organs began to come to the fore. Anthracycline cardiomyopathy was the first serious cardiovascular complication to draw the attention of oncologists and cardiologists around the world. Anthracycline drugs such as doxorubicin, epirubicin, idarubicin are still widely used in oncological practice to treat a wide range of solid and hematological malignancies. Doxorubicin-induced cardiomyopathy is closely associated with an increase in oxidative stress, as evidenced by reactive oxygen species (ROS) nduced damage such as lipid peroxidation, and decreased levels of antioxidants. Myofibrillar destruction and dysregulation of intracellular calcium are also important mechanisms, usually associated with doxorubicin-induced cardiotoxicity. Despite the abundance of data on various mechanisms involved in the implementation of doxorubicin-induced cardiotoxicity, a final understanding of the mechanism of the development of doxorubicin cardiomyopathy has not yet been formed. It poses the most significant challenges to the development of new methods of prevention and treatment, as well as to the unambiguous choice of a specific treatment regimen using the existing pharmacological tools. In order to resolve these issues new models that could reflect the development of the chemotherapy drugs effects are needed. In this review we have summarized and analyzed information on the main existing models of doxorubicin cardiomyopathy using small laboratory animals. In addition, this paper discusses further areas of research devoted to the development and validation of new improved models of doxorubicin cardiomyopathy suitable both for studying the mechanisms of its implementation and for the preclinical drugs effectiveness assessment.
Use of mesenchymal stem cell (MSC) transplantation after myocardial infarction (MI) has been found to have infarct-limiting effects in numerous experimental and clinical studies. However, recent meta-analyses of randomized clinical trials on MSC-based MI therapy have highlighted the need for improving its efficacy. There are two principal approaches for increasing therapeutic effect of MSCs: (i) preventing massive MSC death in ischaemic tissue and (ii) increasing production of cardioreparative growth factors and cytokines with transplanted MSCs. In this review, we aim to integrate our current understanding of genetic approaches that are used for modification of MSCs to enable their improved survival, engraftment, integration, proliferation and differentiation in the ischaemic heart. Genetic modification of MSCs resulting in increased secretion of paracrine factors has also been discussed. In addition, data on MSC preconditioning with physical, chemical and pharmacological factors prior to transplantation are summarized. MSC seeding on three-dimensional polymeric scaffolds facilitates formation of both intercellular connections and contacts between cells and the extracellular matrix, thereby enhancing cell viability and function. Use of genetic and non-genetic approaches to modify MSC function holds great promise for regenerative therapy of myocardial ischaemic injury.
The methods of donor heart preservation are aimed at minimizing graft dysfunction caused by ischaemia-reperfusion injury (IRI) which inevitably occurs during the ex vivo transport interval. At present, the standard technique of heart preservation is cardiac arrest followed by static cold storage in a crystalloid heart preservation solution (HPS). This technique ensures an acceptable level of heart protection against IRI for <6 h. In clinical trials, comparable levels of myocardial protection against IRI were provided by various HPSs. The growing shortage of donor hearts is one of the major factors stimulating the development of new techniques of heart preservation. Here, we summarize new HPS formulations and provide a focus for optimization of the composition of existing HPSs. Such methods of donor heart preservation as machine perfusion, preservation at sub-zero temperature and oxygen persufflation are also discussed. Furthermore, we review experimental data showing that pre- and post-conditioning of the cardiac graft can improve its function when used in combination with cold storage. The evidence on the feasibility of cardiac donation after circulatory death, as well as the techniques of heart reconditioning after a period of warm ischaemia, is presented. The implementation of new techniques of donor heart preservation may contribute to the use of hearts from extended criteria donors, thereby expanding the total donor pool.
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