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Physical Activity and Aging: A Life-Long Story


Marching Towards Regenerative Cardiac Therapy with Human Pluripotent Stem Cells

Abstract: Damage in cardiac tissues from ischemia or other pathological conditions leads to heart failure; and cell loss or dysfunction in pacemaker tissues due to congenital heart defects, aging, and acquired diseases can cause severe arrhythmias. The promise of successful therapies with stem cells to treat these conditions has remained elusive to the scientific community. However, recent advances in this field have opened new opportunities for regenerative cardiac therapy. Transplantation of cardiomyocytes derived from human pluripotent stem cells has the potential to alleviate heart disease. Since the initial derivation of human embryonic stem cells, significant progress has been made in the generation and characterization of enriched cardiomyocytes and the demonstration of the ability of these cardiomyocytes to survive, integrate, and function in animal models. The scope of therapeutic potential from pluripotent stem cell-derived cardiomyocytes has been further expanded with the invention of induced pluripotent stem cells, which can be induced to generate functional cardiomyocytes for regenerative cardiac therapy in a patient specific manner. The reprogramming technology has also inspired the recent discovery of direct conversion of fibroblasts into cardiomyocyte-like cells, which may allow endogenous cardiac repair. Regenerative cardiac therapy with human pluripotent stem cells is now moving closer to clinic testing. ... Read more

Exercise Testing in the 21st Century: from an "Old" Diagnostic to a Novel Health Risk Assessment Tool

Abstract: Exercise testing was developed as a diagnostic tool in the first half of the 20th century when people, mostly men, paid the huge cost of coronary artery disease (CAD). Both the changing nature of CAD, which affects both men and women, and the aging of the population led to redefining the use of exercise testing. This test is now mainly used for evaluating overall prognosis. In parallel, new measurement such as exercise capacity and several components of the physiological reserve enrich the information which can be obtained from exercise testing. Therefore, exercise testing has become the major dynamic tool for predicting premature mortality far beyond traditional and disease specific risk markers. The present article reviews the main pieces of information which led to these changes and summarizes the elements which give exercise testing its utility. ... Read more

Genetics and Genetic Testing of Dilated Cardiomyopathy: a New Perspective

Abstract: The completion of the Human Genome Project was a landmark achievement, but as clinical genetic testing becomes more mainstream, the extent of remarkable genetic variation is increasingly being appreciated. Newer DNA sequencing technology can now complete the sequencing of an entire human genome several times over in a matter of days, but this will undoubtedly add new challenges to the difficulty of distinguishing true pathogenic variants from benign variants in diagnostic genetics and in the research setting. The recent discovery of the role of titin gene (TTN) mutations in dilated cardiomyopathy (DCM) will make genetic testing in this disease more efficient. Furthermore, better understanding of genotype-phenotype associations will assist clinicians in identifying early stages of disease and providing more appropriate treatments. This high level of complexity requires an expert genetic team to offer counseling and to manage, deliver, and follow-up over time the results of genetic testing, which is particularly important for screening of family members potentially at risk. In DCM, genetic testing may be useful for the identification of non-carriers and asymptomatic carriers, as well as for prevention strategies, sport recommendations, and defibrillator implantation. It can also guide reproductive decision-making including utilization of pre-implantation genetic diagnostic strategies. ... Read more

Aerobic Exercise in the Elderly: A Key to Successful Aging

Abstract: A decline in maximal aerobic exercise capacity occurs across the adult age-span, accelerating in later years. This age-associated decline in aerobic capacity is accentuated by superimposed comorbidities common to the elderly such as cardiac, pulmonary, and peripheral artery disease. However, observational and training studies demonstrate significant improvement in peak oxygen consumption in both health and disease settings. In addition, exercise training exerts beneficial effects on blood pressure, lipids, glucose tolerance, bone density, depression, and quality of life. A major challenge to physicians and society is to increase the low participation rates of older adults in both home-based exercise and supervised exercise rehabilitation programs. ... Read more

Therapeutic Angiogenesis for Ischemic Disorders: What Is Missing for Clinical Benefits?

Abstract: The idea of promoting angiogenesis in ischemic tissues remains an undisputed therapeutic approach for the treatment of myocardium and skeletal muscles that lack sufficient blood supply. However, clinical experiences from several large trials indicated that delivery of proangiogenic factors to patients suffering from myocardial infarction and leg ischemia has not shown significant benefits. Despite continuous success in various animal disease models, why has this simple principle not shown proof of concept in patients? What has been missing in the trial deign? What are the differences between animal models and patients? What are the optimal components for promoting functional collateral networks? This brief review discusses molecular mechanisms underlying arteriogenesis and proposes novel approaches for improvement of therapeutic outcomes. ... Read more

Identification and Functions of the Plasma Membrane Receptor for Thyroid Hormone Analogues

Abstract: Integrin αvβ3 is a heterodimeric structural protein of the plasma membrane that bears a cell surface receptor for thyroid hormone. The functions of this receptor are distinct from those of the classical nuclear receptor (TR) for thyroid hormone. The integrin is expressed primarily by cancer cells, dividing endothelial and vascular smooth muscle cells, and osteoclasts. The hormone receptor on αvβ3 enables L-thyroxine (T4) and 3, 5, 3'-triiodo-L-thyronine (T3) to stimulate cancer cell proliferation and angiogenesis and to regulate the activity of certain membrane ion pumps. Bound to the receptor, the hormone ligand also stimulates protein trafficking within the cell. A deaminated derivative of T4, tetraiodothyroacetic acid (tetrac), blocks binding and actions of T4 and T3 at the receptor on αvβ3; tetrac also has anti-proliferative actions at the integrin thyroid hormone receptor beyond the effects of antagonizing actions of agonist thyroid hormone analogues at the receptor. The structure-activity relationships of hormone analogues at the receptor have been computer-modeled and indicate that the receptor includes a site that binds T3 and a site that binds both T4 and T3. Mathematical modeling of the kinetics of hormone-binding also suggests the existence of two sites. Cell proliferation is modulated from the T4/T3 site. Tetrac has been re-formulated as a nanoparticle (nanotetrac) that acts exclusively at the αvβ3 receptor and does not enter cells. Nanotetrac disrupts expression of genes in multiple cancer cell survival pathways. The tetrac formulations block human cancer cell proliferation in vitro and in tumor xenografts. Nanotetrac and tetrac inhibit the pro-angiogenic actions in vitro of vascular endothelial growth factor, basic fibroblast factor, and other growth factors. Thus, the receptor described on integrin αvβ3 for T4 and T3, the function of which is materially affected by tetrac and nanotetrac, provides insight into tumor cell biology and vascular biology. ... Read more

Genetically Modified Mesenchymal Stem Cells and Their Clinical Potential in Acute Cardiovascular Disease

Abstract: Adult mesenchymal stem cells (MSCs) are non-hematopoietic cells with multi-lineage potential to differentiate into various tissues of mesodermal origin. They can be isolated from bone marrow and other tissues and have the capacity to extensively proliferate in vitro. Moreover, MSCs have also been shown to produce anti-inflammatory molecules which can modulate humoral and cellular immune responses. Considering their regenerative potential and immunoregulatory effect, MSC therapy is a promising tool in the treatment of degenerative, inflammatory, and autoimmune diseases. However, the current understanding from results of clinical trials is that MSC-therapy is safe but its therapeutic efficiency needs to be improved. In this article we will focus on options for genetic manipulation of MSCs and on current progress in adapting genetically-modified MSCs for clinical use in acute cardiovascular disease. ... Read more

Adipose Tissue-derived Stem Cells in Stroke Treatment: From Bench to Bedside

Abstract: More recently, growing interests have brought cell therapy to the forefront of promising new approaches towards efficacious treatment for stroke. Of all cell-types, adipose tissue-derived mesenchymal stem cells (AD-MSC) are considered good candidates for stroke treatment because of their abundance and easy harvesting without invasive surgery from healthy donors. A wide number of experimental studies have demonstrated the potential of AD-MSC administration for improving functional deficits and have led to the first clinical trials in stroke patients. Trophic factor release and paracrine interactions, transdifferentiation potential, and immunomodulatory effects have all been cited as the main functional mechanisms involved in AD-MSC therapy. These properties make AD-MSC therapy of special interest in fomenting the enhancement of natural brain repair mechanisms such as neurogenesis, gliagenesis, oligodendrogenesis, axonal sprouting, nerve repair, and angiogenesis. This review will focus on studies showing promising results of AD-MSC in stroke treatment. ... Read more

Nanotechnologies for Stimulating and Recording Excitable Events in Neurons and Cardiomyocytes

Abstract: Nanotechnologies are engineered materials and devices that have a functional organization in at least one dimension on the nanometer scale, ranging from a few to about 100 nanometers. Functionally, nanotechnologies can display physical, chemical, and engineering properties that go beyond the component building block molecules or structures that make them up. Given such properties and the physical scale involved, these technologies are capable of interacting and interfacing with target cells and tissues in unique ways. One particular emerging application of wide spread interest is the development of nanotechnologies for stimulating and recording excitable cells such as neurons and cardiomyocytes. Such approaches offer the possibility of achieving high density stimulation and recording at sub-cellular resolutions in large populations of cells. This would provide a scale of electrophysiological interactions with excitable cells beyond anything achievable by current existing methods. In this review we introduce the reader to the key concepts and methods associated with nanotechnology and nanoengineering, and discuss the work of some of the key groups developing nanoscale stimulation and recording technologies. ... Read more

Drug-induced Atrial Fibrillation: Does It Matter?

Abstract: Atrial fibrillation (AF) is a major cause of hospitalization, morbidity, and mortality. Clinical reports indicate that an increasing number of cardiovascular (adenosine, positive inotropics) and non-cardiovascular (cancer chemotherapy, non-steroidal anti-inflammatory agents, high-dose methylprednisolone, and several respiratory medications) drugs can induce AF, increasing the number of hospitalizations. The risk of drug-induced AF (DIAF) would be expected to increase in the elderly, as they present a high incidence of AF and are treated with multiple drugs, and in patients with comorbidities frequently associated with AF. However, because of its short duration and the physicians are not aware about this side-effect, DIAF has received little attention when patients present a new-onset AF and epidemiologic studies to quantify the relation between certain drugs and AF have not yet been performed. Thus, further research is needed to obtain more insight into DIAF, to determine the incidence and risk factors, and whether it can increase the risk of thromboembolism or mortality. Meanwhile, when a patient presents a new-onset AF, it is recommended to review his/her medical and pharmacological history to identify whether any of the prescribed drugs may be responsible for the episode. ... Read more

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