Abstract: Exercise testing was developed as a diagnostic tool in the first half of the 20^th 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

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

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

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

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

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

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

Abstract: Two new classes of orally available anticoagulant drugs, the direct thrombin inhibitor (dabigatran etexilate) and direct factor Xa inhibitors (the -xabans), have been approved for various clinical indications, as alternatives to the vitamin K antagonists (e.g., warfarin). These include the prevention of venous thromboembolism after major orthopedic surgery, the prevention of stroke and systemic embolism in non-valvular atrial fibrillation, and the secondary prevention and treatment of venous thromboembolism including pulmonary embolism. Other clinical indications including the add-on therapy to dual antiplatelet therapy in patients with acute coronary syndrome and extended prophylaxis of venous thromboembolism in acute medically ill patients are currently under clinical investigation. The clinical phase III development and indications of the currently clinically approved novel oral anticoagulants dabigatran etexilate, rivaroxaban, apixaban, and edoxaban are summarized and discussed. ... Read more

Abstract: Following the clinical approval of novel oral anticoagulants as alternatives to the vitamin K antagonists, many additional novel oral anticoagulant drugs are currently in early and advanced stages of clinical development. The majority of the drugs in development belong to the class of direct factor Xa inhibitors (the -xabans). These include betrixaban, letaxaban, darexaban, eribaxaban, and LY517717. Another representative of the class of orally available direct thrombin inhibitors (the -gatrans) is known as AZD0837. Furthermore other coagulation factors with central roles within the coagulation cascade are currently investigated as potential targets for the development of novel oral anticoagulant drugs. Among those, the first direct oral factor IXa inhibitor TTP889 has entered the clinical phase of development. A short summary of novel oral anticoagulant currently in earlier stages of clinical development is provided. ... Read more

Abstract: Proteinase Activated Receptors (PARs) are G-protein coupled receptors (GPCRs) that were discovered in the early 1990's. They are unusual among GPCRs in being activated through proteolytic cleavage of the receptor N-terminus by serine proteinases such as thrombin. Over the last two decades major advances have been made in our understanding of how these receptors function and the roles they play in (patho)physiology. They have also emerged as drug targets for a number of conditions, most notably thrombosis. Recently two different drugs targeting PAR1 have entered clinical trials as anti-platelet agents. This review provides an overview of the proteinase activated receptor family and focuses on the role of PAR1 in regulating the endothelial barrier integrity and its implication on developing PAR antagonists for anti-platelet therapy. ... Read more