Functional and structural adaptations of the coronary macro- and microvasculature to regular aerobic exercise by activation of physiological, cellular, and molecular mechanisms: ESC Working Group on Coronary Pathophysiology and Microcirculation position paper.

Regular aerobic exercise (RAEX) elicits several positive adaptations in all organs and tissues of the body, culminating in improved health and well-being. Indeed, in over half a century, many studies have shown the benefit of RAEX on cardiovascular outcome in terms of morbidity and mortality. RAEX elicits a wide range of functional and structural adaptations in the heart and its coronary circulation, all of which are to maintain optimal myocardial oxygen and nutritional supply during increased demand. Although there is no evidence suggesting that oxidative metabolism is limited by coronary blood flow (CBF) rate in the normal heart even during maximal exercise, increased CBF and capillary exchange capacities have been reported. Adaptations of coronary macro- and microvessels include outward remodelling of epicardial coronary arteries, increased coronary arteriolar size and density, and increased capillary surface area. In addition, there are adjustments in the neural and endothelial regulation of coronary macrovascular tone. Similarly, there are several adaptations at the level of microcirculation, including enhanced (such as nitric oxide mediated) smooth muscle-dependent pressure-induced myogenic constriction and upregulated endothelium-dependent/shear-stress-induced dilation, increasing the range of diameter change. Alterations in the signalling interaction between coronary vessels and cardiac metabolism have also been described. At the molecular and cellular level, ion channels are key players in the local coronary vascular adaptations to RAEX, with enhanced activation of influx of Ca2+ contributing to the increased myogenic tone (via voltage-gated Ca2+ channels) as well as the enhanced endothelium-dependent dilation (via TRPV4 channels). Finally, RAEX elicits a number of beneficial effects on several haemorheological variables that may further improve CBF and myocardial oxygen delivery and nutrient exchange in the microcirculation by stabilizing and extending the range and further optimizing the regulation of myocardial blood flow during exercise. These adaptations also act to prevent and/or delay the development of coronary and cardiac diseases.

Coronary Microvascular and Cardiac Dysfunction Due to Homocysteine Pathometabolism; A Complex Therapeutic Design.

In various metabolic diseases, both the coronary circulation and cardiac metabolism are altered. Here we summarize the effects of a condition called hyperhomocysteinemia (HHcy) - which can develop due to genetic and/or environmental causes - on the function of coronary microvessels and heart. This metabolic disease is underappreciated, yet even mild or moderate elevation of plasma concentrations of homocystein (Hcy, plasma Hcy >16 µM), a sulfur-containing amino acid produced via methionine metabolism) leads to coronary and peripheral artery and even venous vessel diseases, eliciting vasomotor dysfunction and increased thrombosis, consequently increased morbidity and mortality. Yet the underlying mechanisms have not yet been revealed. Recent studies indicated that there are common pathomechanisms, which may affect several cellular functions. With methionin diet-induced HHcy two main pathomechanisms were revealed: the dysfunction of nitric oxide (NO) pathway resulting in reduced dilator responses of arteries and arterioles, and the simultaneously increased thromboxane A2 (TXA2) activity both in vessels and platelets. These changes are likely due to an increased production of reactive oxidative species (oxidative stress) due to increased NADPH oxidase assembly, which eventually lead to inflammatory processes (indicated by increases in TNFα, NFκbeta, p22phox, p67phox, and rac-1, levels) and changes in various gene expressions and morphological remodeling of vessels. Increased superoxide production and reduced availability of NO alter the regulation of mitochondrial function in the myocardium. The interactions of these pathomechanisms may explain why HHcy increases the uptake of glucose and lactate and decreases the uptake of free fatty acid by the heart. The pathological consequences of HHcy could be worsening by the simultaneous presence of other risk factors, such as hyperlipidemia, diabetes mellitus and metabolic syndrome. All in all, HHcy and associated pathometabolism lead to severe changes and dysfunctions of coronary arterial vessels and cardiac function, which may not always be apparent in clinical settings but most likely contribute to the increased prevalence of cardiovascular diseases and mortality, which however can be reduced by appropriate prevention and treatments. We believe that HHcy is an underestimated - likely due to inappropriate clinical trials - but serious disease condition because it promotes the development of atherosclerosis in large arterial vessels, vasomotor dysfunction in microvessels, hypertension and thrombosis. In this review, we will summarize previous functional findings focusing on coronary vessels and cardiac function and the underlying cellular and molecular mechanisms enabling the development of novel treatments.

Current perspectives of catabolic mediators of cancer cachexia.

The development of cancer cachexia is perhaps the most common manifestation of advanced malignant diseases and has been recognized as a poor prognostic sign. The abnormalities associated with the condition include progressive weight loss, anorexia, asthenia, and anemia. The degree of cachexia is inversely correlated with the survival time of the patient and always implies a poor prognosis. Currently there is no established mechanism for cancer cachexia, but the severe metabolic disturbances and marked alterations in carbohydrate, lipid, and protein metabolism in the host finally lead to an increased energy deficiency. Weight loss, the key feature of cachexia, is due to a reduction of food intake, an increase in energy expenditure, or a combination of the two. A variety of changes in nutrient metabolism have been described in patients with cancer cachexia. Patients frequently exhibit a relative glucose intolerance and insulin resistance with increased activity of the Cori cycle. The cancer-bearing state affects protein synthesis and breakdown in different tissues of the body in a different manner. An acute-phase protein response can be presented in a significant proportion of patients with cancer with disease progression. A variety of proinflammatory cytokines appears to play a role in aspects of cachexia and a complex network of cytokines in combination with other factors might be involved. Aside from potential humoral mediators of cachexia, tumor-derived biologically active molecules have been reported recently.

[The molecular biology of aging--therapeutic interventions?]. / Az öregedés molekulárbiológiai meghatározói-- terápiás lehetoségek?

Aging is a complex mechanism of progressive and irreversible processes occurring to molecules, to cells and to the whole organism and ending with death. Genetic - so called "programmed" - factors and the combination of environmental interactions play the most important role in its development. Changes in macromolecules caused by free radicals, non-enzymatic glycosylation and apoptosis have a special role in the pathomechanism of aging. Endocrine and immune systems have also an important influence and control on the process. Those environmental effects, as for example irradiation, toxic chemicals, metal ions, free radicals play a determinant role in the development of aging. Diseases of old age should be distinguished from aging per se, although changes in old age increase the frequency of diseases. Those aging changes, which are associated with a generalized increase in mortality (but not with specific disease) would qualify as biomarkers of aging and would distinguish biological age from chronological age (passage of time). Because of increased average lifetime of people in the "western world", basic and clinical research in connection with aging and geriatrics has special importance in medicine. Better understanding of molecular and cellular mechanisms of aging could improve not only medical care of the elderly but could hold out also some hope in finding feasible solutions to slow down the aging process as well.

[Molecular mechanisms of cancer cachexia]. / A tumoros cachexia molekuláris háttere.

Molecular mechanisms of cancer cachexia. Cancer cachexia is a complex, multifactorial syndrome characterised by a critical weight loss, anorexia, asthenia and anaemia. Most of the patients with advanced cancer suffer from cancer cachexia. The cachectic state is closely associated with progressive expansion of the tumour and leads to a malnutrition status due to the induction of anorexia and decreased food intake. In addition, the competition for nutrients between the tumour and the host leads to malnutrition state, too, which promotes severe metabolic disturbances in the host, including hypermetabolism which leads to an increased energetic inefficiency. Although, the search for the cachectic factors has a long history, we are still far away from knowing the complete answer. The main aim of the present paper is to summarise the different catabolic mediators involved in cancer cachexia. Better understanding of the pathomechanism of cancer cachexia can lead to the discovery of new, effective strategies of the therapy for the future.