LEPTIN AND OBESITY – NEUROENDOCRINE , METABOLIC AND ATHEROGENIC EFFECTS OF LEPTIN

Background. Leptin is an adipocyte-derived hormone that was recently discovered. Leptin and leptin resistance play an important role in the pathogenesis of obesity. Leptin acts by binding to specific receptors in the hypothalamus to alter the expression of several neuropeptides that regulate food intake and energy expenditure. As commonly found, obese persons have leptin resistance and consequently attenuated effects of leptin. Mechanism underlying leptin resistance has not been explained yet: it might be the result of a receptor or post receptor defect, impaired transport of leptin through cerebrovascular barrier or inactivation of leptin by binding proteins. Phase I and II clinical trials proved that recombinant leptin administration to humans is safe. First results of the current phase III clinical trials demonstrated that leptin is moderately effective in the treatment of obesity.Conclusions. Beside anti-obesity effect, leptin can have important metabolic and neuroendocrine effects. It is involved in glucose metabolism and insulin secretion, pathogenesis of polymetabolic syndrome, diabetes and arterial hypertension. In addition it affects some processes of atherothrombosis. It interacts with and significantly influences hypothalamic-pituitaryadrenal, thyroid, sexual glands and growth hormone axes. Explaining the mechanism of leptin resistance could be important for understanding the pathogenesis of obesity and associated pathologic states as polymetabolic syndrom, diabetes, arterial hipertension and atherothrombosis.</p

Trendi v sekundarni preventivi po srčnem infarktu – umestitev novosti

Cilj sekundarne preventive po srčnem infarktu je zmanjšati tveganje za ponovne srčno-žilne dogodke, druge zaplete in umrljivost. Kljub medikamentni terapiji, ki so jo skozi čas priporočale smernice, je vedno ostajalo in še ostaja prisotno določeno preostalo srčno-žilno tveganje. Namen novejših raziskav je bil z dodatkom predvsem protitrombotičnih, hipolipemičnih ali protivnetnih zdravil brez pojavljanja pomembnih neželenih učinkov znižati to prisotno tveganje. V sklopu protitrombotičnega zdravljenja se je tako eno leto po akutnem koronarnem sindromu kot dodatek aspirinu izkazalo učinkovito podaljšano zdravljenje s tikagrelorjem ali z nizkimi odmerki rivaroksabana. Veliko novosti je tudi na področju hipolipemičnega zdravljenja, ki kot najbolj koristno zagovarja čim večje znižanje holesterola LDL. Raziskave kažejo, da so za doseganje ciljev učinkoviti ezetimib in zaviralci PCSK9. Tretja možnost učinkovitega proti-aterosklerotičnega zdravljenja so protivnetna zdravila, ki pa se še niso prebila v klinično prakso. Pri bolnikih po srčnem infarktu s sočasno sladkorno boleznijo dodaten ukrep v izboljšanju srčno-žilne napovedi izida omogoča uporaba agonistov receptorjev GLP-1 (angl. glucagon-like polypeptide-1) in zaviralcev SGLT2 (angl. sodium-glucose co-transporter 2). Če bolniki izpolnjujejo merila za uvedbo novih terapevtskih možnosti, je poleg zdravega življenjskega sloga smiselno čim bolj optimizirati medikamentno zdravljenje, saj lahko ob tem pričakujemo nadaljnje znižanje preostalega srčno-žilnega tveganja in s tem izboljšanje kakovosti življenja po srčnem infarktu

THE IMPORTANCE OF ENDOTHELIAL DYSFUNCTION FOR THE DEVELOPMENT OF PULMONARY ARTERIAL HYPERTENSION AND NEW THERAPEUTIC OPTIONS

Background. Pulmonary arterial hypertension may exist as a primary condition or as a secondary condition, most commonly with collagen vascular disease. Patients with pulmonary arterial hypertension usually have bad prognosis as the effectiveness of conventional treatment is poor. New knowledge about importance of endothelial dysfunction in development of pulmonary arterial hypertension has opened a wide field of possible new treatment options.Conclusions. Endothelial dysfunction in pulmonary vascular bed is characterised by an inappropriate release of vasoactive substances from endothelium producing vasoconstriction, remodeling of arterial wall and increased local tendency for thrombosis. Several new drugs have been already tested in clinical case-controlled studies: prostacyclin and its analogues applied intravenously or in inhalations, inhaled nitric oxide and drugs which increase nitric oxide concentration such as sildenafil and l-arginine, endothelin receptors antagonists in tablets and tromboxane antagonist in tablets. Only tromboxane antagonist was shown to be ineffective whereas all other drugs were effective at least in certain subgroups of patients. New clinical trials will give answer not only in respect to the comparative efficacy of the drugs mentioned earlier and their combinations but also to the recognition of factors that determine the success of treatment in individual patient.</p

Zaviralci SGLT-2

Zaviralci natrij-glukoznega prenašalnega sistema 2 (SGLT-2) so najnovejša skupina zdravil za zdravljenje sladkorne bolezni tipa 2, ki so v klinični uporabi zadnjih nekaj let. V proksimalnih tubulih ledvic zmanjšajo reabsorpcijo glukoze, ki se zato izloči z urinom. Zato se zniža koncentracija glukoze v krvi in nastopi ugodni vpliv na urejenost glikemije, obenem pa s tem ne povečajo tveganja za hipoglikemijo. Zaviralci SGLT-2 imajo tudi ugodne presnovne učinke, in sicer znižajo telesno maso, krvni tlak in koncentracijo sečne kisline v serumu. Upočasnijo tudi napredovanje začetne diabetične ledvične bolezni. Za nekatere predstavnike so tudi pokazali, da pomembno zmanjšujejo pojavnost srčno-žilnih dogodkov in zapletov, vendar mehanizem še ni v celoti raziskan in je predmet intenzivnega preučevanja. Redko povzročijo resne neželene učinke. V prispevku je opisan mehanizem delovanja zaviralcev SGLT-2, njihov vpliv na urejenost glikemije in drugo: presnovni učinki, vpliv na pojavnost srčno-žilnih bolezni in najpogostejši neželeni učinki ter možnosti predpisovanja zaviralcev SGLT-2 v Sloveniji

Associations between cerebral and systemic endothelial function in migraine patients: a post-hoc study

<p>Abstract</p> <p>Background</p> <p>There is a growing interest in the role of the endothelium in migraine. Recently, our group showed differences in endothelial function between the anterior and posterior cerebral circulation in healthy subjects, reduced vasodilatatory capacity of the posterior cerebral circulation and unimpaired systemic endothelial function in migraine patients without comorbidities. However, the relationship between cerebral and systemic endothelial function and the anterior and posterior cerebral endothelial function in migraine patients is still not clear.</p> <p>Methods</p> <p>We compared cerebral and systemic endothelial function through post-hoc linear regression analysis of cerebrovascular reactivity (CVR) to L-arginine between the middle cerebral artery (MCA) and flow-mediated vasodilatation (FMD) of the right brachial artery and the posterior cerebral artery (PCA) and FMD in migraine patients without comorbidities and in healthy subjects. The anterior and posterior cerebral endothelial function was also compared using post-hoc linear regression analysis between CVR to L-arginine in the MCA and the PCA.</p> <p>Results</p> <p>No significant correlation was found between CVR to L-arginine in the MCA and FMD and in the PCA and FMD in migraine patients with aura (p = 0.880 vs. p = 0.682), without aura (p = 0.153 vs. p = 0.179) and in healthy subjects (p = 0.869 vs. p = 0.662). On the other hand, we found a significant correlation between CVR to L-arginine in the MCA and PCA in migraine patients with aura (p = 0.004), without aura (p = 0.001) and in healthy subjects (p = 0.002). Detailed analysis of the linear regression between all migraine patients and healthy subjects did not show any difference in the regression coefficient (slope) (p = 0.382). However, a significant difference in curve elevation (intercept) was found (p = 0.002).</p> <p>Conclusions</p> <p>Our study suggests that the endothelial function in the cerebral and systemic circulation might be different in migraine patients without comorbidities, while that of the anterior and posterior cerebral circulation might be coupled. These results could improve understanding of endothelial function in migraine patients without comorbidities.</p

Inflammatory, Metabolic, and Coagulation Effects on Medial Arterial Calcification in Patients with Peripheral Arterial Disease

Calcium deposits in the vessel wall in the form of hydroxyapatite can accumulate in the intimal layer, as in atherosclerotic plaque, but also in the medial layer, as in medial arterial calcification (MAC) or medial Möenckeberg sclerosis. Once considered a passive, degenerative process, MAC has recently been shown to be an active process with a complex but tightly regulated pathophysiology. Atherosclerosis and MAC represent distinct clinical entities that correlate in different ways with conventional cardiovascular risk factors. As both entities coexist in the vast majority of patients, it is difficult to estimate the relative contribution of specific risk factors to their development. MAC is strongly associated with age, diabetes mellitus, and chronic kidney disease. Given the complexity of MAC pathophysiology, it is expected that a variety of different factors and signaling pathways may be involved in the development and progression of the disease. In this article, we focus on metabolic factors, primarily hyperphosphatemia and hyperglycemia, and a wide range of possible mechanisms by which they might contribute to the development and progression of MAC. In addition, we provide insight into possible mechanisms by which inflammatory and coagulation factors are involved in vascular calcification processes. A better understanding of the complexity of MAC and the mechanisms involved in its development is essential for the development of potential preventive and therapeutic strategies

Inflammatory, Metabolic, and Coagulation Effects on Medial Arterial Calcification in Patients with Peripheral Arterial Disease

Calcium deposits in the vessel wall in the form of hydroxyapatite can accumulate in the intimal layer, as in atherosclerotic plaque, but also in the medial layer, as in medial arterial calcification (MAC) or medial M&ouml;enckeberg sclerosis. Once considered a passive, degenerative process, MAC has recently been shown to be an active process with a complex but tightly regulated pathophysiology. Atherosclerosis and MAC represent distinct clinical entities that correlate in different ways with conventional cardiovascular risk factors. As both entities coexist in the vast majority of patients, it is difficult to estimate the relative contribution of specific risk factors to their development. MAC is strongly associated with age, diabetes mellitus, and chronic kidney disease. Given the complexity of MAC pathophysiology, it is expected that a variety of different factors and signaling pathways may be involved in the development and progression of the disease. In this article, we focus on metabolic factors, primarily hyperphosphatemia and hyperglycemia, and a wide range of possible mechanisms by which they might contribute to the development and progression of MAC. In addition, we provide insight into possible mechanisms by which inflammatory and coagulation factors are involved in vascular calcification processes. A better understanding of the complexity of MAC and the mechanisms involved in its development is essential for the development of potential preventive and therapeutic strategies

Treating Arterial Ageing in Patients with Diabetes: From Mechanisms to Effective Drugs

Diabetes mellitus is a major healthcare problem. It is not only characterized by hyperglycemia and chronic complications, but in longer lasting diabetes and a longer living population, it is also associated with accelerated arterial ageing, which importantly contributes to cardiovascular complications. The accelerated arterial ageing in patients with diabetes should be considered separately from arterial ageing in patients without diabetes. Basic and clinical research have allowed better insight into the mechanisms of arterial ageing. In a simplified mechanistic way, it could be considered that the three tightly connected cornerstone characteristics of arterial ageing in patients with diabetes are: phenotypic presentation as endothelial dysfunction and arterial stiffness, and the underlying basic ageing-facilitating mechanism represented as the impaired expression of genetic longevity pathways. Currently, specific drugs for preventing/treating arterial ageing are not available. Therefore, we aimed to review the capacity of available drugs, particularly antidiabetic drugs, to interfere with the arterial ageing process. In the near future, these characteristics could help to guide therapy in patients with diabetes. Overall, it appears that arterial ageing could become a new target in diabetes. The expanding knowledge regarding the capability of antidiabetic drugs and other available drugs to inhibit/delay arterial aging is therefore essential

Arterial Stiffness and Cardiovascular Therapy

The world population is aging and the number of old people is continuously increasing. Arterial structure and function change with age, progressively leading to arterial stiffening. Arterial stiffness is best characterized by measurement of pulse wave velocity (PWV), which is its surrogate marker. It has been shown that PWV could improve cardiovascular event prediction in models that included standard risk factors. Consequently, it might therefore enable better identification of populations at high-risk of cardiovascular morbidity and mortality. The present review is focused on a survey of different pharmacological therapeutic options for decreasing arterial stiffness. The influence of several groups of drugs is described: antihypertensive drugs (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, beta-blockers, diuretics, and nitrates), statins, peroral antidiabetics, advanced glycation end-products (AGE) cross-link breakers, anti-inflammatory drugs, endothelin-A receptor antagonists, and vasopeptidase inhibitors. All of these have shown some effect in decreasing arterial stiffness. Nevertheless, further studies are needed which should address the influence of arterial stiffness diminishment on major adverse cardiovascular and cerebrovascular events (MACCE)