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Contents
Pp. 190 - 206
Said AbdAlla, Xuebin Fu, Sherif S. Elzahwy, Kristin Klaetschke, Thomas Streichert and Ursula Quitterer
[Open Access Plus] |
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Chronic pressure overload and atherosclerosis are primary etiologic factors for cardiac hypertrophy and failure. However, mechanisms underlying the transition from hypertrophy to heart failure are incompletely understood. We analyzed the development of heart failure in mice with chronic pressure overload induced by aortic constriction and compared the results with aged apolipoprotein E-deficient mice suffering from advanced atherosclerosis. We combined cardiac function analysis by echocardiography and invasive hemodynamics with a comprehensive microarray gene expression study (GSE25765-8). The microarray data showed that the onset of heart failure induced by pressure overload or advanced atherosclerosis was accompanied by a strong up-regulation of key lipid metabolizing enzymes involved in fat synthesis, storage and oxidation. Cardiac lipid overload may be involved in the progression of heart failure by enhancing cardiomyocyte death. Up-regulation of the cardiac lipid metabolism was related to oxygen and ATP depletion of failing hearts because anti-ischemic treatment with ranolazine normalized the cardiac lipid metabolism and improved cardiac function. Vice versa, inhibition of cellular respiration and ATP generation by mild thiol-blocking with cystamine triggered the cardiac lipid metabolism and caused signs of heart failure. Cardiac tissue specimens of patients with heart failure also showed high protein levels of key fat metabolizing enzymes as well as lipid accumulation. Taken together, our data strongly indicate that up-regulation of the cardiac lipid metabolism and myocardial lipid overload are underlying the development of heart failure.
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Pp. 253 - 257
P. J. Blankestijn and H. Rupp
[Open Access Plus] |
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Rationale. The goal of antihypertensive treatment is to reduce risk of cardiovascular morbidity and mortality. Apart from blood pressure lowering per se, also reducing the activities of the renin-angiotensin system and sympathetic nervous system appears to be important. Angiotensin II receptor blocker drugs (ARBs) have provided a useful class of anti-hypertensive drugs. Eprosartan is a relatively new ARB which is chemically distinct (non-biphenyl, non-tetrazole) from all other ARBs (biphenyl tetrazoles). An analysis has been made on available experimental and clinical data on eprosartan which not only is an effective and well tolerated antihypertensive agent, but also lowers the activities of the renin-angiotensin system and sympathetic nervous system. Experimental and pharmacokinetic studies on eprosartan have shown differences with the other ARBs. The distinct properties of this non-biphenyl, non-tetrazole ARB might be relevant in the effort to reduce cardiovascular risk, also beyond its blood pressure lowering capacity.
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Pp. 224 - 228
N. Wohner
[Open Access Plus] |
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Although fibrin forms the core matrix of thrombi, their structure depends also on the cellular elements embedded in its meshwork. Platelets are essential in the initial stages of thrombus formation, because they adhere and aggregate at sites of blood vessel wall injury and then serve as a surface for coagulation reactions, the overall rate of which determines the final structure of fibrin. In addition, platelets affect fibrinolysis through their proteins and phospholipids, which modulate plasmin activity. Leukocytes form mixed aggregates with platelets and thus influence the structure of thrombi. After activation they secrete different proteases (elastase, cathepsin G, matrix metalloproteinases) that enhance the von Willebrand factor-dependent platelet adhesion. Leukocyte-derived enzymes, first of all elastase, effect fibrinolysis by direct digestion of fibrin or indirectly modulate it by partial degradation of zymogens and inhibitors of coagulation and fibrinolytic proteases.
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Pp. 190 - 205
L. Muszbek, Z. Bagoly, Z. Bereczky and E. Katona
[Open Access Plus] |
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It has been known for a long time that blood coagulation factor XIII (FXIII) is essential for maintaining haemostasis, its deficiency leads to severe bleeding complication. Biochemical studies have revealed that FXIII is a key regulator of fibrinolysis and, in addition to its role in haemostasis, it has also been implicated in the pathology of arterial and venous thrombosis. Most recently, the polymorphisms in the FXIII subunit genes and their influence on the risk of thrombotic diseases have stirred a lot of interest. This review, besides including the basic biochemistry of FXIII, mainly concentrates on the biochemical and clinical aspects of the involvement of FXIII in fibrinolysis and thrombosis. Biochemical aspects: Basics on the structure and activation of plasma and cellular FXIII. The enzymological features of activated FXIII and its main substrates. The interaction of FXIIIa with fibrinogen/fibrin and with components of the fibrinolytic system. The impact of cross-linked fibrin clot formation on the fibrinolytic processes. The down-regulation of FXIIIa within the fibrin clot. FXIII polymorphisms and their biochemical consequences. Clinical Aspects: FXIII level and the risk of arterial thrombosis (coronary artery disease, peripheral artery disease, ischemic stroke). The effect of FXIII subunit polymorphisms on the risk of arterial thrombotic diseases. The interplay between FXIII polymorphisms and other factors influencing the risk of arterial thrombosis. FXIII and venous thromboembolism.
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