Biomedical subjects

Albrecht Elsässer

Publications and source records attributed to Albrecht Elsässer.

27 records · Page 2Linked to original sources

PubMed2005

[Oral antithrombotic therapy in primary and secondary prevention].

Cardiovascular disease is the leading cause of death in western societies, with further increasing incidence. Therefore both, primary and secondary prevention play a pivotal role. Medicamentous prevention schemes include the antithrombotic drugs acetylsalicylic acid (ASS) and clopidogrel. A number of studies tested the efficacy and safety of ASS for primary prevention. A meta-analysis of these primary prevention trials could demonstrate a decrease of cardiovascular events only for patients being at high cardiovascular risk. However, since ASS does not influence the mortality but is significantly increasing the risk for bleeding, careful risk stratification is indispensable prior to preventive chronic administration of the drug. Therapy with ASS in the secondary prevention is commonly accepted and clearly evidence-based given that a meta-analysis of 145 trials could demonstrate a significant decrease in mortality. A daily dose of 100 mg has been shown to achieve sufficient antithrombotic effects with an acceptable rate of side effects. Clopidogrel is currently not used for primary prevention, since evidence is lacking and the costs are high. For secondary prevention after acute coronary syndromes, a decrease of cardiovascular events could be demonstrated for clopidogrel. This benefit was especially pronounced after percutaneous coronary interventions. However, clopidogrel could not decrease the mortality. Therefore, long-term treatment with clopidogrel in the secondary prevention should be based on a critical appraisal of risk and benefit on the one hand and socioeconomic aspects on the other hand.

Animals↗

PubMed2005

[Treatment of ST segment elevation myocardial infarctions according to the guidelines].

The guidelines "Akutes Koronarsyndrom" published by the German Society of Cardiology, "Management of acute myocardial infarction in patients presenting with ST-segment elevation", and "Guidelines for percutaneous coronary interventions" published by the European Society of Cardiology evaluate diagnostic tools and treatment strategies for ST segment elevation myocardial infarctions. These guidelines offer evidence-based recommendations and allow a standardized therapeutic approach thereby improving the patient's treatment and reducing the mortality. The optimal care for patients presenting with ST segment elevation myocardial infarctions consists of a prehospital phase where an immediate diagnosis should be reached by means of a twelve-channel ECG followed by basic medical treatment with administration of acetylsalicylic acid, heparin, beta-blocker, and nitrates by an emergency physician. The hospital phase can be optimized by integrated myocardial infarction networks with coronary care units offering primary percutaneous coronary interventions (PCIs) and adjuvant medical treatment including the administration of glycoprotein IIb/IIIa inhibitors. If the onset of symptoms is < 3 h and the transportation time to a coronary care unit > 90 min, the indication of primary fibrinolysis should be given by the emergency physician. If fibrinolysis fails, there is a clear indication for rescue PCI. Even with successful thrombolysis PCI should be performed within 24 h. A dual oral antithrombotic therapy starting immediately after diagnosis with a loading dose of 600 mg clopidogrel should be continued with 75 mg/d clopidogrel for 9-12 months on top of 100 mg/d acetylsalicylic acid.

Angioplasty, Balloon, Coronary↗

PubMed2005

Myocardial energy metabolism in ischemic preconditioning and cardioplegia: a metabolic control analysis.

For both, cardioplegia (CP) and ischemic preconditioning (IP), increased ischemic tolerance with reduction in infarct size is well documented. These cardioprotective effects are related to a limitation of high energy phosphate (HEP) depletion. As CP and IP have to be assumed to act by different mechanisms, their effects on myocardial HEP metabolism cannot be assumed to be identical. Therefore, a systematic analysis of myocardial HEP metabolism for both procedures and their combination was performed, addressing the question whether there are different effects on myocardial HEP metabolism by IP and CP. In this study, metabolic control analysis was used to analyze the regulation of HEP metabolism. In open chest pigs subjected to 45 min LAD occlusion (index ischemia), CP and IP preserved myocardial ATP (control (C) 0.14 +/- 0.05 micromol/g wwt; CP: 0.95 +/- 0.14, IP: 0.61 +/- 0.12; p<0.05 C vs. CP and IP) and reduced myocardial necrosis (infarct size IA/RA: C: 90.0 +/- 3.0%; CP: 0.0 +/- 0.0% but patchy necroses; IP: 5.05 +/- 2.1%; p<0.05 C vs. CP and IP). The effects on HEP metabolism, however, were different: CP acted predominantly by slowing down the breakdown of phosphocreatine (PCr) during early phases of ischemia (C: DeltaPCr 0-2 min: 5.24 +/- 0.32 micromol/g wwt; CP: DeltaPCr 0-2 min: 3.38 +/- 0.23 micromol/g wwt, p<0.05 vs. C), leaving ATP breakdown during later stages unaffected (C: DeltaATP 5-45 min: 1.77 +/- 0.11 micromol/g wwt CP: DeltaATP 5-45 min: 1.59 +/- 0.28 micromol/g wwt, n.s. vs. C). In contrast to CP, in IP PCr breakdown was even increased (IP: DeltaPCr 0-2 min: 7.06 +/- 0.34 micromol/g wwt, p<0.05 vs. C), but ATP depletion greatly attenuated (IP: DeltaATP 5-45 min: 0.48 +/- 0.10 micromol/g wwt, p<0.05 vs. C and CP). Combining IP and CP yielded an additive effect with slowing down the breakdown of both PCr (IP+CP: DeltaPCr 0-2 min: 5.09+/- 0.35 micromol/g wwt, p<0.05 vs. C and IP) and ATP (IP+CP: DeltaATP 5-45 min: 0.56 +/- 0.48 micromol/g wwt, p<0.05 vs. C and CP), resulting in a higher ATP content at the end of index ischemia (1.86 +/- 0.46 micromol/g wwt, p<0.05 vs. C, CP and IP). Compared to IP, combining IP+CP achieved also a further reduction in infarct size (IA/RA: 0.0 +/- 0.0%, p<0.05 vs IP) and--compared to CP--a disappearance of the patchy necroses. The concept of major differences in myocardial HEP metabolism during CP and IP is further supported at a molecular level by metabolic control analysis. CP but not IP slowed down the CK reaction velocity at high PCr levels. In contrast to CP exerting a continuous decline in vATPase for any given ATP level, in IP myocardium ATPase reaction velocity was even increased at higher ATP contents, whereas a marked decrease in ATPase reaction velocity was found if ATP levels decreased. The equilibrium of the CK-reaction remained unchanged following CP, whereas IP induced a changing CK equilibrium, which was the more shifted towards PCr the more myocardial HEP content decreased. The data demonstrate different effects of CP and IP on myocardial HEP metabolism, i.e. PCr and ATP breakdown as well as the apparent equilibrium of the creatine kinase (CK)-reaction. For these reasons the combination of the two protective interventions has an additive effect.

Adenosine Triphosphatases↗

PubMed2004

Human hibernating myocardium is jeopardized by apoptotic and autophagic cell death.

OBJECTIVES: The aim of the present study was to objectify the loss of myocytes and the mechanism by which myocytes die in human hibernating myocardium (HHM). BACKGROUND: Intracellular degeneration, reduced cellular protein synthesis, and the replacement fibrosis contribute to structural disintegration of HHM. METHODS: In 14 patients, HHM was diagnosed by dobutamine echocardiography, radionuclide ventriculography, and thallium-201 scintigraphy. Functional recovery was documented by repeating the preoperative clinical investigations three months after successful coronary artery bypass graft surgery (CABG). During CABG, transmural biopsies were taken from the center of HHM regions and studied by electron microscopy, immunohistochemistry, the terminal deoxynucleotidyl transferase-mediated nick end-labeling (TUNEL) method, reverse transcription-polymerase chain reaction, and Western blotting. Control samples were taken from nondiseased human myocardium. RESULTS: All patients showed significant improvement or normalization of the regional function of HHM. Ubiquitin-related autophagic cell death was evident ultrastructurally by the occurrence of autophagic vacuoles, cellular degeneration, and nuclear disassembly. Ubiquitin-protein complexes were found in 0.03 +/- 0.008% (control: 0%, p < 0.005) of all myocytes. The proteasome 20S subunit/total myocytes were reduced from 63.3 +/- 9.6% in control myocardium to 36.9 +/- 8.4% in HHM. Complement-9, indicating oncosis, was found in only one of 14 biopsies. TUNEL-positive myocytes were 0.002 +/- 0.0003%. Electron microscopy showed apoptotic cells in 3 of 14 samples. However, the bcl-2/bax ratio was significantly reduced. Moreover, caspase-3 messenger ribonucleic acid was 8.5 times upregulated, and caspase-3 was activated. Cell death was absent in controls. CONCLUSIONS: In HHM, ubiquitin-related autophagic cell death and apoptosis cause a loss of myocytes. This plays an important role in progressive tissue damage and causes a reduction of the extent of functional recovery of HHM.

Aged↗

PubMed2003

Myocytes die by multiple mechanisms in failing human hearts.

We tested the hypothesis that myocyte loss in failing human hearts occurs by different mechanisms: apoptosis, oncosis, and autophagic cell death. Explanted hearts from 19 patients with idiopathic dilated cardiomyopathy (EF< or =20%) and 7 control hearts were analyzed. Myocyte apoptosis revealed by caspase-3 activation and TUNEL staining occurred at a rate of 0.002+/-0.0005% (P<0.05 versus control) and oncosis assessed by complement 9 labeling at 0.06+/-0.001% (P<0.05). Cellular degeneration including appearance of ubiquitin containing autophagic vacuoles and nuclear disintegration was present at the ultrastructural level. Nuclear and cytosolic ubiquitin/protein accumulations occurred at 0.08+/-0.004% (P<0.05). The ubiquitin-activating enzyme E1 and the ligase E3 were not different from control. In contrast, ubiquitin mRNA levels were 1.8-fold (P<0.02) elevated, and the conjugating enzyme E2 was 2.3-fold upregulated (P<0.005). The most important finding, however, is the 2.3-fold downregulation of the deubiquitination enzyme isopeptidase-T and the 1.5-fold reduction of the ubiquitin-fusion degradation system-1, which in conjunction with unchanged proteasomal subunit levels and proteasomal activity results in massive storage of ubiquitin/protein complexes and in autophagic cell death. A 2-fold decrease of cathepsin D might be an additional factor responsible for the accumulation of ubiquitin/protein conjugates. It is concluded that in human failing hearts apoptosis, oncosis, and autophagy act in parallel to varying degrees. A disturbed balance between a high rate of ubiquitination and inadequate degradation of ubiquitin/protein conjugates may contribute to autophagic cell death. Together, these different types of cell death play a significant role for myocyte disappearance and the development of contractile dysfunction in failing hearts.

Apoptosis↗

PubMed2003

Progression from compensated hypertrophy to failure in the pressure-overloaded human heart: structural deterioration and compensatory mechanisms.

BACKGROUND: The progression of compensated hypertrophy to heart failure (HF) is still debated. We investigated patients with isolated valvular aortic stenosis and differing degrees of left ventricular (LV) systolic dysfunction to test the hypothesis that structural remodeling, as well as cell death, contributes to the transition to HF. METHODS AND RESULTS: Structural alterations were studied in LV myectomies from 3 groups of patients (group 1: ejection fraction [EF] >50%, n=12; group 2: EF 30% to 50%, n=12; group 3: EF <30%, n=10) undergoing aortic valve replacement. Control patients were patients with mitral valve stenosis but normal LV (n=6). Myocyte hypertrophy was accompanied by increased nuclear DNA and Sc-35 (splicing factor) content. ACE and TGF-beta1 were upregulated correlating with fibrosis, which increased 2.3-, 2.2-, and 3.2-fold over control in the 3 groups. Myocyte degeneration increased 10, 22, and 32 times over control. A significant correlation exists between EF and myocyte degeneration or fibrosis. Ubiquitin-related autophagic cell death was 0.5 per thousand in control and group 1, 1.05 in group 2, and 6.05 per thousand in group 3. Death by oncosis was 0 per thousand in control, 3 per thousand in group 1, and increased to 5 per thousand (groups 2 and 3). Apoptosis was not detectable in control and group 3, but it was present at 0.02 per thousand in group 1 and 0.01 per thousand in group 2. Cardiomyocyte mitosis was never observed. CONCLUSIONS: These structure-function correlations confirm the hypothesis that transition to HF occurs by fibrosis and myocyte degeneration partially compensated by hypertrophy involving DNA synthesis and transcription. Cell loss, mainly by autophagy and oncosis, contributes significantly to the progression of LV systolic dysfunction.

Aged↗

PubMed2003

Increased glycolysis as protective adaptation of energy depleted, degenerating human hibernating myocardium.

In the current study on human hibernating myocardium (HHM), we tested the hypothesis that increased glycolysis might exert a positive effect during a supply-demand balance situation by augmentation of myocardial energy formation. In 14 patients HHM was preoperatively detected by clinical methods and validated by the recovery of contractile function three months following revascularization. During open-heart surgery, transmural biopsies were removed from the hibernating areas and analyzed using biochemical and morphologic methods. Metabolite contents were normalized for the degree of fibrosis (control: 9.8 +/- 0.5%, HHM 28.1 +/- 3.0%; p < 0.05), providing values for cardiomyocytes only. In energy depleted HHM, severe intracellular degeneration, glycogen accumulation and myocyte loss were found. Elevated lactate levels (2.22 +/- 0.26 vs. 25.38 +/- 3.53 micromol/wet wt, p < 0.001) were indicative of an increased anaerobic glycolytic flux. In conclusion the presence of abundant intracellular glycogen and an increased anaerobic glycolysis in HHM is indicative of a protective adaptation of this myocardium, which might balance energy deficit and may limit structural damage.

Adaptation, Physiological↗

PubMed2002

Metabolic control analysis of anaerobic glycolysis in human hibernating myocardium replaces traditional concepts of flux control.

Myocardial hibernation represents an adaptation to sustained ischemia to maintain tissue vitality during severe supply-demand imbalance which is characterized by an increased glucose uptake. To elucidate this adaptive protective mechanism, the regulation of anaerobic glycolysis was investigated using human biopsies. In hibernating myocardium showing an increase in anaerobic glycolytic flux metabolizing exogenous glucose, the adjustment of flux through this pathway was analyzed by flux:metabolite co-responses. By this means, a previously unknown pattern of regulation using multisite modulation was found which largely differs from traditional concepts of metabolic control of the Embden-Meyerhof pathway in normal and diseased myocardium.

Anaerobiosis↗

PubMed2002

Severe energy deprivation of human hibernating myocardium as possible common pathomechanism of contractile dysfunction, structural degeneration and cell death.

OBJECTIVES: We tested the hypothesis that severe alterations in myocardial energy metabolism play an important role in the pathophysiology of human hibernating myocardium (HHM). BACKGROUND: It is well established that a disturbed myocardial energy metabolism results in impairments of contractile performance, structure and viability. All of these are important characteristics of HHM. METHODS: In 16 patients with documented coronary artery disease and impaired left ventricular function, HHM was preoperatively detected by thallium-201 scintigraphy, radionuclide ventriculography and low-dose dobutamine echocardiography. These regions were validated as HHM by their recovery of contractile function three months following revascularization. During open-heart surgery, transmural biopsies were removed from the hibernating areas and analyzed both biochemically and morphologically. These findings were compared to normal human myocardium. All metabolite contents given were normalized for the degree of fibrosis (control: 9.8 +/- 0.5%; HHM: 28.1 +/- 3.0%; p < 0.05), providing myocellular contents. RESULTS: In HHM, decreased contents (micromol/g wet weight) in adenosine triphosphate (ATP) (control: 4.17 +/- 0.26; HHM: 1.72 +/- 0.25; p < 0.001), creatine phosphate (5.67 +/- 0.70 vs. 0.84 +/- 0.13; p < 0.001) and creatine (27.6 +/- 3.19 vs. 11.2 +/- 1.56; p < 0.0001) were found, but contents in lactate (2.22 +/- 0.26 vs. 25.38 +/- 3.53; p < 0.001), purine bases (0.58 +/- 0.09 vs. 1.26 +/- 0.13; p < 0.001) and protons (pH units: 7.199 +/- 0.01 vs. 6.59 +/- 0.07; p < 0.001) were increased. Levels in adenosine diphosphate, adenosine monophosphate and inorganic phosphate remained unchanged. Energy depletion in HHM was reflected by decreases in the free energy of ATP hydrolysis and in energy charge. CONCLUSIONS: These data confirm our hypothesis that HHM is energy-depleted myocardium, exhibiting signs of chronic reduction in resting blood flow and a downregulation of energy turnover. The alterations in energy metabolism observed may become operative in triggering and maintaining contractile dysfunction, continuous tissue degeneration and cardiomyocyte loss.

Aged↗