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Biomedical subjects

A Elsässer

Publications and source records attributed to A Elsässer.

18 recordsLinked to original sources

Clopidogrel in acute coronary syndrome: when, how much, how long?

An important part of the therapy management of acute coronary syndrome (ACS) consists of antiplatelet drugs. Whereas the administration of acetylsalicylic acid (ASA) is well established, the guidelines recommend the additive use of clopidogrel in patients with ACS without persisting ST-elevation. Clopidogrel should be added to ASA as soon as possible in patients with a non-invasive treatment strategy and continued for more than 1 month (class 1A) and up to 9 months (class 1B). In patients for whom a percutaneous coronary intervention (PCI) is planned, an additional loading-dose of 300 mg clopidogrel should be given on top of ASA (100 mg). These recommendations are based on data recently published in the CURE and CREDO trials, which however should be critically discussed: In these trials, an absolute risk reduction of only 2% could be documented by additive use of clopidogrel. The combined endpoint of cardiovascular death, myocardial infarction and stroke is significantly reduced, but there was no improvement taken the individual endpoints alone. In additional, the data for duration of clopidogrel therapy were determined by taken the mean follow-up of these studies. The efficacy of the dual antiplatelet therapy should be discussed in the context of an increased frequency of major bleedings (in total 1%) and should be considered against a reasonable cost effective background. An adequate therapy with clopidogrel in patients presenting ACS should be confirmed by further trials. Until more detailed data are available, the guideline recommendations should be implemented based on of patient's individual risk.

Acute Disease↗

Transcatheter closure of a ruptured ventricular septum after myocardial infarction using a venous approach.

A 65-year old patient was admitted after having sustained a ventricular septum rupture 18 days after an anterior myocardial infarction. He developed acute heart failure. Given the extremely high perioperative risk in surgical approaches in this setting, we decided for a transcatheter closure of the defect with an exclusively venous approach. After a complete recovery, the patient underwent open heart surgery with aorto coronary bypass, aneurysmectomy, and removal of the closure device. This case demonstrates that transcatheter closure of a post infarction ventricular septum rupture is a technically feasible and suitable method.

Aged↗

Treatment of in-stent restenosis with sirolimus-eluting-stents -- a six month clinical and angiographic follow-up.

Treatment of in-stent restenosis (ISR) remains a therapeutic challenge since many pharmacological and mechanical approaches have shown disappointing results except for brachytherapy. Drug-eluting stents (DES) have been reported to effectively reduce ISR in de novo lesions. We studied 55 consecutive patients with ISR in native coronary arteries and 7 with ISR in saphenous vein grafts (SVG) with elective indication for percutaneous coronary intervention (PCI), who underwent successful implantation with DES. No in-hospital postprocedural major adverse cardiac events were observed. All but one patient (n=61) underwent an angiographic follow-up at 183+/-30 days. Grade of stenosis was assessed by quantitative coronary angiography (QCA) at index procedure and at control angiography. Restenosis (>50%) occurred in 5 patients (8.2%). Target vessel revascularization was performed in an additional 4 patients. Minimal intimal hyperplasia was observed in all segments covered by DES (late loss 0.08+/-0.37 mm, loss index 0.11+/-0.47). One patient suffered from subacute stent thrombosis due to discontinuation of clopidogrel medication. At six month follow-up two patients had died. Death was not related to a restenosis in the treated segment. Conclusion Our experiences with DES treatment of ISR lesions show good angiographic and clinical results at index procedure and at the 6 month follow-up with low sub acute thrombosis rate as compared with existing treatment modalities. Restenosis rate seems to be at least as low as reported for brachytherapy.

Blood Vessel Prosthesis↗

[Quantification of valvular lesions in patients with left ventricular dysfunction].

Echocardiography is the preferred method for assessment of aortic and mitral valvular lesions. The pressure gradient in aortic stenosis may be misleading in patients with poor left ventricular function. Aortic valve area planimetry by transesophageal echocardiography results in a flow independent anatomic measurement. Low-dose dobutamine stress echocardiography provides important prognostic information. Quantitative Doppler echocardiography allows accurate assessment of mitral regurgitation severity. However, the definition of what is severe mitral regurgitation is different in patients with left ventricular dysfunction.

Aortic Valve↗

Functional disturbances due to structural remodeling in the failing human heart.

In severely hypertrophied hearts structural remodeling occurs continuously and finally leads to heart failure. The remodeling process involves all structural components of the cardiomyocyte and all protein families and it consists of cellular enlargement accompanied by degeneration in addition to the occurrence of fibrosis. Nuclei are increased in size but the nuclear volume/cell volume ratio is reduced. Transcription and translation are downregulated for contractile and sarcomeric skeleton proteins but both are upregulated for cytoskeletal and membrane-associated proteins. The connexin43 content is significantly reduced. Chronic degeneration finally leads to cell death by ubiquitin-related autophagy, and acute ischemic cell death (oncosis) is also observed. Apoptosis seems to be of minor importance. The morphological alterations described here are the structural correlate of the typical clinical characteristics of heart failure in human patients: of reduced contractile function, of increased ventricular stiffness represented by an increased left end-diastolic pressure and of ventricular arrhythmia.

Arrhythmias, Cardiac↗

Time course of the apoptotic cascade and effects of caspase inhibitors in adult rat ventricular cardiomyocytes.

K. Suzuki, S. Kostin, V. Person, A. Elsässer and J. Schaper. Time Course of the Apoptotic Cascade and Effects of Caspase Inhibitors in Adult Rat Ventricular Cardiomyocytes. Journal of Molecular and Cellular Cardiology (2001) 33, 983-994. Interpretation of the rate of apoptosis in diseased hearts is hampered by the fact that the time course of the apoptotic cascade in adult cardiomyocytes is largely unknown. Therefore, we established a standardized in vitro system, relevant to the in vivo situation of heart failure, using adult de- and redifferentiating cardiomyocytes to determine the time intervals necessary for the different steps of the apoptotic cascade to occur. Apoptosis was induced with 0.1 mmol/l H(2)O(2)in adult rat cardiomyocytes 10 days in culture. Dosages >0.5 mmol/l H(2)O(2)produced necrosis. Disruption of the mitochondrial membrane potential (Deltapsim) was the earliest sign of apoptosis and occurred at 2 h after H(2)O(2)exposure. The number of annexin V (translocation of phosphatidylserine) and PhiPhiLux (activation of caspase-3) positive cells significantly increased after 4 h and remained constant thereafter. Bcl-2 levels decreased. At 9 h, Bax expression was significantly elevated resulting in a reduced Bcl-2/Bax ratio. DNA fragmentation detected by TUNEL and ssDNA peaked at 14 h, parallel to the appearance of apoptotic ultrastructural changes. Although DNA fragmentation was inhibited by zVAD-fmk, Ac-DEVD-CHO, zLEVD-fmk, these caspase inhibitors failed to inhibit disruption of Deltapsim and increased the number of necrotic cells. Catalase inhibited both apoptosis and necrosis. Our results indicate that the occurrence of the different steps of the apoptotic cascade is time-dependent and tightly regulated. Caspase inhibitors reduce apoptosis but increase the rate of necrosis, suggesting that the cells are destined to die upstream of the caspase step, i.e. by mitochondrial damage. These data provide the basis for the critical evaluation and interpretation of the occurrence of apoptosis in failing hearts.

Animals↗

Selective elimination of leukemic CD34(+) progenitor cells by cytotoxic T lymphocytes specific for WT1.

Hematologic malignancies such as acute and chronic myeloid leukemia are characterized by the malignant transformation of immature CD34(+) progenitor cells. Transformation is associated with elevated expression of the Wilm's tumor gene encoded transcription factor (WT1). Here we demonstrate that WT1 can serve as a target for cytotoxic T lymphocytes (CTL) with exquisite specificity for leukemic progenitor cells. HLA-A0201- restricted CTL specific for WT1 kill leukemia cell lines and inhibit colony formation by transformed CD34(+) progenitor cells isolated from patients with chronic myeloid leukemia (CML), whereas colony formation by normal CD34(+) progenitor cells is unaffected. Thus, the tissue-specific transcription factor WT1 is an ideal target for CTL-mediated purging of leukemic progenitor cells in vitro and for antigen-specific therapy of leukemia and other WT1-expressing malignancies in vivo.

Adult↗

Unresolved issues regarding the role of apoptosis in the pathogenesis of ischemic injury and heart failure.

UNLABELLED: Apoptosis is "suicidal" programmed cell death followed by necrosis, i.e. cellular degradation. This review presents a critical evaluation of the methods used for detection of apoptosis and on data regarding the role of apoptosis in ischemia and heart failure. METHODS: DNA laddering by electrophoresis and the TUNEL method in histology for the final stage of apoptosis, Annexin V labeling, evidence of caspase activation, cleavage of substrates, measurements of mitochondrial pro-apoptotic and anti-apoptotic factors (Bcl-2, Bax and others) and determination of the mitochondrial transitional pore potential. Much work has been carried out regarding the mechanism and the importance of apoptosis in ischemia and heart failure but many issues still remain unsolved: (1)Time needed for completion of apoptosis from stimulus to DNA fragmentation? (2)Importance of mitochondrial pathway considering the fact that cardiomyocytes contain the highest volume density of mitochondria of all mammalian cells (25% in humans, 37% in mice)? (3)Means of removal of dead cells, disconnection at the intercalated disc from neighbouring myocytes, time frame of this process? (4)Reversibility of apoptosis? (5)Differences between physiological (postnatal differentiation of the conduction system) v pathological apoptotic cell death? (6)Why do cells, under ischemic conditions, die by either apoptosis or oncosis? (7)Is apoptosis an epiphenomenon or a true cause of heart failure? (8)Quantification of the rate of apoptosis in different pathophysiological situations? Clarification of these unresolved issues will then allow an estimation of the importance of apoptosis in cardiac pathophysiology and, if necessary because the role of apoptosis has been established, the development of new therapeutic concepts.

Animals↗

A self-perpetuating vicious cycle of tissue damage in human hibernating myocardium.

Recently, we proposed the hypothesis that a vicious cycle exists in human hibernating myocardium (HM) between the progression of myocyte degeneration and the development of fibrosis. We now investigated the pathomechanism of this cycle in more detail and established a correlation between the severity of the morphological changes and the degree of postoperative functional recovery of HM. HM was diagnosed by dobutamine echocardiography, thallium-201 scintigraphy and radionuclide ventriculography. Functional recovery was present at 3 months after coronary bypass surgery but remained unchanged at 15 months. Forty patients were subdivided into 2 groups: A with complete and B with incomplete recovery. Biopsies taken during surgery and studied by electron microscopy, immunocytochemistry, rt-PCR, and morphometry revealed myocyte degeneration and inflammatory and fibrinogenic changes in a widened interstitial space. We report here for the first time an upregulation of TGF-beta1 evident by a 5-fold increase of fibroblasts and macrophages exhibiting a TGF-beta1 content 3-fold larger than in control, and a > 3-fold increase in TGF-beta1 mRNAby rt-PCR. The number of angiotensin converting enzyme (ACE) containing structures was increased (n/mrm2: control-11.4, A-17.6, B-19.2, control vs. A and B, p < 0.05). Fibrosis was more severe in group B than A or control (%: C-10.1; A-21.2; B-40.6; p < 0.05). Capillary density was significantly reduced (n/mm2: C-1152; A-782; B-579, p < 0.05) and intercapillary distance was widened (microm: C-29.5, A-36.1, B-43.3, p < 0.05). The number of CD 3 (n/mm2: C-5.0; A-9.6; B-9.4, ns) and CD 68 positive cells (n/mm2: C-37.2; A-80.7; B-55.0, C vs. A p < 0.05) was elevated in HM as compared to control indicating an inflammatory reaction. Cut-off points for functional recovery are fibrosis > 32%, capillary density < 660/mm2 and intercapillary distance > 39.0 microm. In HM a self-perpetuating vicious cycle of tissue alterations leads to progressive replacement fibrosis and continuous intracellular degeneration which should be interrupted by early revascularization.

Adult↗

Assessment of myocardial viability: Dobutamine echocardiography and thallium-201 single-photon emission computed tomographic imaging predict the postoperative improvement of left ventricular function after bypass surgery.

The aim of this study was to evaluate the usefulness of dobutamine echocardiography and quantitative thallium-201 single photon emission computed tomography myocardial scintigraphy with reinjection in the detection of viable myocardium in patients with coronary artery disease and reduced left ventricular function, which will improve after aortocoronary bypass surgery. Forty-eight patients (47 men, aged 61 +/- 6 years) with angiographically documented reduced left ventricular function (ejection fraction 35 +/- 14, 63% with chronic transmural myocardial infarction) were examined by dobutamine two-dimensional echocardiography (before and during low dosage), 201Tl, and gated radionuclide ventriculography before and 3 +/- 2 months after aortocoronary bypass surgery. Four of 55 areas classified viable before operation were revascularized inadequately and discarded. Global left ventricular ejection fraction at rest rose from 35% +/- 14% before operation to 40% +/- 13% (p < 0.05) after operation. Stress-induced perfusion defects involved 40% +/- 19% of the left ventricle circumference after stress and showed a significant reduction of size to 23% +/- 14% (p < 0.01) at rest, 4 hours later, and after reinjection. This value fell to 16% +/- 12% (p < 0.05) 3 months after aortocoronary bypass surgery. We conclude that both dobutamine echocardiography (sensitivity 95%, specificity 80%, positive predictive value 87%, negative predictive value 88%) and 201Tl studies (sensitivity 87%, specificity 98%, positive predictive value 97%, negative predictive value 93%) are suitable and comparable accurate methods for predicting improvement in systolic function 3 months after revascularization in a selected population with a high prevalence of viable but hypokinetic or akinetic myocardium.

Aged↗

Lack of adenosine causes myocardial refractoriness.

OBJECTIVES: This study sought to investigate the myocardial mechanisms causing refractoriness to ischemic preconditioning in pigs. BACKGROUND: Ischemic preconditioning in the pig vanishes after 60 min and cannot be reinstated by a second cycle of brief coronary occlusions at this time point. Ischemic preconditioning has been shown to be mediated by adenosine A1-receptors. Because myocardial adenosine production during ischemia ceases as the number of repeated brief ischemic episodes increases, we hypothesized that this lack of adenosine may cause this myocardial refractoriness. METHODS: In open chest pigs, ischemic preconditioning was achieved by repeated brief coronary occlusions. Myocardial adenosine content was assessed by high performance liquid chromatographic analysis of serial myocardial biopsy samples; infarct size (percent infarcted area of the area at risk) was determined using tetrazolium salts. RESULTS: Ischemic preconditioning by two cycles of occlusion of the left anterior descending coronary artery (10 min) and reperfusion (30 min) decreased infarct size ([mean +/- SEM] 40.4+/-2.9%; control: 76.9+/-1.8%, p < 0.001). Prolonging the second reperfusion period to 60 min caused ischemic preconditioning to vanish (79.0+/-0.5%) and caused refractoriness to a second cycle of preconditioning (70.0+/-2.0%). Myocardial adenosine content increased only during the first coronary occlusion (baseline: 110.9+/-42.0 nmol/g dry weight; first coronary occlusion: 1,686.2+/-244.1, p < 0.001) but not during subsequent coronary occlusions. In refractory myocardium, intramyocardial microinfusion of the adenosine A1-receptor agonist N6-cyclohexyladenosine (CHA [0.3 mmol/liter]) again decreased infarct size (27.4+/-7.0%, p < 0.001 vs. control). CONCLUSIONS: Myocardial refractoriness may be caused by the inability to produce adenosine endogenously. In refractory myocardium, application of CHA reinduces cardioprotection.

Adenosine↗

The extracellular matrix in hibernating myocardium--a significant factor causing structural defects and cardiac dysfunction.

Recently, we described chronic intracellular degeneration accompanied by fibrosis as typical structural features of hibernating myocardium and we concluded that cellular degeneration as a sign of the incomplete adaptation to the reduced blood flow is characteristic of hibernation. This study has been extended by analyzing the composition of the extracellular matrix proteins of the diseased myocardium. Areas of hibernating myocardium were identified in 38 patients by angiography, multigated radionuclide ventriculography, thallium scintigraphy with reinjection and low-dose dobutamine echocardiography. These areas were biopsied at cardiac surgery and were studied by electron microscopic and immunofluorescence techniques. Electron microscopy showed an enlarged extracellular space containing numerous particles of cellular debris, macrophages, fibroblasts, homogeneous matrix material and collagen fibrils. The basement membrane of the cardiomyocytes was thickened by an augmentation of laminin, fibronectin and collagen VI, but these proteins also were present in the matrix itself. Collagen fibrils were numerous and macrophages (CD68) and fibroblasts (vimentin) were increased. In situ hybridization showed an increase in mRNA for laminin, fibronectin and collagen. This observation is consistent with the conclusion that fibrotic scar formation was occurring continuously. It is postulated that fibrosis is the consequence of myocyte loss due to chronic underperfusion in the hibernating tissue. This will further injure myocytes so that a vicious cycle is established that leads to progressive loss of structural integrity and functional capacity. Since these changes are progressive, revascularization should be performed at the earliest time point possible in patients with areas of hibernating myocardium.

Aged↗

Hibernating myocardium: an incomplete adaptation to ischemia.

BACKGROUND: We tested the hypothesis that hibernating myocardium represents an incomplete adaptation to a reduced myocardial oxygen supply. METHODS AND RESULTS: In 38 patients, areas of hibernating myocardium were identified by angiography, multigated radionuclide ventriculography, thallium scintigraphy with reinjection, and low-dose dobutamine echocardiography. Biopsies removed at cardiac surgery showed structural degeneration characterized by a reduced protein and mRNA expression and disorganization of the contractile and cytoskeletal proteins myosin, actin, desmin, titin, alpha-actinin, and vinculin by electron microscopy, immunohistochemistry, and in situ hybridization. Additionally, an increased amount of extracellular matrix proteins resulting in a significant degree of reparative fibrosis was present. Dedifferentiation, ie, expression of fetal proteins, was absent. Apoptosis indicating suicidal cell death was found by the terminal deoxynucleotidyl transferase end-labeling method and electron microscopy. Radionuclide ventriculography showed improvement of regional function at 3 months postoperatively compared with preoperative values (mean values, 23.5% and 48%, respectively), and the echocardiographic wall-motion score index decreased from 3.4 to 1.8. The degree of severity of the morphological changes (three stages) correlated well with the extent of postoperative functional recovery: more advanced clinical improvement was observed in patients with slight and moderate morphological degeneration (stages 1 and 2), but recovery was only partial in severe degeneration (stage 3). CONCLUSIONS: Cellular degeneration rather than adaptation is present in hibernating myocardium. The consequence is progressive diminution of the chance for complete structural and functional recovery after restoration of blood flow. The practical consequence from this study should be early revascularization in patients showing areas of hibernating myocardium.

Adaptation, Physiological↗

[Clinical and morphologic findings in the "hibernating myocardium"].

From the clinical point of view, the diagnosis of "hibernating myocardium" is of predominant importance in patients with LV-dysfunction, because a prediction of a possible functional recovery allows to determine risk and outcome of an intervention. Alone or in combination, thalliumscintigraphy with reinjection and dobutamine echocardiography are suitable to detect "hibernating myocardium". In addition, morphological investigations of biopsies taken from hibernating regions permit the evaluation of structural changes. The spectrum of alterations is wide and at a certain degree of severity they are irreversible. The relation between clinical and morphological results provides further insight into the degree of injury and of functional recovery after adequate revascularization.

Biopsy↗

The role of apoptosis in myocardial ischemia: a critical appraisal.

The role of apoptosis in cardiac ischemia is not clarified yet. Own data show that suicidal cell death is apparently not important in global ischemia where it only affects a small number of myocytes (8 %) while the majority of cells, i.e. 92 % die by oncosis. In acute regional ischemia it is most probably not a decisive factor. However, more solid data are needed to justify this statement. Human hibernating myocardium shows an activation of the apoptotic cascade, i.e., apoptosis might contribute to cell loss in this pathophysiological situation of multiple ischemic episodes. Manifold unresolved issues contribute to problems in determining the role of apoptosis in ischemia. These include 1) Uncertainty of the duration of the apoptotic cascade from activation of death receptors at the cellular membrane until DNA fragmentation occurs, 2) The role of the mitochondrial pathway, 3) The mode of removal of myocytes after cell death has occurred, 4) Technical problems such as specificity of the TUNEL method, detection of low abundance proteins such as activated caspases or cytochrome C, statistical considerations. These issues and many others should be clarified before any definite conclusion as to the role of apoptosis in ischemia may be drawn.

Animals↗