Biomedical subjects
Publications and source records attributed to M Neuss.
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During recent years cardiac re-synchronization has become an important tool in the treatment of patients with signs and symptoms of heart failure and de-synchronized contraction of the heart. This article describes the pathophysiological basis of de-synchronized contraction due to left bundle branch block and the use of conventional echocardiography to unmask whether the electrical abnormality is accompanied by an asynchronous contraction in the individual patient. The altered contraction in the de-synchronized heart is analysed on different levels: atrioventricular dyssynchrony describes the disturbed mechanical coupling of the ventricles and atria, interventricular dyssynchrony describes the disturbed mechanical coupling of the left and right ventricle, and intraventricular dyssynchrony describes the uncoordinated contraction of the left ventricle. Since tissue Doppler imaging is implemented only in the top level echo machines of the respective manufacturers, this article uses parameters derived from standard echo techniques to analyse the different aspects of dyssynchrony.
A rare case of a primary fibrosarcoma of the liver infiltrating the right heart is described in a 72-year-old woman. The patient presented with a history of progressive dyspnea and ascites and her general condition was poor. Preoperative cardiac magnetic resonance (CMR) imaging revealed a large mass, which originated from the liver and had infiltrated the right atrium via the inferior vena cava. The patient underwent tumor resection yet died shortly afterwards. Histologically the mass was classified as a fibrosarcoma with positive immunostaining for vimentin. We report the CMR imaging characteristics in this uncommon case. Preoperative CMR proved to be useful for clinical decision making and the planning of surgery.
PURPOSE: Different centers and vendors use different sequences and contrast agent application schemes for MR myocardial perfusion imaging. The purpose of this study was to evaluate the role of different sequences, dosages, and injection speeds of contrast media for semiquantitative MR-perfusion assessment. METHODS: In a pilot study with 58 consecutive patients three of the most commonly used sequences for MR myocardial perfusion imaging (T1-GrE, GrE-EPI or SSFP) were compared to each other in terms of peak myocardial enhancement and image quality. For the main part of the study dynamic first pass MR perfusion imaging (Philips Intera CV, Best, Tthe Netherlands) was performed in 24 patients using the most favorable sequence from the pilot study (SSFP) after peripheral i.v. administration of Gd-BOPTA during adenosine stress. Two doses (0.05 mmol/kg bw and 0.025 mmol/kg bw) and four different injection speeds (8, 4, 3, 2 ml/s) were used. Signal intensity time curves were determined in the LV and myocardial segments supplied by normal coronary arteries and correlation between LV and myocardial upslope as well as peak enhancement were noted. RESULTS: The SSFP-sequence showed a higher peak enhancement when using 0.05 mmol/kg bw of Gd-BOPTA and a superior image quality for both dosage regimen compared with the other sequences and was consequently applied for the main study. A significant correlation was found between the upslopes in the LV and the myocardium (r square = 0.85, p < 0.001). However, LV and myocardial upslopes were largely independent of the dosage. Myocardial upslope was significantly slower at an injection rate of 2 ml/s compared to 3 and 4 ml/s. Higher Gd-doses led to significantly higher enhancement (p < 0.001). CONCLUSION: In healthy myocardial segments, the myocardial upslope is mainly determined from the LV upslope. Both myocardial enhancement and upslope are largely independent from the injection rate of a contrast agent bolus as long as the injection speed is not below 3 ml/s. Myocardial enhancement, however, is dose dependent. Thus, a simple correction for LV upslope allows to normalize a wide variety of input parameters. Differences of myocardial upslope or peak signal intensity after correction should be mainly dependent on blood flow.
BACKGROUND: Dobutamine stress MR (DSMR) is highly accurate for the detection of inducible wall motion abnormalities (IWMAs). Adenosine has a more favorable safety profile and is well established for the assessment of myocardial perfusion. We evaluated the diagnostic value of IWMAs during dobutamine and adenosine stress MR and adenosine MR perfusion compared with invasive coronary angiography. METHODS AND RESULTS: Seventy-nine consecutive patients (suspected or known coronary disease, no history of prior myocardial infarction) scheduled for cardiac catheterization underwent cardiac MR (1.5 T). After 4 minutes of adenosine infusion (140 microg x kg(-1) x min(-1) for 6 minutes), wall motion was assessed (steady-state free precession), and subsequently perfusion scans (3-slice turbo field echo-echo planar imaging; 0.05 mmol/kg Gd-BOPTA) were performed. After a 15-minute break, rest perfusion was imaged, followed by standard DSMR/atropine stress MR. Wall motion was classified as pathological if > or =1 segment showed IWMAs. The transmural extent of inducible perfusion deficits (<25%, 25% to 50%, 51% to 75%, and >75%) was used to grade segmental perfusion. Quantitative coronary angiography was performed with significant stenosis defined as >50% diameter stenosis. Fifty-three patients (67%) had coronary artery stenoses >50%; sensitivity and specificity for detection by dobutamine and adenosine stress and adenosine perfusion were 89% and 80%, 40% and 96%, and 91% and 62%, respectively. Adenosine IWMAs were seen only in segments with >75% transmural perfusion deficit. CONCLUSIONS: DSMR is superior to adenosine stress for the induction of IWMAs in patients with significant coronary artery disease. Visual assessment of adenosine stress perfusion is sensitive with a low specificity, whereas adenosine stress MR wall motion is highly specific because it identifies only patients with high-grade perfusion deficits. Thus, DSMR is the method of choice for current state-of-the-art treatment regimens to detect ischemia in patients with suspected or known coronary artery disease but no history of prior myocardial infarction.
On occasion of the annual convention of the European Society of Cardiology, general awareness was used to stage an event to inform the public about cardiovascular risk and cardiovascular disease. After the measurement of blood pressure, HDL and total cholesterol and after answering questions on smoking and medication visitors received a printout showing their individual calculated cardiovascular event rate over the next ten years. For the calculation of the expected event rate, the algorithm of the Adult Treatment Panel III was used. Of the 43,500 visitors 1513 were screened, 651 male, 862 female. Of those screened in this primary prevention setting 143 male (22.07%) and 9 female (1.02%) had an expected cardiovascular event rate of 20% or more over the next ten years requiring immediate action according to the current guidelines. The calculated risk scores are considerably lower than would be expected in a representative sample from the population. This indicates that patients with a high cardiovascular risk possibly do not take part in unstructured primary screening events.
To date, 2-[F-18]fluoro-2-deoxy-D-glucose PET (FDG PET) is used as a tool in oncology as well as myocardiological and cerebral functional diagnostics in the clinical routine. False positive results of tumor search imply new possibilities for use in diagnostics of inflammation. The two case reports presented here on aseptic loosening of endoprostheses caused by the rub of polyethylene with histological and immunohistological refurbishing call attention to the possible diagnostic valency of FDG PET as an early warning system regarding aseptic artificial limb loosening induced by the rub of polyethylene. By quantification of glucose metabolism with the "standard uptake value" (SUV) as well as specific storage samples from around the artificial limb, it is the aim of our study group in further examinations to develop an algorithm which permits to distinguish between septic and aseptic loosening.
The main cause of aseptic loosening of cemented stems in total hip arthroplasty is the hydrolytic degradation of the metal-cement interface. In order to prevent this debonding a new multilayer method of coating the implant surface involving the use of a silica-/silane technique to create a durable adhesive bond between metal stem and bone cement has been developed. The biocompatibility of all the elements of the multilayer system was confirmed using a human osteoblast cell culture test. For sterilization purposes, gamma irradiation with a 25 kGy effective dose proved to be the method of choice. The proven biocompatibility and successful sterilization of the coated implants are the main prerequisites for in-vivo usage. On the technical side, the bonding effectiveness of the multilayer coating system was demonstrated by the tensile test, which revealed a significant improvement in the adhesive strength of the cement-metal bond under prolonged moist conditions similar to those met with in the human body.
As the removal of femoral bone cement is one of the most challenging tasks in cemented total Hip Revision, a lot of different technical devices have been developed to aid the surgeon. All of their pros and cons are partly consequences of the specific system-design but mainly arise from the basic physical principles used. The known methods and devices as well as their data-handling have therefore been analysed, reduced to their principles according to the criteria of systematic engineering design and systematized in order to provide a better comparability and starting point for the development of new devices.
A loss of adhesive strength between metal stem and bone cement is clinically found to be a serious problem in total hip arthroplasty and causes many operative revisions. The objective of this study was to improve the long-term adhesive strength at this interface. A new silica/silane interlayer coating system is introduced. The layers are designed to bond the metal stem surface to the polymethylmethacrylate bone cement marginally leakage free. In vitro tensile tests were performed on specimens of TiAl6V4 and CoCrMo that were cemented by pairs with different bone cements with and without the new coating system. The specimens were stored in isotonic saline solution up to 150 days. The adhesive strength decreased about 75% within 30 days of storage on specimens of both metal alloys that were conventionally cemented without the new interlayer system. With the new coating, the high initial adhesive strength (40-50 MPa) could be stabilized for TiAl6V4 over 150 days. For the same 150-day storage period, the adhesive strength of the coated CoCrMo alloy still decreased but the decrease was only half that experienced by the uncoated CoCrMo. The loss of adhesive strength on CoCrMo specimens could be reduced if the metal surface was activated by a plasma treatment. The new coating interface system could help to considerably reduce revision operations caused by debonding effects at the interface metal/polymethylmethacrylate bone cement.
ARC is an apoptotic regulatory protein expressed almost exclusively in myogenic cells. It contains a caspase recruitment domain (CARD) through which it has been shown to block the activation of some initiator caspases. Because ARC also blocks caspase-independent events associated with apoptosis, such as hypoxia-induced cytochrome c release, we examined its role in cell death triggered by exposure to hydrogen peroxide (H(2)O(2)) in the myogenic cell line, H9c2. Cell death in this model was caspase-independent and characterized by dose-dependent reduction in ARC expression accompanied by disruption of the mitochondrial membrane potential (Delta psi(m)) and loss of plasma membrane integrity, typical of necrotic cell death. Ectopic expression of ARC prevented both H(2)O(2)-induced mitochondrial dysfunction and cell death without affecting the stress kinase response, suggesting that ARCs protective effects were downstream of early signaling events and not due to quenching of H(2)O(2). ARC was also effective in blocking H(2)O(2)-induced loss of membrane integrity and/or disruption of Delta psi(m) in two human cell lines in which it is not normally expressed. These results demonstrate that, in addition to its ability to block caspase-dependent and -independent events in apoptosis, ARC also prevents necrosis-like cell death via the preservation of mitochondrial function.
This review will present a summary of a description of apoptotic pathways in the heart, followed by ways to measure it and the experimental and clinical evidence for the role of apoptosis in cardiac disease. An evaluation of the effectiveness of pharmacological and other therapeutic interventions in the prevention of apoptosis in the context of cardiac disease will also be presented.
OBJECTIVES: Angiotensin II (Ang II) induces fibroblast proliferation and collagen synthesis in the myocardium, but its precise mechanisms of action in human hearts are still unknown. Therefore, we investigated whether Ang II directly affects the collagen mRNA content in the human myocardium and in isolated human cardiac fibroblasts or whether the growth factors TGFbeta-1 and osteopontin are involved in this process. METHODS AND RESULTS I: In a first set of experiments, the direct effect of Ang II on collagen I, TGFbeta-1 and osteopontin mRNA content in fresh samples of human atrial myocardium was determined by the use of a short stimulation period. After 4 h, Ang II-stimulated atrial samples gave a significantly higher expression of both TGFbeta-1 (183+/-21% of control, p<0.05) and osteopontin mRNA (275+/-58%, p<0.02) than the controls. In contrast, the expression of collagen I mRNA was unchanged (95+/-8%). Stimulation with TGFbeta-1 led to an increase in collagen I and III mRNA (127+/-10%, p<0.05; 140+/-15%, p<0.02). METHODS AND RESULTS II: In a second protocol, to assess the effects of longer stimulation periods, we determined the effects of Ang II and its potential mediator TGFbeta-1 on collagen I, III and fibronectin mRNA expression and on proliferation of cultured human cardiac fibroblasts. Ang II caused a dose-dependent stimulation of proliferation but did not affect collagen I, II or fibronectin mRNA content after 24 h. In contrast, TGFbeta-1 stimulation significantly increased collagen I and III mRNA expression (124+/-5% and 128+/-5%, p<0.002). CONCLUSIONS: In the human heart, Ang II does not directly increase collagen or fibronectin mRNA, but it does increase TGFbeta-1 and osteopontin mRNA expression. Since TGFbeta-1 induces collagen I and III mRNA in atrial samples and in isolated cardiac fibroblasts, it may represent a necessary mediator of the Ang II effects in the human heart.
We recently demonstrated that alpha(v)beta(3) integrins are involved in the mechanisms of angiotensin II (Ang II)-induced DNA synthesis and collagen gel contractions in rat cardiac fibroblasts (CFBs), cellular mechanisms that are relevant for cardiac remodeling. The aim of the present study was to elucidate the effect of Ang II and other growth factors on the regulation of the alpha(v)beta(3) integrins in fibroblasts from neonatal rat hearts. The alpha(v)beta(3) integrin receptor expression was significantly increased (P<0.05) at the mRNA level after treatment with Ang II, transforming growth factor-beta(1) (TGF-beta(1)), and platelet-derived growth factor (PDGF) for 8 and 16 hours. The surface expression of the alpha(v) and beta(3) integrin subunits was elevated after 32 and 48 hours (P<0.05) as determined with flow cytometry. To investigate fibroblast motility, we performed chemotaxis experiments with transwell chambers. Ang II was chemotactic for CFBs, as tested with checkerboard experiments. The chemotactic effect was concentration dependent and was completely blocked by Ang II type 1 receptor blockers but not by Ang II type 2 receptor blocker PD 123319. Ang II- and PDGF-BB-mediated chemotaxis could be significantly inhibited by RGD peptides and the blocking antibodies against alpha(v)beta(3) integrin (both P<0.01). Adhesion of CFBs to vitronectin was partially inhibited by an antibody to alpha(v)beta(3) integrin but was mainly mediated by an alpha(v)beta(5) integrin. Relevant in vivo expression of alpha(v)beta(3) integrin by CFBs was confirmed with in situ hybridization with probes for alpha(v) and beta(3) mRNA in rat hearts. The present study demonstrates that the expression of alpha(v)beta(3) integrin is augmented by Ang II, PDGF, and TGF-beta(1) in neonatal CFBs. Furthermore, this integrin is involved in the chemotaxis, motility, and adhesion of CFBs. The present findings support the current concept that integrins participate in the control of fibroblast behavior during cardiac remodeling mechanisms.
High resolution two-dimensional electrophoresis (2-DE) and computer-assisted image analysis were used to screen 13 patients suffering from dilated cardiomyopathy (DCM) versus 15 control patients for quantitative and qualitative differences in their myocardial protein expression. Right atrial tissue samples were obtained from end-stage failing explanted hearts and control hearts. Fifty-two spots differed significantly in average intensity between the DCM and the control groups. Myosin light chain 2, ventricular (MLC2) and heat shock protein HSP 27 were identified by protein microsequencing and gel map comparison with other databases. These proteins were found to be characteristic protein markers for DCM in the right atrium. In DCM patients, the spot intensity (protein abundance) of MLC2 is increased to 336% and HSP 27 is decreased to 59%, compared to the control group. The HEART-2DPAGE, a World Wide Web-accessible 2-DE database, was used and extended for the presentation of these disease-associated proteins. Retrievable via Internet we present a list of disease-associated proteins, their altered level of expression in DCM, and their position on a right atrial protein pattern. The accession number to protein sequence databases confers a connection to databases like SWISS-PROT to obtain a detailed functional and structural description of disease-associated proteins. New DCM-associated proteins are detected and their presentation in a 2-DE gel protein database is described.
The actions of angiotensin II in the cardiovascular system are transmitted by two known and possibly some unknown angiotensin receptor types. AT1 and AT2 both correspond to G-protein-coupled receptors with seven hydrophobic transmembrane domains, several N-glycosylation sites and a potential G-protein binding site. Cloning of coding regions and promoter sequences contributed to the understanding of receptor protein function and regulation. Angiotensin receptors with atypical binding properties for the known AT1- and AT2-specific ligands are expressed on human cardiac fibroblasts and in the human ulcrus. In several animal models, receptors with high affinity for angiotensin (1-7) have been described. AT1 stimulation is mediated by the generation of phospholipid-derived second messengers, activation of protein kinase C, the MAPkinase pathway and of immediate early genes. Recently, phosphorylation and dephosphorylation of tyrosine kinases have been associated with AT1- and AT2-mediated signal transduction. ATR are regulated by phosphorylation, internalization, modification of transcription rate and mRNA stability. Regulation is highly cell and organ specific and includes upregulation of ATR in some pathophysiological situations where the renin angiotensin system is activated. Whereas the function of AT1 in the cardiovascular system is relatively well established, there is little information regarding the role of AT2. Recent hypotheses suggest an antagonism between AT1 and AT2 at the signal transduction and the functional level. Transgenic animal models, particularly with targeted disruption of the AT1 and AT2 genes, suggest the contribution of both genes to blood pressure regulation. Genetic polymorphisms have been described in the AT1 and AT2 gene or neighbored regions and are used to analyze the association between gene defects and cardiovascular diseases. AT1 antagonists are now being introduced into the treatment of hypertension and potentially heart failure, and more interesting pharmacological developments are expected from the ongoing basic studies.
Angiotensin receptors have been described in the human heart and are suspected to play a central role in remodeling after myocardial infarction and in cardiac hypertrophy. Two subtypes, AT1 and AT2, have so far been described in humans, with AT2 being the dominant subtype in human atria. We have now determined subtype numbers and distribution by binding in ventricular myocardium from patients with end-stage heart failure. We found about 50-80% of subtype AT2 in the right and left ventricles from patients with end-stage heart failure due to coronary artery disease and cardiomyopathy, indicating that AT2 is the dominant angiotensin receptor subtype in the whole human heart. To determine the cellular localization of angiotensin receptors in human myocardium in addition to the known localization on myocytes, smooth muscle cells and endothelial cells, we investigated cardiac fibroblasts. They express an angiotensin receptor with yet incompletely understood binding characteristics which is coupled to proliferation and DNA synthesis. As AT2 is the dominant angiotensin receptor subtype in human heart, we cloned the complete mRNA sequence by a rapid amplification of cDNA ends (RACE) procedure and thereafter the promoter sequence from a human genomic library. Once the sequence of the mRNA and thus exon 1 was obtained by the RACE-PCR, a probe was constructed for the most 5' region of exon 1 and used for screening of a human genomic DNA bank. After cutting of the positive clones with EcoR1 and Not1, a 4000 bp fragment hybridized with the probe and was further sequenced. A functional AT2 promoter, with > 90% homology with the mouse promoter and 35% homology with the human AT1 promoter containing numerous cis-acting sequences for basal (TFIID) and inducible (AP-1, PEA-3, CBF) transcription factors in the first 1000 bp was identified.
Fibrosis makes an important contribution to the pathophysiological events leading to the development of heart failure in ischemic and hypertensive heart disease. Since cardiac fibroblasts are mainly responsible for the synthesis and deposition of the extracellular matrix, we have established a method for isolating and cultivating human cardiac fibroblasts from explanted human hearts. The cell yield was 2.14+/-0.25x10(6 )cells in five independent isolations and the cell purity was 95-97%, contaminating cells being vascular smooth muscle cells and pericytes. Cultured cells were studied with respect to growth properties, morphology and deposition of components of the extracellular matrix. Isolated cells displayed a differentiated phenotype, including the second passage in culture; they synthesised collagen I, III, IV, fibronectin, vitronectin, tenascin and chondroitin sulphate and expressed an atypical angiotensin receptor. This atypical angiotensin receptor internalised angiotensins II and III but not angiotensin IV in a time-dependent manner. Stimulation of the cells with angiotensins II and III but not with angiotensin IV resulted in a dose-dependent stimulation of DNA synthesis. Co-incubation with the subtype-specific receptor antagonists Losartan and PD 123317 did not prevent the stimulation of DNA synthesis. The further characterisation of this receptor should provide insights into the pathobiochemical events leading to heart failure in hypertension and ischemic heart disease.